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.

Birth cohort-specific consideration in an Emergency Department Hepatitis C Testing Programme: A description of age-related characteristics and outcomes.

The emergency department (ED) has increasingly become an important public health partner in non-targeted hepatitis C virus (HCV) testing and referral to care efforts. HCV has traditionally been an infection associated with the Baby Boomer generation; however, recent exacerbation of the opioid epidemic has resulted in a growing number of younger cohorts, namely Millennials, also impacted by HCV. Examination of this age-related demographic shift, including subsequent linkage success and linkage barriers, from the perspective of an ED-based testing and linkage programme may have implications for future population and health systems interventions. A retrospective descriptive chart review was performed, inclusive of data from August 2015 through December 2020. We compared the quantity of positive HCV screening antibody (Ab) and confirmatory (RNA) tests and further considered linkage rates and correlative demographics (e.g. gender, race). Patient barriers to HCV care linkage (e.g. substance misuse, lack of health insurance, homelessness) were also evaluated. The data set was disaggregated by birth cohort to include Silent Generation (SG) (1928-45), Baby Boomer (BB) (1946-64), Generation X (Gen X) (1965-80), Millennial (1981-96) and Generation Z (1997-2012). Descriptive statistics and chi-square analysis were performed. Overall, 83,817 patients were tested for HCV (50.6% of eligible); 6187 (7.4%) were HCV Ab positive, and 2665 were HCV RNA positive (3.2%). RNA-positive individuals were more likely to be white (70.4%) and male (67.7%); generational distribution was similar (BB 33.3%, Gen X 32.0% and Millennials 32.7%). Amongst Ab-positive patients, white (45.5%), male (47.2%) and Millennial (49.7%) individuals were most likely to be RNA-positive. Overall, 28.1% of the RNA-positive cohort successfully linked to care; linkage to care rates were significantly higher in older generations (38.1% in BB vs. 17.8% in Millennials) (p < .00001). Over 90% were identified as having at least one linkage to care barrier. Younger generations (Gen X and Millennials) were disproportionately impacted by linkage barriers, including incarceration, lack of health insurance, history of mental health and substance use disorders, as well as history of or active injection drug use (IDU) (p < .00001). Older generations (SG and BB) were more likely to be impacted by competing medical comorbidities (p < .00001). The ED population represents a particularly vulnerable, at-risk cohort with a high prevalence of HCV and linkage to care barriers. While past HCV-specific recommendations and interventions have focused on Baby Boomers, this data suggests that younger generations, including Gen X and Millennials, are increasingly affected by HCV and face disparate social risk and social need factors which impede definitive care linkage and treatment.

Sociodemographic inequities in food allergy: Insights on food allergy from birth cohorts.

A large and growing corpus of epidemiologic studies suggests that the population-level burden of pediatric FA is not equitably distributed across major sociodemographic groups, including race, ethnicity, household income, parental educational attainment, and sex. As is the case for more extensively studied allergic disease states such as asthma and atopic dermatitis epidemiologic data suggest that FA may be more prevalent among certain populations experiencing lower socioeconomic status (SES), particularly those with specific racial and ethnic minority backgrounds living in highly urbanized regions. Emerging data also indicate that these patients may also experience more severe FA-related physical health, psychosocial, and economic outcomes relating to chronic disease management. However, many studies that have identified sociodemographic inequities in FA burden are limited by cross-sectional designs that are subject to numerous biases. Compared with cross-sectional study designs or cohorts established later in life, birth cohorts offer advantages relative to other study designs when investigators seek to understand causal relationships between exposures occurring during the prenatal or postnatal period and the atopic disease status of individuals later in life. Numerous birth cohorts have been established across recent decades, which include evaluation of food allergy-related outcomes, and a subset of these also have measured sociodemographic variables that, together, have the potential to shed light on the existence and possible etiology of sociodemographic inequities in food allergy. This manuscript reports the findings of a comprehensive survey of the current state of this birth cohort literature and draws insights into what is currently known, and what further information can potentially be gleaned from thoughtful examination and further follow-up of ongoing birth cohorts across the globe.

Birth-cohort patterns of e-cigarette and other tobacco use among adolescents in the US.

