Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheeze. There are few mechanistic data linking chromosome 17q12-q21 to wheezing illness. OBJECTIVE: We investigated whether 17q12-q21 risk alleles were associated with impaired interferon responses to rhinovirus. METHODS: In a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells with rhinovirus A1 (RV-A1) and rhinovirus A16 (RV-A16) and measured IFN and IFN-induced C-X-C motif chemokine ligand 10 (aka IP10) responses in supernatants. We investigated associations between virus-induced cytokines and 6 SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. RESULTS: Five SNPs (in high linkage disequilibrium, r2 ≥ 0.8) were significantly associated with RV-A1-induced IFN-ß (rs9303277, P = .010; rs11557467, P = .012; rs2290400, P = .006; rs7216389, P = .008; rs8079416, P = .005). A reduction in RV-A1-induced IFN-ß was observed among individuals with asthma risk alleles. There were no significant associations for RV-A1-induced IFN-α or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified 3 clusters that differed in IFN-ß induction to RV-A1 (low, medium, high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-ß responses was characterized by a very high probability of being homozygous for the asthma risk allele for all SNPs. Children with persistent wheeze were almost 3 times more likely to be in clusters with reduced/average RV-A1-induced IFN-ß responses than in the high immune response cluster. CONCLUSIONS: Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-ß, suggesting a novel mechanism-impaired IFN-ß induction-links 17q12-q21 risk alleles with asthma/wheeze.

Clarifying the relationship between mental illness and recidivism using machine learning: A retrospective study.

OBJECTIVE: There is currently inconclusive evidence regarding the relationship between recidivism and mental illness. This retrospective study aimed to use rigorous machine learning methods to understand the unique predictive utility of mental illness for recidivism in a general population (i.e.; not only those with mental illness) prison sample in the United States. METHOD: Participants were adult men (n = 322) and women (n = 72) who were recruited from three prisons in the Midwest region of the United States. Three model comparisons using Bayesian correlated t-tests were conducted to understand the incremental predictive utility of mental illness, substance use, and crime and demographic variables for recidivism prediction. Three classification statistical algorithms were considered while evaluating model configurations for the t-tests: elastic net logistic regression (GLMnet), k-nearest neighbors (KNN), and random forests (RF). RESULTS: Rates of substance use disorders were particularly high in our sample (86.29%). Mental illness variables and substance use variables did not add predictive utility for recidivism prediction over and above crime and demographic variables. Exploratory analyses comparing the crime and demographic, substance use, and mental illness feature sets to null models found that only the crime and demographics model had an increased likelihood of improving recidivism prediction accuracy. CONCLUSIONS: Despite not finding a direct relationship between mental illness and recidivism, treatment of mental illness in incarcerated populations is still essential due to the high rates of mental illnesses, the legal imperative, the possibility of decreasing institutional disciplinary burden, the opportunity to increase the effectiveness of rehabilitation programs in prison, and the potential to improve meaningful outcomes beyond recidivism following release.

Effects of Bundling Medication for Opioid Use Disorder With an mHealth Intervention Targeting Addiction: A Randomized Clinical Trial.

OBJECTIVE: Medication for opioid use disorder (MOUD) improves treatment retention and reduces illicit opioid use. A-CHESS is an evidence-based smartphone intervention shown to improve addiction-related behaviors. The authors tested the efficacy of MOUD alone versus MOUD plus A-CHESS to determine whether the combination further improved outcomes. METHODS: In an unblinded parallel-group randomized controlled trial, 414 participants recruited from outpatient programs were assigned in a 1:1 ratio to receive either MOUD alone or MOUD+A-CHESS for 16 months and were followed for an additional 8 months. All participants were on methadone, buprenorphine, or injectable naltrexone. The primary outcome was abstinence from illicit opioid use; secondary outcomes were treatment retention, health services use, other substance use, and quality of life; moderators were MOUD type, gender, withdrawal symptom severity, pain severity, and loneliness. Data sources were surveys comprising multiple validated scales, as well as urine screens, every 4 months. RESULTS: There was no difference in abstinence between participants in the MOUD+A-CHESS and MOUD-alone arms across time (odds ratio=1.10, 95% CI=0.90-1.33). However, abstinence was moderated by withdrawal symptom severity (odds ratio=0.95, 95% CI=0.91-1.00) and MOUD type (odds ratio=0.57, 95% CI=0.34-0.97). Among participants without withdrawal symptoms, abstinence rates were higher over time for those in the MOUD+A-CHESS arm than for those in the MOUD-alone arm (odds ratio=1.30, 95% CI=1.01-1.67). Among participants taking methadone, those in the MOUD+A-CHESS arm were more likely to be abstinent over time (b=0.28, SE=0.09) than those in the MOUD-alone arm (b=0.06, SE=0.08), although the two groups did not differ significantly from each other (∆b=0.22, SE=0.11). MOUD+A-CHESS was also associated with greater meeting attendance (odds ratio=1.25, 95% CI=1.05-1.49) and decreased emergency department and urgent care use (odds ratio=0.88, 95% CI=0.78-0.99). CONCLUSIONS: Overall, MOUD+A-CHESS did not improve abstinence relative to MOUD alone. However, MOUD+A-CHESS may provide benefits for subsets of patients and may impact treatment utilization.

