X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes.

BACKGROUND: Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. RESULTS: XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. CONCLUSIONS: We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome's role in regulating gene expression and sex differences in humans.

Genomic, molecular, and cellular divergence of the human brain.

While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological mechanisms that endow human traits as well as associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, in molecular, morphological, and functional features of conserved neural cell types, as well as temporal differences in brain development. Here, we summarize recent data on unique features of the human brain and their complex implications for the study and treatment of brain diseases. We also consider key outstanding questions in the field and discuss the technologies and foundational knowledge that will be required to accelerate understanding of human neurobiology.

Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1+ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.

Astrocytes Regulate Neuronal Network Burst Frequency Through NMDA Receptors in a Species- and Donor-Specific Manner.

Background: Development of synaptic activity is a key neuronal characteristic that relies largely on interactions between neurons and astrocytes. Although astrocytes have known roles in regulating synaptic function and malfunction, the use of human- or donor-specific astrocytes in disease models is still rare. Rodent astrocytes are routinely used to enhance neuronal activity in cell cultures, but less is known about how human astrocytes influence neuronal activity. Methods: We established human induced pluripotent stem cell-derived neuron-astrocyte cocultures and studied their functional development on microelectrode array. We used cell lines from 5 neurotypical control individuals and 3 pairs of monozygotic twins discordant for schizophrenia. A method combining NGN2 overexpression and dual SMAD inhibition was used for neuronal differentiation. The neurons were cocultured with human induced pluripotent stem cell-derived astrocytes differentiated from 6-month-old astrospheres or rat astrocytes. Results: We found that the human induced pluripotent stem cell-derived cocultures developed complex network bursting activity similar to neuronal cocultures with rat astrocytes. However, the effect of NMDA receptors on neuronal network burst frequency (NBF) differed between cocultures containing human or rat astrocytes. By using cocultures derived from patients with schizophrenia and unaffected individuals, we found lowered NBF in the affected cells. We continued by demonstrating how astrocytes from an unaffected individual rescued the lowered NBF in the affected neurons by increasing NMDA receptor activity. Conclusions: Our results indicate that astrocytes participate in the regulation of neuronal NBF through a mechanism that involves NMDA receptors. These findings shed light on the importance of using human and donor-specific astrocytes in disease modeling.

Nerve cell connections called synapses are formed in interaction with astrocytes, the main non-neuronal cell type of the brain. In vitro work commonly uses rodent astrocytes to enhance activity in human-derived neuronal cell cultures, but differences in using rodent versus human astrocytes are not well understood. We found that the electrical activity of nerve cell networks in cultures consisting of human cortical nerve cells and human astrocytes is altered when the astrocytes are from patients with schizophrenia, relative to neurotypical individuals. The effect of human astrocytes on these networks differed from rodent astrocytes, indicating the potential importance of a fully human culture system.

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Pairwise association of key lifestyle factors and risk of solid cancers - A prospective pooled multi-cohort register study.

Smoking, alcohol consumption, obesity, and physical inactivity are key lifestyle risk factors for cancer. Previously these have been mostly examined singly or combined as an index, assuming independent and equivalent effects to cancer risk. The aim of our study was to systematically examine the joint pairwise and interactive effects of these lifestyle factors on the risk of a first solid primary cancer in a multi-cohort prospective setting. We used pooled data from seven Finnish health survey studies during 1972-2015, with 197,551 participants diagnosed with 16,373 solid malignant primary tumors during follow-up. Incidence of any cancer was analyzed separately without and with lung cancers using Poisson regression with main and interaction effects of key lifestyle factors. When excluding lung cancer, the highest risk of any cancer in men was observed for smokers with a BMI of ≥25 kg/m2 (HR 1.36, 95 % CI 1.25-1.48) and in women for smokers consuming alcohol (HR 1.22, 1.14-1.30). No statistically significant interactions between any studied risk factor pairs were observed. When including lung cancer, the highest HRs among men were observed for smokers who consume alcohol (HR 1.72, 1.57-1.89) and among women for smokers who were physically inactive (HR 1.38, 1.27-1.49). Smoking combined with other lifestyle factors at any exposure level resulted in highest pairwise risks, both in men and women. These results highlight the importance of smoking prevention, but also the importance of preventing obesity and reducing alcohol consumption.

Trajectories of hospitalizations after age-based statutory retirement.

