Sodium Chloride versus Lactose as a Carrier for House Dust Mite Allergen in Allergen Chamber Studies: A Clinical Study to Assess Noninferiority.

INTRODUCTION: In the Fraunhofer allergen challenge chamber (ACC), a standardized, universal, good manufacturing practice-conforming technology using a spray dried solution of lactose (L) and allergen extract has been established. In this study, we investigated the noninferiority of hypertonic sodium chloride (S) versus L as a carrier for house dust mite (HDM) allergen to simplify manufacturing, reduce costs, and allow for wider use. METHODS: Using a participant-blinded, sham exposure-controlled, single-arm, sequential intervention study, we challenged adults with HDM allergic rhinitis five times in the ACC. Participants were first exposed to S, L, and clean air (block 1), followed by S + HDM and L + HDM (block 2). Primary endpoints were mean total nasal symptom score (TNSS) and mean nasal secretion weight. RESULTS: 19 participants were enrolled in the study (10 females; mean age 32 years [22-49], 4 with mild allergic asthma). The safety profile of S + HDM and L + HDM was similar; eight participants experienced mild procedure-related adverse events including tiredness, cough, and dyspnea. Due to dropouts, 13 participants completed the study and were evaluated. Mean TNSS and nasal secretion were as follows: S 0.98, 0.28 g; L 1.1, 0.20 g; clean air 1.1, 0.23 g; S + HDM 5.7, 4.8 g; L + HDM 5.1, 5.1 g. Separate block 1/block 2 MANOVAs with TNSS and nasal secretion as dependent variables revealed no significant differences between the carriers, neither alone and compared with clean air (p = 0.2059, Wilk's λ = 0.78) nor combined with HDM (p = 0.3474, Wilk's λ = 0.89). Noninferiority of S was established using a meta-analysis-based minimal clinical important difference of -0.55: mean TNSS difference between S + HDM and L + HDM was 0.62 (90% CI: -0.51 to 1.74). CONCLUSION: S as an HDM carrier was safe and well tolerated. It was noninferior to L which makes it an adequate and easy-to-use carrier substitute.

Development of a non-target strategy for evaluation of potential biological effects of inhalable aerosols generated during purposeful room conditioning using an in vitro inhalation model.

OBJECTIVES: An integrated in vitro inhalation approach was outlined to estimate potential adverse acute inhalation effects of aerosols from commercial nebulizer applications used for purposeful room conditioning such as disinfection, scenting or others. Aerosol characterization, exposure estimation and evaluation of acute biological effects by in vitro inhalation were included to generate dose-response data, allowing for determination of in vitro lowest observable adverse effect levels (LOAELs). Correlation of these to estimates of human lung deposition was included for quantitative in vitro to in vivo extrapolation approach (QIVIVE) for acute effects during human exposure. METHODS: To test the proposed approach, a case study was undertaken using two realistic test materials. An acute in vitro inhalation setup with air-liquid interface A549-cells in an optimized exposure situation (P.R.I.T.® ExpoCube®) was used to expose cells and analysis of relevant biological effects (viability, mitochondrial membrane potential, stress, IL-8 release) was carried out. RESULTS: The observed dose-responsive effects in a sub-toxic dose-range could be attributed to the main component of one test material and its presence in the aerosol phase of the nebulized material. QIVIVE resulted in a factor of at least 256 between the in vitro LOAEL and the estimated acute human lung exposure for this test material. CONCLUSIONS: The case-study shows the value of the non-target in vitro inhalation testing approach especially in case of a lack of knowledge on complex product composition. It is expected that approaches like this will be of high value for product safety and environmental health in the future.

Design of a routine in vitro inhalation approach to estimate biological effects of nebulized products.Application in a case study on a potential real product for purposeful room conditioning by use of a commercial nebulizer.Combining results from aerosol characterization and in vitro inhalation experiments allowed for comprehensive correlation of product composition, aerosol properties and biological effects.Assignment of sub-toxic biological effects to a specific product component enabled identification of a product composition with potentially even less biological effect.Combined in vivo exposure estimation and in vitro LOAEL determination enabled a QIVIVE approach.

Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer.