Identification of differences in CD4+ T-cell gene expression between people with asthma and healthy controls.

Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein-protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).

Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of five birth cohorts.

BACKGROUND: Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. OBJECTIVES: To demonstrate that a more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. METHODS: We derived six multidimensional variables of eczema spells from birth to 18 years of age (including duration, temporal sequencing and the extent of persistence/recurrence). Spells were defined as consecutive observations of eczema separated by no eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2-3 years); preschool/early school age (4-5 years); middle childhood (8-10 years); adolescence (14-18 years). We applied Partitioning Around Medoids clustering on these variables to derive clusters of the temporal patterns of eczema. We then investigated the stability of the clusters, within-cluster homogeneity and associated risk factors, including FLG mutations. RESULTS: Analysis of 7464 participants with complete data identified five clusters: (i) no eczema (51.0%); (ii) early transient eczema (21.6%); (iii) late-onset eczema (LOE; 8.1%); (iv) intermittent eczema (INT; 7.5%); and (v) persistent eczema (PE; 11.8%). There was very-high agreement between the assignment of individual children into clusters when using complete or imputed (n = 15 848) data (adjusted Rand index = 0.99; i.e. the clusters were very stable). Within-individual symptom patterns across clusters confirmed within-cluster homogeneity, with consistent patterns of symptoms among participants within each cluster and no overlap between the clusters. Clusters were characterized by differences in associations with risk factors (e.g. parental eczema was associated with all clusters apart from LOE; sensitization to inhalant allergens was associated with all clusters, with the highest risk in the PE cluster). All clusters apart from LOE were associated with FLG mutations. Of note, the strongest association was for PE [relative risk ratio (RRR) 2.70, 95% confidence interval (CI) 2.24-3.26; P < 0.001] followed by INT (RRR 2.29, 95% CI 1.82-2.88; P < 0.001). CONCLUSIONS: Clustering of multidimensional variables identified stable clusters with different genetic architectures. Using multidimensional variables may capture eczema development and derive stable and internally homogeneous clusters. However, deriving homogeneous symptom clusters does not necessarily mean that these are underpinned by completely unique mechanisms.

Short subcutaneous infusions for symptom control in palliative medicine.

OBJECTIVES: To investigate the efficacy and safety of short subcutaneous infusions (SSCIs) for refractory symptoms in the palliative setting. METHODS: A retrospective chart review of SSCIs in a single palliative care centre over an 18-month period. All clinical notes, medication administration records and infusion monitoring documentation were examined to ascertain therapeutic aim, efficacy and tolerability. RESULTS: 111 patients received one or more SSCIs, 28 in the community and 83 in the inpatient hospice (21% of all admissions). SSCIs were used for a wide variety of reasons including loading doses (to achieve steady state and, thus, symptom relief, sooner), as required doses (for medications too irritant to give as bolus SC injections) and regular maintenance doses (where continuous subcutaneous infusion (CSCI), were unnecessary). 84 single drug SSCIs types and 51 admixtures SSCIs types (2 or more medications) were given. One infusion was poorly absorbed, but SSCIs were otherwise well tolerated. CONCLUSIONS: SSCIs appear to be a promising additional option for administering medicines that are too irritant or large in volume for SC bolus injection. For medications with longer half-lives (eg, phenobarbital, valproate, levetiracetam), SSCI loading doses would be expected to achieve steady state and, thus, symptom relief, sooner than CSCIs alone.

