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Shared picture-book reading is well-recognized as beneficial for children’s early language development, especially where ‘dialogic book-sharing’ techniques are used. Possible benefits of dialogic book-sharing to other aspects of child development have been little investigated, and it has not been widely studied in European populations. We conducted a randomized trial of dialogic book-sharing in Children’s Centers in the UK, with parents of 2-4-year-old children, hypothesizing that it would benefit parenting and a range of child developmental outcomes.\ud Intervention group parents (n = 110) received seven, weekly, group training sessions and control parents (n = 108) the usual center input. Parenting and a range of child outcomes (language, attention, executive function, social development and emotional-behavior difficulties) were assessed on three occasions: before, after, and 4-6 month following intervention. For all study outcomes we compared controls with each of the Intention-to-Treat population and the perprotocol population (participants attending the requisite number of sessions); and, for primary child outcomes only, the population of parents who engaged well with the intervention. There were substantial benefits of dialogic book-sharing training to parental behavior during booksharing, especially for sensitivity and cognitive scaffolding. For all three sets of comparisons there were small-medium effects of on child expressive language, and, for the per protocol and engaged populations, similar sized effects on child receptive language and attention. There was no evidence of benefit of dialogic book-sharing for the other areas of child development; we suggest that specific intervention components need to be added to standard dialogic book-sharing to effect change in these areas.

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.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease with limited therapeutic options. Current evidence suggests that IPF may be initiated by repeated epithelial injury in the distal lung followed by abnormal wound healing responses which occur due to intrinsic and extrinsic factors. Mechanisms contributing to chronic damage of the alveolar epithelium in IPF include dysregulated cellular processes such as apoptosis, senescence, abnormal activation of developmental pathways, aging, as well as genetic mutations. Therefore, targeting the regenerative capacity of the lung epithelium is an attractive approach in the development of novel therapies for IPF. Endogenous lung regeneration is a complex process involving coordinated cross-talk between multiple cell types and re-establishment of a normal extracellular matrix environment. This review will describe the current knowledge of reparative epithelial progenitor cells in the alveolar region of the lung and discuss potential novel therapeutic approaches for IPF focusing on endogenous alveolar repair. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

SummaryThe respiratory epithelium consists of multiple, functionally distinct cell-types and is maintained by regionally-specific progenitor populations which repair the epithelium following injury. Several in vitro methods exist for studying lung epithelial repair using primary murine lung epithelial 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 which give rise to differentiated epithelia in multiple in vitro assays. In contrast to 3DLD-isolated distal progenitor cells, classic manual tracheal ligation methods followed by lobe removal resulted in co-isolation of rare proximal progenitors with distal cells which altered the transcriptional landscape of distal organoid cultures. Thus, cell isolation with the 3DLD generates reproducible distal versus proximal progenitor populations and minimizes the potential for contaminating populations to confound in vitro assays.Highlights3DLD reproducibly separates lung lobes and extrapulmonary airways (bronchi/trachea)3DLD cell isolation yields consistent isolation of distal epithelial cells (DECs)Contamination of proximal cells in classic DEC isolations may alter in vitro results3DLD allows for simultaneous isolation of proximal and DECs from single animalseTOC blurbAlsafadi et al. describes a new method for simultaneous isolation of lung epithelial proximal and distal progenitors using the aid of a 3D printed device (3DLD). Both isolated cell types differentiate in multiple in vitro assays. The 3DLD guide minimized contamination of proximal cells in distal cell isolations whose presence can alter the transcriptional landscape of distal epithelial organoids.

Mother-infant interactions, including culturally specific features, have been found to predict child socio-emotional development (e.g., social communication and emotion regulation (ER)). However, research is lacking on the specific processes involved. We used a cross-cultural, longitudinal design, and a microanalytic coding approach to address this issue. Fifty-two mother-infant dyads were recruited from the UK ( N = 21) and Italy ( N = 31), representing Northern European and Mediterranean cultures, respectively. While these cultures share core features of parent-child relationships, their values about emotional expressiveness differ. We observed face-to-face mother-infant interactions at 2 months (T1), and coded infant socio-emotional behavior and maternal responses. Children were seen again at 2 years (T2), when their ER in the face of frustration, using the Barrier Task, was assessed, and the occurrence of different “mature” strategies (communicative and autonomous) coded. Results revealed common features of interactions at T1 (infant socio-emotional expressions, and maternal positive responses), but also cultural variation in the frequency of different infant cues (more pre-speech in UK infants, more smiles in Italians), and of maternal responses to them. While greater overall maternal responsiveness at T1 predicted more mature ER in general at T2, cultural differences in early responsiveness to specific infant behaviors predicted later group differences in children’s use of particular ER strategies, with UK children using more communicative strategies, and Italians more autonomous. Findings indicate that positive maternal behaviors that are common across cultures (e.g., responsiveness) promote overall successful child emotion regulation, while culturally specific features of interactions are associated with how child socio-emotional outcomes are expressed.

