A germline STAT6 gain-of-function variant is associated with early-onset allergies.

BACKGROUND: The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans. OBJECTIVE: We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members. METHODS: Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines. RESULTS: We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient's father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules. CONCLUSIONS: A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.

Unraveling the Immunogenetics of STAT Proteins: Clinical Perspectives on Gain-of-Function and Loss-of-Function Variants.

Signal Transducer and Activator of Transcription (STAT) proteins play pivotal roles in immune regulation. The dysregulation of these proteins, attributed to both gain-of-function (GOF) and loss-of-function (LOF) variants, has emerged as a substantial and intricate area of research. This comprehensive review delves into the intricate details of the diverse clinical spectrum associated with STAT variants and the immunological findings linked to these genetic alterations. Although this review does not encompass the treatment of each individual disease, we discuss investigative approaches ranging from immunophenotyping assessment to evaluation of STAT protein activity. These investigations play a crucial role in identifying affected patients and understanding the complexities of STAT.

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium.

INTRODUCTION: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups. METHODS: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models. RESULTS: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs. DISCUSSION: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.

A pilot study into bosentan (Tracleer®) as an immunomodulating agent in patients with Behçet's disease.

BACKGROUND: Behçet's disease (BD) is an auto-inflammatory vasculitis characterized by aphthous oro-genital ulcers, inflammatory skin changes and uveitis. Treatment is mainly immunosuppressive. Interestingly, elevated endotheline-1 (ET-1) levels suggest a possible beneficial effect of treatment with an ET-1 receptor antagonist. OBJECTIVE: The aim of our study was to investigate the possible beneficial effect of the ET-1 inhibitor bosentan. METHODS: We performed a prospective double-blind placebo controlled pilot study into the effect and safety of bosentan in BD patients. Disease activity was measured using the Behçet Disease Current Activity Form. The primary objective of the study was to determine whether bosentan is therapeutically effective in patients with BD. Secondary endpoints were safety, tapering of medication and the effect of bosentan on possible disease activity markers such as ET-1, circulating endothelial cells (CECs), soluble interleukin-2 receptor (sIL2R) and cytokine levels. RESULTS: Ten patients were randomized to either bosentan or placebo. Overall, no effect on disease activity was observed, although one patient responded clinically and continued treatment after the study period. Despite one SAE, bosentan seems safe to use. No effect on tapering of medication, CECs, sIL2R and cytokine levels was found. In the bosentan group, ET-1 levels were elevated during the treatment period, with no correlation with disease activity. CONCLUSIONS: Although this is a small pilot study, bosentan appears to be safe in BD patients. One patient had a durable and significant clinical response. Our observations should be confirmed and extended in a larger patient cohort to be of significant impact in the treatment options for BD.

Monthly Patterns of Ammonia Over the Contiguous United States at 2-km Resolution.

Monthly, high-resolution (∼2 km) ammonia (NH3) column maps from the Infrared Atmospheric Sounding Interferometer (IASI) were developed across the contiguous United States and adjacent areas. Ammonia hotspots (95th percentile of the column distribution) were highly localized with a characteristic length scale of 12 km and median area of 152 km2. Five seasonality clusters were identified with k-means++ clustering. The Midwest and eastern United States had a broad, spring maximum of NH3 (67% of hotspots in this cluster). The western United States, in contrast, showed a narrower midsummer peak (32% of hotspots). IASI spatiotemporal clustering was consistent with those from the Ammonia Monitoring Network. CMAQ and GFDL-AM3 modeled NH3 columns have some success replicating the seasonal patterns but did not capture the regional differences. The high spatial-resolution monthly NH3 maps serve as a constraint for model simulations and as a guide for the placement of future, ground-based network sites.

[Raising awareness for dementia risk reduction through a public health campaign: a pre-post study]. / Een publiekscampagne om bewustwording over risicoreductie van dementie te verhogen: een pre-post studie.

