Tobacco endgame measures and their adaptation in selected European countries: A narrative review synthesis.

Due to the continued detrimental effects of tobacco use, a growing number of countries are embracing the idea of tobacco endgame, meaning ending the tobacco epidemic instead of controlling it. This narrative review aims to synthesize and update the evidence from earlier scientific reviews on effective tobacco endgame measures, as well as to assess their integration to current national strategies among European countries with official tobacco endgame goals. The synthesis of the prior scientific literature found most evidence on product-focused and some evidence for supply-focused policies. Little evidence was detected for user- and institutional-focused measures. An update for the tobacco-free generation measure showed uncertainty in reducing smoking prevalence, especially for adolescents' reactions to age-restrictive laws. All the countries that established a tobacco endgame strategy have included product standards in their measures, predominantly based on European Union regulations on conventional tobacco products, yet standards above this level and considering other products were also common. Cessation measures were given strong emphasis in strategies, yet none of the countries linked these to specific endgame measures. Despite commonly mentioning vulnerable groups, such as youth and pregnant women, adoption of measures to reduce tobacco use among these groups was scarce. Lastly, the decline in tobacco use seems to be modest, implying challenges in meeting the endgame goals. To meet these goals, European countries should reinforce the implementation of known effective tobacco control measures such as tax increases. Furthermore, new innovative strategies and measures to meet the objective of an endgame should be explored.

SCGB1D2 inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease.

Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Using epidemiological and genetic data from FinnGen and Estonian Biobank, we identify two previously known variants and an unknown common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. Using live Borrelia burgdorferi (Bb) we find that recombinant reference SCGB1D2 protein inhibits the growth of Bb in vitro more efficiently than the recombinant protein with SCGB1D2 P53L deleterious missense variant. Finally, using an in vivo murine infection model we show that recombinant SCGB1D2 prevents infection by Borrelia in vivo. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection and opens an exciting therapeutic avenue for Lyme disease.

Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defects.

BACKGROUND: Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database. RESULTS: We discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327. CONCLUSIONS: Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

Nightmares share genetic risk factors with sleep and psychiatric traits.

Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to examine the genetic risk factors for nightmares and estimate correlation or causality between nightmares and comorbidities. We performed a genome-wide association study (GWAS) in 45,255 individuals using a questionnaire-based assessment on the frequency of nightmares during the past month and genome-wide genotyping data. While the GWAS did not reveal individual risk variants, heritability was estimated at 5%. In addition, the genetic correlation analysis showed a robust correlation (rg > 0.4) of nightmares with anxiety (rg = 0.671, p = 7.507e-06), depressive (rg = 0.562, p = 1.282e-07) and posttraumatic stress disorders (rg = 0.4083, p = 0.0152), and personality trait neuroticism (rg = 0.667, p = 4.516e-07). Furthermore, Mendelian randomization suggested causality from insomnia to nightmares (beta = 0.027, p = 0.0002). Our findings suggest that nightmares share genetic background with psychiatric traits and that insomnia may increase an individual's liability to experience frequent nightmares. Given the significant correlations with psychiatric and psychological traits, it is essential to grow awareness of how nightmares affect health and disease and systematically collect information about nightmares, especially from clinical samples and larger cohorts.

An immunogenetic basis for lung cancer risk.

Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.

Genetic Analysis of Obstructive Sleep Apnea and Its Relationship with Severe COVID-19.

RATIONALE: While patients with obstructive sleep apnea (OSA) have a higher risk for COVID-19 hospitalization, the causal relationship has remained unexplored. OBJECTIVES: To understand the causal relationship between OSA and COVID-19 leveraging data from vaccination and electronic health records, genetic risk factors from genome-wide association studies (GWAS) and Mendelian randomization. METHODS: We elucidated genetic risk factors for OSA using FinnGen (N total = 377,277 individuals) performing genome-wide association. We used the associated variants as instruments for univariate and multivariate Mendelian randomization (MR) analyses and computed absolute risk reduction (ARR) against COVID-19 hospitalization with or without vaccination. MEASUREMENTS AND MAIN RESULTS: We identified 9 novel loci for OSA and replicated our findings in the Million Veterans Program. Furthermore, MR analysis showed that OSA was a causal risk factor for severe COVID-19 (P=9.41x10-4). Probabilistic modelling showed that the strongest genetic risk factor for OSA at the FTO locus reflected a signal of higher BMI, whereas BMI independent association was seen with the earlier reported SLC9A4 locus and a MECOM locus which is a transcriptional regulator with 210-fold enrichment in the Finnish population. Similarly, Multivariate MR (MVMR) analysis showed that the causality for severe COVID-19 was driven by body mass index (BMI), (P MVMR = 5.97x10-6, beta=0.47). Finally, vaccination reduced the risk for COVID-19 hospitalization more in the OSA patients than in the non-OSA controls: ARR = 13.3% vs. ARR = 6.3% in the OSA vs. non-OSA population. CONCLUSIONS: Our analysis identified novel genetic risk factors for OSA and showed that OSA is a causal risk factor for severe COVID-19. The effect is predominantly explained by higher BMI and suggests BMI-dependent effects at the level of individual variants and at the level of comorbid causality.

