Volatile Compound Emissions from Stereolithography Three-Dimensional Printed Cured Resin Models for Biomedical Applications.

Stereolithography three-dimensional printing is used increasingly in biomedical applications to create components for use in healthcare and therapy. The exposure of patients to volatile organic compounds (VOCs) emitted from cured resins represents an element of concern in such applications. Here, we investigate the biocompatibility in relation to inhalation exposure of volatile emissions of three different cured commercial resins for use in printing a mouthpiece adapter for sampling exhaled breath. VOC emission rates were estimated based on direct analysis using a microchamber/thermal extractor coupled to a proton transfer reaction-mass spectrometer. Complementary analyses using comprehensive gas chromatography-mass spectrometry aided compound identification. Major VOCs emitted from the cured resins were associated with polymerization agents, additives, and postprocessing procedures and included alcohols, aldehydes, ketones, hydrocarbons, esters, and terpenes. Total VOC emissions from cubes printed using the general-purpose resin were approximately an order of magnitude higher than those of the cubes printed using resins dedicated to biomedical applications at the respective test temperatures (40 and 25 °C). Daily inhalation exposures were estimated and compared with daily tolerable intake levels or standard thresholds of toxicological concerns. The two resins intended for biomedical applications were deemed suitable for fabricating an adapter mouthpiece for use in breath research. The general-purpose resin was unsuitable, with daily inhalation exposures for breath sampling applications at 40 °C estimated at 310 µg day-1 for propylene glycol (tolerable intake (TI) limit of 190 µg day-1) and 1254 µg day-1 for methyl acrylate (TI of 43 µg day-1).

Online Volatile Compound Emissions Analysis Using a Microchamber/Thermal Extractor Coupled to Proton Transfer Reaction-Mass Spectrometry.

Indoor air is a complex and dynamic mixture comprising manifold volatile organic compounds (VOCs) that may cause physiological and/or psychological discomfort, depending on the nature of exposure. This technical note presents a novel approach to analyze VOC emissions by coupling a microchamber/thermal extractor (µ-CTE) system to a proton transfer reaction-mass spectrometer (PTR-MS). This configuration provides an alternative to conventional emissions testing of small objects. The dynamic emission profiles of VOCs from a representative 3D-printed model are presented as a proof-of-concept analysis. Emission profiles are related to the target compound volatility, whereby 2-propanol and acetaldehyde exhibited the highest emissions and most rapid changes compared to the less volatile vinyl crotonate, 2-hydroxymethyl methacrylate, and mesitaldehyde, which were present at lower concentrations and showed different dynamics. Comparative measurements of the emission profiles of these compounds either with or without prior static equilibration yielded stark differences in their dynamics, albeit converging to similar values after 15 min of sampling time. Further, the utility of this system to determine the time required to capture a specific proportion of volatile emissions over the sampling period was demonstrated, with a mean duration of 8.4 ± 0.3 min to sample 50% of emissions across all compounds. This novel configuration provides a means to characterize the dynamic nature of VOC emissions from small objects and is especially suited to measuring highly volatile compounds, which can present a challenge for conventional sampling and analysis approaches. Further, it represents an opportunity for rapid, targeted emissions analyses of products to screen for potentially harmful volatiles.

Genome-wide association study identifies 74 loci associated with educational attainment.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Exposure Assessment of Toxicologically Relevant Volatile Organic Compounds Emitted from Polymer-Based Costume Masks.

Plastic costume masks regularly exhibit unpleasant odors that may be associated with the emissions of volatile organic compounds (VOCs). Upon inhalation, VOCs might adversely affect the wearer's health if the exposure exceeds regulatory threshold values. The VOCs emitted from a selection of costume masks (n = 12) were characterized semiquantitatively with a screening method based on GC/MS measurements in dynamic headspace sampling mode. Furthermore, odors associated with the masks were evaluated by a sensory panel. Two masks emitted particularly high concentrations of ethylbenzene, xylenes, and cyclohexanone and exhibited the most intense and unpleasant odors, which were described as rubber-like, pungent, and leather-like. To simulate and assess the inhalation exposures for wearers of these masks, an innovative experimental setup based on a doll's head was developed, with sampling of emitted volatiles on adsorption material and subsequent analysis by thermal desorption-GC/MS. The measured inhalable concentrations of cyclohexanone exceeded the derived no-effect level (DNEL) for systemic effects on the general population over several hours of wearing, and also after repeated use. Importantly, the cyclohexanone DNEL was reevaluated in relation to a recent study on inhalation toxicity in rodents and was found to be significantly lower (1.4 mg·m-3) compared to the industry-derived values (10-20 mg·m-3), thus aggravating the health risks associated with inhalation exposure from some of the costume masks tested. Finally, a comparison of the inhalable concentrations derived from the simulated exposure assessments with those derived from measurements in miniaturized emission test chambers indicate that microchambers represent a useful tool for high-throughput analysis. The influences of temperature and inhalation/exhalation flow rates on VOC exposures were also studied.

