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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/).

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.

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...

IntroductionHaemorrhage causes most preventable prehospital trauma deaths and about a third of in-hospital trauma deaths. Tranexamic acid (TXA), administered soon after hospital arrival in certain trauma systems, is an effective therapy in preventing or managing acute traumatic coagulopathy. However, delayed administration of TXA appears to be ineffective or harmful. The effectiveness of prehospital TXA, incidence of thrombotic complications, benefit versus risk in advanced trauma systems and the mechanism of benefit remain uncertain.Methods and analysisThe Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH-Trauma study) is comparing TXA, initiated prehospital and continued in hospital over 8 hours, with placebo in patients with severe trauma at risk of acute traumatic coagulopathy. We present the trial protocol and an overview of the statistical analysis plan. There will be 1316 patients recruited by prehospital clinicians in Australia, New Zealand and Germany. The primary outcome will be the eight-level Glasgow Outcome Scale Extended (GOSE) at 6 months after injury, dichotomised to favourable (GOSE 5–8) and unfavourable (GOSE 1–4) outcomes, analysed using an intention-to-treat (ITT) approach. Secondary outcomes will include mortality at hospital discharge and at 6 months, blood product usage, quality of life and the incidence of predefined adverse events.Ethics and disseminationThe study was approved by The Alfred Hospital Research and Ethics Committee in Victoria and also approved in New South Wales, Queensland, South Australia, Tasmania and the Northern Territory. In New Zealand, Northern A Health and Disability Ethics Committee provided approval. In Germany, Witten/Herdecke University has provided ethics approval. The PATCH-Trauma study aims to provide definitive evidence of the effectiveness of prehospital TXA, when used in conjunction with current advanced trauma care, in improving outcomes after severe injury.Trial registration numberNCT02187120.

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.

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.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)–dependent manner. Gas6 ...

Background Smoking and aberrant epithelial responses are risk factors for lung cancer as well as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. In these conditions, disease progression is associated with epithelial damage and fragility, airway remodelling and sub-epithelial fibrosis. The aim of this study was to assess the acute effects of cigarette smoke on epithelial cell phenotype and pro-fibrotic responses in vitro and in vivo. Results Apoptosis was significantly greater in unstimulated cells from COPD patients compared to control, but proliferation and CXCL8 release were not different. Cigarette smoke dose-dependently induced apoptosis, proliferation and CXCL8 release with normal epithelial cells being more responsive than COPD patient derived cells. Cigarette smoke did not induce epithelial-mesenchymal transition. In vivo, cigarette smoke exposure promoted epithelial apoptosis and proliferation. Moreover, mimicking a virus-induced exacerbation by exposing to mice to poly I:C, exaggerated the inflammatory responses, whereas expression of remodelling genes was similar in both. Conclusions Collectively, these data indicate that cigarette smoke promotes epithelial cell activation and hyperplasia, but a secondary stimulus is required for the remodelling phenotype associated with COPD. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0565-2) contains supplementary material, which is available to authorized users.

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.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated.ObjectivesThe aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function.Methods and resultsMCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC–fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)–induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis.ConclusionNintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.

Background Facial mimicry is crucial in the recognition of others’ emotional state. Thus, the observation of others’ facial expressions activates the same neural representation of that affective state in the observer, along with related autonomic and somatic responses. What happens, therefore, when someone cannot mimic others’ facial expressions? Methods We investigated whether psychophysiological emotional responses to others’ facial expressions were impaired in 13 children (9 years) with Moebius syndrome (MBS), an extremely rare neurological disorder (1/250,000 live births) characterized by congenital facial paralysis. We inspected autonomic responses and vagal regulation through facial cutaneous thermal variations and by the computation of respiratory sinus arrhythmia (RSA). These parameters provide measures of emotional arousal and show the autonomic adaptation to others’ social cues. Physiological responses in children with MBS were recorded during dynamic facial expression observation and were compared to those of a control group (16 non-affected children, 9 years). Results There were significant group effects on thermal patterns and RSA, with lower values in children with MBS. We also observed a mild deficit in emotion recognition in these patients. Conclusion Results support “embodied” theory, whereby the congenital inability to produce facial expressions induces alterations in the processing of facial expression of emotions. Such alterations may constitute a risk for emotion dysregulation.

Background Children in many low- and middle-income countries (LMICs) are at high risk for exposure to violence and later violent behaviour. The World Health Organization has declared an urgent need for the evaluation and implementation of low-cost parenting interventions in LMICs to prevent violence. Two areas of significant early risk are harsh parenting and poor child cognitive and socio-emotional development. Parenting interventions suitable for LMIC contexts have been developed targeting these risk factors and have been shown to have promising effects. However, their impact on child aggression, a key precursor of violence, has yet to be determined. The Pelotas Trial of Parenting Interventions for Aggression (PIÁ) has been designed to address this issue. Methods We are conducting a randomised controlled trial to evaluate two early parenting interventions for mothers of children aged between 30 and 42 months in a Brazilian city. The first of these, dialogic book-sharing (DBS), aims to promote child cognitive and socio-emotional development; and the second, the ACT Raising Safe Kids Program (ACT), is designed to reduce harsh parenting. These interventions are being compared with a control group receiving neither intervention. Three hundred and sixty-nine families in a birth cohort are being randomly allocated to one of the three groups (DBS, ACT, Control). Facilitators deliver the interventions to groups of five to 10 mothers at weekly sessions for 8 weeks in DBS and 9 weeks in ACT. Independent assessments of parenting and child development are being made before the interventions, shortly afterwards, and at follow-up 6 months later. The primary outcome is child aggression, and the two main secondary outcomes are: (1) child cognitive and socio-emotional development and (2) harsh parenting. Longer-term outcomes will be investigated as the birth cohort is followed into late childhood, adolescence, and adulthood. Discussion The Pelotas Trial of Parenting Interventions for Aggression (PIÁ) aims to evaluate the impact of two early parenting interventions on child aggression and several other key risk factors for the development of violence, including aspects of parenting and child cognition and socio-emotional functioning. The study is being carried out in a LMIC context where violence constitutes a major social and health burden. Since the two interventions are brief and, with modest levels of training, readily deliverable in LMIC settings, a demonstration that they benefit parenting and reduce risk factors for violence would be of major significance. Trial registration Brazilian Ministry of Health Register of Clinical Trials, ID: RBR-2kwfsk . Registered on 6 June 2018.

