Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods. https://www.trialregister.nl/trial/795

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function

Hidden inequalities amongst the international workforce

This chapter focuses on low status expatriates who have been largely ‘hidden’ from managerial scholarship. They are ‘hidden’ because they are ignored by the migrant literature which looks at people trying to remain in their new society and gain citizenship; and ignored by the expatriation literature which is mainly concerned with high-status ‘top’ talent. These hidden expatriates are typically maids, drivers, security guards, and construction workers - low status and low paid, unable to obtain citizenship, and liable to be sent home, unemployed, at the whim of their employer. If we, as scholars, are to contribute to the betterment of society by elevating the health and well-being of those who live in it, then we must recognise the existence of and address the management issues and concerns of those at the ‘bottom of the pyramid’. We use Organisational Justice theory and draw on examples from Turkey, Singapore and the Middle East to examine the position, the concerns, and the issues of such workers and their often-unequal place in the workforce

Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955

From Complex Organizations with Simple Jobs to Simple Organizations with Complex Jobs

Contains fulltext : 25883___.PDF (publisher's version ) (Open Access

MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial

Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent ‘on-target, off-tumor’ toxicity and a maximum tolerated dose of 1.0 × 108 cells

Quality and Quantity of Sleep and Factors Associated With Sleep Disturbance in Hospitalized Patients

Importance: Although inadequate sleep has a proven negative association with health care outcomes, to date, no large-scale studies have examined sleep in general hospital wards. Objectives: To assess the subjective quantity and quality of sleep and to identify the hospital-related factors associated with sleep disturbances in hospitalized patients. Design: For this nationwide, single-day, multicenter, cross-sectional, observational study, which took place on February 22, 2017, all hospitals in the Netherlands were encouraged by word of mouth and conventional and social media to participate in this study. A total of 39 hospitals participated. Included patients were at least 18 years of age, were able to give informed consent, and had spent at least 1 night in a regular-care hospital ward. Exposures: Hospitalization in a regular-care ward. Main Outcomes and Measures: Quantity and quality of last night's sleep in the hospital compared with habitual sleep at home the month before hospitalization. The Consensus Sleep Diary and the Dutch-Flemish Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance item bank were used. Complementary questions assessed sleep-disturbing factors. Results: A total of 2005 patients were included (median age, 68 years; interquartile range, 57-77 years; 994 of 1935 [51.4%] were male [70 patients did not identify their sex]). Compared with habitual sleep at home, the total sleep time in the hospital was 83 minutes (95% CI, 75-92 minutes; P < .001) shorter. The mean number of nocturnal awakenings was 2.0 (95% CI, 1.9-2.1) times at home vs 3.3 (95% CI, 3.2-3.5) times during hospitalization (P < .001). Patients woke up 44 minutes (95% CI, 44-45 minutes; P < .001) earlier than their habitual wake-up time at home. A total of 1344 patients (70.4%) reported having been awakened by external causes, which in 718 (35.8%) concerned hospital staff. All aspects of sleep quality measured using PROMIS questions were rated worse during hospitalization than at home. The most reported sleep-disturbing factors were noise of other patients, medical devices, pain, and toilet visits. Conclusions and Relevance: This study demonstrated that the duration and quality of sleep in hospitalized patients were significantly affected and revealed many potentially modifiable hospital-related factors negatively associated with sleep. Raising awareness about the importance of adequate sleep in the vulnerable hospital population and introducing interventions to target sleep-disturbing factors may improve healing

Fluorinated steroids do not improve outcome of isolated atrioventricular block

Introduction Congenital atrioventricular block (CAVB) is a rare disorder with a significant morbidity and mortality. Consensus regarding the prescription and efficacy of prenatal corticosteroids is lacking. This nationwide study was initiated to evaluate the effects of prenatal treatment with corticosteroids on the outcome of CAVB in The Netherlands. Methods All fetuses identified with isolated congenital AVB-II° or AVB-III° in any of the eight academic fetal heart centers of The Netherlands between 2003 and 2013 were included and reviewed. Results Fifty-six fetuses were included. Fourteen (25%) fetuses were treated with dexamethasone. We found no differences between the steroid-treated and untreated cases regarding in utero progression of the AVB (63% vs 67% respectively), survival to birth (86% vs 84%), pacemaker implantations (74% vs 58%) or long-term dilated cardiomyopathy (13% vs 17%). Steroid treated fetuses demonstrated more in utero growth restriction (38% vs 11%). Conclusion No benefit from prenatal corticosteroid treatment was demonstrated for fetuses with isolated CAVB in this study. However, we found negative side effects. Our data provide no evidence to support the routine administration of corticosteroids for the treatment of fetal CAVB