Breath Biomarkers in Diagnostic Applications.

The detection of chemical compounds in exhaled human breath presents an opportunity to determine physiological state, diagnose disease or assess environmental exposure. Recent advancements in metabolomics research have led to improved capabilities to explore human metabolic profiles in breath. Despite some notable challenges in sampling and analysis, exhaled breath represents a desirable medium for metabolomics applications, foremost due to its non-invasive, convenient and practically limitless availability. Several breath-based tests that target either endogenous or exogenous gas-phase compounds are currently established and are in practical and/or clinical use. This review outlines the concept of breath analysis in the context of these unique tests and their applications. The respective breath biomarkers targeted in each test are discussed in relation to their physiological production in the human body and the development and implementation of the associated tests. The paper concludes with a brief insight into prospective tests and an outlook of the future direction of breath research.

Factors affecting flavor perception in space: Does the spacecraft environment influence food intake by astronauts?

The intention to send a crewed mission to Mars involves a huge amount of planning to ensure a safe and successful mission. Providing adequate amounts of food for the crew is a major task, but 20 years of feeding astronauts on the International Space Station (ISS) have resulted in a good knowledge base. A crucial observation from the ISS is that astronauts typically consume only 80% of their daily calorie requirements when in space. This is despite daily exercise regimes that keep energy usage at very similar levels to those found on Earth. This calorie deficit seems to have little effect on astronauts who spend up to 12 months on the ISS, but given that a mission to Mars would take 30 to 36 months to complete, there is concern that a calorie deficit over this period may lead to adverse effects in crew members. The key question is why astronauts undereat when they have a supply of food designed to fully deliver their nutritional needs. This review focuses on evidence from astronauts that foods taste different in space, compared to on Earth. The underlying hypothesis is that conditions in space may change the perceived flavor of the food, and this flavor change may, in turn, lead to underconsumption by astronauts. The key areas investigated in this review for their potential impact on food intake are the effects of food shelf life, physiological changes, noise, air and water quality on the perception of food flavor, as well as the link between food flavor and food intake.

Delta-Like 4 Activates Notch 3 to Regulate Self-Renewal in Skeletal Muscle Stem Cells.

Notch signaling is essential to maintain skeletal muscle stem cells in quiescence. However, the precise roles of different Notch receptors are incompletely defined. Here, we demonstrate a role for Notch3 (N3) in the self-renewal of muscle stem cells. We found that N3 is active in quiescent C2C12 reserve cells (RCs), and N3 over-expression and knockdown studies in C2C12 and primary satellite cells reveal a role in self-renewal. The Notch ligand Delta-like 4 (Dll4) is expressed by newly formed myotubes and interaction with this ligand is sufficient to maintain N3 activity in quiescent C2C12 RCs to prevent activation and progression into the cell cycle. Thus, our data suggest a model whereby during regeneration, expression of Dll4 by nascent muscle fibers triggers N3 signaling in associated muscle stem cells to recruit them to quiescence, thereby renewing the stem cell pool. Stem Cells 2018;36:458-466.

Genetic evidence for natural selection in humans in the contemporary United States.

Recent findings from molecular genetics now make it possible to test directly for natural selection by analyzing whether genetic variants associated with various phenotypes have been under selection. I leverage these findings to construct polygenic scores that use individuals' genotypes to predict their body mass index, educational attainment (EA), glucose concentration, height, schizophrenia, total cholesterol, and (in females) age at menarche. I then examine associations between these scores and fitness to test whether natural selection has been occurring. My study sample includes individuals of European ancestry born between 1931 and 1953 who participated in the Health and Retirement Study, a representative study of the US population. My results imply that natural selection has been slowly favoring lower EA in both females and males, and are suggestive that natural selection may have favored a higher age at menarche in females. For EA, my estimates imply a rate of selection of about -1.5 mo of education per generation (which pales in comparison with the increases in EA observed in contemporary times). Although they cannot be projected over more than one generation, my results provide additional evidence that humans are still evolving-albeit slowly, especially compared with the rapid changes that have occurred over the past few generations due to cultural and environmental factors.