Trials comparing the effects of transfusing RBC units of different storage durations have considered mortality or morbidity as outcomes. We perform the first economic evaluation alongside a full age of blood clinical trial with a large population assessing the impact of RBC storage duration on quality-of-life and costs in critically ill adults.Quality-of-life was measured at 6 months post randomization using the EuroQol 5-dimension 3-level instrument. The economic evaluation considers quality-adjusted life year and cost implications from randomization to 6 months. A generalized linear model was used to estimate incremental costs (2016 U.S. dollars) and quality-adjusted life years, respectively while adjusting for baseline characteristics.Fifty-nine ICUs in five countries.Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit.Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service.EuroQol 5-dimension 3-level utility scores were similar at 6 months-0.65 in the short-term and 0.63 in the long-term storage group (difference, 0.02; 95% CI, -0.00 to 0.04; p = 0.10). There were no significant differences in resource use between the two groups apart from 3.0 fewer hospital readmission days (95% CI, -5.3 to -0.8; p = 0.01) during follow-up in the short-term storage group. There were no significant differences in adjusted total costs or quality-adjusted life years between the short- and long-term storage groups (incremental costs, -$2,358; 95% CI, -$5,586 to $711) and incremental quality-adjusted life years: 0.003 quality-adjusted life years (95% CI, -0.003 to 0.008).Without considering the additional supply cost of implementing a freshest available RBC strategy for critical care patients, there is no evidence to suggest that the policy improves quality-of-life or reduces other costs compared with standard transfusion practice.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause, characterised by progressive worsening in lung function and dyspnoea with an associated prognosis similar to or worse than many cancers. As a better understanding emerges around the pathogenesis and mechanisms driving disease pathology, a host of novel agents are being tested both pre-clinically and clinically. However even with this deeper understanding and positive pre-clinical supportive data, negative trial outcomes are frequently reported, highlighting the problems faced in treating such a heterogeneous disease with a varied clinical course. Recently, two therapies that slow disease progression, nintedanib and pirfenidone, have been approved for the treatment of IPF, yet the clinical unmet need is still high for IPF patients given their failure to stop disease progression and their potential side-effect profiles. Efforts are being made to not only understand the underlying pathways and genetics that might influence the clinical course of the disease, but also the non-invasive biomarkers that reflect the activity of specific pathways which in turn may highlight progressive treatment plans for individual patients. The cumulative data may be based on the identification of subgroups of patients via biomarker analysis of ongoing clinical trials, or investigation of cohorts of patients over time to understand the relative role of these mediators in their disease progression. Below we review the ongoing quest for novel therapeutic approaches and highlight, where appropriate attempts have been made to identify patients for which a specific pathway or mediator may be driving disease progression.

A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby the patient experiences a pronounced worsening of disease symptoms. Moreover, acute exacerbations may also be a marker of insufficient disease management. The underlying cause of an acute exacerbation can be due to insults such as pathogens or environmental pollutants, or the cause can be unknown. For each acute exacerbation, the patient may require medical intervention such as rescue medication, or in more severe cases, hospitalization and ventilation and have an increased risk of death. Biologics, such as monoclonal antibodies, are being developed for chronic respiratory diseases including asthma, COPD and IPF. This therapeutic approach is particularly well suited for chronic use based on the route and frequency of delivery and importantly, the potential for disease modification. In recent clinical trials, the frequency of acute exacerbation has often been included as an endpoint, to help determine whether the investigational agent is impacting disease. Therefore the significance of acute exacerbations in driving disease, and their potential as a marker of disease activity and progression, has recently received much attention. There is also now a need to standardize the definition of an acute exacerbation in specific disease settings, particularly as this endpoint is increasingly used in clinical trials to also assess therapeutic efficacy. Moreover, specifically targeting exacerbations may offer a new therapeutic approach for several chronic respiratory diseases.