This study evaluates a public health campaign initiated by the Alzheimer Center Limburg of Maastricht University. The aim was to increase awareness of the influence of a healthy lifestyle on lowering the risk of dementia in community-dwelling inhabitants of the Province of Limburg (aged 40 - 75 years). The campaign used mass media and public events, supported by a campaign website and mobile application (MijnBreincoach app).  An additional district-oriented approach was chosen in the municipalities of Roermond, Landgraaf and Brunssum, in which local stakeholders were involved in the design and execution of campaign-related events. Population-level difference in awareness before and after the campaign was assessed in two independent samples. No pre-post difference was observed in the level of awareness of dementia risk reduction. An additional analyses in the post-campaign sample revealed that the group that reported to have heard of the campaign, was more often aware of dementia risk reduction and reported higher motivation for behavioural change than the group that had not heard of the campaign. The district-oriented approach resulted in better recognition of campaign-material and the mobile application. With regard to the individual lifestyle factors, healthy diet and physical activity were identified more often post-campaign. Cognitive activity was identified most often at both pre- and post-assessment, but there was no increase in awareness after the campaign.

Network trade-offs and homeostasis in Arabidopsis shoot architectures.

Understanding the optimization objectives that shape shoot architectures remains a critical problem in plant biology. Here, we performed 3D scanning of 152 Arabidopsis shoot architectures, including wildtype and 10 mutant strains, and we uncovered a design principle that describes how architectures make trade-offs between competing objectives. First, we used graph-theoretic analysis to show that Arabidopsis shoot architectures strike a Pareto optimal that can be captured as maximizing performance in transporting nutrients and minimizing costs in building the architecture. Second, we identify small sets of genes that can be mutated to shift the weight prioritizing one objective over the other. Third, we show that this prioritization weight feature is significantly less variable across replicates of the same genotype compared to other common plant traits (e.g., number of rosette leaves, total volume occupied). This suggests that this feature is a robust descriptor of a genotype, and that local variability in structure may be compensated for globally in a homeostatic manner. Overall, our work provides a framework to understand optimization trade-offs made by shoot architectures and provides evidence that these trade-offs can be modified genetically, which may aid plant breeding and selection efforts.

Safeguarding Female Reproductive Health against Endocrine Disrupting Chemicals-The FREIA Project.

Currently available test methods are not well-suited for the identification of chemicals that disturb hormonal processes involved in female reproductive development and function. This renders women's reproductive health at increasing risk globally, which, coupled with increasing incidence rates of reproductive disorders, is of great concern. A woman's reproductive health is largely established during embryonic and fetal development and subsequently matures during puberty. The endocrine system influences development, maturation, and function of the female reproductive system, thereby making appropriate hormone levels imperative for correct functioning of reproductive processes. It is concerning that the effects of human-made chemicals on the endocrine system and female reproductive health are poorly addressed in regulatory chemical safety assessment, partly because adequate test methods are lacking. Our EU-funded project FREIA aims to address this need by increasing understanding of how endocrine disrupting chemicals (EDCs) can impact female reproductive health. We will use this information to provide better test methods that enable fit-for-purpose chemical regulation and then share our knowledge, promote a sustainable society, and improve the reproductive health of women globally.

COVID-19 in children: Heterogeneity within the disease and hypothetical pathogenesis.

The disease course of coronavirus disease 2019 (COVID-19) is usually mild and self-limiting in previously healthy children, but they may also develop severe disease. Severe COVID-19 infection is especially observed in very young children or those with underlying comorbidities. Moreover, a multisystem inflammatory syndrome that mimics the Kawasaki disease shock syndrome can develop in children that are genetically predisposed to displaying an overactive immune response to SARS-CoV-2 infection. In this review, we describe the clinical phenotypes of mild and severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We also discuss the possible immunobiological mechanisms that may be involved in the protection of children against COVID-19 and the development of multisystem inflammatory syndrome.

Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production.

High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33-Th2 cytokine production causing upregulation of the inhibitory FcγRIIb, as well as by modulating IFN-γ signaling. The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels. Strikingly, no upregulation of FcγRIIb expression was found, but instead a decreased expression of the activating FcγRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-γR2 subunit of the IFN-γR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcγRs and IFN-γR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-γ. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment. Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 and not by upregulation of FcγRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.

Towards an Improved LAI Collection Protocol via Simulated and Field-Based PAR Sensing.

