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.

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.

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.

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.

Parental Scaffolding during Book-Sharing Predicts Child General Intelligence.

While much variance in general intelligence or g is genetic, a substantial environmental component suggests a possible role for parent-child interaction. In particular, previous evidence suggests the importance of parental scaffolding, or provision of cognitive structure to shape child behaviour. A role for scaffolding is consistent with the proposal that, in adult cognition, a critical aspect of g is decomposition of complex problems into a structure of simpler parts. Building on previous work, we recruited 162 parents attending Children's Centres with a child aged 2-4 years, and examined parental scaffolding during a book-sharing activity. Scaffolding was measured as the first principal component of a variety of parental behaviours, including sensitivity, focusing attention, extending comprehension, and promoting child participation. Child g was measured as the first principal component of a broad cognitive battery, including language, attention, working memory, and executive function. Importantly, we assessed contributions of the parent's own intelligence, education, and family income. Though these variables were all associated with both child g and parental scaffolding, scaffolding remained predictive of child g even once the influence of these variables was removed. In contrast to the correlation with cognitive proficiency, scaffolding did not predict child pro-social behaviour. We suggest that parental scaffolding supports the child's development of a broad skill of attentional structuring, promoting the across-the-board cognitive proficiency that is reflected in g.

Epithelial senescence in idiopathic pulmonary fibrosis is propagated by small extracellular vesicles.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects 3 million people worldwide. Senescence and small extracellular vesicles (sEVs) have been implicated in the pathogenesis of IPF, although how sEVs promote disease remains unclear. Here, we profile sEVs from bronchial epithelial cells and determine small RNA (smRNA) content. METHODS: Conditioned media was collected and sEVs were isolated from normal human bronchial epithelial cells (NHBEs) and IPF-diseased human bronchial epithelial cells (DHBEs). RESULTS: Increased sEV release from DHBEs compared to NHBEs (n = 4; p < 0.05) was detected by nanoparticle tracking analysis. NHBEs co-cultured with DHBE-derived sEVs for 72 h expressed higher levels of SA-ß-Gal and γH2AX protein, p16 and p21 RNA and increased secretion of IL6 and IL8 proteins (all n = 6-8; p < 0.05). sEVs were also co-cultured with healthy air-liquid interface (ALI) cultures and similar results were observed, with increases in p21 and p16 gene expression and IL6 and IL8 (basal and apical) secretion (n = 6; p < 0.05). Transepithelial electrical resistance (TEER) measurements, a reflection of epithelial barrier integrity, were decreased upon the addition of DHBE-derived sEVs (n = 6; p < 0.05). smRNA-sequencing identified nineteen significantly differentially expressed miRNA in DHBE-derived sEVs compared to NHBE-derived sEVs, with candidate miRNAs validated by qPCR (all n = 5; p < 0.05). Four of these miRNAs were upregulated in NHBEs co-cultured with DHBE-derived sEVs and three in healthy ALI cultures co-cultured with DHBE-derived sEVs (n = 3-4; p < 0.05). CONCLUSIONS: This data demonstrates that DHBE-derived sEVs transfer senescence to neighbouring healthy cells, promoting the disease state in IPF.

Preventing falls in older people on mental health inpatient wards: a quality improvement project.

Older people on mental health inpatient wards are at high risk of falls due to a combination of physiological, pathophysiological and pharmacological factors. Falls prevention should therefore be a priority for nursing staff caring for this patient group. This article describes a quality improvement project conducted on four older adult mental health inpatient wards in Scotland. The project aimed to reduce the number of falls, increase staff's adherence to person-centred falls prevention care planning, and ensure every fall would prompt a post-fall review. Nursing staff participated in a falls prevention training session and registered nurses received, in addition, one-to-one coaching sessions on person-centred care planning. Despite the challenges faced by mental healthcare professionals at the time of the project, staff responded positively and there was a decrease in the number of falls, including falls resulting in harm.

Simultaneous isolation of proximal and distal lung progenitor cells from individual mice using a 3D printed guide reduces proximal cell contamination of distal lung epithelial cell isolations.

The respiratory epithelium consists of multiple, functionally distinct cell types and is maintained by regionally specific progenitor populations that repair the epithelium following injury. Several in vitro methods exist for studying lung epithelial repair using primary murine lung cells, but isolation methods are hampered by a lack of surface markers distinguishing epithelial progenitors along the respiratory epithelium. Here, we developed a 3D printed lobe divider (3DLD) to aid in simultaneous isolation of proximal versus distal lung epithelial progenitors from individual mice that give rise to differentiated epithelia in multiple in vitro assays. In contrast to 3DLD-isolated distal progenitor cells, commonly used manual tracheal ligation methods followed by lobe removal resulted in co-isolation of rare proximal cells with distal cells, which altered the transcriptional landscape and size distribution of distal organoids. The 3DLD aids in reproducible isolation of distal versus proximal progenitor populations and minimizes the potential for contaminating populations to confound in vitro assays.

Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient-derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung-derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type-dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma.

Dialogic Book-Sharing as a Privileged Intersubjective Space.

Parental reading to young children is well-established as being positively associated with child cognitive development, particularly their language development. Research indicates that a particular, "intersubjective," form of using books with children, "Dialogic Book-sharing" (DBS), is especially beneficial to infants and pre-school aged children, particularly when using picture books. The work on DBS to date has paid little attention to the theoretical and empirical underpinnings of the approach. Here, we address the question of what processes taking place during DBS confer benefits to child development, and why these processes are beneficial. In a novel integration of evidence, ranging from non-human primate communication through iconic gestures and pointing, archaeological data on Pre-hominid and early human art, to experimental and naturalistic studies of infant attention, cognitive processing, and language, we argue that DBS entails core characteristics that make it a privileged intersubjective space for the promotion of child cognitive and language development. This analysis, together with the findings of DBS intervention studies, provides a powerful intellectual basis for the wide-scale promotion of DBS, especially in disadvantaged populations.