It is estimated that postpartum depression affects up to 25% of men. Despite such high prevalence, the majority of studies on postpartum depression are focused on mothers, and the role of paternal depression and its effects on infant development have been overlooked by researchers and clinicians. The present study aimed to fill this gap by investigating the effect of paternal postpartum depression on father-infant interactions. In addition, we examined whether differences in face recognition mediated the effects of paternal postpartum depression on father-infant interactions. A total of 61 father-infant dyads (17 postpartum depression, 44 controls) took part in the study. Results revealed that compared to controls, fathers with postpartum depression had a worse pattern of interaction with their infants on measures of responsiveness, mood, and sensitivity; they also had greater difficulty in recognizing happy adult faces, but greater facility in recognizing sad adult faces. Depressed fathers attributed greater intensities to sad adult and infant faces. The tendency to attribute greater intensity to sad adult faces was confirmed as a partial mediator of the effect of paternal postpartum depression on measures of father responsiveness and as a full mediator of the effects of paternal depression on father sensitivity. Clinical implications and suggestions for further studies are discussed.Se estima que la depresión posterior al parto afecta hasta un 25% de los hombres. A pesar de tan alta prevalencia, la mayoría de los estudios sobre la depresión posterior al parto se enfocan en las madres, y los investigadores y clínicos han pasado por alto el papel de la depresión paterna y sus efectos en el desarrollo del infante. El presente estudio se propuso llenar ese vacío investigando el efecto que la depresión paterna posterior al parto tiene en las interacciones papá-infante. Adicionalmente, examinamos si las diferencias en reconocer las caras mediaron los efectos que la depresión paterna posterior al parto tiene en las interacciones papá-infante. Sesenta y una díadas papá-infante (17 en el grupo de depresión posterior al parto, 44 en el grupo de control) participaron en el estudio. Los resultados revelaron que, comparados con el grupo de control, los papás con depresión posterior al parto presentaban un peor patrón de interacción con sus infantes en medidas de capacidad de respuesta, estado de ánimo y sensibilidad; ellos también tuvieron mayores dificultades en reconocer caras adultas felices, pero con mayor facilidad reconocieron caras adultas tristes. Los padres deprimidos atribuyeron una mayor intensidad a las caras tristes de adultos e infantes. Se confirmó la tendencia de atribuir una mayor intensidad a las caras adultas tristes como un mediador parcial del efecto que la depresión paterna posterior al parto tiene sobre la calidad de respuesta del papá y como un completo mediador de los efectos que la depresión paterna tiene sobre la sensibilidad del papá. Se discuten las implicaciones y sugerencias clínicas para futuros estudios.On estime que la dépression postpartum affect jusqu’à 25% des hommes. En dépit d'une telle prévalence élevée la majorité des études sur la dépression postpartum porte sur les mères et le rôle de la dépression paternelle et de ses effets sur le développement du nourrisson a été négligé par les chercheurs et les cliniciens. Cette étude s'est donné pour but de remplir ce fossé en recherchant l'effet de la dépression postpartum sur les interactions père-nourrisson. De plus, nous avons examiné si les différences dans la reconnaissance faciale ont assuré la médiation des effets de la dépression paternelle postpartum sur les interactions père-nourrisson. 