In support of NASA's next-generation spectrometer-the Hyperspectral Infrared Imager (HyspIRI)-we are working towards assessing sub-pixel vegetation structure from imaging spectroscopy data. Of particular interest is Leaf Area Index (LAI), which is an informative, yet notoriously challenging parameter to efficiently measure in situ. While photosynthetically-active radiation (PAR) sensors have been validated for measuring crop LAI, there is limited literature on the efficacy of PAR-based LAI measurement in the forest environment. This study (i) validates PAR-based LAI measurement in forest environments, and (ii) proposes a suitable collection protocol, which balances efficiency with measurement variation, e.g., due to sun flecks and various-sized canopy gaps. A synthetic PAR sensor model was developed in the Digital Imaging and Remote Sensing Image Generation (DIRSIG) model and used to validate LAI measurement based on first-principles and explicitly-known leaf geometry. Simulated collection parameters were adjusted to empirically identify optimal collection protocols. These collection protocols were then validated in the field by correlating PAR-based LAI measurement to the normalized difference vegetation index (NDVI) extracted from the "classic" Airborne Visible Infrared Imaging Spectrometer (AVIRIS-C) data ( R 2 was 0.61). The results indicate that our proposed collecting protocol is suitable for measuring the LAI of sparse forest (LAI < 3-5 ( m 2 / m 2 )).

A computational approach to enzyme design: predicting ω-aminotransferase catalytic activity using docking and MM-GBSA scoring.

Enzyme design is an important area of ongoing research with a broad range of applications in protein therapeutics, biocatalysis, bioengineering, and other biomedical areas; however, significant challenges exist in the design of enzymes to catalyze specific reactions of interest. Here, we develop a computational protocol using an approach that combines molecular dynamics, docking, and MM-GBSA scoring to predict the catalytic activity of enzyme variants. Our primary focuses are to understand the molecular basis of substrate recognition and binding in an S-stereoselective ω-aminotransferase (ω-AT), which naturally catalyzes the transamination of pyruvate into alanine, and to predict mutations that enhance the catalytic efficiency of the enzyme. The conversion of (R)-ethyl 5-methyl-3-oxooctanoate to (3S,5R)-ethyl 3-amino-5-methyloctanoate in the context of several ω-AT mutants was evaluated using the computational protocol developed in this work. We correctly identify the mutations that yield the greatest improvements in enzyme activity (20-60-fold improvement over wild type) and confirm that the computationally predicted structure of a highly active mutant reproduces key structural aspects of the variant, including side chain conformational changes, as determined by X-ray crystallography. Overall, the protocol developed here yields encouraging results and suggests that computational approaches can aid in the redesign of enzymes with improved catalytic efficiency.

Long-term safety of hyaluronidase-facilitated subcutaneous immunoglobulin 10%: a European post-authorization study.

Aim: To assess the long-term safety of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in European routine clinical practice.Materials & methods: This prospective, noninterventional, open-label, post-authorization safety study (EUPAS5812) sourced data on adverse events, immunogenicity, treatment regimens and product administration for 106 adult patients prescribed fSCIG 10% across 17 sites in six European countries from July 2014 to February 2020.Results: In total, 1171 treatment-emergent adverse events were reported in 94 patients (88.7%); 25.5% of these events were considered related to fSCIG 10%. Positive binding antibody titers developed in three patients; no neutralizing antibodies to recombinant human hyaluronidase were detected.Conclusion: This real-world study of fSCIG 10% is the longest to date and confirms its long-term safety and tolerability in adults with antibody deficiency diseases.

One way that the immune system fights infection is by making proteins known as antibodies, also called immunoglobulins. In conditions known as primary immunodeficiency diseases or secondary immunodeficiency diseases, the immune system may not work properly and so treatment with immunoglobulins might be needed. This study looked at the use of an antibody treatment called hyaluronidase-facilitated subcutaneous immunoglobulin (or fSCIG) in European adults mostly with primary immunodeficiency diseases in the real world. Details of adverse events and how fSCIG was used was taken from patient medical records and other documents, and information provided by patients. Of 106 patients, 94 (88.7%) reported 1171 adverse events which started during fSCIG treatment, and 25.5% of these events were considered related to patients receiving fSCIG. For the 105 patients who had information available, 66 patients (62.9%) were treated with fSCIG every 4 weeks. The study results support that fSCIG has a beneficial safety profile in adults with primary or secondary immunodeficiency diseases.