Rationale: Open lung ventilation strategies have been recommended in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine whether a maximal lung recruitment strategy re...

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-β-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.

Monitoring and optimisation of brain tissue oxygen tension (PbtO

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.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant repair that diminishes lung function via mechanisms that remain poorly understood. CC chemokine receptor (CCR10) and its ligand CCL28 were both elevated in IPF compared with normal donors. CCR10 was highly expressed by various cells from IPF lungs, most notably stage-specific embryonic antigen-4-positive mesenchymal progenitor cells (MPCs). In vitro, CCL28 promoted the proliferation of CCR10+ MPCs while CRISPR/Cas9-mediated targeting of CCR10 resulted in the death of MPCs. Following the intravenous injection of various cells from IPF lungs into immunodeficient (NOD/SCID-γ, NSG) mice, human CCR10+ cells initiated and maintained fibrosis in NSG mice. Eph receptor A3 (EphA3) was among the highest expressed receptor tyrosine kinases detected on IPF CCR10+ cells. Ifabotuzumab-targeted killing of EphA3+ cells significantly reduced the numbers of CCR10+ cells and ameliorated pulmonary fibrosis in humanized NSG mice. Thus, human CCR10+ cells promote pulmonary fibrosis, and EphA3 mAb-directed elimination of these cells inhibits lung fibrosis.

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-b-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.

Phenotypic changes in lung fibroblasts are believed to contribute to the development of Idiopathic Pulmonary Fibrosis (IPF), a progressive and fatal lung disease. Long intergenic non-coding RNAs (lincRNAs) have been identified as novel regulators of gene expression and protein activity. In non-stimulated cells, we observed reduced proliferation and inflammation but no difference in the fibrotic response of IPF fibroblasts. These functional changes in non-stimulated cells were associated with changes in the expression of the histone marks, H3K4me1, H3K4me3 and H3K27ac indicating a possible involvement of epigenetics. Following activation with TGF-β1 and IL-1β, we demonstrated an increased fibrotic but reduced inflammatory response in IPF fibroblasts. There was no significant difference in proliferation following PDGF exposure. The lincRNAs, LINC00960 and LINC01140 were upregulated in IPF fibroblasts. Knockdown studies showed that LINC00960 and LINC01140 were positive regulators of proliferation in both control and IPF fibroblasts but had no effect upon the fibrotic response. Knockdown of LINC01140 but not LINC00960 increased the inflammatory response, which was greater in IPF compared to control fibroblasts. Overall, these studies demonstrate for the first time that lincRNAs are important regulators of proliferation and inflammation in human lung fibroblasts and that these might mediate the reduced inflammatory response observed in IPF-derived fibroblasts.

The lung epithelium is rich in celltype diversity including several progenitors. These distinct regional progenitors have traditionally been identified using lineage tracing or single cell RNAseq. Isolation and use of such cells are hampered by the lack of specific markers that distinguish them in different airway compartments. Thus, a robust method is needed to reliably isolate progenitors from their respective location in the airway. Further, isolation of cells from the same mouse allows for direct analysis of regional disease specific effects and reduction in overall animal numbers. Here, we developed a 3D-printed lobe divider (3DLD) to simultaneously isolate proximal and distal epithelial cells from the same lung. We evaluated isolated cells by their capacity to differentiate in standard in vitro assays. Proximal and distal cells isolated with 3DLD gave rise to differentiated airway and alveolar epithelia respectively as evident by air-liquid-interface cultures and organoid assays with colony forming efficiency (CFE) matching literature. 3DLD method yielded distal organoids with increased CFE and smaller organoid diameters with median of 107µm compared to 171µm from those isolated without 3DLD. We used RNAseq in combination with computational deconvolution to evaluate differences in celltype representation among these cultures. We found that separation of proximal and distal compartments prior cell isolation altered the initial cell populations, likely due to the presence of proximal airway progenitors in single cell suspensions of distal epithelial cells. 3DLD is an inexpensive and reproducible method for isolating proximal and distal progenitors from individual mice.

Introduction: Dysregulation of the alveolar epithelium by repeated injury is recognised as a driver of idiopathic pulmonary fibrosis (IPF). However, access to relevant pre-clinical models of alveolar epithelial injury in IPF is limited. Aims and objectives: We sought to develop a disease model of alveolar epithelial injury in IPF using alveolar epithelial organoids derived from human induced pluripotent stem cells (iPSCs) for drug discovery. Methods: Alveolar epithelial organoids were derived from iPSCs and treated with a fibrosis cocktail (FC) of the pro-fibrotic and inflammatory cytokines TGFβ, TNFα, PDGF-AB and LPA. IPF-related changes were evaluated by RNA-Seq, qRT-PCR, and Western blot. To evaluate the potential of this system for testing anti-fibrotic compounds, we performed prophylactic treatment with the marketed IPF drug nintedanib for 72 h and screened for well-known hallmarks of IPF by qRT-PCR. Results: The FC induced changes known to be observed in IPF, such as epithelial injury and reprogramming (e.g. loss of SFTPC expression and induced VIM expression), production of extracellular matrix and induction of cellular senescence- associated genes. Interestingly, FC treatment also increased expression of KRT17 and KRT8, both recently identified in single-cell RNA-Seq studies as markers of dysregulated epithelial repair in IPF. Treatment with nintedanib partially prevented transcriptional changes in extracellular matrix components, matrix-modifying enzymes and mediators of several signaling pathways associated with IPF. Conclusions: FC treatment of iPSC-derived alveolar epithelial cells successfully models several key aspects of IPF and some of these changes can be prevented with nintedanib, demonstrating that this system can be used for disease modeling of IPF and drug discovery.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87, 95% confidence interval: 2.03–4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10−20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need., Ryan Dhindsa et al. conducted an exome-wide association study to identify a rare variant in SPDL1 as a risk factor for idiopathic pulmonary fibrosis (IPF). Their findings implicate mitotic checkpoint signalling as a new mechanism underlying IPF.