Cross-sectional study of the associations between the implementation of the WHO FCTC tobacco advertising, promotion and sponsorship bans and current e-cigarette use among youth from countries with different income levels.

BACKGROUND: The WHO Framework Convention on Tobacco Control (WHO FCTC) Article 13 requires countries to ban tobacco advertising, promotion and sponsorship (TAPS), and bans are recommended to cover electronic cigarettes (e-cigarettes). We examined youth e-cigarette prevalence by TAPS regulations in countries with different income levels. METHODS: We analysed data on 165 299 respondents from 48 countries with 2016/2018 WHO FCTC implementation reports and 2016-2019 Global Youth Tobacco Survey. We used multilevel logistic regressions to examine associations between TAPS regulations and current e-cigarette use, stratified by country income. RESULTS: About 1 in 10 respondents was currently using e-cigarettes. Respondents in countries with TAPS bans on the internet were less likely to use e-cigarettes (adjOR=0.58; 95% CI 0.39 to 0.86) than youth in countries without such bans. In lower middle-income and low-income countries, bans on displaying tobacco products at the point of sale (adjOR=0.55; 95% CI 0.34 to 0.90), bans on product placement (adjOR=0.44; 95% CI 0.28 to 0.69) and strength of additional TAPS measures were associated with lower prevalence of e-cigarette use among students. Being taught about the dangers of the use of tobacco in school was associated with lower odds of e-cigarette use. No differences in the use of e-cigarettes were observed by types of TAPS among respondents in high-income countries. CONCLUSIONS: Strengthening implementation of TAPS policies and assuring they cover new and emerging products, online channels and points of sales are essential, especially in lower income countries. Maintaining tobacco health education is also important to protect youth from e-cigarette use.

Have there been changes in daily smoking and cigarette consumption among adolescents? Investigation between 1999 and 2019 among Finnish adolescents.

BACKGROUND AND AIMS: It is postulated that due to decreased smoking rates and increased denormalisation of smoking, those who start and maintain smoking have more socially disadvantaged characteristics and are more dependent on nicotine than those who do not (the so-called 'hardening' hypothesis). The aim of this study was to measure changes in daily smoking and cigarette consumption among Finnish adolescents according to background factors. DESIGN AND SETTING: A repeated cross-sectional study using data from European School Survey Project on Alcohol and other Drugs (ESPAD) on six representative cross-sections of 15- to 16-year-old students between 1999 and 2019 in Finland. PARTICIPANTS: A total of 11 377 males and 12 247 females. MEASUREMENTS: The outcome measures included the proportion of daily smokers among current smokers, daily smoking and the estimated mean number of smoked cigarettes per day (CPD). Substance use, parental monitoring and school performance were used as independent variables. All measures were self-reported. FINDINGS: Daily smoking decreased over time and daily smokers constituted a smaller part of current smokers in 2019 compared with 1999 (the ratio among boys 0.68 and 0.43, respectively; among girls 0.59 and 0.43). Boys using cannabis (interaction between cannabis*survey year: P = 0.020; in 2019 odds ratio [OR]: 3.68, 95% confidence interval [CI] 2.23-6.08) and girls with heavy episodic drinking (interaction between heavy episodic drinking*survey year: P = 0.006, in 2019 OR: 9.00, 95% CI 5.61-14.42) had elevated adjusted odds for daily smoking over time. The estimated mean number of CPD decreased among daily smokers from 9.0 in 1999 to 7.2 in 2019 (P = 0.0002) and the differences diminished between groups based on gender, snus/alcohol use and parental monitoring. The between-group differences remained with regard to cannabis use (P = 0.0233 in 2019) and school performance (P = 0.0111 in 2019). CONCLUSIONS: Among currently smoking Finnish adolescents, the proportion of daily smokers decreased between 1999 and 2019, as did the number of cigarettes smoked per day (CPD) among daily smokers, suggesting an absence of 'hardening' in this group. However, differences were observed related to the odds of daily smoking and the mean number of CPD, indicating the change has been less favorable among some adolescent groups than others.