BACKGROUND: E-cigarette use has increased considerably among US adolescents. While many studies have described cross-sectional prevalence trends of youth e-cigarette use, less is known about cohort or generational initiation and use patterns. METHODS: We used data from the US National Youth Tobacco Survey (NYTS) from 2014 to 2022 and age-period-cohort models to analyze age-specific patterns of e-cigarette use initiation and prevalence by cohort and calendar. For comparison, we also examined initiation and prevalence for cigarettes, cigars, and smokeless tobacco, using NYTS data from 1999 to 2022. RESULTS: Age-specific e-cigarette initiation and prevalence varied considerably by calendar year and birth cohort. There was a rapid increase in e-cigarette initiation and prevalence starting with the 1995 birth cohort, peaking with the 2005 birth cohort, and showing signs of decline with more recent cohorts. In contrast, there were substantial continuous reductions in cigarette, cigar, and smokeless use initiation and prevalence by birth cohort. While the reductions in cigarette smoking started with the 1980s birth cohorts, cigar and smokeless initiation and prevalence did not decrease until the 1990-1995 cohorts. CONCLUSIONS: Despite their recent emergence, e-cigarette use has varied considerably across US adolescent cohorts. After early increases, e-cigarette use and initiation peaked with the 2005 birth cohort. These patterns are in contrast with the continuous decreases by cohort in cigarette, cigar, and smokeless use and initiation. As the tobacco product landscape continues to evolve, it will be essential to monitor patterns of use of adolescent and young adult cohorts as they age into adulthood.

Life-course social participation and physical activity in midlife: longitudinal associations in the 1970 British Cohort Study (BCS70).

A hypothesized benefit of social participation is that it encourages people to be more physically active. However, limited evidence exists on the association between social participation over the life-course and physical activity in midlife. We sought to apply a life-course framework to examine the association of social participation and device measured physical activity in midlife in the UK. We used the 1970 British Birth Cohort Study (BCS70), which includes all people born in Britain during a single week in 1970. Social participation was assessed at ages 16, 30, 34 and 42. Physical activity was measured by accelerometery at age 46, as mean daily step count and time spent in moderate to vigorous physical activity (MVPA). The associations of social participation and physical activity were tested using two different life-course models: the sensitive period model and the accumulation model. Individuals with medium and high participation compared to no social participation over their life-course had higher mean daily step count and MVPA in midlife, supporting the accumulation model. In the sensitive period model, only those that actively participated at age 42 had higher mean daily steps and MVPA compared to those who did not participate. Our study provides empirical evidence on the importance of sustaining social participation at all ages over the life-course rather than at a particular timepoint of someone's life. If our findings reflect causal effects, interventions to promote social participation throughout the life-course could be an avenue to promote physical activity in middle life.

Latent Class Analysis of Sexual Partnerships and Substance Use Across Generations.

Sexually transmitted infections (STIs) remain an important public health concern for people of all age groups, with older age groups experiencing a notable increase in STI burden. Historically, most research into STI risk behaviors has focused on adolescents and young adults, leaving a paucity of research on the ways STI risk factors change over the life course. Additionally, age and cohort trends in STI risk factors can be challenging to investigate with standard statistical tools as they can be collinear and are subject to sociocultural and generational influences. To help address these issues, we used multi-group latent class analysis to identify and compare risk behavior profiles defined by responses to three sexual activity and three substance use variables, across and within four age groups. We identified six behavior profiles in the unstratified dataset and five behavior profiles in each of the four age stratified groups. The five behavior profiles identified in each of the age categories appear to reflect a similar set of five underlying profile "archetypes," with the exact composition of each age category's five profiles varying in the magnitude that specific behaviors are endorsed. Interestingly, despite the similarity of profiles across the four age groups, analyses indicate that the experience of belonging to any one of these five archetypes differs by age group. This variance is likely due group specific age, period, and cohort effects, and may indicate that, when estimating one's STI risk, it is better to compare them to their peers than to the population as a whole.

Responses to Sexual and Gender Identity Measures in Population-Level Data by Birth Cohort: A Research Note.

