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Background Although pediatric travelers comprise < 10% of US international travelers, they account for almost half of all measles importations among returning travelers. For travelers 1–18 years with no other evidence of measles immunity, the Advisory Committee on Immunization Practices (ACIP) recommends 2 MMR vaccine doses before departure; 1 dose is recommended for infant travelers (6 to <12 months) and does not count toward their primary immunization series. All US travelers (6 months to < 6 years) are at risk for being undervaccinated for measles because MMR is routinely given at 1 years and 4–6 years. Methods We developed a decision tree model to evaluate the clinical impact and cost per case averted of pretravel health encounters (PHE) that vaccinate MMR-eligible pediatric international travelers. We compared 2 strategies for infant (6 to < 12 months) and preschool-aged (1 to <6 years) travelers: (1) no PHE: travelers departed with baseline MMR vaccination status vs. (2) PHE: MMR-eligible travelers were offered vaccination. All simulated travelers experienced a destination-specific risk of measles exposure during travel (mean, 237exposures/10M travelers; range, 19–6,750 exposures/10M travelers); if exposed to measles, travelers were at risk of illness stratified by age and MMR vaccination status (range, 0.03–0.90). Costs include direct medical costs and lost work wages for guardians. Model outcomes included measles cases, costs, and cost per case averted. We varied inputs in sensitivity analyses. Results Compared with no PHE, PHE averted 451 measles cases at $985,000/case averted for infant travelers and 54 measles cases at $1.5 million/case averted for preschool-aged travelers (table, bottom). PHE can be cost-saving for travelers to regions with higher risk of measles exposure and if more MMR-eligible travelers are vaccinated at PHE (Figure 1). At a risk of exposure associated with European travel, PHE had better value when a measles importation led to a higher number of contacts or more US-acquired cases per importation (Figure 2). Conclusion PHE for pediatric travelers (6 months to <6 years) decreased the number of imported measles cases and saved costs, especially if targeted to travelers with higher-risk destinations, if more MMR-eligible travelers are vaccinated at PHE, or if outbreaks are larger. Disclosures All authors: No reported disclosures.

There has been increasing interest in the role of endocannabinoids as critical modulators of the female reproductive processes. Endocannabinoids are natural ligands of cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. Together with their receptors, enzymes and downstream signaling targets, they form the endocannabinoid system (ECS). While the ECS is known to modulate pain and neurodevelopment, it is also known to impact the female reproductive system where it affects folliculogenesis, oocyte maturation, and ovarian endocrine secretion. In addition, the ECS affects oviductal embryo transport, implantation, uterine decidualization and placentation. There is a complex interplay between the ECS and the hypothalamic-pituitary-ovarian axis, and an intricate crosstalk between the ECS and steroid hormone production and secretion. Exogenous cannabinoids, derived from plants such as Cannabis sativa , are also ligands for cannabinoid receptors. These have been shown to have clinical outcomes related to ECS dysregulation, including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis, along with adverse effects on female reproduction. The aim of this review is to describe and discuss data from human, animal, and in vitro studies that support the important role of the endocannabinoid system in female reproductive tissues and processes. In particular, we will discuss some of the mechanisms by which endocannabinoid signaling can affect ovarian function in both physiological and pathophysiological states.

The objective of this study is to determine whether obstructive sleep apnea (OSA) is associated with reduced fetal growth, and whether nocturnal oxygen desaturation precipitates acute fetal heart rate changes. We performed a prospective observational study, screening 371 women in the second trimester for OSA symptoms. 41 subsequently underwent overnight sleep studies to diagnose OSA. Third trimester fetal growth was assessed using ultrasound. Fetal heart rate monitoring accompanied the sleep study. Cord blood was taken at delivery, to measure key regulators of fetal growth. Of 371 women screened, 108 (29%) were high risk for OSA. 26 high risk and 15 low risk women completed the longitudinal study; 14 had confirmed OSA (cases), and 27 were controls. The median (interquartile range) respiratory disturbance index (number of apnoeas, hypopnoeas or respiratory related arousals/hour of sleep) was 7.9 (6.1-13.8) for cases and 2.2 (1.3-3.5) for controls (p<0.001). Impaired fetal growth was observed in 43% (6/14) of cases, vs 11% (3/27) of controls (RR 2.67; 1.25-5.7; p = 0.04). Using logistic regression, only OSA (OR 6; 1.2-29.7, p = 0.03) and body mass index (OR 2.52; 1.09-5.80, p = 0.03) were significantly associated with impaired fetal growth. After adjusting for body mass index on multivariate analysis, the association between OSA and impaired fetal growth was not appreciably altered (OR 5.3; 0.93-30.34, p = 0.06), although just failed to achieve statistical significance. Prolonged fetal heart rate decelerations accompanied nocturnal oxygen desaturation in one fetus, subsequently found to be severely growth restricted. Fetal growth regulators showed changes in the expected direction- with IGF-1 lower, and IGFBP-1 and IGFBP-2 higher- in the cord blood of infants of cases vs controls, although were not significantly different. OSA may be associated with reduced fetal growth in late pregnancy. Further evaluation is warranted to establish whether OSA may be an important contributor to adverse perinatal outcome, including stillbirth.

Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo.  .

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.

For a sound practitioner specifically, micro and macro implications and questions arise; on one hand, about how the relationship between individuals and sonic material is navigated in the presence of difficult sound work; on the other, how the structural or industrial aspects of professional sound work affect the lived experience of the practitioner. [...]an approach bypasses the rich lived complexities inherent in sound production, and also overlooks the potentially fraught issues inseparable from professional sound work, such as problematic industrial work practices or mental and physical health concerns. [...]a perspective is useful in avoiding reductionist ideas of listening to an auditory mechanism located in the ear, rather highlighting the coaction of bodily responses that occur during a listening experience. [...]for local industries described as 'porous to both America and Europe', such as Australia and New Zealand, these two very different agendas produce tensions between 'consumer and culture' and 'market and citizenship' (Hartley 5), a polarity which impacts industry structure.

Plasmids are major vectors of bacterial antibiotic resistance, but understanding of factors associated with plasmid antibiotic resistance gene (ARG) carriage is limited. We curated > 14,000 publicly available plasmid genomes and associated metadata. Duplicate and replicate plasmids were excluded; where possible, sample metadata was validated externally (Bac Dive database). Using Generalised Additive Models (GAMs) we assessed the influence of 12 biotic/abiotic factors (e.g. plasmid genetic factors, isolation source, collection date) on ARG carriage, modelled as a binary outcome. Separate GAMs were built for 10 major ARG types. Multivariable analysis indicated that plasmid ARG carriage patterns across time (collection years), isolation sources (human/livestock) and host bacterial taxa were consistent with antibiotic selection pressure as a driver of plasmid-mediated antibiotic resistance. Only 0.42% livestock plasmids carried carbapenem resistance (compared with 12% human plasmids); conversely, tetracycline resistance was enriched in livestock vs human plasmids, reflecting known prescribing practices. Interpreting results using a timeline of ARG type acquisition (determined by literature review) yielded additional novel insights. More recently acquired ARG types (e.g. colistin and carbapenem) showed increases in plasmid carriage during the date range analysed (1994–2019), potentially reflecting recent onset of selection pressure; they also co-occurred less commonly with ARGs of other types, and virulence genes. Overall, this suggests that following acquisition, plasmid ARGs tend to accumulate under antibiotic selection pressure and co-associate with other adaptive genes (other ARG types, virulence genes), potentially re-enforcing plasmid ARG carriage through co-selection.

Background Genome-wide DNA methylation (DNAm) profiling has allowed for the development of molecular predictors for a multitude of traits and diseases. Such predictors may be more accurate than the self-reported phenotypes and could have clinical applications. Results Here, penalized regression models are used to develop DNAm predictors for ten modifiable health and lifestyle factors in a cohort of 5087 individuals. Using an independent test cohort comprising 895 individuals, the proportion of phenotypic variance explained in each trait is examined for DNAm-based and genetic predictors. Receiver operator characteristic curves are generated to investigate the predictive performance of DNAm-based predictors, using dichotomized phenotypes. The relationship between DNAm scores and all-cause mortality ( n  = 212 events) is assessed via Cox proportional hazards models. DNAm predictors for smoking, alcohol, education, and waist-to-hip ratio are shown to predict mortality in multivariate models. The predictors show moderate discrimination of obesity, alcohol consumption, and HDL cholesterol. There is excellent discrimination of current smoking status, poorer discrimination of college-educated individuals and those with high total cholesterol, LDL with remnant cholesterol, and total:HDL cholesterol ratios. Conclusions DNAm predictors correlate with lifestyle factors that are associated with health and mortality. They may supplement DNAm-based predictors of age to identify the lifestyle profiles of individuals and predict disease risk.