The impact of distance on post-ICU disability.

BACKGROUND: Nonurban residential living is associated with adverse outcomes for a number of chronic health conditions. However, it is unclear what effect it has amongst survivors of critical illness. OBJECTIVES: The purpose of this study is to determine whether patients living greater than 50 km from the treating intensive care unit (ICU) have disability outcomes at 6 months that differ from people living within 50 km. METHODS: This was a multicentre, prospective cohort study conducted in five metropolitan ICUs. Participants were adults admitted to the ICU, who received >24 h of mechanical ventilation and survived to hospital discharge. In a secondary analysis of these data, the cohort was dichotomised based on residential distance from the treating ICU: <50 km and ≥50 km. The primary outcome was patient-reported disability using the 12-item World Health Organization's Disability Assessment Schedule (WHODAS 2.0). This was recorded at 6 months after ICU admission by telephone interview. Secondary outcomes included health status as measured by EQ-5D-5L return to work and psychological function as measured by the Hospital Anxiety and Depression Scale (HADS). Multivariable logistic regression was used to assess the association between distance from the ICU and moderate to severe disability, adjusted for potential confounders. Variables included in the multivariable model were deemed to be clinically relevant and had baseline imbalance between groups (p < 0.10). These included marital status and hours of mechanical ventilation. Sensitivity analysis was also conducted using distance in kilometres as a continuous variable. RESULTS: A total of 262 patients were enrolled, and 169 (65%) lived within 50 km of the treating ICU and 93 (35%) lived ≥50 km from the treating ICU (interquartile range [IQR] 10-664 km). There was no difference in patient-reported disability at 6 months between patients living <50 km and those living ≥50 km (WHODAS total disability % [IQR] 10.4 [2.08-25] v 14.6 [2.08-20.8], P = 0.74). There was also no difference between groups for the six major life domains of the WHODAS. There was no difference in rates of anxiety or depression as measured by HADS score (HADS anxiety median [IQR] 4 [1-7] v 3 [1-7], P = 0.60) (HADS depression median [IQR] 3 [1-6] v 3 [1-6], P = 0.62); health status as measured by EQ-5D (mean [SD] 66.7 [20] v 69.8 [22.2], P = 0.24); or health-related unemployment (% (N) 39 [26] v 25 [29.1], P = 0.61). After adjusting for confounders, living ≥50 km from the treating ICU was not associated with increased disability (odds ratio 0.61, 95% confidence interval: 0.33-1.16; P = 0.13) CONCLUSIONS: Survivors of intensive care in Victoria, Australia, who live at least 50 km from the treating ICU did not have greater disability than people living less than 50 km at 6 months after discharge. Living 50 km or more from the treating ICU was not associated with disability, nor was it associated with anxiety or depression, health status, or unemployment due to health.

First 1,000 days: enough for mothers but not for children? Long-term outcomes of an early intervention on maternal depressed mood and child cognitive development: follow-up of a randomised controlled trial.

BACKGROUND: Child cognitive development is often compromised in contexts of poverty and adversity, and these deficits tend to endure and affect the child across the life course. In the conditions of poverty and violence that characterise many low- and middle-income countries (LMIC), the capacity of parents to provide the kind of care that promotes good child development may be severely compromised, especially where caregivers suffer from depression. One avenue of early intervention focuses on the quality of the early mother-infant relationship. The aim of this study was to examine the long-term impact of an early intervention to improve the mother-infant relationship quality on child cognitive outcomes at 13 years of age. We also estimated the current costs to replicate the intervention. METHOD: We re-recruited 333 children from an early childhood maternal-infant attachment intervention, 'Thula Sana', when the children were 13 years old, to assess whether there were impacts of the intervention on child cognitive outcomes, and maternal mood. We used the Kaufman Assessment Battery to assess the child cognitive development and the Patient Health Questionnaire (PHQ-9) and the Self-Reporting Questionnaire (SRQ-20) to assess maternal mental health. RESULTS: Effect estimates indicated a pattern of null findings for the impact of the intervention on child cognitive development. However, the intervention had an effect on caregiver psychological distress (PHQ-9, ES = -0.17 [CI: -1.95, 0.05] and SRQ-20, ES = -0.30 [CI: -2.41, -0.19]), but not anxiety. The annual cost per mother-child pair to replicate the Thula Sana intervention in 2019 was estimated at ZAR13,365 ($780). CONCLUSION: In a socio-economically deprived peri-urban settlement in South Africa, a home visiting intervention, delivered by community workers to mothers in pregnancy and the first six postpartum months, had no overall effect on child cognitive development at 13 years of age. However, those caregivers who were part of the original intervention showed lasting improvements in depressed mood. Despite the fact that there was no intervention effect on long-term child outcomes, the improvements in maternal mood are important.

Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF.

The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-ß-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.

Book-Sharing for Parenting and Child Development in South Africa: A Randomized Controlled Trial.

This study evaluated the impact of a parenting intervention on children's cognitive and socioemotional development in a group of caregivers and their 21-to-28-month-old children in a low-income South African township. A randomized controlled trial compared an experimental group (n = 70) receiving training in dialogic book-sharing (8 weekly group sessions) with a wait-list control group (n = 70). They were assessed before the intervention, immediately following it, and at a six month follow-up. The intervention had positive effects on child language and attention, but not behavior problems, prosocial behavior, or theory of mind. Intervention caregivers were less verbally and psychologically harsh, showed more sensitivity and reciprocity and more complex cognitive talk. This program benefitted parenting and child development and holds promise for low-income contexts.