The measurement of sexual and gender identity in the United States has been evolving to generate more precise demographic estimates of the population and a better understanding of health and well-being. Younger cohorts of sexual- and gender-diverse adults are endorsing identities outside of the lesbian, gay, bisexual, and transgender (LGBT) labels. Current population-level surveys often include a category such as "something else" without providing further details, and doing so inadequately captures these diverse identities. In this research note, our analysis of the most recent federal data source to incorporate sexual and gender identity measures-the Household Pulse Survey-reveals that younger birth cohorts are more likely to select "something else" for their sexual identity and "none of these" for their gender identity. The observed sexual and gender identity response patterns across birth cohorts underscore the importance of developing and applying new strategies to directly measure sexual- and gender-diverse adults who identify with identities outside of those explicitly captured on surveys. The integration of sexual and gender identity measures in population-level surveys carries broader implications for civil rights and for addressing health inequities and therefore must be responsive to cohort differences in identification.

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.

25 Years of translational research in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC).

The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother-child cohorts have provided a foundation of 25 years of research on the origins, prevention, and natural history of childhood asthma and related disorders. COPSAC's approach is characterized by clinical translational research with longitudinal deep phenotyping and exposure assessments from pregnancy, in combination with multi-omic data layers and embedded randomized controlled trials. One trial showed that fish oil supplementation during pregnancy prevented childhood asthma and identified pregnant women with the highest benefits from supplementation, thereby creating the potential for personalized prevention. COPSAC revealed that airway colonization with pathogenic bacteria in early life is associated with an increased risk of asthma. Further, airway bacteria were shown to be a trigger of acute asthma-like symptoms, with benefit from antibiotic treatment. COPSAC identified an immature gut microbiome in early life as a risk factor for asthma and allergy and further demonstrated that asthma can be predicted by infant lung function. At a molecular level, COPSAC has identified novel susceptibility genes, early immune deviations, and metabolomic alterations associated with childhood asthma. Thus, the COPSAC research program has enhanced our understanding of the processes causing childhood asthma and has suggested means of personalized prevention and treatment.

A territory-wide opportunistic, hospital-based HCV screening in the general population from northern Italy: The 1969-1989 birth-cohort.

BACKGROUND AND AIM: The World Health Organization (WHO) goal of Hepatitis C Virus (HCV) elimination by 2030 rose awareness about the need of screening plans, worldwide. In Italy, graduated screening starting from people born in 1969-1989 might be the most-effective strategy. We performed an opportunistic HCV screening study in the general population attending health facilities in Lombardy region, Northern Italy. METHODS: This is a prospective, multicenter, territory-wide, opportunistic study supported by the Regional Government of Lombardy, Italy. Between June 2022 and December 2022, all subjects born in 1969-1989, hospitalized or accessing blood collection centres were offered anti-HCV and HCV-RNA tests. Patients with known anti-HCV positivity and/or previous anti-HCV treatment were excluded. Demographic features were uploaded into a regional web-based platform. RESULTS: In total, 120 193 individuals were screened in 75 centres. Mean age was 44 (±6) years, 65.2% were females, 83.7% were tested at blood collection centres. Anti-HCV tested positive in 604 (0.50%) subjects: mean age 47 (±5), 51.1% females. HCV seroprevalence was higher in males (p < 0.00001), elderly (p < 0.00001) and in- vs. outpatients (p = 0.0009). HCV-RNA was detectable in 125 out of 441 (28.3%) anti-HCV positive subjects. Actively infected patients were 46 (±6) years old, mainly males (56.8%). The overall prevalence of active HCV infection was 0.10%, higher in elderly (p = 0.0003) and in in-patients (p = 0.0007). Among 93 HCV-RNA positive patients, the median age was 48 years, 58% males, 62% Italian born, median HCV-RNA levels were 6,1 log IU/mL, liver stiffness measurement (LSM) values 5.5 (3.1-29.9) kPa and ALT levels 48 U/L. CONCLUSIONS: The prevalence of active HCV infection in the 1969-1989 population attending health facilities in Lombardy was low. Most viremic patients were Italian-born, with mild liver disease but high-HCV-RNA levels. Due to the higher prevalence in the elderly, the extension of such opportunistic screening programs to lower birth cohorts would be warranted.

Understanding progression from pre-school wheezing to school-age asthma: Can modern data approaches help?