Clinical neuropathology practice news 2-2013: immunohistochemistry pins IDH in glioma - molecular testing procedures under scrutiny.

Isocitrate dehydrogenase 1 (IDH1) gene mutations occur in ~ 60 - 90% of diffuse and anaplastic gliomas and secondary glioblastomas. IDH status is strongly associated with patient survival times and IDH testing is relevant for clinical patient management and for stratification in clinical trials. A recent interlaboratory ring trial shows that immunohistochemistry is a highly reliable method to detect the most common IDH mutation (R132H), while IDH gene sequencing is less robust. These results support initial immunohistochemistry and subsequent gene sequencing in cases with negative or inconclusive immunostaining result as valid algorithm for IDH testing. Furthermore, they highlight the need for strict quality control of DNA-based biomarker analyses on formalinfixed and paraffin-embedded tumor samples.

Recommendations for an exercise intervention and core outcome set for older patients after hospital discharge: Results of an international Delphi study.

For older adults, acute hospitalization is a high-risk event with poor health outcomes, including functional decline. In absence of practical guidelines and high quality randomized controlled trials, this Delphi study was conducted. The aim of this study was to obtain consensus on an exercise intervention program, a core outcome set (COS) and handover information to prevent functional decline or restore physical function in acutely hospitalized older patients transitioning from hospital to home. An internal panel of experts in the field of exercise interventions for acutely hospitalized older adults were invited to join the study. In the Delphi study, relevant topics were recognized, statements were formulated and ranked on a 9-point Likert scale in two additional rounds. To reaching consensus, a score of 7-9 was classified as essential. Results were expressed as median and semi-interquartile range (SIQR), and consensus threshold was set at SIQR≤0.5. Fifteen international experts from eight countries participated in the panel. The response rate was 93%, 93% and 80% for the three rounds respectively. After three rounds, consensus was reached on 167 of the 185 (90.3%) statements, of which ninety-five (51.4%) were ranked as essential (median Likert-score ≥7.0, SIQR ≤0.5). This Delphi study provides starting points for developing an exercise intervention, a COS and handover information. The results of this Delphi study can assist physical therapists to provide a tailored exercise intervention for older patients with complex care needs after hospital discharge, to prevent functional decline and/or restore physical function.

Summary of night noise guidelines for Europe.

Considering the scientific evidence on the threshold of night noise exposure indicated by L night as defined in the Environmental Noise Directive (2002/49/EC), L night value of 40 dB should be the target of the night noise guideline (NNG) to protect the public, including the most vulnerable groups such as children, the chronically ill and the elderly. L night value of 55 dB is recommended as an interim target for countries which cannot follow NNG in the short term for various reasons and where policy-makers choose to adopt a stepwise approach. These guidelines may be considered an extension to the previous World Health Organization (WHO) guidelines for community noise (1999).

Aircraft noise effects on sleep: mechanisms, mitigation and research needs.

There is an ample number of laboratory and field studies which provide sufficient evidence that aircraft noise disturbs sleep and, depending on traffic volume and noise levels, may impair behavior and well-being during the day. Although clinical sleep disorders have been shown to be associated with increased risk of cardiovascular diseases, only little is known about the long-term effects of aircraft noise disturbed sleep on health. National and international laws and guidelines try to limit aircraft noise exposure facilitating active and passive noise control to prevent relevant sleep disturbances and its consequences. Adopting the harmonized indicator of the European Union Directive 2002/49/EC, the WHO Night Noise Guideline for Europe (NNG) defines four Lnight , outside ranges associated with different risk levels of sleep disturbance and other health effects ( < 30, 30-40, 40-55, and> 55 dBA). Although traffic patterns differing in number and noise levels of events that lead to varying degrees of sleep disturbance may result in the same Lnight , simulations of nights with up to 200 aircraft noise events per night nicely corroborate expert opinion guidelines formulated in WHO's NNG. In the future, large scale field studies on the effects of nocturnal (aircraft) noise on sleep are needed. They should involve representative samples of the population including vulnerable groups like children and chronically ill subjects. Optimally, these studies are prospective in nature and examine the long-term consequences of noise-induced sleep disturbances. Furthermore, epidemiological case-control studies on the association of nocturnal (aircraft) noise exposure and cardiovascular disease are needed. Despite the existing gaps in knowledge on long-term health effects, sufficient data are available for defining limit values, guidelines and protection concepts, which should be updated with the availability of new data.