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.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.This was a multicentre, prospective cohort study conducted in five metropolitan ICUs. Participants were adults admitted to the ICU, who received24 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 (p0.10). These included marital status and hours of mechanical ventilation. Sensitivity analysis was also conducted using distance in kilometres as a continuous variable.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 living50 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.

A pilot randomized controlled trial (RCT) was conducted in El Salvador of an intervention ('Thula Sana') previously shown to enhance maternal sensitivity and infant security of attachment in a South African sample. In El Salvador, trained community workers delivered the intervention from late pregnancy to 6 months postpartum as part of a home-visiting programme. The sample comprised 64 pregnant adolescent women, aged 14-19 years, living in predominantly rural settings. They were randomised to receive either the intervention or normal care. Demographic information was collected at baseline and, immediately post-intervention, blind assessments were made of parental sensitivity and infant emotion regulation. The intervention was found to have a substantial positive impact on maternal sensitivity. Further, compared to control group, infants in the intervention group showed more regulated behaviour: in a social challenge task they showed more attempts to restore communication, and in a non-social challenge task they showed more social and goal-directed behaviour. This replication and extension of the South African findings in a small El Salvador sample shows promise and justifies the conduct of a large-scale RCT in a Central or South American context.Un ensayo piloto controlado al azar se llevó a cabo en El Salvador sobre una intervención (‘Thula Sana’) que previamente había mostrado en un grupo muestra sudafricano el mejoramiento de la sensibilidad materna y la seguridad de la afectividad del infante. En El Salvador, trabajadores entrenados de la comunidad llevaron la intervención como parte de un programa de visitas a casa a partir de la última etapa del embarazo hasta seis meses después del parto. El grupo muestra estuvo compuesto por 64 mujeres adolescentes embarazadas, de entre 14 y 19 años, que vivían en áreas predominantemente rurales. Ellas fueron asignadas al azar para recibir o la intervención o el cuidado normal. Al inicio, se recogió la información demográfica e, inmediatamente después de la intervención, se llevaron a cabo evaluaciones ciegas sobre la sensibilidad de la progenitora y la regulación de la emoción del infante. Se determinó que la intervención tenía un impacto positivo considerable sobre la sensibilidad materna. Es más, comparados con el grupo de control, los infantes en el grupo de intervención mostraron una conducta más regulada: en una tarea de reto social mostraron más intentos de restaurar la comunicación, y en una tarea que no era de reto social, mostraron una conducta más sociable y enfocada en el objetivo. La reproducción y extensión de los resultados sudafricanos en un pequeño grupo muestra en el Salvador es prometedora y justifica que se lleve a cabo un ensayo controlado al azar (RCT) a mayor escala dentro de un contexto centro o suramericano.The Impact of a Mother-Infant Intervention on Parenting and Infant Response to Challenge: a pilot randomized controlled trial with Adolescent Mothers in El Salvador Un essai randomisé contrôlé pilote a été fait au Salvador, d'une intervention (‘Thuna Sana’) dont on avait précédemment démontré dans un échantillon Sud-Africain qu'elle améliore la sensibilité maternelle et la sécurité de l'attachement du nourrisson. Au Salvador des agents communautaires formés ont fourni l'intervention de la fin de la grossesse à six mois postpartum, comme faisant partie d'un programme de visite à domicile. L’échantillon a consisté en 64 adolescentes enceintes, âgées de 14 à 19 ans, vivant principalement en milieux ruraux. Elles ont été randomisées afin de recevoir soit l'intention soit les soins normaux. Les renseignements démographiques ont été recueillis au début de l’étude et, immédiatement après l'intervention des évaluations aveugles ont été faites de la sensibilité parentale et de la régulation de l’émotion du bébé. Nous avons trouvé que l'intervention s'est avérée avoir un impact positif important sur la sensibilité maternelle. De plus, comparés au groupe contrôle, les nourrissons du