Retirement years are ideally spent in good health. We aimed to produce new information using person-oriented methods by identifying groups of statutory retirees who did or did not achieve this objective and the factors that distinguish these groups from each other. Our particular focus was on the years directly after the transition into retirement, and the pre-retirement factors that explained the development of health, using a more severe health-related outcome-hospitalization. We studied the retirement, hospitalizations, education, and work characteristics of former employees of the City of Helsinki, Finland (N = 6569), from complete registers. We used group-based trajectory models and identified groups of constant low, constant high, decreasing, and temporarily occurring hospitalizations, and one group of increasing hospitalizations among women and two groups of earlier and later increasing hospitalizations among men. Multinomial regression models showed that among women, belonging to groups with less favourable health was associated with secondary education, older age at retirement, and reduced working hours. Education and work characteristics before retirement both contribute to the development of health, as indicated by hospitalizations directly after retirement. Our findings show that socioeconomic inequalities in health are persistent and should also be addressed after transition into retirement.

Trajectories of CVD medication after statutory retirement: contributions of pre-retirement sociodemographic, work and health-related factors: a register study in Finland.

BACKGROUND: Cardiovascular diseases (CVDs) are prevalent in older people, but few studies focus on developmental patterns in CVD medication directly after transition to statutory retirement. We thus aimed to identify trajectories of CVD medication after retirement, and their sociodemographic, work and health-related determinants. METHODS: We used complete register data of former employees of the City of Helsinki, Finland. All who reached their statutory retirement in 2000-2013, with five-year follow-up data (n = 6,505, 73% women), were included. Trajectories of CVD medication were identified with group-based trajectory modelling using data from Finnish Social Insurance Institution's reimbursement register. Sociodemographic, work and health-related determinants of trajectory group membership were analysed using multinomial logistic regression. RESULTS: Six trajectories of CVD medication were distinguished: "constant low" (35%), "late increase" (6%), "early increase" (5%), "constant high" (39%), "high and decreasing " (8%), and "low and decreasing" (7%). The majority (74%) of the retirees fell into the "constant low" and "constant high" categories. Lower occupational class and increased pre-retirement sickness absence were associated with the "constant high" trajectory. Further, those with lower educational attainment were more prone to be in the "early increase" trajectory. CONCLUSIONS: Individuals in lower socioeconomic positions or with a higher number of pre-retirement sickness absence may be considered at higher risk and might benefit from early interventions, e.g. lifestyle interventions and interventions targeting working conditions, or more frequent monitoring.

Robust induction of functional astrocytes using NGN2 expression in human pluripotent stem cells.

Emerging evidence of species divergent features of astrocytes coupled with the relative inaccessibility of human brain tissue underscore the utility of human pluripotent stem cell (hPSC) technologies for the generation and study of human astrocytes. However, existing approaches for hPSC-astrocyte generation are typically lengthy or require intermediate purification steps. Here, we establish a rapid and highly scalable method for generating functional human induced astrocytes (hiAs). These hiAs express canonical astrocyte markers, respond to pro-inflammatory stimuli, exhibit ATP-induced calcium transients and support neuronal network development. Moreover, single-cell transcriptomic analyses reveal the generation of highly reproducible cell populations across individual donors, mostly resembling human fetal astrocytes. Finally, hiAs generated from a trisomy 21 disease model identify expected alterations in cell-cell adhesion and synaptic signaling, supporting their utility for disease modeling applications. Thus, hiAs provide a valuable and practical resource for the study of basic human astrocyte function and dysfunction in disease.

Long-term sickness absence trajectories among ageing municipal employees - the contribution of social and health-related factors.

BACKGROUND: The ageing work force is heterogeneous, following distinct development in work ability. This study aims to identify trajectories of long-term sickness absence (SA) in later careers and to examine potentially modifiable factors associated with the development of SA. METHODS: Data comprised of municipal employees of the city of Helsinki aged 50-60 years during 2004-2018 (N = 4729, 80% women). The developmental trajectories of long-term (> 10 working days) SA were examined with Group-based trajectory modelling (GBTM) using SA records of the Social Insurance Institution of Finland during 2004-2018. All-cause and diagnosis-specific (mental disorder- and musculoskeletal disease-related) SA days were analysed. The association of social and health-related factors with trajectory membership was examined using multinomial logistic regression (odds ratios and 95% confidence intervals). RESULTS: A model with three trajectories was selected for both all-cause and diagnosis-specific SA. Regarding all-cause long-term SA trajectories, 42% had no long-term SA, 46% had low levels of SA, and 12% had a high rate of SA during follow-up. Lower occupational class, reporting smoking, overweight or obesity, moderate or low leisure-time physical activity, and sleep problems were associated with a higher likelihood of belonging to the trajectory with a high rate of SA in both all-cause and diagnosis-specific models. CONCLUSIONS: Most ageing employees have no or little long-term SA. Modifiable factors associated with trajectories with more SA could be targeted when designing and timing interventions in occupational healthcare.

