Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients.

BackgroundWe previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP).MethodsThe original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression.ResultsAt baseline, a significantly higher level of expression (p < 0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD.ConclusionsFunctional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy.Trial registrationNCT01401062

Acquisition of the majority language in Norwegian ECEC: Relating language-learning environment in ECEC to expressive vocabulary

Developing proficiency in the language(s) spoken in any given society is crucial for the inclusion and attainment of children in that society. With an enrolment rate in Norwegian early childhood education and care (ECEC) of 93.4% for children between age one and five, ECEC constitutes an important out-of-home learning environment for children in Norway. In this study, we examine how the quality of language-learning environments in toddler and preschool groups predicts children’s expressive vocabulary in the majority language depending on children’s home languages. Data from the quality rating scales ITERS R and ECERS-R were used to model quality factors related to expressive vocabulary in toddler and preschool groups. The sample included 1,078 children (876 children with parents who spoke the majority language exclusively, 104 children with one parent who spoke the majority language and one parent who spoke another language, and 57 children with no majority language speaking parents). The results show that the quality of the language-learning environment in toddler and preschool groups is positively associated with expressive vocabulary in the majority language at age three and five, but only for children whose parents spoke the majority language exclusively.publishedVersio

Outcomes and predictors of functioning, mental health, and health-related quality of life in adults born with very low birth weight: a prospective longitudinal cohort study

Background - Very low birth weight (VLBW: ≤1500 g) is associated with multiple short and long-term complications. This study aimed to examine outcomes and predictors of functioning, mental health, and health-related quality of life in adults born with VLBW. Methods - In this prospective longitudinal cohort study, 67 VLBW and 102 control participants were assessed using the Adult Self-Report of the Achenbach System of Empirically Based Assessment and Global Assessment of Functioning at 26 years, and the Hospital Anxiety and Depression Scale and Short Form-36 at 28 years of age. Associations between perinatal and childhood predictors and adult functioning were assessed using linear regression. Results - Compared with controls, the VLBW group had lower mean raw scores on the Function and Symptom subscales of the Global Assessment of Functioning at 26 years, a higher sum score of symptoms of anxiety and depression due to more depressive symptoms, and poorer mental health-related quality of life at 28 years. The mean group differences ranged from 0.42 to 0.99 SD. Within the VLBW group, lower birth weight and gestational age, a higher number of days with respiratory support and poorer motor function at 14 years were associated with a higher sum score of symptoms of anxiety and depression at 28 years. Days with respiratory support and motor function at 14 years were also predictive of Global Assessment of Functioning scores at 26 years, and mental health-related quality of life at 28 years. Poorer motor and cognitive function at five years were associated with poorer physical health-related quality of life at 28 years. Parental socioeconomic status was related to mental and physical health-related quality of life. Conclusion - In this study, VLBW adults reported poorer functioning and mental health-related quality of life, and more depressive symptoms than their term born peers. Days with respiratory support and adolescent motor function predicted most of the adult outcomes. This study explicates perinatal and developmental markers during childhood and adolescence which can be target points for interventions

Rib abnormalities and their association with focal dark spots in Atlantic salmon fillets

publishedVersio

Health-related quality of life from 20 to 32 years of age in very low birth weight individuals : a longitudinal study

Background Preterm birth with very low birth weight (VLBW, birth weight < 1500 g) is associated with health problems later in life. How VLBW individuals perceive their physical and mental health-related quality of life (HRQoL) is important to understand their putative burden of disease. Previous studies have shown mixed results, and longitudinal studies into adulthood have been requested. This study aimed to investigate differences in HRQoL between preterm VLBW and term born individuals at 32 years of age, and to study changes in HRQoL from 20 to 32 years. Methods In a geographically based longitudinal study, 45 VLBW and 68 term born control participants completed the Short Form 36 Health Survey (SF-36) at 32 years of age. Data from three previous timepoints was also available (20, 23 and 28 years of age). The SF-36 yields eight domain scores as well as a physical and a mental component summary. Between-group differences in these variables were investigated. We also performed subgroup analyses excluding individuals with disabilities, i.e., cerebral palsy and/or low estimated intelligence quotient. Results At 32 years of age, the physical component summary was 5.1 points lower (95% confidence interval (CI): 8.6 to 1.6), and the mental component summary 4.1 points lower (95% CI: 8.4 to - 0.3) in the VLBW group compared with the control group. For both physical and mental component summaries there was an overall decline in HRQoL from 20 to 32 years of age in the VLBW group. When we excluded individuals with disabilities (n = 10), group differences in domain scores at 32 years were reduced, but physical functioning, bodily pain, general health, and role-emotional scores remained lower in the VLBW subgroup without disabilities compared with the control group. Conclusion We found that VLBW individuals reported lower HRQoL than term born controls at 32 years of age, and that HRQoL declined in the VLBW group from 20 to 32 years of age. This was in part, but not exclusively explained by VLBW individuals with disabilities.Peer reviewe