groupe d'intervention ont fait preuve de plus de comportement régulé: lors d'une tâche de défi sociale ils ont fait preuve de plus de tentatives pour restaurer la communication et durant une tâche de défi non-social ils ont fait preuve d'un comportement plus social et plus orienté vers un but. Cette réplique et extension des résultats Sud-Africains dans un petit échantillon du Salvador est prometteur et justifier un essai randomisé contrôlé à large échelle dans un contexte Sud-Américain et en Amérique Centrale.Der Einfluss einer Mutter-Kind-Intervention auf Elternkompetenzen und die kindliche Reaktion auf Herausforderung: Eine randomisierte kontrollierte Pilotstudie mit jugendlichen Müttern in El Salvador In El Salvador wurde eine randomisierte kontrollierte Pilotstudie mit einer Intervention („Thula Sana“) durchgeführt, bei der zuvor an einer südafrikanischen Stichprobe gezeigt werden konnte, dass sie sowohl mütterliche Sensibilität als auch kindliche Bindungssicherheit verbessert. Geschulte Sozialarbeiter:innen führten die Intervention von der späten Schwangerschaft bis sechs Monate nach der Geburt im Rahmen eines Hausbesuchsprogramms durch. Die Stichprobe umfasste 64 schwangere, jugendliche Frauen im Alter von 14 bis 19 Jahren, die in überwiegend ländlichen Regionen lebten. Sie wurden randomisiert entweder der Interventionsgruppe oder einer Kontrollgruppe zugeteilt, die die übliche Betreuung erhielt. Zu Studienbeginn wurden demografische Daten gesammelt und unmittelbar nach der Intervention wurden verblindet Beurteilungen der elterlichen Sensibilität und der kindlichen Emotionsregulation vorgenommen. Es wurde festgestellt, dass die Intervention einen signifikanten positiven Einfluss auf die mütterliche Sensibilität hat. Im Vergleich zur Kontrollgruppe zeigten Säuglinge in der Interventionsgruppe ein stärker reguliertes Verhalten: Bei einer Aufgabe mit sozialer Herausforderung zeigten sie mehr Versuche, die Kommunikation wiederherzustellen, und bei einer Aufgabe mit einer nicht-sozialen Herausforderung zeigten sie mehr soziales und zielgerichtetes Verhalten. Diese Replikation und Erweiterung der südafrikanischen Ergebnisse in einer kleinen salvadorianischen Stichprobe sind vielversprechend und können die Grundlage für groß angelegten RCT`s in mittel- oder südamerikanischen Kontexten darstellen.母-子介入が養育と乳児の挑戦課題への反応に及ぼす影響:エルサルバドルの青年期の母親を対象にした予備的無作為化比較試験 すでに南アフリカの対象者に関して報告されている、母親の感受性と乳児の安定したアタッチメントを向上させるための介入“トゥラサナ”の予備的な無作為化比較試験がエルサルバドルで実施された。エルサルバドルでは、訓練を受けた自治体の職員が家庭訪問プログラムの一環として、妊娠後期から産後6か月まで介入を提供した。対象者は、主に農村部に住む14〜19歳の青年期の妊婦64名であった。対象者は、この介入もしくは通常のケアのいずれかを受けるように無作為に振分けられた。ベースラインとして人口統計学的情報が収集され、介入直後に、養育の感受性と乳児の感情調整について盲検評価が行われた。この介入は、母親の感受性に実質的な正の影響を与えることがわかった。さらに、介入群の乳児は対照群と比較して、より調整された行動を示した。すなわち、社会的挑戦課題ではコミュニケーションを回復するためにより多くの試みを示し、非社会的挑戦課題において、より社会的で目標志向的な行動を示した。エルサルバドルの小規模サンプルにおいて南アフリカでの実施知見の再現と拡張が見られたことは、中南米の状況における大規模なRCT (無作為化比較試験) の実施に見込みと正当性があることを示している。.在萨尔瓦多进行了一项试验性的随机对照试验, 对先前在南非样本中开展的一种干预措施 (“Thula Sana”) 进行了研究, 以提高孕产妇依恋的敏感性和婴儿依恋的安全性。在萨尔瓦多, 作为家访计划的一部分, 经过培训的社区工作人员, 对孕产妇从妊娠晚期到产后六个月开展了干预措施。样本包括64名怀孕的青少年妇女, 年龄在14至19岁之间, 主要生活在农村地区。他们被随机分配为接受干预组或常规护理组。试验开始时收集了人口统计信息, 并在干预后立即对育儿敏感性和婴儿情绪调节进行盲测。研究发现, 这项干预措施对孕产妇的敏感性有很大的积极影响。此外, 与对照组相比, 干预组的婴儿表现出更为规范的行为:在社交挑战任务中, 他们表现出更多恢复沟通的尝试;在非社交挑战任务中, 他们表现出更多的社交和目标导向行为。在萨尔瓦多的一个小样本中复制和扩展了南非的研究结果, 这预示着试验的成功, 并证明了在中美洲或南美洲进行大规模RCT的合理性。.تأثير تدخل تجريبي مع ثنائيات الأم والطفل على عملية الرعاية الوالدية واستجابة الرضع للتحدي: تجربة استطلاعية معشاة ذات شواهد مع الأمهات المراهقات في السلفادور أجريت تجربة استطلاعية معشاة ذات شواهد في السلفادور على التدخل التجريبي (Thula Sana) الذي سبق أن أظهر تأثيراً على عينة جنوب أفريقيا من حيث تعزيز حساسية الأمهات وأمان التعلق لدى الرضع. وفي السلفادور، قام العاملون المجتمعيون المدربون بالتدخل من مرحلة الحمل المتأخر إلى فترة ما بعد الولادة لمدة ستة أشهر كجزء من برنامج الزيارات المنزلية. واشتملت العينة على 64 من المراهقات الحوامل، اللاتي تتراوح أعمارهن بين 14 و 19 سنة، ويعشن في بيئات ريفية في الغالب. وتم توزيع العينة عشوائياً إلى مجموعة تجريبية تتلقى التدخل أو مجموعة ضابطة تتلقى الرعاية العادية. وتم جمع المعلومات الديمغرافية عند نقطة البداية، وأجريت، بعد التدخل مباشرة، تقييمات عمياء لحساسية الوالدين وتنظيم المشاعر عند الرضع. وتبين أن هذا التدخل له أثر إيجابي كبير على حساسية الأمهات. وعلاوة على ذلك، وبالمقارنة مع المجموعة الضابطة، أظهر الرضع في مجموعة التدخل سلوكاً أكثر تنظيماً: ففي مهمة التحدي الاجتماعي أظهروا المزيد من المحاولات لاستعادة التواصل، وفي مهمة التحدي غير الاجتماعي أظهروا سلوكاً اجتماعياً وموجهاً نحو الأهداف. وهذا التكرار والامتداد لنتائج جنوب أفريقيا في عينة صغيرة من السلفادور يدعم إجراء تجارب على نطاق واسع في مجتمعات أمريكا الوسطى أو الجنوبية.