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase.

2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We found that a small fraction of human induced pluripotent stem cell (iPSC)-derived neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), despite very low levels of its expression in neurons. The presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout infected cells, and an increase in the level of viral RNA in the culture medium (viral release) within the first 48 h of infection suggested that the infection was productive. Productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of the viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface spike protein, which can occur at the plasma membrane or from endosomes or lysosomes. We found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases, including transmembrane serine protease 2 (TMPRSS2). Inhibition of cathepsin L also did not significantly block infection. In contrast, the neuronal infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K), which regulates early to late endosome maturation. IMPORTANCE COVID-19 is a disease caused by the coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures, and encephalopathy, as well as anatomical abnormalities, such as changes in brain morphology. SARS-CoV-2 infection of the human brain has been documented, but it is unclear whether the observed neurological symptoms are linked to direct brain infection. The mechanism of virus entry into neurons has also not been characterized. Here, we investigated SARS-CoV-2 infection by using a human iPSC-derived neural cell model and found that a small fraction of cortical-like neurons was naturally susceptible to infection. The productive infection was ACE2 dependent and TMPRSS2 independent. We also found that the virus used the late endosomal and lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of cellular PIK5K.

Trajectories in physical functioning by occupational class among retiring women: the significance of type of retirement and social and health-related factors.

BACKGROUND: Occupational class inequalities in physical functioning and their changes after retirement are poorly understood. We examined occupational class trajectories in physical functioning 10 years before and after transition to old-age and disability retirement. We included working conditions and behavioural risk factors as covariates, given their established link to health and retirement. METHODS: We used the Helsinki Health Study cohort data from surveys 2000-2002 to 2017, and included 3901 women, who were employed by the City of Helsinki, Finland, and retired during the follow-up. Mixed-effect growth curve models were used to examine changes in RAND-36 Physical Functioning subscale (range 0-100) 10 years before and after the retirement date by occupational class. RESULTS: Old-age (n=3073) and disability retirees (n=828) lacked class differences in physical functioning 10 years before retirement. By retirement transition, physical functioning declined and class inequalities emerged, the predicted scores being 86.1 (95% CI 85.2 to 86.9) for higher class and 82.2 (95% CI 81.5 to 83.0) for lower class old-age retirees, and 70.3 (95% CI 67.8 to 72.9) for higher class and 62.2 (95% CI 60.4 to 63.9) for lower class disability retirees. Physical functioning declined and class inequalities slightly widened among old-age retirees after the retirement, whereas among disability retirees the decline plateaued and class inequalities narrowed over time after retirement. Physical work and body mass index somewhat attenuated the class inequalities after adjustment. CONCLUSIONS: Class inequalities in physical functioning widened after old-age retirement and narrowed after disability retirement. The examined work and health-related factors contributed weakly to the inequalities.

Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages.

Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular and cellular mechanisms will require scalable approaches. Here, we describe a "cell village" experimental platform we used to analyze genetic, molecular, and phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors. Through rapid induction of human stem cell-derived neural progenitor cells, measurements of natural genetic variation, and CRISPR-Cas9 genetic perturbations, we identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus. We also detected expression QTLs corresponding to GWAS loci for brain traits and discovered novel disease-relevant regulators of progenitor proliferation and differentiation such as CACHD1. This approach provides scalable ways to elucidate the effects of genes and genetic variation on cellular phenotypes.

Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons.

The maturation of neurons and the development of synapses, although emblematic of neurons, also relies on interactions with astrocytes and other glia. Here, to study the role of glia-neuron interactions, we analyze the transcriptomes of human pluripotent stem cell (hPSC)-derived neurons, from 80 human donors, that were cultured with or without contact with glial cells. We find that the presence of astrocytes enhances synaptic gene-expression programs in neurons when in physical contact with astrocytes. These changes in neurons correlate with increased expression, in the cocultured glia, of genes that encode synaptic cell adhesion molecules. Both the neuronal and astrocyte gene-expression programs are enriched for genes associated with schizophrenia risk. Our results suggest that astrocyte-expressed genes with synaptic functions are associated with stronger expression of synaptic genetic programs in neurons, and they suggest a potential role for astrocyte-neuron interactions in schizophrenia.