Development and Validation of a Food-Associated Olfactory Test (FAOT).

Olfactory tests are an important tool in human nutritional research for studying food preferences, yet comprehensive tests dedicated solely to food odors are currently lacking. Therefore, within this study, an innovative food-associated olfactory test (FAOT) system was developed. The FAOT comprises 16 odorant pens that contain representative food odors relating to different macronutrient classes. The test underwent a sensory validation based on identification rate, intensity, hedonic value, and food association scores. The accuracy of the test was further compared to the accuracy of the established Sniffin' Sticks identification test. The identification rates and intensities of this new FAOT were found to be comparable to the Sniffin' Sticks olfactory identification test. The odorant pens were also assessed chemo-analytically and were found to be chemically stable for at least 24 weeks. Overall, this new identification test for use in assessing olfaction in a food-associated context is valid both in terms of its use in sensory perception studies and its chemical stability. The FOAT is particularly suited to examinations of the sense of smell regarding food odors.

Intranasal odorant concentrations in relation to sniff behavior.

Knowledge on how odorants are transported through the nasal cavity to the olfactory epithelium is limited. One facet of this is how the sniffing behavior affects the abundance of odorants transferred to the olfactory cleft and in turn influences odor perception. A novel system that couples an online mass spectrometer with an odorant pulse delivery olfactometer was employed to characterize intranasal odorant concentrations of butane-2,3-dione (or butanedione, commonly known as diacetyl) at the interior naris and the olfactory cleft. Volunteers (n=12) were asked to perform different modes of sniffing in relation to the sniff intensity that were categorized as 'normal', 'rapid' and 'forced'. The highest concentrations of butanedione at both positions in the nose were observed during normal sniffing, with the lowest concentrations correlating with periods of forced sniffs. This corresponded to the panelists' ratings that normal sniffing elicited the highest odor intensities. These feasibility assessments pave the way for more in-depth analyses with a variety of odorants of different chemical classes at various intranasal positions, to investigate the passage and uptake of odorants within the nasal cavity.

Why it is hard to find genes associated with social science traits: theoretical and empirical considerations.

OBJECTIVES: We explain why traits of interest to behavioral scientists may have a genetic architecture featuring hundreds or thousands of loci with tiny individual effects rather than a few with large effects and why such an architecture makes it difficult to find robust associations between traits and genes. METHODS: We conducted a genome-wide association study at 2 sites, Harvard University and Union College, measuring more than 100 physical and behavioral traits with a sample size typical of candidate gene studies. We evaluated predictions that alleles with large effect sizes would be rare and most traits of interest to social science are likely characterized by a lack of strong directional selection. We also carried out a theoretical analysis of the genetic architecture of traits based on R.A. Fisher's geometric model of natural selection and empirical analyses of the effects of selection bias and phenotype measurement stability on the results of genetic association studies. RESULTS: Although we replicated several known genetic associations with physical traits, we found only 2 associations with behavioral traits that met the nominal genome-wide significance threshold, indicating that physical and behavioral traits are mainly affected by numerous genes with small effects. CONCLUSIONS: The challenge for social science genomics is the likelihood that genes are connected to behavioral variation by lengthy, nonlinear, interactive causal chains, and unraveling these chains requires allying with personal genomics to take advantage of the potential for large sample sizes as well as continuing with traditional epidemiological studies.

Revisiting the rationale of mandatory masking.