61 dyades père-bébé (17 dépression postpartum, 44 contrôles) ont pris part à l’étude. Les résultats ont révélé que, comparés aux contrôles, les pères avec la dépression postpartum faisaient état d'un pattern d'interaction avec leur bébé pire sur les mesures de réactivité, d'humeur et de sensibilité. Ils avaient aussi plus de difficulté à reconnaître les visages adultes heureux mais une plus grande facilité à reconnaître les visages adultes tristes. Les pères déprimés ont attribué de plus grandes intensités aux visages tristes de l'adulte et du bébé. La tendance à attribuer une plus grande intensité aux visages tristes de l'adulte a été confirmée comme un médiateur partiel de l'effet de la dépression paternelle postpartum sur la réaction du père et comme un médiateur total sur les effets de la dépression paternelle sur la sensibilité du père. Les implications cliniques et des suggestions de recherche sont discutées.Es wird geschätzt, dass bis zu 25% der Männer von einer postpartalen Depression betroffen sind. Trotz dieser hohen Prävalenz konzentriert sich die Mehrheit der Studien über postpartale Depression auf Mütter, und die Rolle der väterlichen Depression und ihre Auswirkungen auf die Säuglingsentwicklung wurden von Forschern und Klinikern übersehen. Die vorliegende Studie zielte darauf ab, diese Lücke zu schließen, indem sie die Auswirkungen der väterlichen postpartalen Depression auf die Interaktion zwischen Vater und Säugling untersucht. Zusätzlich untersuchten wir, ob Unterschiede in der Gesichtserkennung die Auswirkungen der väterlichen postpartalen Depression auf die Interaktion zwischen Vater und Säugling mediierten. 61 Vater-Säuglings-Dyaden (17 mit postpartaler Depression, 44 Kontrollen) nahmen an der Studie teil. Die Ergebnisse zeigten, dass Väter mit postpartaler Depression im Vergleich zur Kontrollgruppe ein schlechteres Interaktionsmuster mit ihren Säuglingen in Bezug auf die Responsivität, Stimmung und Sensitivität hatten; sie hatten auch größere Schwierigkeiten bei der Erkennung glücklicher Gesichter von Erwachsenen, während ihnen die Erkennung trauriger Gesichter von Erwachsenen leichter fiel. Depressive Väter schrieben traurigen Gesichtern von Erwachsenen und Säuglingen größere Intensitäten zu. Die Tendenz, traurigen Gesichtern von Erwachsenen eine größere Intensität zuzuschreiben, wurde als partieller Mediator der Auswirkungen der väterlichen postpartalen Depression auf die Responsivität des Vaters und als vollständiger Mediator der Auswirkungen der väterlichen Depression auf die Sensitivität des Vaters bestätigt. Klinische Implikationen und Vorschläge für weitere Studien werden diskutiert.男性の産後うつ病の父親-乳児相互作用への影響:顔認識の仲立ちする役割 産後うつ病は男性の最大25%に影響を及ぼす疾患と推定されている。男性の産後うつ病はこのように有病率が高いにもかかわらず、大半の研究は母親に焦点が当てられている。そのため男性のうつ病の役割とそれが乳児の発達に及ぼす影響は、研究者や臨床家に見過ごされてきた。本研究は、父親-乳児相互作用に対して父親の産後うつ病が及ぼす影響を調査しこの格差を埋めることを目的としている。それに加えて、私たちは顔認識の違いが父親-乳児相互作用に対する父親の産後うつ病の影響を仲立ちするかどうかについて検討した。父親と乳児の61組(産後うつ病群17、対象群44)が研究に参加した。結果は、対象群に比べ、産後うつ病の父親は、反応性、気分および感受性尺度において、乳児との相互作用のパターンが劣悪であった。さらに楽しい大人の顔を認識することは極めて困難であるが、悲しい大人の顔を認識することは極めて容易であった。うつ病の父親は悲しい大人と乳児の顔に極めて強い感度を示した。悲しい大人の顔に極めて強い感度を示す傾向は、父親の産後うつ病が父親の反応性に部分的な仲立ち、また父親の感受性に全面的な仲立ちとして影響していることが確認された。臨床的意義と今後の研究への示唆について考察した。.男性產後抑鬱對父嬰互動的影響:面部訊息處理的中介作用 據估計, 產後抑鬱症影響高達25％的男性。儘管如此普遍, 大多數關於產後抑鬱症的研究都集中在母親身上, 研究人員和臨床醫生忽視了父系抑鬱症的作用及其對嬰兒發育的影響。本研究旨在通過調查父親產後抑鬱對父嬰互動的影響來填補這一空白。此外, 我們檢查了面部識別的差異是否介導了父親產後抑鬱對父嬰互動的影響。 61個父嬰組合 (產後抑鬱症17個, 對照組44個) 參加這項研究。結果顯示, 與對照組相比, 產後抑鬱症的父親在測量反應性丶情緒和敏感度方面與嬰兒的互動模式較差;他們在識別快樂的成人面孔方面也有較大的困難, 但在識別悲傷的成人面孔方面表現較好。抑鬱的父親對悲傷的成人和嬰兒臉孔反應較強。較大強化悲傷成人面孔的傾向, 被確認為父親產後抑鬱對父親反應影響的部分中介, 並且是父親抑鬱對父親敏感性影響的完全中介變數。作者討論研究結果的臨床意義和對進一步研究的建議。.الاكتئاب بعد الولادة عند الرجال وآثاره علي التفاعل بين الأب والرضيع: الدور الوسيط للتعرف على الوجه تشير التقديرات إلى ان الاكتئاب بعد الولادة يؤثر علي ما يصل إلى 25 ٪ من الرجال. وعلي الرغم من هذا الانتشار المرتفع ، تركز معظم الدراسات المتعلقة باكتئاب ما بعد الولادة علي الأمهات ، وقد أغفل الباحثون والأطباء دور الاكتئاب الأبوي وأثاره علي نمو الرضع. تهدف الدراسة الحالية إلى سد هذه الفجوة عن طريق التحقيق في تاثير الاكتئاب الأبوي بعد الولادة علي تفاعلات الأب والرضيع. بالاضافه إلى ذلك ، درسنا ما إذا كانت الاختلافات في التعرف علي الوجوه توسطت آثار الاكتئاب الأبوي بعد الولادة علي تفاعلات الأب والرضيع. اشتملت عينة الدراسة على 61 من ثنائيات الأباء والرضع (17 من حالات الاكتئاب بعد الولادة ، 44 كمجموعة ضابطة). وكشفت النتائج انه ، مقارنه بالمجموعة الضابطة ، كان لدي الاباء المصابين باكتئاب ما بعد الولادة نمطا اسوأ من التفاعل مع أطفالهم الرضع على مقاييس الاستجابة والمزاج والحساسية ؛ كما كان لديهم أيضا صعوبة أكبر في التعرف على وجوه البالغين السعيدة ، ولكن سهولة أكثر في التعرف على وجوه الكبار الحزينة. وأبدى الاباء المكتئبون تركيزاً أكبر على وجوه البالغين والرضع الحزينة. وأكد الميل إلى التركيز الأكبرعلى وجوه البالغين الحزينه على وجود تأثير وسيط جزئي لاكتئاب الآباء بعد الولادة علي استجابه الأب وكوسيط كلي لآثار الاكتئاب الأبوي علي حساسية الأب. وتناقش الدراسة التطبيقات الإكلينيكية والاقتراحات لمزيد من الدراسات.