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 (8weekly 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.

Prophylactic hypothermia, often used in critically ill patients with traumatic brain injury, reduces energy expenditure and may affect energy delivered by nutrition therapy. The primary objective of this study was to measure energy expenditure in hypothermic patients over the first 3 days after traumatic brain injury (TBI). Secondary objectives included comparison of measured energy expenditure and nutrition delivery to day 7.A prospective sub-study of a randomized controlled trial conducted in patients with severe TBI, investigating prophylactic hypothermia (33-35 °C) as a neuroprotective therapy. In two centers, indirect calorimetry was initiated within 24 h of randomization and repeated up to twice daily to day 7. Data are presented as n (%), mean (standard deviation (SD)), median [interquartile range (IQR)], and mean difference (95% confidence interval (CI)).Forty patients were included (20 in each group), with 17 patients in the hypothermic and 16 in the normothermic group having an indirect calorimetry measurement in the first 3 days. Over the first 3 days, the mean temperature in the hypothermic and normothermic groups was 33.5 (0.6) ºC (n = 17) and 37 (0.5) ºC (n = 16), p 0.0001, and the mean measured energy expenditure, was 21 (5) and 27 (4) kcal/kg, p = 0.002, representing a mean difference of 5 (95% CI: 2-8) kcal/kg. Energy expenditure was 20% (95% CI: 9.5-29%) less in hypothermia patients compared to normothermia patients. Hypothermia patients also had higher gastric residual volumes across the 7 day study period (438 (237) mls vs 184 (103) mls, p 0.0001) and higher use of metoclopramide and erythromycin as prokinetics. Despite enteral nutrition intolerance, hypothermia patients received 93% of measured energy expenditure over 7 days.In TBI patients, energy expenditure was 20% less when receiving prophylactic hypothermia compared to normothermia. Greater gastric residual volumes, use of prokinetics and energy delivery that approximated measured energy expenditure was also observed in hypothermia patients.POLAR-RCT: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235. This sub-study was not registered separately.