Proactive avoidance behaviour and pace-of-life syndrome in Atlantic salmon

Individuals in a fish population differ in key life history traits such as growth rate and body size. This raises the question if such traits cluster along a fast-slow growth continuum according to a pace-of-life syndrome (POLS). Fish species like salmonids may develop a bimodal size distribution, providing an opportunity to study the relationships between individual growth and behavioural responsiveness. Here we test whether proactive characteristics (bold behaviour coupled with low post-stress cortisol production) are related to fast growth and developmental rate in Atlantic salmon (Salmo salar). Boldness was tested in a highly controlled two-tank hypoxia test were oxygen levels were gradually decreased in one of the tanks. All fish became inactive close to the bottom at 70% oxygen saturation. At oxygen saturation level of 40% a fraction of the fish actively sought out to avoid hypoxia. A proactive stress coping style was verified by lower cortisol response to a standardized stressor. Two distinct clusters of bimodal growth trajectories were identified, with fast growth and early smoltification in 80% of the total population. There was a higher frequency of proactive individuals in this fast-developing fraction of fish. The smolts were associated with higher post-stress plasma cortisol than parr, and the proactive smolts leaving hypoxia had significant lower post-stress cortisol than the stayers. The study demonstrated a link between a proactive coping and fast growth and developmental ratio, and suggests that selection for domestic production traits promotes this trait cluster

High-dimensional analysis of the aging immune system: verification of age-associated differences in immune signaling responses in healthy donors.

BACKGROUND Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors. METHODS In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)]. RESULTS Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets. CONCLUSIONS These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies

Common core assessments in follow-up studies of adults born preterm-Recommendation of the Adults Born Preterm International Collaboration

Of all newborns, 1%-2% are born very preterm (VP; <32 weeks) or with very low birthweight (VLBW; ≤1500 g). Advances in prenatal and neonatal care have substantially improved their survival, and the first generations who have benefited from these advances are now entering middle age. While most lead healthy lives, on average these adults are characterised by a number of adversities. These include cardiometabolic risk factors, airway obstruction, less physical activity, poorer visual function, lower cognitive performance, and a behavioural phenotype that includes inattention and internalising and socially withdrawn behaviour that may affect life chances and quality of life. Outcomes in later adulthood are largely unknown, and identifying trajectories of risk or resilience is essential in developing targeted interventions. Joint analyses of data and maintenance of follow-up of cohorts entering adulthood are essential. Such analyses are ongoing within the Adults Born Preterm International Collaboration (APIC; www.apic-preterm.org). Joint analyses require data harmonisation, highlighting the importance of consistent assessment methodologies. To present an expert recommendation on Common Core Assessments to be used in follow-up assessments of adults born preterm. Principles of Common Core Assessments were discussed at APIC meetings. Experts for each specific outcome domain wrote the first draft on assessments pertaining to that outcome. These drafts were combined and reviewed by all authors. Consensus was reached by discussion at APIC meetings. We present a recommendation by APIC experts on consistent measures to be used in adult follow-up assessments. The recommendation encompasses both "core" measures which we recommend to use in all assessments of adults born preterm that include the particular outcome. This will allow comparability between time and location. The recommendation also lists optional measures, focusing on current gaps in knowledge. It includes sections on study design, cardiometabolic and related biomarkers, biological samples, life style, respiratory, ophthalmic, cognitive, mental health, personality, quality of life, sociodemographics, social relationships, and reproduction. [Abstract copyright: © 2020 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.

Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors

<p>Abstract</p> <p>Background</p> <p>Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV) dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2) is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease.</p> <p>Methods</p> <p>Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation.</p> <p>Results</p> <p>Mean strain was -21% ± 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% ± 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain ≤ -20%, mean -25% ± 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 ≥ 77 μg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03).</p> <p>Conclusions</p> <p>Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.</p

Health-related quality-of-life outcomes of very preterm or very low birth weight adults : evidence from an individual participant data meta-analysis

Background and Objective Assessment of health-related quality of life for individuals born very preterm and/or low birthweight (VP/VLBW) offers valuable complementary information alongside biomedical assessments. However, the impact of VP/VLBW status on health-related quality of life in adulthood is inconclusive. The objective of this study was to examine associations between VP/VLBW status and preference-based health-related quality-of-life outcomes in early adulthood. Methods Individual participant data were obtained from five prospective cohorts of individuals born VP/VLBW and controls contributing to the ‘Research on European Children and Adults Born Preterm’ Consortium. The combined dataset included over 2100 adult VP/VLBW survivors with an age range of 18–29 years. The main exposure was defined as birth before 32 weeks’ gestation (VP) and/or birth weight below 1500 g (VLBW). Outcome measures included multi-attribute utility scores generated by the Health Utilities Index Mark 3 and the Short Form 6D. Data were analysed using generalised linear mixed models in a one-step approach using fixed-effects and random-effects models. Results VP/VLBW status was associated with a significant difference in the Health Utilities Index Mark 3 multi-attribute utility score of − 0.06 (95% confidence interval − 0.08, − 0.04) in comparison to birth at term or at normal birthweight; this was not replicated for the Short Form 6D. Impacted functional domains included vision, ambulation, dexterity and cognition. VP/VLBW status was not associated with poorer emotional or social functioning, or increased pain. Conclusions VP/VLBW status is associated with lower overall health-related quality of life in early adulthood, particularly in terms of physical and cognitive functioning. Further studies that estimate the effects of VP/VLBW status on health-related quality-of-life outcomes in mid and late adulthood are needed