To determine predictors of inability to return to work due to health six-months after intensive care admission; and compare functional recovery between patients who had not returned to work and employed patients.Participants were working adults admitted to ICU who received24 h of mechanical ventilation. Outcomes included inability to return to work due to health at six-months post-ICU admission, disability, health status, anxiety, depression and post-traumatic stress.Of 107 patients, 31 (29%) were unable to return to work due to health at six-months after ICU admission. Predictors of inability to return to work included longer hospital stay (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02-1.08; P = .004); lower Glasgow Coma Scale (GCS) at admission (OR, 0.86; CI, 0.75-0.99; P = .03); and admission due to major trauma (OR, 8.83; CI, 2.57-30.38; P .001). Compared to employed patients, those who had not returned to work reported higher levels of disability and psychological distress, and poorer health-related quality of life.Major trauma, lower GCS and increased hospital length of stay predicted inability to return to work due to health at six-months post-ICU admission. Compared to employed patients, those who had not returned to work reported poorer functional recovery.

IF 12.784 (2016); International audience; Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury. Deletion of the Ppl gene in mice improved survival and reduced lung fibrosis development after bleomycin-induced injury. Notably, Ppl deletion promoted an antiinflammatory alveolar environment linked to profound changes in type 2 alveolar epithelial cells, including overexpression of antiinflammatory cytokines, decreased expression of profibrotic mediators, and altered cell signaling with a reduced response to TGF-β1. These results identify periplakin as a previously unidentified regulator of the response to injury in the lung.

BackgroundCognitive–behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder.ObjectivesThis study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated.DesignParticipants were randomised to receive (i) child cognitive–behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive–behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother–child interactions (MCIs) (CCBT + MCI).SettingA NHS university clinic in Berkshire, UK.ParticipantsTwo hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder.InterventionsAll families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact.Main outcome measuresPrimary clinical outcomes were the child’s primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality-adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost–utility analysis framework with associated uncertainty.ResultsMCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62,p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67,p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59,p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53,p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost-effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%.ConclusionsGood outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group.Trial registrationCurrent Controlled Trials ISRCTN19762288.FundingThis trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (09/800/17) and will be published in full inHealth Technology Assessment; Vol. 19, No. 38.

BackgroundMaternal postnatal depression occurs following 10–15% of births and is associated with a range of negative child outcomes. Risks to children are particularly increased when postnatal depression is persistent. We aimed to examine whether a parenting video-feedback therapy (VFT) intervention versus a control treatment of progressive muscle relaxation (PMR), both added to cognitive behavioural therapy (CBT) for persistent postnatal depression, would lead to improved child outcomes at age 2 years.MethodsIn this two-arm, parallel-design, individually randomised controlled trial, we recruited a community sample of women aged 18 years or older living within 50 miles of Oxford, UK, between 4·5 and 9·0 months post partum. All participants met diagnostic criteria for current major depressive disorder that had persisted for at least 3 months and had infants at 35 or more weeks of gestation, with a birthweight of 2000 g or greater, and without serious neonatal complications. Through a centralised service, women were randomly assigned by use of a minimisation algorithm, to receive either VFT or PMR, balanced for child sex, temperament, age, socioeconomic status, and severity of depression. Both groups also received CBT for depression. Primary outcomes were child cognitive development, language development, behaviour problems, and attachment security at age 2 years. There were 11 home-based treatment sessions before child age 1 year, followed by two booster sessions in the second year. Assessors were masked to treatment group allocation. All analyses were done according to the intention-to-treat principle. This trial is registered with the ISRCTN registry, number ISRCTN07336477.FindingsBetween March 18, 2011, and Dec 9, 2013, we randomly assigned 144 women, 72 to each group. Primary outcome data were available for 62–64 (86–89%) VFT and 67–68 (93–94%) PMR participants. There were no group differences in child outcome (cognitive development, adjusted difference −1·01 [95% CI −5·11 to 3·09], p=0·63; language development, 1·33 [–4·16 to 6·82], p=0·63; behaviour problems, −1·77 [–4·39 to 0·85], p=0·19; attachment security, 0·02 [–0·06 to 0·10], p=0·58), with both groups achieving scores similar to non-clinical norms on all outcomes. There were six serious adverse events: five in the VFT group (in two participants) and one in the PMR group. None was treatment-related.InterpretationThe effect of persistent postnatal depression on children is a major public health issue. For both treatment groups there was sustained remission from depression, and child development outcomes were in the normal range. The precise mechanisms accounting for the observed positive child outcomes cannot be ascertained from this study.

Background: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. Methods: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. Findings: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). Interpretation: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. Funding: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults.In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality.From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.7 to 3.1; P=0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, -2.1 to 3.0; P=0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome.The age of transfused red cells did not affect 90-day mortality among critically ill adults. (Funded by the Australian National Health and Medical Research Council and others; TRANSFUSE Australian and New Zealand Clinical Trials Registry number, ACTRN12612000453886 ; ClinicalTrials.gov number, NCT01638416 .).

In the Results section, under the subheading “Return to work or usual activities”, the second sentence should read.

The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell–derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium., Elevated VEGF is associated with less severe disease in IPF patients, and VEGF overexpression ameliorates bleomycin-induced lung fibrosis in a murine model.

This chapter explores the vocal ecology of older singers, focusing on three categories of singers: the professional and/or successful soloist who is approaching the end of a singing career; the amateur chorister; and the community singing group participant. It provides an overview of the physical impacts of vocal aging, and addresses also how personality traits can affect a person’s attitude toward aging and his or her ability to manage the effects of vocal aging. Being—or becoming—a singer in this phase of life offers a range of cognitive insights and challenges to the singer and the singing teacher. Through case studies of five singers, and data from a community choir averaging 85 years old, the chapter examines teaching strategies that can be used to ensure that singers can be supported and encouraged to continue to receive the psycho-social and physical benefits of singing, no matter what their age.