Acceptability of Personal Sensing Among People With Alcohol Use Disorder: Observational Study.

BACKGROUND: Personal sensing may improve digital therapeutics for mental health care by facilitating early screening, symptom monitoring, risk prediction, and personalized adaptive interventions. However, further development and the use of personal sensing requires a better understanding of its acceptability to people targeted for these applications. OBJECTIVE: We aimed to assess the acceptability of active and passive personal sensing methods in a sample of people with moderate to severe alcohol use disorder using both behavioral and self-report measures. This sample was recruited as part of a larger grant-funded project to develop a machine learning algorithm to predict lapses. METHODS: Participants (N=154; n=77, 50% female; mean age 41, SD 11.9 years; n=134, 87% White and n=150, 97% non-Hispanic) in early recovery (1-8 weeks of abstinence) were recruited to participate in a 3-month longitudinal study. Participants were modestly compensated for engaging with active (eg, ecological momentary assessment [EMA], audio check-in, and sleep quality) and passive (eg, geolocation, cellular communication logs, and SMS text message content) sensing methods that were selected to tap into constructs from the Relapse Prevention model by Marlatt. We assessed 3 behavioral indicators of acceptability: participants' choices about their participation in the study at various stages in the procedure, their choice to opt in to provide data for each sensing method, and their adherence to a subset of the active methods (EMA and audio check-in). We also assessed 3 self-report measures of acceptability (interference, dislike, and willingness to use for 1 year) for each method. RESULTS: Of the 192 eligible individuals screened, 191 consented to personal sensing. Most of these individuals (169/191, 88.5%) also returned 1 week later to formally enroll, and 154 participated through the first month follow-up visit. All participants in our analysis sample opted in to provide data for EMA, sleep quality, geolocation, and cellular communication logs. Out of 154 participants, 1 (0.6%) did not provide SMS text message content and 3 (1.9%) did not provide any audio check-ins. The average adherence rate for the 4 times daily EMA was .80. The adherence rate for the daily audio check-in was .54. Aggregate participant ratings indicated that all personal sensing methods were significantly more acceptable (all P<.001) compared with neutral across subjective measures of interference, dislike, and willingness to use for 1 year. Participants did not significantly differ in their dislike of active methods compared with passive methods (P=.23). However, participants reported a higher willingness to use passive (vs active) methods for 1 year (P=.04). CONCLUSIONS: These results suggest that active and passive sensing methods are acceptable for people with alcohol use disorder over a longer period than has previously been assessed. Important individual differences were observed across people and methods, indicating opportunities for future improvement.

Using Machine Learning of Online Expression to Explain Recovery Trajectories: Content Analytic Approach to Studying a Substance Use Disorder Forum.