Preschool wheezing and childhood asthma create a heavy disease burden which is only exacerbated by the complexity of the conditions. Preschool wheezing exhibits both "curricular" and "aetiological" heterogeneity: that is, heterogeneity across patients both in the time-course of its development and in its underpinning pathological mechanisms. Since these are not fully understood, but clinical presentations across patients may nonetheless be similar, current diagnostic labels are imprecise-not mapping cleanly onto underlying disease mechanisms-and prognoses uncertain. These uncertainties also make a identifying new targets for therapeutic intervention difficult. In the past few decades, carefully designed birth cohort studies have collected "big data" on a large scale, incorporating not only a wealth of longitudinal clinical data, but also detailed information from modalities as varied as imaging, multiomics, and blood biomarkers. The profusion of big data has seen the proliferation of what we term "modern data approaches" (MDAs)-grouping together machine learning, artificial intelligence, and data science-to make sense and make use of this data. In this review, we survey applications of MDAs (with an emphasis on machine learning) in childhood wheeze and asthma, highlighting the extent of their successes in providing tools for prognosis, unpicking the curricular heterogeneity of these conditions, clarifying the limitations of current diagnostic criteria, and indicating directions of research for uncovering the etiology of the diseases underlying these conditions. Specifically, we focus on the trajectories of childhood wheeze phenotypes. Further, we provide an explainer of the nature and potential use of MDAs and emphasize the scope of what we can hope to achieve with them.

Evolution of Eczema, Wheeze, and Rhinitis from Infancy to Early Adulthood: Four Birth Cohort Studies.

Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Occupational differences in mortality and life expectancy persist after retirement and throughout life.

AIMS: There are substantial differences in remaining life expectancy at higher ages between occupational groups. These differences may be the effect of work-related exposures, lifestyle factors of workers in specific occupations, socioeconomic position or a combination of this. The scope of this paper is the extent to which occupational differences in remaining life expectancy persist after retirement, which would suggest that occupational exposures alone are not likely to explain all the difference. METHODS: All individuals born between 1925 and 1939 who reported occupational information in the Census 1985 and were residents in Sweden to the end of 2020 or who died were included and followed for death until 2020. The Nordic Classification of Occupations was used to create nine occupational groups. Partial life expectancy and age-specific death rates were applied to examine mortality differentials. RESULTS: This study showed substantial differences in partial life expectancy across the occupational cohorts with the biggest difference being about 2 years. The mortality differences persisted with increasing age, both when measured as absolute numbers as well as relative numbers. CONCLUSIONS: The lack of convergence in mortality at high ages suggests that factors associated with lifestyle may play a larger role than occupational factors for the mortality differences between occupational groups at high ages. However, it cannot be ruled out that long-lasting effects of earlier occupational exposures also contribute. Regardless of the exact mechanism, we conclude that there is room for further reduction in mortality at high ages and, thus, for further improvement in life expectancy.

Infants were introduced to complementary feeding earlier in 2018 compared with 2003.

AIM: Until 2001, the Swedish advice was to postpone the introduction of eggs, fish and peanuts until the age of 1 year. One reason was to reduce the risk of food allergy. The earlier introduction of complementary feeding is now advised. Our aim was to study adherence to current recommendations and whether the time of introduction changed between 2003 and 2018. METHODS: Data were obtained from two prospective, longitudinal, population-based cohort studies of children born in 2003 (n = 4987) and in 2018 (n = 3936). Parents answered comparable questionnaires when the children were 6 and 12 months old. RESULTS: At 6 months, in the 2018 cohort, eggs were introduced to 67.2% of the infants, fish to 78.9%, gluten to 89.1%, cow's milk to 76.6% and peanuts to 46.2%. In adjusted Cox regression analyses, introduction of complementary feeding with gluten, fish and eggs was made significantly earlier in the 2018 cohort compared with the 2003 cohort, adjusted for heredity, own allergic disease and parental educational level (p < 0.01). CONCLUSION: Complementary feeding with eggs, fish and gluten was introduced earlier in infants born in 2018 compared with 2003, possibly reducing the risk of developing allergic disease. Current recommendations from child welfare centres are being followed.

Psychological distress from early adulthood to early old age: evidence from the 1946, 1958 and 1970 British birth cohorts.