In this perspective, we review the evidence for the efficacy of face masks to reduce the transmission of respiratory viruses, specifically severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and consider the value of mandating universal mask wearing against the widespread negative impacts that have been associated with such measures. Before the SARS-CoV-2 pandemic, it was considered that there was little to no benefit in healthy people wearing masks as prophylaxis against becoming infected or as unwitting vectors of viral transmission. This accepted policy was hastily reversed early on in the pandemic, when districts and countries throughout the world imposed stringent masking mandates. Now, more than three years since the start of the pandemic, the amassed studies that have investigated the use of masks to reduce transmission of SARS-CoV-2 (or other pathogens) have led to conclusions that are largely inconsistent and contradictory. There is no statistically significant or unambiguous scientific evidence to justify mandatory masking for general, healthy populations with the intention of lessening the viral spread. Even if mask wearing could potentially reduce the transmission of SARS-CoV-2 in individual cases, this needs to be balanced against the physical, psychological and social harms associated with forced mask wearing, not to mention the negative impact of innumerable disposed masks entering our fragile environment. Given the lack of unequivocal scientific proof that masks have any effect on reducing transmission, together with the evident harms to people and the environment through the use of masks, it is our opinion that the mandatory use of face masks in the general population is unjustifiable and must be abandoned in future pandemic countermeasures policies.

Cross-validation of the peppermint benchmarking experiment across three analytical platforms.

The Peppermint Experiment is a breath analysis benchmarking initiative that seeks to address the lack of inter-comparability of outcomes across independent breath biomarker studies. In this experiment, the washout profiles of volatile terpene constituents of encapsulated peppermint oil (mainlyα-pinene,ß-pinene, limonene and 1,8-cineole) in exhaled breath are characterized through a series of measurements at defined sampling intervals up to 6 h after ingestion of the capsule. In the present work, the Peppermint Experiment was carried out on a cohort of volunteers (n= 11) that provided breath samples in three sittings on different days (i.e. triplicates per volunteer) for concurrent analysis by three different analytical platforms. These platforms were proton transfer reaction-time-of-flight-mass spectrometry (PTR-TOFMS) interfaced with a buffered end-tidal (BET) breath sampler, gas chromatography-ion mobility spectrometry (GC-IMS) in conjunction with a compatible handheld direct breath sampler, and thermal desorption comprehensive two-dimensional gas chromatography-time-of-flight-mass spectrometry (TD-GC×GC-TOFMS) with a Respiration Collection forin-vitroAnalysis (ReCIVA) system for trapping breath volatiles onto adsorbent tubes. Regression analysis yielded mean washout times across the cohort of 448 min (PTR-TOFMS and GC-IMS) and 372 min (TD-GC×GC-TOFMS), which are in good alignment with published benchmark values. Large variations in washout profiles were observed at the individuals level, both between (inter-individual) and within (intra-individual) participants, indicating high variability in the degree of absorption, distribution, metabolism and excretion of volatile terpenes in the body within individuals and across the cohort. The comparably low inter-instrument variability indicates that differences in benchmark values from independent studies reported in the literature are driven by biological variability rather than different performances between sampling methods or analytical platforms.

Emissions and uptake of volatiles by sampling components in breath analysis.

The first and most crucial step in breath research is adequate sampling, which plays a pivotal role in quality assurance of breath datasets. In particular, the emissions or uptake of volatile organic compounds (VOCs) by sampling interface materials present a risk of disrupting breath gas samples. This study investigated emissions and uptake by three interface components, namely a silicon facemask, a reusable 3D-printed mouthpiece adapter, and a pulmonary function test filter compatible with the commercial Respiration Collector forIn-VitroAnalysis (ReCIVA) breath sampling device. Emissions were examined before and after (hydro-)thermal treatment of the components, and uptake was assessed by exposing each material to 12 representative breath VOCs comprising alcohols, aldehydes, ketones, carboxylic acids, terpenes, sulphurous and nitrogenous compounds at different target concentration ranges (∼10 ppbVand ∼100 ppbV). Chemical analyses of VOCs were performed using proton transfer reaction-time-of-flight-mass spectrometry (PTR-TOFMS) with supporting analyses via thermal desorption comprehensive two-dimensional gas chromatography-TOFMS (TD-GC×GC-TOFMS). The filter exhibited the lowest overall emissions compared to the mask or adapter, which both had equivalently high emissions (albeit for different compounds). Treatment of the materials reduced the total VOC emissions by 62% in the mask, 89% in the filter and 99% in the adapter. Uptakes of compounds were lowest for the adapter and most pronounced in the mask. In particular, 1-butanol, acetone, 2-butanone, 1,8-cineole and dimethyl sulphide showed negligible uptake across all materials, whereas ethanol, nonanal, acetic acid, butanoic acid, limonene and indole exhibited marked losses. Knowledge of emissions and/or uptake by sampling components is key to reducing the likelihood of erroneous data interpretation, ultimately expediting progress in the field of breath test development.

Most reported genetic associations with general intelligence are probably false positives.