BACKGROUND: Smartphone-based apps are increasingly used to prevent relapse among those with substance use disorders (SUDs). These systems collect a wealth of data from participants, including the content of messages exchanged in peer-to-peer support forums. How individuals self-disclose and exchange social support in these forums may provide insight into their recovery course, but a manual review of a large corpus of text by human coders is inefficient. OBJECTIVE: The study sought to evaluate the feasibility of applying supervised machine learning (ML) to perform large-scale content analysis of an online peer-to-peer discussion forum. Machine-coded data were also used to understand how communication styles relate to writers' substance use and well-being outcomes. METHODS: Data were collected from a smartphone app that connects patients with SUDs to online peer support via a discussion forum. Overall, 268 adult patients with SUD diagnoses were recruited from 3 federally qualified health centers in the United States beginning in 2014. Two waves of survey data were collected to measure demographic characteristics and study outcomes: at baseline (before accessing the app) and after 6 months of using the app. Messages were downloaded from the peer-to-peer forum and subjected to manual content analysis. These data were used to train supervised ML algorithms using features extracted from the Linguistic Inquiry and Word Count (LIWC) system to automatically identify the types of expression relevant to peer-to-peer support. Regression analyses examined how each expression type was associated with recovery outcomes. RESULTS: Our manual content analysis identified 7 expression types relevant to the recovery process (emotional support, informational support, negative affect, change talk, insightful disclosure, gratitude, and universality disclosure). Over 6 months of app use, 86.2% (231/268) of participants posted on the app's support forum. Of these participants, 93.5% (216/231) posted at least 1 message in the content categories of interest, generating 10,503 messages. Supervised ML algorithms were trained on the hand-coded data, achieving F1-scores ranging from 0.57 to 0.85. Regression analyses revealed that a greater proportion of the messages giving emotional support to peers was related to reduced substance use. For self-disclosure, a greater proportion of the messages expressing universality was related to improved quality of life, whereas a greater proportion of the negative affect expressions was negatively related to quality of life and mood. CONCLUSIONS: This study highlights a method of natural language processing with potential to provide real-time insights into peer-to-peer communication dynamics. First, we found that our ML approach allowed for large-scale content coding while retaining moderate-to-high levels of accuracy. Second, individuals' expression styles were associated with recovery outcomes. The expression types of emotional support, universality disclosure, and negative affect were significantly related to recovery outcomes, and attending to these dynamics may be important for appropriate intervention.

Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life.

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P < 0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P < 0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (meta-analyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P < 0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.

Three-quarters of children hospitalized for wheezing or asthma symptoms are preschool-aged. Some will continue to experience breathing difficulties through childhood and adulthood. Others will undergo a complete resolution of their symptoms by the time they reach elementary school. The varied trajectories of young children with wheezing suggest that it is not a single disease. There are likely different genetic or environmental causes. Despite these differences, wheezing treatments for young children are 'one size fits all.' Studying the genetic underpinnings of wheezing may lead to more customized treatment options. Granell et al. studied the genetic architecture of different patterns of wheezing from infancy to adolescence. To do so, they used machine learning technology to analyze the genomes of 9,568 individuals, who participated in five studies in the United Kingdom from birth to age 18. The experiments found a new genetic variation in the ANXA1 gene linked with persistent wheezing starting in early childhood. By comparing mice with and without this gene, Granell et al. showed that the protein encoded by ANXA1 controls inflammation in the lungs in response to allergens. Animals lacking the protein develop worse lung inflammation after exposure to dust mite allergens. Identifying a new gene linked to a specific subtype of wheezing might help scientists develop better strategies to diagnose, treat, and prevent asthma. More studies are needed on the role of the protein encoded by ANXA1 in reducing allergen-triggered lung inflammation to determine if this protein or therapies that boost its production may offer relief for chronic lung inflammation.

Challenges in Managing Gonorrhea and New Advances in Prevention.

Gonorrhea is the second most common bacterial sexually transmitted infection in the United States. Rates are increasing, and multiple challenges compound management, including worsening antimicrobial resistance. New therapeutics, enhanced screening and partner notification, and treatment through point-of-care testing and expedited partner therapy, as well as primary prevention efforts provide opportunities for success in combating these trends.

The Importance of Mitral Valve Prolapse Doming Volume in the Assessment of Left Ventricular Stroke Volume with Cardiac MRI.

There remains a debate whether the ventricular volume within prolapsing mitral valve (MV) leaflets should be included in the left ventricular (LV) end-systolic volume, and therefore factored in LV stroke volume (SV), in cardiac magnetic resonance (CMR) assessments. This study aims to compare LV volumes during end-systolic phases, with and without the inclusion of the volume of blood on the left atrial aspect of the atrioventricular groove but still within the MV prolapsing leaflets, against the reference LV SV by four-dimensional flow (4DF). A total of 15 patients with MV prolapse (MVP) were retrospectively enrolled in this study. We compared LV SV with (LV SVMVP) and without (LV SVstandard) MVP left ventricular doming volume, using 4D flow (LV SV4DF) as the reference value. Significant differences were observed when comparing LV SVstandard and LV SVMVP (p < 0.001), and between LV SVstandard and LV SV4DF (p = 0.02). The Intraclass Correlation Coefficient (ICC) test demonstrated good repeatability between LV SVMVP and LV SV4DF (ICC = 0.86, p < 0.001) but only moderate repeatability between LV SVstandard and LV SV4DF (ICC = 0.75, p < 0.01). Calculating LV SV by including the MVP left ventricular doming volume has a higher consistency with LV SV derived from the 4DF assessment. In conclusion, LV SV short-axis cine assessment incorporating MVP dooming volume can significantly improve the precision of LV SV assessment compared to the reference 4DF method. Hence, in cases with bi-leaflet MVP, we recommend factoring in MVP dooming into the left ventricular end-systolic volume to improve the accuracy and precision of quantifying mitral regurgitation.