Maternal-infant feeding interactions are a primary context for engagement between mothers and their infants, and constitute a unique space in which reciprocity, attunement and maternal sensitivity can be expressed. Increasingly, research demonstrates the importance of the psychological and social nature of the feeding context, and how it may be affected by maternal mental state, feeding skills and sensitivity. As such, feeding interactions may provide useful contexts for observations of maternal sensitivity, reflecting well on day-to-day maternal sensitivity.This paper is a post hoc examination of the impact of an intervention on maternal sensitivity during a feeding interaction when the infants were 6 months old.A total of 449 women consented to participate in the original intervention and were randomly assigned to the intervention or control groups. Mothers and infants were assessed during pregnancy, and then at 2, 6, 12 and 18 months of infant age. At the 6 month follow-up visit, 79% (354 out of 449) of the participants were retained. Post hoc analyses were conducted on the original sample to determine breastfeeding status. Sixty-nine percent of the women completed the feeding observation at the 6 months follow-up visit, of which 47% reported exclusively breastfeeding and 22% reported bottle-feeding.Results demonstrated that during a feeding interaction, maternal sensitivity was significantly improved among non-breastfeeding mothers who received the intervention. Particularly, maternal responsiveness to infant cues and synchronous interactions was higher among non-breastfeeding intervention mothers compared to control group mothers. The results also show that non-breastfeeding mothers who received the intervention were significantly less intrusive in their interactions with their infants.The intervention had particular beneficial effects for mothers who were not breastfeeding and suggest that the intervention offered a protective effect for non-breastfeeding mothers.Trasfondo: Las interacciones materno-infantiles de alimentación son un contexto primario de compromiso interactivo entre madres y sus infantes. Alimentar al infante es un proceso complejo que requiere no sólo que se provean los nutrientes, sino también una relación social entre el cuidador y el infante. Metas y Objetivos: Este artículo es un examen a posteriori del impacto de una intervención sobre la sensibilidad materna durante una interacción de alimentación cuando los infantes tenían seis meses de edad. Participantes: Un total de 449 mujeres consintieron en participar en la intervención original y fueron asignadas al azar a la propia intervención o a los grupos de control. A la visita de seguimiento de los seis meses, el 79% (354 de las 449) de las participantes aún se mantenían. Se llevaron a cabo análisis a posteriori en el grupo muestra original para determinar la condición de amamantamiento. Resultados: Durante una interacción de alimentación, la sensibilidad materna mejoró significativamente entre las madres que no amamantaban y que recibieron la intervención. La sensibilidad materna a las señales del infante y a las interacciones sincrónicas fue más alta entre madres de la intervención que no amamantaban tal como se les comparó con las madres del grupo de control. Conclusión: Estos resultados demuestran particularmente los efectos beneficiosos para las madres en el grupo de intervención que no estaban amamantando, y sugieren que la intervención ofreció un efecto de protección para las madres que no amamantaban.Contexte: Les interactions maternelles-bébé durant l'alimentation sont un contexte primaire pour l'engagement entre les mères et leurs bébés. Nourrir son bébé est un processus complexe qui inclut non seulement le transfert d’éléments nutritifs mais également une relation sociale entre la personne prenant soin du bébé et le bébé. Buts et Objectifs: Cet article est une étude post hoc de l'impact d'une intervention sur la sensibilité maternelle durant une interaction d'alimentation lorsque les bébés avaient six mois. Participantes: Un total de 449 femmes ont consenti à participer à l'intervention originelle et ont été réparties au hasard au groupe d'intervention ou au groupe de contrôle. A la visite de suivi de six mois 79% (354 sur 449) des participantes ont été retenues. Les analyses post hoc analyses ont été faites sur l’échantillon