Genetics of sleep medication purchases suggests causality from sleep problems to psychiatric traits.

STUDY OBJECTIVES: Over 10% of the population in Europe and in the United States use sleep medication to manage sleep problems. Our objective was to elucidate genetic risk factors and clinical correlates that contribute to sleep medication purchase and estimate the comorbid impact of sleep problems. METHODS: We performed epidemiological analysis for psychiatric diagnoses, and genetic association studies of sleep medication purchase in 797 714 individuals from FinnGen Release 7 (N = 311 892) and from the UK Biobank (N = 485 822). Post-association analyses included genetic correlation, co-localization, Mendelian randomization (MR), and polygenic risk estimation. RESULTS: In a GWAS we identified 27 genetic loci significantly associated with sleep medication, located in genes associated with sleep; AUTS2, CACNA1C, MEIS1, KIRREL3, PAX8, GABRA2, psychiatric traits; CACNA1C, HIST1H2BD, NUDT12. TOPAZ1 and TSNARE1. Co-localization and expression analysis emphasized effects on the KPNA2, GABRA2, and CACNA1C expression in the brain. Sleep medications use was epidemiologically related to psychiatric traits in FinnGen (OR [95% (CI)] = 3.86 [3.78 to 3.94], p < 2 × 10-16), and the association was accentuated by genetic correlation and MR; depression (rg = 0.55 (0.027), p = 2.86 × 10-89, p MR = 4.5 × 10-5), schizophrenia (rg = 0.25 (0.026), p = 2.52 × 10-21, p MR = 2 × 10-4), and anxiety (rg = 0.44 (0.047), p = 2.88 × 10-27, p MR = 8.6 × 10-12). CONCLUSIONS: These results demonstrate the genetics behind sleep problems and the association between sleep problems and psychiatric traits. Our results highlight the scientific basis for sleep management in treating the impact of psychiatric diseases.

Implementation of the Article 13 WHO FCTC measures and changes in cigarette smoking among youth in 42 countries.

INTRODUCTION: Despite a decline in global smoking prevalence among adolescents, around 21 million youth report current cigarette smoking. Exposure to tobacco advertising, promotion and sponsorship (TAPS) is a risk factor for smoking initiation, and therefore the Article 13 of the WHO Framework Convention on Tobacco Control (WHO FCTC) requires comprehensive TAPS bans. We examined the associations between changes in youth cigarette smoking and implementation of Article 13. METHODS: We used two rounds of cross-sectional data from the Global Youth Tobacco Survey (GYTS) for 42 countries: first between 2006 and 2015, and second between 2017 and 2020. The GYTS data were linked with the WHO FCTC implementation reports from 2016 and 2018. The outcome was current smoking. Multilevel binary logistic regression models, stratified by country income level, were used to test the prevalence differences between the latest and previous GYTS rounds and their associations with TAPS bans with postestimations using marginal analyses. RESULTS: The percentage of students currently smoking decreased from 10.0% (95% CI 8.0 to 12.1) to 7.7% (95% CI 6.1 to 9.3) from first to second GYTS rounds (p<0.001), adjusting for country clustering. In low-income and lower-middle-income countries, the degree of decrease significantly differed between countries with versus without bans on display, partial internet TAPS ban, ban on depiction of tobacco products and by number of TAPS measures, adjusting for age and sex of the respondents. In high-income and upper-middle-income countries, the degree of decrease significantly differed by presence (or absence) of partial or full internet TAPS ban, ban on product placement and by number of TAPS measures. CONCLUSION: Implementation of TAPS bans is associated with decreased smoking among adolescents both in high-income and low-income countries. Enhanced and continuous efforts are necessary to protect youth from the promotion of tobacco and nicotine products.

Causal Association Between Subtypes of Excessive Daytime Sleepiness and Risk of Cardiovascular Diseases.

BACKGROUND: Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. METHODS AND RESULTS: We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6-9 hours), short (<6 hours), and long (>9 hours), and compared these with a nonsleepy, normal-sleep-duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2-sample Mendelian randomization for each outcome. Compared with healthy sleep, long-sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21-2.77]) during 8.2-year median follow-up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long-sleep EDS subtype in MI (inverse-variance weighted ß=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). CONCLUSIONS: Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long-sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.