To use the World Health Organisation’s International Classification of Functioning to measure disability following critical illness using patient-reported outcomes. A prospective, multicentre cohort study conducted in five metropolitan intensive care units (ICU). Participants were adults who had been admitted to the ICU, received more than 24 h of mechanical ventilation and survived to hospital discharge. The primary outcome was measurement of disability using the World Health Organisation’s Disability Assessment Schedule 2.0. The secondary outcomes included the limitation of activities and changes to health-related quality of life comparing survivors with and without disability at 6 months after ICU. We followed 262 patients to 6 months, with a mean age of 59 ± 16 years, and of whom 175 (67%) were men. Moderate or severe disability was reported in 65 of 262 (25%). Predictors of disability included a history of anxiety/depression [odds ratio (OR) 1.65 (95% confidence interval (CI) 1.22, 2.23), P = 0.001]; being separated or divorced [OR 2.87 (CI 1.35, 6.08), P = 0.006]; increased duration of mechanical ventilation [OR 1.04 (CI 1.01, 1.08), P = 0.03 per day]; and not being discharged to home from the acute hospital [OR 1.96 (CI 1.01, 3.70) P = 0.04]. Moderate or severe disability at 6 months was associated with limitation in activities, e.g. not returning to work or studies due to health (P

Background Clear recognition of the damaging effects of poverty on early childhood development has fueled an interest in interventions aimed at mitigating these harmful consequences. Psychosocial interventions aimed at alleviating the negative impacts of poverty on children are frequently shown to be of benefit, but effect sizes are typically small to moderate. However, averaging outcomes over an entire sample, as is typically done, could underestimate efficacy because weaker effects on less susceptible individuals would dilute estimation of effects on those more disposed to respond. This study investigates whether a genetic polymorphism of the serotonin transporter gene moderates susceptibility to a psychosocial intervention. Methods and findings We reanalyzed data from a randomized controlled trial of a home-visiting program delivered by community health workers in a black, isiXhosa-speaking population in Khayelitsha, South Africa. The intervention, designed to enhance maternal-infant attachment, began in the third trimester and continued until 6 mo postpartum. Implemented between April 1999 and February 2003, the intervention comprised 16 home visits delivered to 220 mother–infant dyads by specially trained community health workers. A control group of 229 mother–infant dyads did not receive the intervention. Security of maternal-infant attachment was the main outcome measured at infant age 18 mo. Compared to controls, infants in the intervention group were significantly more likely to be securely attached to their primary caregiver (odds ratio [OR] = 1.7, p = 0.029, 95% CI [1.06, 2.76], d = 0.29). After the trial, 162 intervention and 172 control group children were reenrolled in a follow-up study at 13 y of age (December 2012–June 2014). At this time, DNA collected from 279 children (134 intervention and 145 control) was genotyped for a common serotonin transporter polymorphism. There were both genetic data and attachment security data for 220 children (110 intervention and 110 control), of whom 40% (44 intervention and 45 control) carried at least one short allele of the serotonin transporter gene. For these 220 individuals, carrying at least one short allele of the serotonin transporter gene was associated with a 26% higher rate of attachment security relative to controls (OR = 3.86, p = 0.008, 95% CI [1.42, 10.51], d = 0.75), whereas there was a negligible (1%) difference in security between intervention and control group individuals carrying only the long allele (OR = 0.95, p = 0.89, 95% CI [0.45, 2.01], d = 0.03). Expressed in terms of absolute risk, for those with the short allele, the probability of secure attachment being observed in the intervention group was 84% (95% CI [73%, 95%]), compared to 58% (95% CI [43%, 72%]) in the control group. For those with two copies of the long allele, 70% (95% CI [59%, 81%]) were secure in the intervention group, compared to 71% (95% CI [60%, 82%]) of infants in the control group. Controlling for sex, maternal genotype, and indices of socioeconomic adversity (housing, employment, education, electricity, water) did not change these results. A limitation of this study is that we were only able to reenroll 49% of the original sample randomized to the intervention and control conditions. Attribution of the primary outcome to causal effects of intervention in the present subsample should therefore be treated with caution. Conclusions When infant genotype for serotonin transporter polymorphism was taken into account, the effect size of a maternal-infant attachment intervention targeting impoverished pregnant women increased more than 2.5-fold when only short allele carriers were considered (from d = 0.29 for all individuals irrespective of genotype to d = 0.75) and decreased 10-fold when only those carrying two copies of the long allele were considered (from d = 0.29 for all individuals to d = 0.03). Genetic differential susceptibility means that averaging across all participants is a misleading index of efficacy. The study raises questions about how policy-makers deal with the challenge of balancing equity (equal treatment for all) and efficacy (treating only those whose genes render them likely to benefit) when implementing psychosocial interventions. Trial Registration Current Controlled Trials ISRCTN25664149, In light of genetic information Barak Morgan and colleagues re-analyze data from a randomized controlled trial to explore the genetic susceptibility to a psychosocial intervention., Author summary Why was this study done? It has been shown that individuals with the short form of a gene involved in nerve signaling in the brain are generally sensitive, or “susceptible,” to psychosocial interventions (i.e., they benefit), whereas individuals with the long form of the gene are insensitive, or “nonsusceptible,” deriving little benefit from the same intervention. This study was conducted to investigate whether such a gene × intervention interaction was present in a previously conducted randomized controlled home-visiting intervention trial designed to increase levels of secure maternal-infant attachment at 18 mo of age in a population in South Africa. What did the researchers do and find? Genotyping revealed that 40% of the study sample (n = 89) carried at least one short allele of the serotonin transporter gene, while 60% of the sample (n = 131) carried two long alleles of this gene. We reanalyzed the original maternal-infant attachment results and found that the increase in secure attachment found for the intervention in the original trial (odds ratio = 1.7, effect size d = 0.29) was almost entirely attributable to children with the short form of the gene (odds ratio = 3.86, effect size d = 0.75). For children not carrying the short allele, there was no significant increase in secure attachment with the intervention (odds ratio = 0.95, effect size d = 0.03). Children carrying the short form of the gene whose mothers received the intervention were 3.86 times more likely to be securely attached at 18 mo (84% were secure) than children carrying the short form whose mothers did not receive the intervention (58% were secure). Among children without the short form, the number who were securely attached did not differ based on whether their mothers received the intervention (71% were secure) or not (70% were secure). What do these findings mean? These results indicate the importance of genetic differences when considering the efficacy of psychosocial interventions aimed at improving developmental outcomes in children living in the context of socioeconomic adversity. The findings also raise complex questions regarding spending limited resources implementing costly interventions on individuals who may not benefit because of their genetic makeup and who may comprise the majority of the population (60% in this case), but where these same interventions may nevertheless confer large benefit for a subgroup of genetically susceptible individuals (40% in this case).