d'origine afin de déterminer le statut d'allaitement au sein. Résultats: Durant une interaction d'alimentation, la sensibilité maternelle a été améliorée de manière importante chez les mères de donnant pas le sein qui recevaient l'intervention. La réaction maternelle aux signes du bébé et les interactions synchronisées étaient plus élevées chez les mères du groupe d'intervention de non allaitement au sein comparées au groupe de mères de contrôle. Conclusion: Ces résultats dénotent des effets particulièrement favorables pour les mères du groupe d'intervention qui n'allaitaient pas au sein, et suggèrent que l'intervention a offert un effet protecteur pour les mères n'allaitant pas leurs bébé au sein.Verbesserung der Mutter-Kind-Interaktion während des Fütterns: Eine randomisierte, kontrollierte Studie in einer einkommensschwachen Gemeinde in Südafrika Hintergrund: Die Interaktion zwischen Mutter und Kind beim Füttern stellt einen primären Kontext in der Mutter-Kind-Beziehung dar. Das Füttern eines Säuglings ist ein komplexer Prozess, bei dem nicht nur Nährstoffe weiter gegeben werden, sondern auch eine soziale Beziehung zwischen Bezugsperson und Säugling entsteht. Untersuchungsziele: In dieser Studie wurden die Effekte einer Intervention auf die mütterliche Sensibilität während einer Fütterungsinteraktion mit sechs Monate alten Säuglingen post-hoc untersucht. Teilnehmerinnen: Insgesamt 449 Frauen erklärten sich mit einerr Teilnahme an der ursprünglichen Intervention einverstanden und wurden nach dem Zufallsprinzip den Interventions- oder Kontrollgruppen zugeordnet. Bei dem Follow-up-Besuch nach 6 Monaten blieben 79% (354 von 449) der Teilnehmerinnen der Studie erhalten. An der ursprünglichen Stichprobe wurden Post-hoc-Analysen durchgeführt, um den Stillstatus zu bestimmen. Ergebnisse: Die Sensibilität beim Füttern wurde bei nicht stillenden Müttern, die die Intervention erhalten hatten, signifikant verbessert. Die mütterliche Reaktionsfähigkeit auf die vom Säugling ausgehenden Zeichen und die Synchronität der Interaktion war in der Gruppe der nicht stillenden Mütter, die die Intervention erhalten hatten, höher als bei den Müttern der Kontrollgruppe. Fazit: Diese Ergebnisse zeigen die insbesondere für nicht stillende Mütter vorteilhafte Wirkung der Intervention und legen nahe, dass die Intervention eine schützende Wirkung auf nicht stillende Mütter hatte.授乳中の母-乳児の相互作用を改善する:南アフリカの低所得者地域における無作為化比較対照試験 背景:母-乳児の授乳中の相互作用は、母親とその乳児間の没頭に関する最初の 重要な場面である。乳児の授乳は、栄養を運ぶということだけでなく、養育者と 乳児間の社会的な関係が伴う複雑な過程である。 目的:本論文は、乳児が6ヶ月の際の授乳の相互作用時に母親の感受性に対する 介入の影響の事後調査である。 対象者:449人の女性が最初の介入に参加することに同意し、介入群かコントロ ール群に無作為に割り当てられた。6ヶ月児のフォローアップの訪問で、79% ( 449人の内354人) の対象者が保持された。母乳育児の状態の測定のために事後分 析が元のサンプルに実施された。 結果:授乳中の相互作用において、母親の感受性は、介入群の母乳育児をしてい ない母親において有意に向上した。乳児の合図に対する母親の応答と同調相互作 用は、コントロール群の母親に比べ、母乳育児をしていない介入群の母親の方が 高かった。 結論:これらの結果は、母乳育児をしていない介入群の母親に対して特に優位に 効果があることを実証し、介入が母乳育児でない母親について保護効果を提供し ていることを示唆している。.研究背景:母婴喂养互动是母婴互动的主要内容。婴儿喂养是一个复杂的过程, 不仅涉及营养物质的转移, 还涉及照顾者与婴儿之间的社会关系。研究目的:本文是对六个月大的婴儿在喂养互动过程中, 采取干预行为对母亲敏感性的影响进行的事后检验。研究对象:共有449名妇女同意参与到最初的干预行为中, 她们被随机分配到各个干预组或对照组。在六个月的随访中, 79% (354/449) 的参与者被保留下来。我们对原始样本进行了事后分析, 以确定母乳喂养的状况。检验结果:在喂养互动中, 接受干预的非母乳喂养母亲的母亲敏感性显著提高。与对照组母亲相比, 非母乳喂养干预组的母亲对婴儿提示和同步互动的回应更积极。研究结论:检验结果表明, 干预组中非母乳喂养的母亲尤为受益, 干预行为对其具有保护作用。.تحسين التفاعل بين الأم والرضيع أثناء الإطعام: تجربة معشاة ذات شواهد في مجتمع منخفض الدخل في جنوب أفريقيا الخلفية: التفاعلات بين الأمهات والرضع هي سياق أساسي للمشاركة بين الأمهات وأطفالهن. وإطعام الرضع عملية معقدة لا تنطوي على نقل المغذيات فحسب، بل تشمل أيضا ً علاقة اجتماعية بين مقدم الرعاية والرضيع. الأهداف: هذه الورقة هي دراسة بعدية لتأثير التدخل التجريبي على حساسية الأم أثناء تفاعل التغذية عندما كان عمر الرضع ستة أشهر. المشاركون: وافق مجموعة من 449 امرأة على المشاركة في التدخل الأصلي وتم تعيينهن عشوائياً في المجموعة التجريبية أو الضابطة. وفي زيارة المتابعة التي استمرت ستة أشهر، تم الاحتفاظ بنسبة 79 في المائة (354 من أصل 449) من المشاركين. أجريت تحليلات بعدية على العينة الأصلية لتحديد حالة الرضاعة الطبيعية. النتائج: خلال تفاعل التغذية، تحسنت حساسية الأمهات بشكل كبير بين الأمهات غير المرضعات اللاتي تلقين التدخل. كانت استجابة الأمهات لإشارات الرضع والتفاعلات المتزامنة أعلى بين الأمهات غير المرضعات في المجموعة التجريبية مقارنة بأمهات المجموعة الضابطة. الاستنتاج: تُظهر هذه النتائج آثاراً مفيدة بشكل خاص للأمهات في مجموعة التدخل التي لم تكن ترضع رضاعة طبيعية، وتشير إلى أن التدخل كان له أثر وقائي على الأمهات غير المرضعات.