Efficient generation of lower induced motor neurons by coupling Ngn2 expression with developmental cues.

Human pluripotent stem cells (hPSCs) are a powerful tool for disease modeling of hard-to-access tissues (such as the brain). Current protocols either direct neuronal differentiation with small molecules or use transcription-factor-mediated programming. In this study, we couple overexpression of transcription factor Neurogenin2 (Ngn2) with small molecule patterning to differentiate hPSCs into lower induced motor neurons (liMoNes/liMNs). This approach induces canonical MN markers including MN-specific Hb9/MNX1 in more than 95% of cells. liMNs resemble bona fide hPSC-derived MN, exhibit spontaneous electrical activity, express synaptic markers, and can contact muscle cells in vitro. Pooled, multiplexed single-cell RNA sequencing on 50 hPSC lines reveals reproducible populations of distinct subtypes of cervical and brachial MNs that resemble their in vivo, embryonic counterparts. Combining small molecule patterning with Ngn2 overexpression facilitates high-yield, reproducible production of disease-relevant MN subtypes, which is fundamental in propelling our knowledge of MN biology and its disruption in disease.

Life-course socioeconomic circumstances in acute, chronic and disabling pain among young employees: a double suffering.

BACKGROUND: Pain is known to be socioeconomically patterned and associated with disability. However, knowledge is scarce concerning life-course socioeconomic circumstances and pain among young adults. Our aim was to examine the associations of childhood and current socioeconomic circumstances with acute pain and chronic pain with low and high disability levels among young Finnish municipal employees. METHODS: We analysed questionnaire data retrieved from the Young Helsinki Health Study (n=4683) covering 18-39-year-old employees of the City of Helsinki, Finland. We included multiple indicators of childhood and current socioeconomic circumstances and examined their associations with acute pain and with chronic pain with low and high disability levels. The level of chronic pain-related disability was assessed by the chronic pain grade questionnaire. Multinomial logistic regression analyses were conducted with stepwise adjustments for sociodemographic, socioeconomic and health-related covariates. RESULTS: Childhood and current socioeconomic disadvantage were associated with acute and chronic pain, particularly with chronic pain with high disability level. The strongest associations after adjustments for covariates remained between chronic pain with high disability level and low educational level (odds ratio (OR) 3.38, 95% confidence interval (CI) 2.18-5.24), manual occupation (OR 3.75, 95% CI 1.92-7.34) and experiencing frequent economic difficulties (OR 3.07, 95% CI 2.00-4.70). CONCLUSIONS: Pain is a common complaint that contributes to disability among young employees, particularly the most socioeconomically vulnerable. There is a socioeconomic gradient in both pain chronicity and the level of chronic pain-related disability. Life-course socioeconomic factors should be considered in pain-preventing strategies and in clinical practice.

Associations between low parental education, childhood adversities and sickness absence in midlife public sector employees.

AIMS: Parental education and childhood adversities are associated with long-term work disability but their contribution to sickness absence is largely unknown. We aimed to examine the associations between parental education, childhood adversities and self-certified and medically-certified sickness absence among midlife employees. METHODS: The Helsinki Health Study baseline survey data (2000-2002) of 40-to-60-year-old municipal employees were linked with sickness absence data from the employer's register. Self-certified (1-3 days) and medically-certified (>3 days) sickness absence spells were followed from 2003 until the end of 2008. The study included 5728 employees. The analyses were made by Poisson regression and the results are presented as rate ratios (RRs) and their 95% confidence intervals (CIs). RESULTS: Low maternal education was associated with self-certified sickness absence (RR 1.32, 95% CI 1.13-1.55) among women only whereas both low maternal (1.49, 1.26-1.77) and low paternal education (1.48, 1.32-1.67) were associated with medically-certified sickness absence. Adjustment for own occupational class mainly abolished these associations. Having experienced any childhood adversity was associated with self-certified (1.18, 1.12-1.25) and medically-certified (1.22, 1.15-1.30) sickness absence. In addition, childhood economic difficulties, childhood illness, parental divorce, parental mental illness, parental alcohol problems and bullying were each associated both with self-certified and with medically-certified sickness absence. The associations mainly remained after adjustments for occupational class, marital status, working condition, body mass index and health behaviours. CONCLUSIONS: Low parental education and childhood adversities contributed to midlife sickness absence. Promoting well-being of families with children might help sustain adult work ability and prevent sickness absence still in midlife.