Children's Independent Mobility to School in Seven European Countries: A Multinomial Logit Model.

The determinants of children's independent school mobility and the contextual discrepancies between these determinants have not been comprehensively investigated in previous studies. It is important to examine these determinants because independent school mobility is associated with children's physical activity, according to the literature. This paper examined the associations of different groups of variables such as household, mobility, perceptions, and the built environment with independent school mobility of children between 9 and 12 years using a sample of 1304 girls (50.9%) and boys (49.1%) in seven European countries. The sample was analyzed by Multinomial Logistic Regression, Chi-square test of independence, and Proportional Reduction in Error methods. According to the findings, father's and mother's commute mode choice, child's mode choice of commute to school, child's bike ownership, parent's perception of safety, parent's evaluation of bike lane and sidewalk quality, child's commute distance, number of driving licenses in the household, accessibility of public transport, and population density in the neighborhood and around the school proved to be very strong and significant determinants of children's independent school mobility in the Europe-wide sample. The comparison of the levels of independent school mobility did not show any significant differences between high-income countries such as Germany, Italy, and the Netherlands, and emerging economies and developing countries like Poland, Greece, Turkey, and Croatia. However, a direct comparison between Poland (emerging economy) (33.6%) and the Netherlands (high-income) (31.7%) revealed significant differences in the level of independent school mobility. This study found the motives for this discrepancy due to the significant difference in bike ownership, the number of household members working outside of the house, household size, commute distances of parents, and driving license possession.

Experimental Investigation of the Oxidative Coupling of Methane in a Porous Membrane Reactor: Relevance of Back-Permeation.

Novel reactor configurations for the oxidative coupling of methane (OCM), and in particular membrane reactors, contribute toward reaching the yield required to make the process competitive at the industrial scale. Therefore, in this work, the conventional OCM packed bed reactor using a Mn-Na2WO4/SiO2 catalyst was experimentally compared with a membrane reactor, in which a symmetric MgO porous membrane was integrated. The beneficial effects of distributive feeding of oxygen along the membrane, which is the main advantage of the porous membrane reactor, were demonstrated, although no significant differences in terms of performance were observed because of the adverse effects of back-permeation prevailing in the experiments. A sensitivity analysis carried out on the effective diffusion coefficient also indicated the necessity of properly tuning the membrane properties to achieve the expected promising results, highlighting how this tuning could be addressed.

Aerotoxic syndrome, discussion of possible diagnostic criteria.

Introduction: The term aerotoxic syndrome (ATS) was proposed 20 years ago to describe a constellation of symptoms reported by pilots and cabin crew following exposure to hydraulic fluids, engine oil, and pyrolysis products during flight. Hydraulic fluids and engine oil contain a large number of potentially toxic chemicals, including various organophosphate compounds (OPCs). However, ATS is not yet recognised as a valid diagnosis in aviation or general medicine, because the incidence and aetiology continues to be debated.Discussion: Early studies report findings from symptom surveys or cognitive assessments of small samples of self-selected aircrew, but objective measures of exposure were lacking. Over the last decade, researchers have used more sophisticated techniques to measure exposure, such as on board monitoring studies and biomarkers of exposure (e.g., reduced levels of serum butyrylcholinesterases [BChE]) and more sophisticated techniques to detect nervous system injuries such as fMRI and autoantibody testing. Consideration has also been given to inter-individual differences in the ability to metabolise certain chemical compounds as a result of genetic polymorphisms and exclusion of other potential causes of ill health.Conclusions: We discuss factors which suggest a diagnosis of probable ATS; recommend an assessment protocol which incorporates the aforementioned techniques; and propose diagnostic criteria for probable ATS, based on our previously reported findings in aircrew and the results of recent studies.