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite significant progress, the genetic determinants of this disease remain incompletely defined. Using next generation sequencing data from 752 individuals with sporadic IPF and 119,055 controls, we performed both variant- and gene-level analyses to identify novel IPF genetic risk factors. Our variant-level analysis revealed a novel rare missense variant in SPDL1 (NM_017785.5 p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87). This signal was independently replicated in the FinnGen cohort (combined p = 2.2 × 10−20), firmly associating this variant as a novel IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. Our results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

Neutrophils are the most abundant inflammatory cells at the earliest stages of wound healing and play important roles in wound repair and fibrosis. Formyl peptide receptor 1 (FPR-1) is abundantly expressed on neutrophils and has been shown to regulate their function, yet the importance of FPR-1 in fibrosis remains ill defined. FPR-1–deficient (fpr1–/–) mice were protected from bleomycin-induced pulmonary fibrosis but developed renal and hepatic fibrosis normally. Mechanistically, we observed a failure to effectively recruit neutrophils to the lungs of fpr1–/– mice, whereas neutrophil recruitment was unaffected in the liver and kidney. Using an adoptive transfer model we demonstrated that the defect in neutrophil recruitment to the lung was intrinsic to the fpr1–/– neutrophils, as C57BL/6 neutrophils were recruited normally to the damaged lung in fpr1–/– mice. Finally, C57BL/6 mice in which neutrophils had been depleted were protected from pulmonary fibrosis. In conclusion, FPR-1 and FPR-1 ligands are required for effective neutrophil recruitment to the damaged lung. Failure to recruit neutrophils or depletion of neutrophils protects from pulmonary fibrosis., FPR-1 is the primary receptor driving neutrophil recruitment to the injured lung, and absence of FPR-1 or depletion of neutrophils protects from pulmonary fibrosis.

Background: This study evaluated whether clinical and economic outcomes from CBT for child anxiety disorders in the context of maternal anxiety disorders are improved by adding treatment focused on (i) maternal anxiety disorders, or (ii) mother-child interactions. Methods: 211 children (7 – 12 years, 85% White British, 52% female) with a primary anxiety disorder, whose mothers also had a current anxiety disorder, were randomised to receive (i) child-focused CBT with non-specific control interventions (CCBT+Con), (ii) CCBT with CBT for the maternal anxiety disorder (CCBT+MCBT), or (iii) CCBT with an intervention targeting the mother-child interaction (CCBT+MCI). A cost-utility analysis from a societal perspective was conducted using mother/child combined Quality Adjusted Life Years (QALYs). [Trial registration: https://doi.org/10.1186/ISRCTN19762288]. Results: MCBT was associated with immediate reductions in maternal anxiety compared to the non-specific control; however, after children had also received CCBT, maternal outcomes in the CCBT+MCI and CCBT+Con arms improved and CCBT+MCBT was no longer superior. Neither CCBT+MCBT nor CCBT+MCI conferred a benefit over CCBT+Con in terms of child anxiety disorder diagnoses post-treatment [primary outcome] (adj RR: 1.22 (95% CI 0.88, 1.67), p = .23; adj RR: 1.21 (95% CI 0.88, 1.65), p = .24 respectively) or global improvement ratings (adj RR 1.25 (95% CI 0.99, 1.57), p = .06; adj RR 1.18 (95% CI 0.93, 1.50), p = .17) or six and 12 months later. No significant differences between the groups were found on the main economic outcome measures (child/mother combined QALY mean difference: CCBT+MCBT vs CCBT+Con: -0.04 (95% CI -0.12, 0.04), p = 0.29; CCBT+MCI vs CCBT+Con: 0.02 (95% CI -0.05, -0.09), p = 0.54). CCBT+MCI was associated with non-significantly higher costs than CCBT (mean difference: £154 (95% CI -£1239, £1547), p = 0.83) but, when taking into account sampling uncertainty, it may be cost-effective compared with CCBT alone. Conclusions: Good outcomes were achieved for children and their mothers across treatment arms. There was no evidence of significant clinical benefit from supplementing CCBT with either CBT for the maternal anxiety disorder or treatment focussed on mother-child interactions, but the addition of MCI (and not MCBT) may be cost-effective. Keywords: Child; anxiety; mother; parent-child interaction; CBT.

Background: Social anxiety disorder (SAD) aggregates in families. To elucidate intergenerational transmission of risk, we examined whether childhood SAD and symptoms of anxiety were prospectively predicted by stable infant temperamental inhibition, maternal SAD, maternal generalized anxiety disorder (GAD) and maternal parenting behaviours. Methods: We conducted a longitudinal study beginning prenatally with follow‐up at 4, 10, 14 and 58 months postnatally. Mothers were assessed for anxiety disorders prenatally and assigned to one of three groups: SAD (n = 67), GAD (n = 56) and nonanxious controls (n = 94). We assessed infant temperamental inhibition at 4 and 14 months, maternal parenting behaviours at 10 and 58 months, and child anxiety disorders and symptoms at 58 months. Results: Child SAD at 58 months was predicted by prenatal maternal SAD (OR = 23.76, 95% CI = 1.15–60.37), but not by prenatal maternal GAD (OR = 7.44, 95% CI = 0.32–124.49), stable temperamental inhibition or maternal behaviours. Child anxiety symptoms at 58 months were predicted specifically by maternal SAD (but not GAD), and also by concurrent maternal intrusiveness. Stable temperamental inhibition moderated the association between 10‐month maternal encouragement and 58‐month child anxiety symptoms. Conclusions: We found evidence for specificity of risk for child SAD and anxiety symptoms from maternal SAD compared to maternal GAD. Childhood anxiety symptoms were also predicted by an interaction between a lack of maternal encouragement in infancy and stable temperamental inhibition, as well as concurrent maternal intrusiveness. The findings have clinical implications for targeted prevention of child anxiety.