General intelligence (g) and virtually all other behavioral traits are heritable. Associations between g and specific single-nucleotide polymorphisms (SNPs) in several candidate genes involved in brain function have been reported. We sought to replicate published associations between g and 12 specific genetic variants (in the genes DTNBP1, CTSD, DRD2, ANKK1, CHRM2, SSADH, COMT, BDNF, CHRNA4, DISC1, APOE, and SNAP25) using data sets from three independent, well-characterized longitudinal studies with samples of 5,571, 1,759, and 2,441 individuals. Of 32 independent tests across all three data sets, only 1 was nominally significant. By contrast, power analyses showed that we should have expected 10 to 15 significant associations, given reasonable assumptions for genotype effect sizes. For positive controls, we confirmed accepted genetic associations for Alzheimer's disease and body mass index, and we used SNP-based calculations of genetic relatedness to replicate previous estimates that about half of the variance in g is accounted for by common genetic variation among individuals. We conclude that the molecular genetics of psychology and social science requires approaches that go beyond the examination of candidate genes.

3D-printed mouthpiece adapter for sampling exhaled breath in medical applications.

The growing use of 3D printing in the biomedical sciences demonstrates its utility for a wide range of research and healthcare applications, including its potential implementation in the discipline of breath analysis to overcome current limitations and substantial costs of commercial breath sampling interfaces. This technical note reports on the design and construction of a 3D-printed mouthpiece adapter for sampling exhaled breath using the commercial respiration collector for in-vitro analysis (ReCIVA) device. The paper presents the design and digital workflow transition of the adapter and its fabrication from three commercial resins (Surgical Guide, Tough v5, and BioMed Clear) using a Formlabs Form 3B stereolithography (SLA) printer. The use of the mouthpiece adapter in conjunction with a pulmonary function filter is appraised in comparison to the conventional commercial silicon facemask sampling interface. Besides its lower cost - investment cost of the printing equipment notwithstanding - the 3D-printed adapter has several benefits, including ensuring breath sampling via the mouth, reducing the likelihood of direct contact of the patient with the breath sampling tubes, and being autoclaveable to enable the repeated use of a single adapter, thereby reducing waste and associated environmental burden compared to current one-way disposable facemasks. The novel adapter for breath sampling presented in this technical note represents an additional field of application for 3D printing that further demonstrates its widespread applicability in biomedicine.

Sampling Volatile Organic Compound Emissions from Consumer Products: A Review.

Volatile organic compounds (VOCs) are common constituents of many consumer products. Although many VOCs are generally considered harmless at low concentrations, some compound classes represent substances of concern in relation to human (inhalation) exposure and can elicit adverse health effects, especially when concentrations build up, such as in indoor settings. Determining VOC emissions from consumer products, such as toys, utensils or decorative articles, is of utmost importance to enable the assessment of inhalation exposure under real-world scenarios with respect to consumer safety. Due to the diverse sizes and shapes of such products, as well as their differing uses, a one-size-fits-all approach for measuring VOC emissions is not possible, thus, sampling procedures must be chosen carefully to best suit the sample under investigation. This review outlines the different sampling approaches for characterizing VOC emissions from consumer products, including headspace and emission test chamber methods. The advantages and disadvantages of each sampling technique are discussed in relation to their time and cost efficiency, as well as their suitability to realistically assess VOC inhalation exposures.

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals.

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

On the sources of the height-intelligence correlation: new insights from a bivariate ACE model with assortative mating.

A robust positive correlation between height and intelligence, as measured by IQ tests, has been established in the literature. This paper makes several contributions toward establishing the causes of this association. First, we extend the standard bivariate ACE model to account for assortative mating. The more general theoretical framework provides several key insights, including formulas to decompose a cross-trait genetic correlation into components attributable to assortative mating and pleiotropy and to decompose a cross-trait within-family correlation. Second, we use a large dataset of male twins drawn from Swedish conscription records and examine how well genetic and environmental factors explain the association between (i) height and intelligence and (ii) height and military aptitude, a professional psychologist's assessment of a conscript's ability to deal with wartime stress. For both traits, we find suggestive evidence of a shared genetic architecture with height, but we demonstrate that point estimates are very sensitive to assumed degrees of assortative mating. Third, we report a significant within-family correlation between height and intelligence (p^ = 0.10), suggesting that pleiotropy might be at play.