Interleukin- 33 (IL-33) is an epithelial-derived cytokine that initiates type 2 immune responses to allergens, though whether IL-33 has the ability to modify responses to respiratory viral infections ...remains unclear. This study aimed to investigate the effects of IL-33 on rhinovirus (RV)-induced immune responses by circulating leukocytes from people with allergic asthma, and how this response may differ from non-allergic controls. Our experimental approach involved co-exposing peripheral blood mononuclear cells to IL-33 and RV in order to model how the functions of virus-responsive lymphocytes could be modified after recruitment to an airway environment enriched in IL-33. In the current study, IL-33 enhanced RV-induced IL-5 and IL-13 release by cells from people with allergic asthma, but had no effect on IL-5 and IL-13 production by cells from healthy donors. In asthmatic individuals, IL-33 also enhanced mRNA and surface protein expression of ST2 (the IL-33 receptor IL1RL1), while soluble ST2 concentrations were low. In contrast, IL-33 had no effect on mRNA and surface expression of ST2 in healthy individuals. In people with allergic asthma, RV-activated ST2
innate lymphoid cells (ST2
ILC) were the predominant source of IL-33 augmented IL-13 release. In contrast, RV-activated natural killer cells (NK cells) were the predominant source of IL-33 augmented IFNγ release in healthy individuals. This suggests that the effects of IL-33 on the cellular immune response to RV differ between asthmatic and healthy individuals. These findings provide a mechanism by which RV infections and IL-33 might interact in asthmatic individuals to exacerbate type 2 immune responses and allergic airway inflammation.
Caring for individuals with fetal alcohol spectrum disorders (FASD) puts a substantial and often life-long burden on affected families. Caregivers’ specific needs and demands are, however, not well ...understood so far. We thus aimed at systematically collecting data on the needs of individuals caring for children and adolescents with FASD.
Between May 2019 and November 2020, a quantitative survey among caregivers and professionals from across Germany was performed. Participants completed a questionnaire collecting information on the perceived support caregivers receive from various sources as well as the current fulfilment of caregivers’ needs. Specifically, the fulfilment of a variety of specific needs summarised in five categories was rated by the participants on a scale ranging from 1 (very good) to 6 (insufficient).
Both caregivers and professionals rated the overall fulfilment of needs rather poorly (mean: 3.94 and 4.27, respectively). Caregivers indicated needs concerning coordination of support (4.74) and relief services (4.44) to be fulfilled the least while needs in the relief services category also received the lowest average grade among professionals (4.57). The needs that the caregivers regarded as most sufficiently fulfilled were their own knowledge about FASD (mean: 1.95) and their knowledge about the causes of their child's problems (mean: 1.87).
The results of the present study indicate that FASD caregivers are supported insufficiently, while most of their needs remain unmet. Health care planners and providers thus urgently need to identify and implement measures to better address FASD caregivers’ needs and demands.
•Caring for children with FASD constitutes a great challenge for parents.•There is very little research on the needs of families with children with FASD.•Caregivers and professionals rated the fulfilment of needs very poorly in Germany.•There is urgent need for action to improve support for caregivers of FASD patients.
Fetal alcohol spectrum disorder is one of the most common chronic diseases at birth. It is very often not or falsely diagnosed. This leads to inadequate, ineffective care and treatment of the ...affected children as well as to insufficient support of their families. The result is not only a high rate of secondary disorders, but it also leads to fewer opportunities for secondary and tertiary prevention for each child and family. With the right diagnosis these opportunities are guaranteed. The primary prevention in the field of alcohol consumption during pregnancy and fetal alcohol spectrum disorder should be planned and performed by the medical and political partners in a structured interdisciplinary and scientifically based way. Besides health promotion and education of the general population, the knowledge transfer to doctors and other medical, psychological, and pedagogical professionals is of particular relevance.
Plasma nitriding is widely used in various industrial applications to improve surface hardness and wear properties. Especially for tool steels, it is also used to improve the support and adhesion of ...diamond-like carbon (DLC) coatings. The properties of the nitrided zone produced by plasma nitriding are influenced by the applied process parameter, in particular temperature and time. However, for high-alloy tool steels, a deeper understanding of the underlying diffusion processes of the nitrogen and the interaction with the existing microstructure, as well as the effects on the case depth is still lacking. Therefore, in this study, specimens of high-alloy tool steel X153CrMoV12 were plasma nitrided at varying temperatures (480 °C, 520 °C, 560 °C) and treatment times (2 h, 4 h, 16 h). The resulting nitrided zones were investigated by optical and scanning electron microscopy (OM and SEM), depth-dependent glow discharge optical emission spectroscopy (GDOES), X-ray diffraction (XRD), and hardness measurements to characterize their microstructure, chemical composition, and hardness depending on the process parameters. The distribution of carbides (M7C3), e.g., chromium carbides, affects the diffusion of the nitrogen and the layer growth. An increase of temperature and duration leads to an increased layer thickness. The composition of the compound layer is, e.g., influenced by the process parameters: ε nitrides (Fe2–3N) occurred preferentially at lower temperatures, while γ′ nitrides (Fe4N) appeared mostly at higher temperatures. In order to investigate the influence of the carbides of the high-alloy tool steel on the nitriding process, a new methodology was developed by means of finite element analysis (FE), which makes it possible to analyze this influence on the development of the nitrogen concentration profile. This methodology makes it possible for the first time to map the heterogeneous nitrogen evolution and distribution.