WNT2 acts as a pro-angiogenic factor in placental vascularization and increases angiogenesis in liver sinusoidal endothelial cells (ECs) and other ECs. Increased WNT2 expression is detectable in many carcinomas and participates in tumor progression. In human colorectal cancer (CRC), WNT2 is selectively elevated in cancer-associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer, angiogenesis was not addressed so far. We demonstrate that WNT2 enhances EC migration/invasion, while it induces canonical WNT signaling in a small subset of cells. Knockdown of WNT2 in CAFs significantly reduced angiogenesis in a physiologically relevant assay, which allows precise assessment of key angiogenic properties. In line with these results, expression of WNT2 in otherwise WNT2-devoid skin fibroblasts led to increased angiogenesis. In CRC xenografts, WNT2 overexpression resulted in enhanced vessel density and tumor volume. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs by mass spectrometry and cytokine arrays revealed that proteins associated with pro-angiogenic functions are elevated by WNT2. These included extracellular matrix molecules, ANG-2, IL-6, G-CSF, and PGF. The latter three increased angiogenesis. Thus, stromal-derived WNT2 elevates angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.

Midwives' engagement in smoking- and alcohol-prevention in prenatal care before and after the introduction of practice guidelines in Switzerland: comparison of survey findings from 2008 and 2018.

BACKGROUND: Evidence suggests that cigarette smoking and alcohol consumption during pregnancy negatively impacts fetal health. Health agencies across countries have developed specific guidelines for health professionals in perinatal care to strengthen their role in smoking and alcohol use prevention. One such example is the "Guideline on Screening and Counselling for prevention of cigarette smoking and alcohol consumption before, during, and after pregnancy" introduced by the Swiss Midwives Association in 2011. The current study assesses the changes in midwives' engagement in smoking and alcohol use prevention before (2008) and after the introduction of the Guideline (2018). Further, the current study examines differences across regions (German vs. French speaking regions), graduation years (before and after the introduction of the Guideline) and different work settings (hospital vs. self-employed). METHODS: Survey data were collected in 2008 (n = 366) and in 2018 (n = 459). Differences in how midwives engaged in smoking and alcohol use prevention between 2008 and 2018 were assessed with chi-square tests, as were differences across German and French speaking regions, graduation years (before and after the introduction of the Guideline) and across different work settings (working in hospitals or as self-employed). RESULTS: An increase in midwives' awareness of the risks of consuming even small quantities of cigarettes and alcohol for the unborn child between 2008 and 2018 is evident. Explaining the risks to pregnant women who smoke or use alcohol remained the most frequently reported prevention strategy. However, engagement with more extensive smoking and alcohol use preventive strategies across the whole course of pregnancy, such as assisting women in the elaboration of a plan to stop smoking/alcohol use, remained limited. CONCLUSIONS: Seven years after its introduction, the effectiveness of the Guideline in increasing midwives' engagement in smoking and alcohol use prevention appears limited despite midwives' increased awareness.

Connecting action control and agency: Does action-effect binding affect temporal binding?

The sense of agency, i.e., the notion that we, as agents, are in control of our own actions and can affect our environment by acting, is an integral part of human volition. Recent work has attempted to ground agency in basic mechanisms of human action control. Along these lines, action-effect binding has been shown to affect explicit judgments of agency. Here, we investigate if such action-effect bindings are also related to temporal binding which is often used as an implicit measure of agency. In two experiments, we found evidence for the establishment of short-term action-effect bindings as well as temporal binding effects. However, the two phenomena were not associated with each other. This finding suggests that the relation of action control and agency is not a simple one, and it adds to the evidence in favor of a dissociation between subjective agency and perceptual biases such as temporal binding.

Action-effect binding and agency.

The sense of agency is a pervasive phenomenon that accompanies conscious acting and extends to the consequences of one's actions in the environment. Subjective feelings of agency are typically explained in terms of predictive processes, based on internal forward models inherent to the sensorimotor system, and postdictive processes, i.e., explicit, retrospective judgments by the agent. Only recently, research has begun to elucidate the link between sense of agency and more basic processes of human action control. The present study was conducted in this spirit and explored the relation between short-term action-effect binding and explicit agency judgments. We found evidence for such a link in that the participants' short-term action-effect binding predicted subsequent agency ratings. This offers a new perspective on the sense of agency, providing an additional mechanism (together with predictive and postdictive processes) that may underlie its formation.

A methodology for the assessment of inhalation exposure to aluminium from antiperspirant sprays.

