Publications by authors named "Juha Auvinen"

125 Publications

22-year trends in dysglycemia and body mass index: A population-based cohort study in Savitaipale, Finland.

Prim Care Diabetes 2021 Oct 11. Epub 2021 Oct 11.

Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.

Aims: We describe a 22-year prospective observational population-based study that determined the prevalence and incidence of type 2 diabetes (T2D) and intermediate hyperglycaemia (IH), obesity, hypertension, and disorders of lipid metabolism in a middle-age population in the Finnish municipality of Savitaipale.

Methods: 1151 people participated in the baseline survey in 1996-1999, following two follow-up examinations, in 2007-2008 and 2018-2019. Follow-up studies comprised clinical measurements, 2-h oral glucose tolerance test and other biochemistry, questionnaires, and registry data.

Results: The prevalence of T2D quadrupled to 27% and the proportion of normoglycemic people decreased from 73% to 44% while IH increased only slightly during the 22-year follow-up. A large proportion of people who died between the surveys were diabetic. The mean body mass index (BMI) did not, whereas mean waist circumference increased significantly, by 5-6 cm (P = 0.001) during the 22 years. Systolic blood pressure increased by 13-15 mmHg from baseline (P = 0.0001) but diastolic blood pressure did not. The mean plasma levels of total and LDL-cholesterol decreased 10.8% and 8.9% in women (P = 0.001), 21.5% and 22.2% in men (P = 0.001), respectively, while HDL-cholesterol and triglycerides remained stable. The proportion of those achieving targets in the treatment of dyslipidaemia increased significantly (P < 0.001).

Conclusions: In this 22-year prospective follow-up study of in middle-aged Europeans with high participation rates, the progression of dysglycaemia to overt diabetes with aging was rapid, even without a significant change in BMI.
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http://dx.doi.org/10.1016/j.pcd.2021.09.010DOI Listing
October 2021

Long-term dysglycemia as a risk factor for faster cognitive decline during aging: A 12-year follow-up study.

Diabetes Res Clin Pract 2021 Sep 9;180:109045. Epub 2021 Sep 9.

Centre for Life Course Health Research, Faculty of Medicine, University of Oulu, Finland; Unit of Primary Care, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland; Healthcare and Social Services of Selänne, Pyhäjärvi, Finland.

Aims: This longitudinal study evaluated associations between glucose metabolism and cognitive performance during a 12-year follow-up.

Methods: We included 714 subjects, which were followedfrom the age 55 to 70 years. Using oral glucose tolerance tests the population was classified as normoglycemic (NGT) and based on WHO diagnostic criteria for diabetes and prediabetes. Cognitive performance was assessed with a verbal fluency (category) test and wordlist learning tests of CERAD-nb, a verbal fluency (letter) test, and trail-making tests A and B.

Results: Compared to the normal group subjects with long-lasting prediabetes showed significantly greater decline (4.6 versus 2.9 words) on the verbal fluency (category) test (p = 0.041); subjects with long-lasting type 2 diabetes showed significantly greater decline (13 versus 6 s) on the trail making A test (p = 0.021) and on the wordlist learning test (3.3 versus 1.7 words) (p = 0.013); and a combined group of subjects with prediabetes or incident type 2 diabetes showed significantly greater cognitive decline (3.8 versus 2.9 words) in the verbal fluency (category) test (p = 0.039).

Conclusion: Prediabetes was associated with cognitive decline during aging. This finding should be incorporated into prevention strategies, because both type 2 diabetes and dementia are increasing world-wide.
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http://dx.doi.org/10.1016/j.diabres.2021.109045DOI Listing
September 2021

Cohort Profile: 46 years of follow-up of the Northern Finland Birth Cohort 1966 (NFBC1966).

Int J Epidemiol 2021 Aug 29. Epub 2021 Aug 29.

Northern Finland Birth Cohorts, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu Center for Life Course Health Research, Faculty of Medicine, University of Oulu Research Unit of Clinical Neuroscience, Department of Psychiatry, University of Oulu.

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http://dx.doi.org/10.1093/ije/dyab109DOI Listing
August 2021

Association of temporomandibular disorders with pain sensitivity: A cohort study.

Eur J Pain 2021 Jul 20. Epub 2021 Jul 20.

Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.

Background: Pain related to temporomandibular disorders (TMD) can be linked with multiple site pain (MSP), and may associate with increased pain sensitivity, more frequently among women than men. The aim of the study was to examine the associations of pressure pain threshold (PPT) and tolerance (PPTo) with TMD and associated MSP in the Northern Finland Birth Cohort 1966 (NFBC1966) study.