Associations between sleep medication use and alcohol consumption over 36 years in Finnish twins.

BACKGROUND: Sleep medication use is an indicator of underlying sleep problems that might be induced by various factors such as alcohol use. However, the longitudinal relationship between drinking and sleep problems remains poorly understood. We investigated associations between sleep medication and alcohol use throughout adulthood, and examined the role of familial and potential confounding factors contributing to these associations. METHODS: We used information of zygosity and self-report questionnaire data over a follow-up period of 36 years from the Older Finnish Twin Cohort (N=13,851). RESULTS: Logistic regression analyses suggested consistent associations between sleep medication use and heavy/binge drinking at all four time points (OR range =1.36-3.18, P <0.05), implying that increased drinking is associated with increased sleep medication use over time. Cross-lagged path analyses suggested that moderate/heavy and binge drinking predict sleep medication use at most time points (OR range = 1.15-1.94, P <0.05), whilst sleep medication use predicts subsequent abstaining from alcohol (OR range =2.26-2.47, P <0.05). Within-pair analyses implied that familial factors play a role, and quantitative genetic modelling estimated genetic factors to explain approximately 80% of the lifetime association of sleep medication use with moderate/heavy and binge drinking. CONCLUSIONS: Drinking is associated with sleep medication use throughout adulthood. Further, our results suggest that drinking is likely to predict sleep medication use, thereby potentially constituting a risk factor for sleep problems, and that genetic factors contribute to the association. These findings are important in terms of better understanding the development of sleep and alcohol use disorders.

SIRPα controls CD47-dependent platelet clearance in mice and humans.

Over the last decade, more data has revealed that increased surface expression of the "don't eat me" CD47 protein on cancer cells plays a role in immune evasion and tumor progression, with CD47 blockade emerging as a new therapy in immuno-oncology. CD47 is critical in regulating cell homeostasis and clearance, as binding of CD47 to the inhibitory receptor SIRPα can prevent phagocytosis and macrophage-mediated cell clearance. The purpose of this study was to examine the role of the CD47-SIRPα signal in platelet homeostasis and clearance. Therapeutic reagents targeting the CD47-SIRPα axis are very promising for treatment of hematologic malignancies and solid tumors, but lead to transient anemia or thrombocytopenia in a subset of patients. We found that platelet homeostatic clearance is regulated through the CD47-SIRPα axis and that therapeutic blockade to disrupt this interaction in mice and in humans has a significant impact on platelet levels. Furthermore, we identified genetic variations at the SIRPA locus that impact platelet levels in humans such that higher SIRPA gene expression is associated with higher platelet levels. SIRPA expression at either end of the normal range may affect clinical outcomes of treatment with anti-CD47 therapy.

Tobacco endgame in the WHO European Region: Feasibility in light of current tobacco control status.

INTRODUCTION: To assess the feasibility of developing World Health Organization (WHO) European Region countries' goals and measures in line with tobacco endgame objectives, information on the current tobacco control context and capacity is needed. The aim of this study was to assess the implementation of the Framework Convention on Tobacco Control (WHO FCTC) and MPOWER measures in the region. METHODS: In this cross-sectional study we used data from the WHO FCTC implementation reports and MPOWER from 2020 in 53 WHO European Region countries. Six domains (i.e. capacity, taxation and price policies, other national key regulations, public awareness raising and communication, tobacco use cessation, and monitoring) were formed. Subsequently, available indicators under these domains were scored and the level of implementation was computed for each country. Mann-Whitney tests were carried out to compare the scores between the group of countries with and without official endgame goals. RESULTS: Overall, implementation of the WHO FCTC with the selected indicators at the country level ranged from 28% to 86%, and of MPOWER from 31% to 96%. Full implementation was achieved by 28% of WHO FCTC Parties in the region in taxation and price policies, 12% in public awareness raising and communication, and 42% in monitoring. In capacity, tobacco use cessation and other national key regulations, none of the Parties in the region reached full implementation. Overall median WHO FCTC scores were significantly higher in countries with official endgame goals than in those without (p<0.001). CONCLUSIONS: There is unequal implementation of both WHO FCTC and MPOWER measures among WHO European Region countries. MPOWER and WHO FCTC provide all the measures for the necessary first steps, followed by innovative measures, to accomplish tobacco endgame goals.

BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep.

Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.

Changes in smoking due to COVID-19 pandemic among persons of migrant origin compared with the general population: a population-based study.

AIMS: Prior studies have implied that smokers may have changed their smoking behaviour during the COVID-19 pandemic. However, little is known about changes in smoking behaviour and correlates of change due to the pandemic among persons of migrant origin compared with the general population. METHODS: Population-based cross-sectional studies with comparable study protocols and measures, one focusing on persons of migrant origin living in Finland (n = 3587, response rate 60%) and the other on the general Finnish population (n = 3444, response rate 56%), were utilised. The outcome measure was self-reported change in smoking behaviour due to COVID-19 among current smokers. Explanatory factors included sociodemographic-, health-, and COVID-19-related factors. Multinomial logistic regression was used in the analyses. RESULTS: Most of the current smokers reported no change in their smoking behaviour. In the adjusted model, younger age was positively associated with increased smoking, while region of origin (Russia, Africa, Asia, and Latin America) and worrying about getting infected with COVID-19 were associated with decreased smoking among persons of migrant origin. In the general population, younger age, female sex, being other than employed/student, increased loneliness, and decreased contact with close ones were associated with increased smoking, while reduced working capacity and worries that someone close to the respondent will be infected with COVID-19 were associated with decreased smoking. CONCLUSIONS: The findings of this study contribute to better identification of at-risk populations in future crises situations. This will allow for more efficient targeting and tailoring of health promotion services, including smoking cessation.

Changes in prevalence and sociodemographic correlates of tobacco and nicotine use in Finland during the COVID-19 pandemic.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on tobacco and nicotine use remains debated. We examined whether the prevalence of tobacco and nicotine use and nicotine-replacement therapy (NRT) changed during the COVID-19 pandemic and whether changes differed by sociodemographic groups. METHODS: Repeated cross-sectional study of three national surveys in Finland (2018, 2019 and 2020; n = 58 526 adults aged 20 and over). Outcomes were daily and occasional smoking, smokeless tobacco (snus) use, e-cigarettes use, total tobacco or nicotine use and NRT use. We examined changes for each outcome by sex, age, educational tertiles, marital status, mother tongue and social participation. RESULTS: Daily smoking decreased among males by 1.15 percentage points (pp) [95% confidence interval (CI) -2.10 to -0.20] between 2018 and 2020 and 0.86 pp among females (95% CI -1.58 to -0.15). Daily snus use remained stable in both sexes. Daily e-cigarette use was below 1% and remained stable. We found weak evidence of a reduction in total tobacco or nicotine use between 2018 and 2020 (males -1.18 pp, 95% CI -2.68 to 0.32 and females -0.8 pp, 95% CI -1.81 to 0.22). NRT use remained stable. Snus and NRT use decreased among 60- to 74-year-olds but remained stable in other age groups. We did not find evidence of interactions by subgroup for other outcomes. CONCLUSIONS: Daily smoking decreased in Finland between 2018 and 2020, but other forms of tobacco use did not experience a reduction. The COVID-19 pandemic does not seem to have altered the sustained reduction of smoking in Finland, although substantial sociodemographic differences persist.

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections.

BACKGROUND: Poor sleep is associated with an increased risk of infections and all-cause mortality but the causal direction between poor sleep and respiratory infections has remained unclear. We examined if poor sleep contributes as a causal risk factor to respiratory infections. METHODS: We used data on insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital records in the UK Biobank (N ≈ 231,000) and FinnGen (N ≈ 392,000). We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and performed Mendelian randomization analyses to assess causality. FINDINGS: Utilizing 23 years of registry data and follow-up, we discovered that insomnia diagnosis associated with increased risk for infections (FinnGen influenza Cox's proportional hazard (CPH) HR = 4.34 [3.90, 4.83], P = 4.16 × 10-159, UK Biobank influenza CPH HR = 1.54 [1.37, 1.73], P = 2.49 × 10-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (inverse-variance weighted (IVW) OR = 1.65, P = 5.86 × 10-7), URI (IVW OR = 1.94, P = 8.14 × 10-31), COVID-19 infection (IVW OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (IVW OR = 1.47, P = 4.96 × 10-5). INTERPRETATION: Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens. FUNDING: Instrumentarium Science Foundation, Academy of Finland, Signe and Ane Gyllenberg Foundation, National Institutes of Health.

Evaluation of C4 Gene Copy Number in Pediatric Acute Neuropsychiatric Syndrome.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.