Inhalative exposure can occur accidentally when using cosmetic spray products. Usually, a tiered approach is applied for exposure assessment, starting with rather conservative, simplistic calculation models that may be improved with measured data and more refined modelling. Here we report on an advanced methodology to mimic in-use conditions for antiperspirant spray products to provide a more accurate estimate of the amount of aluminium possibly inhaled and taken up systemically, thus contributing to the overall body burden. Four typical products were sprayed onto a skin surrogate in defined rooms. For aluminium, size-related aerosol release fractions, i.e. inhalable, thoracic and respirable, were determined by a mass balance method taking droplet maturation into account. These data were included into a simple two-box exposure model, allowing calculation of the inhaled aluminium dose over 12 min. Systemic exposure doses were calculated for exposure of the deep lung and the upper respiratory tract using the Multiple Path Particle Deposition Model (MPPD) model. The total systemically available dose of aluminium was in all cases found to be less than 0.5 µg per application. With this study it could be demonstrated that refinement of the input data of the two-box exposure model with measured data of released airborne aluminium is a valuable approach to analyse the contribution of antiperspirant spray inhalation to total aluminium exposure as part of the overall risk assessment. We suggest the methodology which can also be applied to other exposure modelling approaches for spray products, and further is adapted to other similar use scenarios.

Airway and systemic inflammatory responses to ultrafine carbon black particles and ozone in older healthy subjects.

Increased adverse health effects in older subjects due to exposure to ambient air pollutants may be related to the inflammatory response induced by these contaminants. The aim of this study was to assess airway and systemic inflammatory responses in older healthy subjects to a controlled experimental exposure with spark-generated elemental carbon black ultrafine particles (cbUFPs) and ozone (O3). Twenty healthy subjects, age 52-75 years, were exposed on three occasions separated by at least 8 weeks. The exposures to filtered air (FA), to cbUFP (50 µg/m3), or to cbUFP in combination with 250 ppb ozone (cbUFP + O3) for 3 h with intermittent exercise were performed double blind, and in random order. Sputum and blood samples were collected 3.5 h after each exposure. Exposure to cbUFP + O3 significantly increased plasma club cell protein 16 (CC16), the number of sputum cells, the number and percent of sputum neutrophils, and sputum interleukin 6 and matrix metalloproteinase 9. Exposure to cbUFP alone exerted no marked effect, except for an elevation in sputum neutrophils in a subgroup of 13 subjects that displayed less than 65% sputum neutrophils after FA exposure. None of the inflammatory markers was correlated with age, and serum cardiovascular risk markers were not markedly affected by cbUFP or cbUFP + O3. Exposure to cbUFP+O3 induced a significant airway and systemic inflammatory response in older healthy volunteer subjects. The effects induced by cbUFP alone suggest that the inflammation was predominantly mediated by O3, although one cannot rule out that the interaction of cbUFP and O3 played a role.

The being a patient effect: negative expectations based on group labeling and corresponding treatment affect patient performance.

Patient studies provide insights into mechanisms underlying diseases and thus represent a cornerstone of clinical research. In this study, we report evidence that differences between patients and controls might partly be based on expectations generated by the patients' knowledge of being invited and treated as a patient: the Being a Patient effect (BP effect). This finding extends previous neuropsychological reports on diagnosis threat. Participants with mild allergies were addressed either as patients or control subjects in a clinical study. We measured the impact of this group labeling and corresponding instructions on pain perception and cognitive performance. Our results provide evidence that the BP effect can indeed affect physiological and cognitive measures in clinical settings. Importantly, these effects can lead to systematic overestimation of genuine disease effects and should be taken into account when disease effects are investigated. Finally, we propose strategies to avoid or minimize this critical confound.

Smooth criminal: convicted rule-breakers show reduced cognitive conflict during deliberate rule violations.

Classic findings on conformity and obedience document a strong and automatic drive of human agents to follow any type of rule or social norm. At the same time, most individuals tend to violate rules on occasion, and such deliberate rule violations have recently been shown to yield cognitive conflict for the rule-breaker. These findings indicate persistent difficulty to suppress the rule representation, even though rule violations were studied in a controlled experimental setting with neither gains nor possible sanctions for violators. In the current study, we validate these findings by showing that convicted criminals, i.e., individuals with a history of habitual and severe forms of rule violations, can free themselves from such cognitive conflict in a similarly controlled laboratory task. These findings support an emerging view that aims at understanding rule violations from the perspective of the violating agent rather than from the perspective of outside observer.