Methods: Altogether 1961 NFBC1966 subjects attended clinical medical and dental examination at the Institute of Dentistry, University of Oulu in 2012-2013. Clinical examinations were carried out using a modified Diagnostic Criteria for TMD protocol (DC/TMD). MSP was defined based on questions regarding body pain sites. Additionally, PPT and PPTo were assessed using algometer measurements. Mann-Whitney U-test and Tobit regression models were used to analyse associations between TMD sub-diagnoses, MSP, PPT and PPTo, stratified by sex. Further models were adjusted with anxiety and depressive symptoms, which were assessed using Hopkins Symptom Checklist-25 (HSCL-25) and two-way interaction terms.

Results: Among females, lower PPT and PPTo were associated with myalgia and arthralgia. Among males, lower PPT and PPTo were associated with MSP-linked TMD. Tobit regression analysis showed significantly lower PPT and PPTo values in the myalgia and arthralgia subgroups among female TMD subjects. Among females, disc displacement with reduction had an inverse association with PPT and PPTo. Among males, lower PPTo was associated with degenerative joint disease and MSP-linked TMD.

Conclusions: The pain regulatory mechanisms behind TMD act differently between the genders as local TMD among females and MSP-linked TMD among males were associated with pain sensitivity.

Significance: The study shows that there are differences in the associations of painful TMD with pressure pain tolerance, pressure pain sensitivity and MSP between male and female subjects.
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http://dx.doi.org/10.1002/ejp.1844DOI Listing
July 2021

Association of long-term obesity and weight gain with periodontal pocketing: Results of the Northern Finland Birth Cohort 1966 study.

J Clin Periodontol 2021 10 4;48(10):1344-1355. Epub 2021 Aug 4.

Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.

Aim: To investigate whether obesity, central obesity, and weight gain are associated with periodontal pocketing.

Materials And Methods: A never-smoking sub-population (n = 725) of the Northern Finland Birth Cohort 1966 was categorized based on body mass index (BMI; participants with normal weight, overweight, and obesity) and waist circumference (WC; participants without central obesity and with central obesity) at ages 31 and 46. The categories were combined to define whether the participants stayed in the respective BMI and WC categories or moved on to a higher category during follow-up. A periodontal examination was done at age 46.

Results: WC was more consistently associated with periodontal pocketing than BMI. The relative risks for the number of sites with periodontal pocket depth (PPD) ≥4 mm and bleeding PPD ≥4 mm in participants with central obesity both at age 31 and at age 46 were 1.7 (95% confidence interval [CI] 1.4-2.0) and 2.1 (95% CI 1.6-2.6). The corresponding values for participants who had no central obesity at age 31 but had central obesity at age 46 were 1.6 (95% CI 1.4-1.8) and 1.9 (95% CI 1.6-2.3).

Conclusion: Of all the studied measures, central obesity appeared to be most strongly associated with the inflammatory condition of the periodontium.
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http://dx.doi.org/10.1111/jcpe.13524DOI Listing
October 2021

A Childhood Farm Environment Protects from Allergic Sensitization until Middle Age but Not from New-Onset Sensitization in Adulthood: A 15 Year Longitudinal Study.

Int J Environ Res Public Health 2021 07 2;18(13). Epub 2021 Jul 2.

Department of Dermatology, University Hospital of Oulu, Finland and Medical Research Center, PEDEGO Research Group, University of Oulu, 90014 Oulu, Finland.

Data are insufficient on the protective effect of a farm environment in childhood regarding sensitization in middle age and new-onset sensitization in adulthood. A skin prick test (SPT) and questionnaire data from the Northern Finland Birth Cohort 1966 study (NFBC66) were used to investigate sensitization at age 46 years related to childhood living environment. A subpopulation of 3409 participants was analyzed to study factors related to new-onset sensitization between ages of 31 and 46 years. Data on complete SPTs were available for 5373 cohort members at age 46. Professional farming by parents (odds ratio (OR) 0.54; 95% confidence interval (CI) 0.43-0.68) and keeping of farm animals (OR 0.53; 95% CI 0.43-0.66) in infancy were associated with a lower risk of sensitization at age 46. Sensitization (OR 0.58; 95% CI 0.47-0.72) and polysensitization (OR 0.43; 95% CI 0.32-0.57) were less common in those who lived in a rural area in infancy compared to a city area. The childhood living environment had no effect on new-onset sensitization between ages 31 and 46. We conclude that living on a farm or in a rural environment in childhood had a protective effect on sensitization even in middle age, but these factors did not protect from new-onset sensitization in adults.
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http://dx.doi.org/10.3390/ijerph18137078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297149PMC
July 2021

Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia.

Sci Adv 2021 Jul 14;7(29). Epub 2021 Jul 14.

Biocenter Oulu, 90014 Oulu, Finland.

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans ( = 7175) and used Mendelian randomization (MR) to evaluate potential causality ( = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes and in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.
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http://dx.doi.org/10.1126/sciadv.abi4822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279517PMC
July 2021

Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment.