Changes in occupational class differences in leisure-time physical activity and the contribution of retirement.

Occupational class differences in leisure-time physical activity (LTPA) are well recognized. Less is known about how these differences develop as individuals age, and how retirement is associated with this change. We investigated how occupational class differences in LTPA change in a cohort over a 15-17 years follow-up. We further examined, how the transition into mandatory or disability retirement contributed to the change in LTPA levels and occupational class differences. We used the data from the Helsinki Health Study surveying the aging City of Helsinki employees. In all, 8773 individuals were included in the analyses. We evaluated LTPA levels using weekly metabolic equivalent task (MET) hours and used generalized linear mixed effect models (GLMM) to estimate the development of LTPA levels. Commuting was included in the LTPA measure. Occupational class differences in LTPA emerged and widened during the follow-up. The physical activity levels decreased in the lower occupational class and slightly increased in the higher occupational class, resulting in a difference of 4.3 MET-hours at the end of follow-up, accounting for 50 min of brisk walking per week. The occupational class differences emerged during transition into mandatory retirement and persisted after this. Transition into disability retirement temporarily widened the occupational class differences in LTPA levels, but the differences diminished during the follow-up. Research on interventions to counteract the declining LTPA is needed to discover ways to prevent the widening of occupational health disparities during aging. The transition into old-age retirement could be an optimal period for focusing these interventions.

Association of alcohol use with years lived without major chronic diseases: A multicohort study from the IPD-Work consortium and UK Biobank.

Background: Heavy alcohol consumption increases the risk of several chronic diseases. In this multicohort study, we estimated the number of life-years without major chronic diseases according to different characteristics of alcohol use. Methods: In primary analysis, we pooled individual-level data from up to 129,942 adults across 12 cohort studies with baseline data collection on alcohol consumption, drinking patterns, and history between 1986 and 2005 (the IPD-Work Consortium). Self-reported alcohol consumption was categorised according to UK guidelines - non-drinking (never or former drinkers); moderate consumption (1-14 units); heavy consumption (>14 units per week). We further subdivided moderate and heavy drinkers by binge drinking pattern (alcohol-induced loss of consciousness). In addition, we assessed problem drinking using linked data on hospitalisations due to alcohol abuse or poisoning. Follow-up for chronic diseases for all participants included incident type 2 diabetes, coronary heart disease, stroke, cancer, and respiratory disease (asthma and chronic obstructive pulmonary disease) as ascertained via linkage to national morbidity and mortality registries, repeated medical examinations, and/or self-report. We estimated years lived without any of these diseases between 40 and 75 years of age according to sex and characteristics of alcohol use. We repeated the main analyses using data from 427,621 participants in the UK Biobank cohort study. Findings: During 1·73 million person-years at risk, 22,676 participants in IPD-Work cohorts developed at least one chronic condition. From age 40 to 75 years, never-drinkers [men: 29·3 (95%CI 27·9-30·8) years, women 29·8 (29·2-30·4) years)] and moderate drinkers with no binge drinking habit [men 28·7 (28·4-29·0) years, women 29·6 (29·4-29·7) years] had the longest disease-free life span. A much shorter disease-free life span was apparent in participants who experienced alcohol poisoning [men 23·4 (20·9-26·0) years, women 24·0 (21·4-26·5) years] and those with self-reported heavy overall consumption and binge drinking [men: 26·0 (25·3-26·8), women 27·5 (26·4-28·5) years]. The pattern of results for alcohol poisoning and self-reported alcohol consumption was similar in UK Biobank. In IPD-Work and UK Biobank, differences in disease-free years between self-reported moderate drinkers and heavy drinkers were 1·5 years or less. Interpretation: Individuals with alcohol poisonings or heavy self-reported overall consumption combined with a binge drinking habit have a marked 3- to 6-year loss in healthy longevity. Differences in disease-free life between categories of self-reported weekly alcohol consumption were smaller. Funding: Medical Research Council, National Institute on Aging, NordForsk, Academy of Finland, Finnish Work Environment Fund.