Dog ownership in infancy is protective for persistent wheeze in 17q21 asthma-risk carriers.

BACKGROUND: Asthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results. OBJECTIVES: We sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze. METHODS: Wheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed. RESULTS: rs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10-4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed. CONCLUSIONS: Among dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.

College students' momentary stress and prescription drug misuse in daily life: Testing direct links and the moderating roles of global stress and coping.

Prior survey-based research has documented associations between greater levels of stress and increased prescription drug misuse behaviour. These studies uniformly rely on assessments of both the stress experiences and the substance behaviour after they occurred (commonly spanning 6-12 month retrospective timeframes). Less is known about the extent to which variations in momentary stress predict the actual occurrence of prescription misuse in daily life among college students with elevated risk for engaging in the behaviour. In this study, 297 participants (69% females; Mage  = 19.5 years, SDage  = 0.71) completed a 28-day ecological momentary assessment procedure that collected self-reported stress and other contextual experiences in moments preceding prescription drug misuse. Analyses tested the within-person association between momentary stress and prescription drug misuse and examined the extent to which the relation between stress and misuse was moderated by participants' assigned sex or global stress and coping levels. Results from hierarchical generalised linear modelling indicated a significant within-person association between momentary stress (i.e., higher than usual relative to one's own mean) and greater likelihood of prescription misuse in daily life, accounting for the number of stressors and timing covariates. No significant moderation by participant sex was found, and moderation effects by global stress and coping levels were not in the expected directions. Direct results highlight the role of momentary stress experiences on health-relevant substance behaviours and provide future directions for research and applied efforts.

Alcohol's effects during uncertain and uncontrollable stressors in the laboratory.

Alcohol's effects on reactivity to stressors depends on the nature of the stressor and the reactivity being assessed. Research identifying characteristics of stressors that modulate reactivity and clarifies the neurobehavioral, cognitive, and affective components of this reactivity may help prevent, reduce or treat the negative impacts of acute and chronic alcohol use with implications for other psychopathology involving maladaptive reactivity to stressors. We used a novel, multi-measure, cued electric shock stressor paradigm in a greater university community sample of adult recreational drinkers to test how alcohol (N=64), compared to No-alcohol (N=64), effects reactivity to stressors that vary in both their perceived certainty and controllability. Preregistered analyses suggested alcohol significantly dampened subjective anxiety (self-report) and defensive reactivity (startle potentiation) more during uncertain than during certain stressors regardless of controllability, suggesting that stressor uncertainty -but not uncontrollability- may be sufficient to enhance alcohol's stress reactivity dampening and thus negative reinforcement potential.

A systems immunology approach to investigate cytokine responses to viruses and bacteria and their association with disease.

Patterns of human immune responses to viruses and bacteria and how this impacts risk of infections or onset/exacerbation of chronic respiratory diseases are poorly understood. In a population-based birth cohort, we measured peripheral blood mononuclear cell responses (28 cytokines) to respiratory viruses and bacteria, Toll-like receptor ligands and phytohemagglutinin, in 307 children. Cytokine responses were highly variable with > 1000-fold differences between children. Machine learning revealed clear distinction between virus-associated and bacteria-associated stimuli. Cytokines clustered into three functional groups (anti-viral, pro-inflammatory and T-cell derived). To investigate mechanisms potentially explaining such variable responses, we investigated cytokine Quantitative Trait Loci (cQTLs) of IL-6 responses to bacteria and identified nine (eight novel) loci. Our integrative approach describing stimuli, cytokines and children as variables revealed robust immunologically and microbiologically plausible clustering, providing a framework for a greater understanding of host-responses to infection, including novel genetic associations with respiratory disease.