Genome Med 2021 Jun 21;13(1):104. Epub 2021 Jun 21.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors.

Methods: We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000).

Results: We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure.

Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.
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http://dx.doi.org/10.1186/s13073-021-00914-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215837PMC
June 2021

Is climacterium by the mid-40s associated with thyroid dysfunction or autoimmunity? A population-based study.

Menopause 2021 05 17;28(9):1053-1059. Epub 2021 May 17.

Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Oulu University Hospital and University of Oulu, OYS, Finland.

Objective: We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction.

Methods: This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status.

Results: At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1-2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6-6.6; P < 0.001) were associated with a higher prevalence of thyroid dysfunction.

Conclusions: More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity.
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http://dx.doi.org/10.1097/GME.0000000000001800DOI Listing
May 2021

Work-related risk factors for ulnar nerve entrapment in the Northern Finland Birth Cohort of 1966.

Sci Rep 2021 05 11;11(1):10010. Epub 2021 May 11.

Department of Hand Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Ulnar nerve entrapment (UNE) is the second most common entrapment neuropathy in the upper extremity. The aetiology of UNE is multifactorial and is still not fully understood. The aim of the study was to identify occupational risk factors for UNE and to determine whether smoking modifies the effects of work-related factors on UNE. The study population consisted of the Northern Finland Birth Cohort of 1966 (NFBC1966). In total, 6325 individuals active in working life participated at baseline in 1997. Occupational risk factors were evaluated by a questionnaire at baseline. The data on hospitalizations due to UNE were obtained from the Care Register for Health Care between 1997 and 2018. The incidence rate of hospitalization due to UNE was 47.6 cases per 100,000 person-years. After adjusting for confounders, entrepreneurs (Hazard ratio (HR) = 3.68, 95% CI 1.20-11.27), smokers (HR = 2.51, 95% CI 1.43-4.41), workers exposed to temperature changes (HR = 1.72, 95% CI 1.00-2.93), workers with physically demanding jobs (HR = 3.02, 95% CI 1.39-6.58), and workers exposed to hand vibration (HR = 1.94, 95% CI 1.00-3.77) were at an increased risk of hospitalization for UNE. Exposure to work requiring arm elevation increased the risk of hospitalization due to UNE among smokers (HR = 2.62, 95% CI 1.13-6.07), but not among non-smokers. Work-related exposure to vibration and temperature changes, and physically demanding work increase the risk of hospitalization for UNE. Smoking may potentiate the adverse effects of work-related factors on UNE.
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http://dx.doi.org/10.1038/s41598-021-89577-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113547PMC
May 2021

Early-onset climacterium is not associated with impaired vitamin D status: a population-based study.

Menopause 2021 05 3;28(8):899-908. Epub 2021 May 3.

PEDEGO Research Unit, University of Oulu, Oulu, Finland.

Objective: To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes.

Methods: A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were divided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo, n = 351) and 2) preclimacteric women (FSH <25 IU/L and having regular/irregular menstrual cycles, n = 2,193). Serum 25-hydroxyvitamin D (25(OH)D) concentrations were compared between the groups. A linear regression model was performed to investigate which factors are associated with 25(OH)D status.

Results: Mean serum 25(OH)D concentrations were higher in climacteric compared with preclimacteric women (68.1 ± 19.8 nmol/L vs 65.2 ± 19.3 nmol/L, P = 0.01). However, in the linear regression model, climacteric status was not associated with 25(OH)D status (multivariable adjusted mean difference 4.5 nmol/L, 95% confidence interval -1.4 to 10.4, P = 0.137). A total of 76 of the climacteric women were using systemic estrogen hormone therapy (HT). In a subanalysis, including only climacteric women, the use of HT was associated with higher 25(OH)D status (multivariable adjusted mean difference 5.9 nmol/L, 95% confidence interval 1.3-10.5, P = 0.013).

Conclusions: The onset of the climacteric phase by age 46 was not associated with inadequate 25(OH)D concentrations, whereas HT use was associated with higher 25(OH)D status in women with early-onset climacterium.
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http://dx.doi.org/10.1097/GME.0000000000001781DOI Listing
May 2021

Compensatory IgM to the Rescue: Patients with Selective IgA Deficiency Have Increased Natural IgM Antibodies to MAA-LDL and No Changes in Oral Microbiota.

Immunohorizons 2021 04 23;5(4):170-181. Epub 2021 Apr 23.

Medical Microbiology and Immunology, Research Unit of Biomedicine, University of Oulu, Oulu, Finland.