BACKGROUND: Existing evidence on profiles of psychological distress across adulthood uses cross-sectional or longitudinal studies with short observation periods. The objective of this research was to study the profile of psychological distress within the same individuals from early adulthood to early old age across three British birth cohorts. METHODS: We used data from three British birth cohorts: born in 1946 (n = 3093), 1958 (n = 13 250) and 1970 (n = 12 019). The profile of psychological distress - expressed both as probability of being a clinical case or a count of symptoms based on comparable items within and across cohorts - was modelled using the multilevel regression framework. RESULTS: In both 1958 and 1970 cohorts, there was an initial drop in the probability of being a case between ages 23-26 and 33-34. Subsequently, the predicted probability of being a case increased from 12.5% at age 36 to 19.5% at age 53 in the 1946 cohort; from 8.0% at age 33 to 13.7% at age 42 in the 1958 cohort and from 15.7% at age 34 to 19.7% at age 42 in the 1970 cohort. In the 1946 cohort, there was a drop in the probability of caseness between ages 60-64 and 69 (19.5% v. 15.2%). Consistent results were obtained with the continuous version of the outcome. CONCLUSIONS: Across three post-war British birth cohorts midlife appears to be a particularly vulnerable phase for experiencing psychological distress. Understanding the reasons for this will be important for the prevention and management of mental health problems.

Implementation of HCV screening in the 1969-1989 birth-cohort undergoing COVID-19 vaccination.

BACKGROUND AND AIM: The World Health Organization (WHO) goal of hepatitis C virus (HCV) elimination by 2030 relies on the scaling-up of both identification and linkage to care of the infected population, worldwide. In Italy, the estimated burden of HCV carriers who are unaware of their infection amounts to 200 000 persons, a projection that reinforces the need for broadening population access to effective screening programmes. METHODS: A pivotal screening programme targeting subjects born between 1969 and 1989 has been conducted in Lombardy, Northern Italy, where point-of-care (POC) testing was offered for free concomitantly to COVID-19 vaccination. RESULTS: Amongst 7219 subjects born between 1969 and 1989 who underwent HCV screening through POC, 7 (0.10%) subjects tested anti-HCV positive: 5 (0.07%) had confirmed anti-HCV positivity (Table 1) and 4 of them (0.05%) were HCV-RNA positive by standard confirmation tests. CONCLUSIONS: This pivotal study demonstrated the feasibility of a POC-based anti-HCV screening programme in young adults undergoing COVID-19 vaccination. The prevalence of HCV infection in subjects born in the 1969-1989 cohort in Italy seems to be lower than previously estimated. Whether the extension of this programme to subjects born before 1969 could lead to improved screening effectiveness should be a matter of debate.

Prenatal exposure to PM10 and changes in DNA methylation and telomere length in cord blood.

BACKGROUND: Air pollution exposure in pregnancy can cause molecular level alterations that might influence later disease susceptibility. OBJECTIVES: We investigated DNA methylation (DNAm) and telomere length (TL) in the cord blood in relation to gestational PM10 exposure and explored potential gestational windows of susceptibility. METHODS: Cord blood epigenome-wide DNAm (N = 384) and TL (N = 500) were measured in children of the Italian birth cohort Piccolipiù, using the Infinium Methylation EPIC BeadChip and qPCR, respectively. PM10 daily exposure levels, based on maternal residential address, were estimated for different gestational periods using models based on satellite data. Epigenome-wide analysis to identify differentially methylated probes (DMPs) and regions (DMRs) was conducted, followed by a pathway analysis and replication analysis in an second Piccolipiù dataset. Distributed lag models (DLMs) using weekly exposures were used to study the association of PM10 exposure across pregnancy with telomere length, as well as with the DMPs that showed robust associations. RESULTS: Gestational PM10 exposure was associated with the DNA methylation of more than 250 unique DMPs, most of them identified in early gestation, and 1 DMR. Out of 151 DMPs available in the replication dataset, ten DMPs showed robust associations: eight were associated with exposure during early gestation and 2 with exposure during the whole pregnancy. These exposure windows were supported by the DLM analysis. The PM10 exposure between 15th and 20th gestational week seem to be associated with shorter telomeres at birth, while exposure between 24th and 29th was associated with longer telomeres. DISCUSSION: The early pregnancy period is a potential critical window during which PM10 exposure can influence cord blood DNA methylation. The results from the TL analysis were consistent with previous findings and merit further exploration in future studies. The study underlines the importance of considering gestational windows outside of the predefined trimesters that may not always overlap with biologically relevant windows of exposure.

Genetics of Asthma and Allergic Diseases.