Summary Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In ...recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic–pituitary–adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a ‘stress reactivity test’ (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the ‘high reactivity’ (HR) and the ‘low reactivity’ (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an ‘intermediate reactivity’ (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety-related behavior, exploratory drive, locomotor activity, and depression-like behavior point to phenotypic similarities with behavioral changes observed in depressive patients. In general, HR males and females were ‘hyperactive’ in some behavioral paradigms, resembling symptoms of restlessness and agitation often seen in melancholic depression. LR mice, on the other hand, showed more passive-aggressive coping styles, corresponding to signs of retardation and retreat observed in atypical depression. Several morphometric and neuroendocrine findings further support this view. For example, monitoring the circadian rhythm of glucocorticoid secretion revealed clearly increased trough levels in HR mice, resulting in a flattened diurnal rhythm, again adding to the neuroendocrine similarities to patients suffering from melancholic depression. Taken together, our results suggest that distinct mechanisms influencing the function and regulation of the HPA axis are involved in the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate molecular genetic, neuroendocrine, and behavioral parameters associated with altered stress reactivity, thereby improving our understanding of affective disorders, presumably including the symptomatology and pathophysiology of specific subtypes of major depression.
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated ...with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
Fluoropyrimidines (fluorouracil 5-FU, capecitabine) and irinotecan are commonly prescribed chemotherapy agents for gastrointestinal (GI) malignancies. Pharmacogenetic (PGx) testing for germline
and
...variants associated with reduced enzyme activity holds the potential to identify patients at high risk for severe chemotherapy-induced toxicity. Slow adoption of PGx testing in routine clinical care is due to implementation barriers, including long test turnaround times, lack of integration in the electronic health record (EHR), and ambiguity in test cost coverage. We sought to establish PGx testing in our health system following the Exploration, Preparation, Implementation, Sustainment (EPIS) framework as a guide. Our implementation study aims to address barriers to PGx testing.
The Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI) study is a non-randomized, pragmatic, open-label implementation study at three sites within a major academic health system. Eligible patients with a GI malignancy indicated for treatment with 5-FU, capecitabine, or irinotecan will undergo PGx testing prior to chemotherapy initiation. Specimens will be sent to an academic clinical laboratory followed by return of results in the EHR with appropriate clinical decision support for the care team. We hypothesize that the availability of a rapid turnaround PGx test with specific dosing recommendations will increase PGx test utilization to guide pharmacotherapy decisions and improve patient safety outcomes. Primary implementation endpoints are feasibility, fidelity, and penetrance. Exploratory analyses for clinical effectiveness of genotyping will include assessing grade ≥3 treatment-related toxicity using available clinical data, patient-reported outcomes, and quality of life measures.
We describe the formative work conducted to prepare our health system for
and
testing. Our prospective implementation study will evaluate the clinical implementation of this testing program and create the infrastructure necessary to ensure sustainability of PGx testing in our health system. The results of this study may help other institutions interested in implementing PGx testing in oncology care.
https://clinicaltrials.gov/ct2/show/NCT04736472, identifier NCT04736472.
Objectives
A common dilemma rarely mentioned during doctoral training is career/family balance—especially the timing of children. This dilemma extends to professional anthropologists and includes ...questions surrounding the benefits and challenges of taking children to the field. We analyzed survey data from tenure‐track and tenured anthropologists to determine if fieldwork in general and fieldwork with or without their children on site impacts career/family balance. We hypothesized that having children and the burden of fieldwork puts more strain on women than on men in anthropology.
Methods
We compared 297 tenure‐track and tenured anthropologists by gender, tenure status, and mean annual time spent conducting fieldwork using survey data collected for the Family and the Field study. Analysis was conducted using a combination of hierarchical multivariate analysis of variance and regression to analyze the differing factors affecting various groups.
Results
The primary differences in career/family balance occurred between tenure‐track and tenured anthropologists, not women and men, and that fieldwork requirements do not necessarily make achieving personal balance harder for anthropologists than other academics.
Conclusions
The need to conduct fieldwork may dissuade some people with or planning to have children from becoming anthropologists. However, upon obtaining tenure‐track positions, the burdens impacting “balance” taper off and become less stressful. We offer policy suggestions for buffering stress related to career/family balance that may negatively impact decisions to pursue or continue in anthropology as a career.
Evidence regarding impact of community policies and programs (CPPs) to prevent child obesity is limited, and which combinations of strategies and components are most important is not understood. The ...Healthy Communities Study was an observational study to assess relationships of characteristics and intensity of CPPs with adiposity, diet, and physical activity in children, taking advantage of variation across the U.S. in community actions to prevent child obesity. The study examined the association of CPPs to prevent child obesity with measured BMI and waist circumference, hypothesizing that communities with more-comprehensive CPPs would have children with lower adiposity.
The study included 130 communities selected by probability-based sampling or because of known CPPs targeting child obesity. Data were collected at home visits on 5,138 children during 2013–2015. CPPs were scored for multiple attributes to create a CPP intensity score. A CPP target behavior score reflected the number of distinct target behaviors addressed. Scores were standardized with the smallest observed score across communities being 0 and the largest 1. Multilevel regression analysis in 2016 adjusted for community, household, and individual characteristics.
Higher CPP target behavior score was significantly associated with lower BMI and waist circumference in a dose−response relationship, with magnitude for the past 3 years of CPPs of 0.843 (p=0.013) for BMI and 1.783 cm (p=0.020) for waist circumference.
This study provides plausible evidence that comprehensive CPPs targeting a greater number of distinct physical activity and nutrition behaviors were associated with lower child adiposity.
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