Three arguments are advanced from human and nonhuman primate infancy research for the exaptation of ingestive mouth movements (tongue protrusion and lip smacking) for the purposes of social communication: their relation to affiliative behaviours, their sensitivity to social context, and their role in social development. Although these behaviours may have an aerodigestive function, such an account of their occurrence is only partial.

Lymphocytes are increasingly associated with idiopathic pulmonary fibrosis (IPF). Semaphorin 7a (Sema 7a) participates in lymphocyte activation.To define the relationship between Sema 7a and lymphocytes in IPF.We characterized the significance of Sema 7a+ lymphocytes in humans with IPF and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-β1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4+CD25+FoxP3+ in TGF-β1-induced murine lung fibrosis.Subjects with IPF show expression of Sema 7a on lung CD4+ cells and circulating CD4+ or CD19+ cells. Sema 7a expression is increased on CD4+ cells and CD4+CD25+FoxP3+ regulatory T cells, but not CD19+ cells, in subjects with progressive IPF. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-β1-transgenic mice. Sema 7a expressing bone marrow-derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-γ, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4+CD25+FoxP3+ cells, Sema7a+CD4+CD25+FoxP3+ cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-β1-exposed murine lung.Sema 7a+CD4+CD25+FoxP3+ regulatory T cells are associated with disease progression in subjects with IPF and induce fibrosis in the TGF-β1-exposed murine lung.

Perspective on the paper by Hiscock et al ( see page 952 ) It is normal for infants to wake and feed at night during the first few months, especially when breast fed. Indeed, such behaviour is adaptive, since it secures the nutrition necessary for physical development and brain growth, and is particularly important for vulnerable infants.1 These adaptive aspects of frequent night waking become increasingly less important as the infant grows, and by around 6 months of age infants are usually able to sustain prolonged periods of sleep when they do not wake to feed, without any costs in terms of their physical development. Nevertheless, a substantial proportion of infants aged 6 months and older may wake and then have difficulty settling back to sleep without their parents’ active intervention (see Stein and Barnes2 for a review). In fact, it is this settling difficulty, rather than the awakening per se, that is the key factor distinguishing between infants with and without sleep problems.3–5 Although there are cultural variations, daytime demands on parents in many societies are such that getting the infant to sleep throughout the night without the need to actively intervene is often a high priority. Indeed, it is well-established that sleep difficulties in infants, and the associated reduction in parental sleep, are associated with impairments in family relationships, lower parental mood and poorer daytime functioning3 6 7; and when infant sleep problems are marked, they are predictive of subsequent child behaviour problems.8–10 The development of infant sleeping habits is a complex matter: individual differences in infant state-regulation capacities, and in the ability to shut out stimulation, can directly affect the ease with which the infant can slip smoothly into …

Objective To assess the efficacy of an intervention designed to improve the mother-infant relationship and security of infant attachment in a South African peri-urban settlement with marked adverse socioeconomic circumstances. Design Randomised controlled trial. Setting Khayelitsha, a peri-urban settlement in South Africa. Participants 449 pregnant women. Interventions The intervention was delivered from late pregnancy and for six months postpartum. Women were visited in their homes by previously untrained lay community workers who provided support and guidance in parenting. The purpose of the intervention was to promote sensitive and responsive parenting and secure infant attachment to the mother. Women in the control group received no therapeutic input from the research team. Main outcome measures Primary outcomes: quality of mother-infant interactions at six and 12 months postpartum; infant attachment security at 18 months. Secondary outcome: maternal depression at six and 12 months. Results The intervention was associated with significant benefit to the mother-infant relationship. At both six and 12 months, compared with control mothers, mothers in the intervention group were significantly more sensitive (6 months: mean difference=0.77 (SD 0.37), t=2.10, P

Objective:Early mother-infant interactions are impaired in the context of infant cleft lip and are associated with adverse child psychological outcomes, but the nature of these interaction difficulties is not yet fully understood. The aim of this study was to explore adult gaze behavior and cuteness perception, which are particularly important during early social exchanges, in response to infants with cleft lip, in order to investigate potential foundations for the interaction difficulties seen in this population.Methods:Using an eye tracker, eye movements were recorded as adult participants viewed images of infant faces with and without cleft lip. Participants also rated each infant on a scale of cuteness.Results:Participants fixated significantly longer on the mouths of infants with cleft lip, which occurred at the expense of fixation on eyes. Severity of cleft lip was associated with the strength of fixation bias, with participants looking even longer at the mouths of infants with the most severe clefts. Infants with cleft lip were rated as significantly less cute than unaffected infants. Men rated infants as less cute than women overall but gave particularly low ratings to infants with cleft lip.Conclusions:Results demonstrate that the limited disturbance in infant facial configuration of cleft lip can significantly alter adult gaze patterns and cuteness perception. Our findings could have important implications for early interactions and may help in the development of interventions to foster healthy development in infants with cleft lip.