Asthma genes have been identified through a range of approaches, from candidate gene association studies and family-based genome-wide linkage analyses to genome-wide association studies (GWAS). The first GWAS of asthma, reported in 2007, identified multiple markers on chromosome 17q21 as associates of the childhood-onset asthma. This remains the best replicated asthma locus to date. However, notwithstanding undeniable successes, genetic studies have produced relatively heterogeneous results with limited replication, and despite considerable promise, genetics of asthma and allergy has, so far, had limited impact on patient care, our understanding of disease mechanisms, and development of novel therapeutic targets. The paucity of precise replication in genetic studies of asthma is partly explained by the existence of numerous gene-environment interactions. Another important issue which is often overlooked is that of time of the assessment of the primary outcome(s) and the relevant environmental exposures. Most large GWASs use the broadest possible definition of asthma to increase the sample size, but the unwanted consequence of this is increased phenotypic heterogeneity, which dilutes effect sizes. One way of addressing this is to precisely define disease subtypes (e.g. by applying novel mathematical approaches to rich phenotypic data) and use these latent subtypes in genetic studies.

Associations between childhood and adulthood socioeconomic position and grip strength at age 46 years: findings from the 1970 British Cohort Study.

BACKGROUND: Muscle weakness is a key criterion for important age-related conditions, including sarcopenia and frailty. Research suggests lower childhood socioeconomic position (SEP) may be associated with muscle weakness in later life but there is little evidence on associations in younger adults closer to peak muscle strength. We aimed to examine relationships between indicators of SEP in childhood and adulthood and grip strength at age 46y. METHODS: We examined 7,617 participants from the 1970 British Cohort Study with grip strength measurements at 46y. We used sex-specific linear regression models to test associations between five different indicators of SEP in childhood and adulthood (paternal occupational class and parental education levels at age 5 and own occupational class and education level at age 46) and maximum grip strength. Models were adjusted for birth weight, BMI in childhood and adulthood, adult height, disability in childhood, leisure-time physical activity in childhood and adulthood, sedentary behaviour in childhood and adulthood, occupational activity and smoking at age 46. RESULTS: Among women, lower SEP in childhood and adulthood was associated with weaker grip strength even after adjustments for covariates. For example, in fully-adjusted models, women whose mothers had no qualifications at age five had mean grip strength 0.99 kg (95% CI: -1.65, -0.33) lower than women whose mothers were educated to degree and higher. Among men, lower levels of father's education and both adult SEP indicators were associated with stronger grip. The association between own occupational class and grip strength deviated from linearity; men in skilled-manual occupations (i.e. the middle occupational group) had stronger grip than men in the highest occupational group (Difference in means: 1.33 kg (0.60, 2.06)) whereas there was no difference in grip strength between the highest and lowest occupational groups. Adjustment for occupational activity largely attenuated these associations. CONCLUSION: Findings highlight the need to identify age and sex-specific interventions across life to tackle inequalities in important age-related conditions related to weakness.

How is the distribution of psychological distress changing over time? Who is driving these changes? Analysis of the 1958 and 1970 British birth cohorts.

AIMS: The main objective of this study was to investigate distributional shifts underlying observed age and cohort differences in mean levels of psychological distress in the 1958 and 1970 British birth cohorts. METHODS: This study used data from the 1958 and 1970 British birth cohorts (n = 24,707). Psychological distress was measured by the Malaise Inventory at ages 23, 33, 42 and 50 in the 1958 cohort and 26, 34, 42 and 46-48 in the 1970 cohort. RESULTS: The shifts in the distribution across age appear to be mainly due to changing proportion of those with moderate symptoms, except for midlife (age 42-50) when we observed polarisation in distress- an increase in proportions of people with no symptoms and multiple symptoms. The elevated levels of distress in the 1970 cohort, compared with the 1958 cohort, appeared to be due to an increase in the proportion of individuals with both moderate and high symptoms. For instance, at age 33/34 42.3% endorsed at least two symptoms in the 1970 cohort vs 24.7% in 1958, resulting in a shift in the entire distribution of distress towards the more severe end of the spectrum. CONCLUSIONS: Our study demonstrates the importance of studying not only mean levels of distress over time, but also the underlying shifts in its distribution. Due to the large dispersion of distress scores at any given measurement occasion, understanding the underlying distribution provides a more complete picture of population trends.