PurposeThis paper aims to update the chapter by Sutton and Murray in Support from the Start by providing an overview of: research linking the development and experiences of infants and toddlers with the risks of later antisocial behaviour; and evidence on effective interventions for children aged 0‐2 and their families.Design/methodology/approachThe authors give a narrative review on the effects on mothers and their babies of postnatal depression.FindingsThe review examines the effects on mothers and their babies of postnatal depression, impaired bonding, insecure attachment as well as the impact of maltreatment in childhood. It considers a number of evidence‐based preventive interventions implemented in the UK to help children aged 0‐2 and their parents.Originality/valueThe paper provides an overview of recent evidence for the factors contributing to difficulties for parents of young children and identifies interventions demonstrated in high‐quality studies to prevent or address these problems.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology with considerable morbidity and mortality. Cigarette smoking is one of the most recognized risk factors for development of IPF. Furthermore, recent work suggests that smoking may have a detrimental effect on survival of patients with IPF. The mechanism by which smoking may contribute to the pathogenesis of IPF is largely unknown. However, accumulating evidence suggests that increased oxidative stress might promote disease progression in IPF patients who are current and former smokers. In this review, potential mechanisms by which cigarette smoking affects IPF, the effects of cigarette smoking on accelerated loss of lung function in patients with IPF, key genetic studies evaluating the potential candidate genes and gene-environment (smoking) interaction, diagnosis, and treatment with emphasis on recently closed and ongoing clinical trials are presented.

Importance After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. Objective To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. Design, Setting, and Participants The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury–Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. Interventions There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. Main Outcomes and Measures The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale–Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. Results Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale–Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, –9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. Conclusions and Relevance Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury. Trial Registration clinicaltrials.gov Identifier:NCT00987688; Anzctr.org.au Identifier:ACTRN12609000764235

Profibrotic cells derived from circulating CD14+ monocytes include fibrocytes and alternatively activated macrophages. These cells are associated with interstitial lung disease (ILD) and are implicated in the pathogenesis of systemic sclerosis (SSc); however, the simultaneous presence of profibrotic cells and their associated mediators in the circulation of these patients has not been defined. We hypothesized that monocytes from patients with SSc-related ILD (SSc-ILD) would show profibrotic characteristics when compared with normal controls. We recruited patients with SSc-ILD (n=12) and normal controls (n=27) and quantified circulating collagen-producing cells by flow cytometry for CD45 and pro-collagen I. The in vitro activation potential of CD14+ monocytes in response to lipopolysaccharide was assessed using flow cytometry for CD163, and by ELISA for CCL18 and IL-10 secretion. Profibrotic mediators in plasma were quantified using Luminex-based assays. The concentration of circulating collagen-producing cells was increased in the SSc-ILD patients when compared with controls. These cells were composed of both CD34+ fibrocytes and a population of CD34+CD14+ cells. Cultured CD14+ monocytes from SSc-ILD patients revealed a profibrotic phenotype characterized by expression of CD163 and by enhanced secretion of CCL18 and IL-10 in response to proinflammatory activation. Plasma levels of IL-10, MCP-1, IL-1RA, and TNF levels were significantly elevated in the plasma of the SSc-ILD cohort. Subgroup analysis of the normal controls revealed that unlike the subjectsor =35 years, subjectsor =60 years old showed higher levels of circulating CD34+CD14+ cells, collagen-producing CD14+ monocytes, CD163+ monocytes, IL-4, IL-10, IL-13, MCP-1, and CCL18. These data indicate that the blood of patients with SSc-ILD and of healthy aged controls is enriched for fibrocytes, profibrotic monocytes, and fibrosis-associated mediators. Investigations defining the factors responsible for this peripheral blood profile may provide new insight into SSc-ILD as well as the pathophysiology of aging.

Airway remodeling in asthma is associated with the accumulation of fibroblasts, the primary cell responsible for synthesis and secretion of extracellular matrix proteins. The process by which the number of fibroblasts increases in asthma is poorly understood, but epithelial-mesenchymal transition (EMT) may play a significant role.To evaluate whether EMT occurs in primary airway epithelial cells (AECs), the mechanisms involved, and if this process is altered in asthmatic AECs.AECs were obtained from subjects with asthma (n = 8) and normal subjects without asthma (n = 10). Monolayer and air-liquid interface-AEC (ALI-AEC) cultures were treated with transforming growth factor (TGF)-beta1 (10 ng/ml) for 72 hours and assayed for mesenchymal and epithelial markers using quantitative polymerase chain reaction, confocal microscopy, and immunoblot. The involvement of BMP-7, Smad3, and MAPK-mediated signaling were also evaluated.TGF-beta1-induced EMT in AEC monolayers derived from subjects with asthma and normal donors. EMT was characterized by changes in cell morphology, increased expression of mesenchymal markers EDA-fibronectin, vimentin, alpha-smooth muscle actin, and collagen-1, and loss of epithelial markers E-cadherin and zonular occludin-1. Inhibition of TGF-beta1-induced signaling with Smad3-inhibiting siRNA or TGF-beta1-neutralizing antibodies prevented and reversed EMT, respectively, whereas BMP-7 had no effect. In ALI-AEC cultures derived from normal subjects, EMT was confined to basally situated cells, whereas in asthmatic ALI-AEC cultures EMT was widespread throughout the epithelium.TGF-beta1 induces EMT in a Smad3-dependent manner in primary AECs. However, in asthmatic-derived ALI-AEC cultures, the number of cells undergoing EMT is greater. These findings support the hypothesis that epithelial repair in asthmatic airways is dysregulated.