IgA is the most abundant Ab in the human body. However, most patients with selective IgA deficiency (SIgAD) are asymptomatic. IgM, and to lesser extent IgG Abs, are generally presumed to compensate for the lack of IgA in SIgAD by multiplying and adopting functions of IgA. We used data from the Northern Finland Birth Cohort 1966 to investigate whether SIgAD patients have differences in levels of natural Abs to oxidized epitopes compared with 20 randomly selected healthy controls. First, we screened the saliva and serum samples from the Northern Finland Birth Cohort 1966 cohort ( 1610) for IgA concentration. We detected five IgA-deficient subjects, yielding a prevalence of 0.3%, which is consistent with the general prevalence of 0.25% in the Finnish population. To detect natural Abs, we used malondialdehyde acetaldehyde-low-density lipoprotein (MAA-LDL), an Ag known to bind natural Abs. In this study, we show that natural secretory IgM and IgG Abs to MAA-DL were significantly increased in subjects with SIgAD. Given that secretory IgA is an important part of mucosal immune defense and that, in the gut microbiota, dysbiosis with SIgAD patients has been observed, we characterized the oral bacterial microbiota of the subjects with and without SIgAD using high-throughput 16S rRNA gene sequencing. We found no significant alterations in diversity and composition of the oral microbiota in subjects with SIgAD. Our data suggest that increased levels of secretory natural Abs in patients with SIgAD could be a compensatory mechanism, providing alternative first-line defense against infections and adjusting mucosal milieu to maintain a healthy oral microbiota.
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http://dx.doi.org/10.4049/immunohorizons.2100014DOI Listing
April 2021

Factors predicting 31-year survival among a population cohort in Northern Finland.

Int J Circumpolar Health 2021 12;80(1):1909334

Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.

We evaluated the survival of a subarctic population and the significance of traditional risk factors for mortality, causes of death and their seasonal variation from the period of 1984-2014. By the end of 2014 (follow-up), 644 (34.4% from 1,869) participants had died (42.1% of cardiovascular causes, 22.4% of neoplastic diseases). The average age at death±SD was 74.6±11.4 years for women (n=284) and 70.2±12.0 years for men (n=360). After adjusting for baseline age, the major risk factors predicting death were male sex (hazard ratio [HR] 1.80; 95% confidence interval [CI] 1.54-2.10), current smoking (HR 1.85; 95% CI 1.58-2.17), obesity (HR 1.75; 95% CI 1.45-2.12), high blood pressure (HR 1.46; 95% CI 1.24-1.72), cardiovascular disease (HR 1.62; 95% CI 1.36-1.93) and depression (HR 1.61; 95% CI 1.21-2.14) at baseline.The most common causes of death and the main risk factors predicting death in this population were the same as reported globally. Lifestyle factors had an important impact in predicting survival. The most common causes of death were the same for men and women. There was no significant difference in overall mortality rate between winter and summer, but cerebrovascular and pulmonary causes of death were more common during winter.
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http://dx.doi.org/10.1080/22423982.2021.1909334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057088PMC
December 2021

PCSK9 Levels and Metabolic Profiles in Elderly Subjects with Different Glucose Tolerance under Statin Therapy.

J Clin Med 2021 Mar 2;10(5). Epub 2021 Mar 2.

Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of glu-cose metabolism and statin therapy are still unclear.

Method: we investigated a large cohort of 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR metabolomics and PCSK9 plasma levels.

Results: PCSK9 plasma levels did not significantly differ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost.

Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, but statins reduced the LDL-C and VLDL-C levels.
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http://dx.doi.org/10.3390/jcm10050994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957894PMC
March 2021

One-hour post-load glucose improves the prediction of cardiovascular events in the OPERA study.

Ann Med 2021 12;53(1):478-484

Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Background: To estimate the ability of fasting, 1-h, and 2-h post-load glucose to predict cardiovascular outcomes.

Methods: We examined a population-based study consisting of 977 middle-aged subjects who underwent an oral glucose tolerance test with glucose values measured at 0, 60, and 120 min. Participants were followed up to 24 years, and cardiovascular outcomes were collected from national registers. Predictive abilities of fasting, 1-h, and 2-h glucose were evaluated alone and in the prediction models with traditional cardiovascular risk factors using Cox proportional hazard models, the likelihood-ratio test, Harrell's concordance index and integrated discrimination improvement.

Results: Cardiovascular endpoint occurred in 222 (22.7%) participants during a median follow-up of 19.8 years. In the prognostic models, 1-h glucose (HR 1.67, 95%CI 1.10-2.53), but not fasting or 2-h glucose, predicted cardiovascular events statistically significantly. In addition, when adding glucose parameters into the model including traditional cardiovascular risk factors, only 1-h glucose improved the predictive ability (LR-test =.046). Finally, 1-h glucose found slightly over 50% more cardiovascular endpoints that were not recognized by fasting or 2-h glucose levels.

Conclusions: Our findings support the earlier ones suggesting that 1-h glucose would be a better long-term predictor of cardiovascular morbidity and mortality than fasting or 2-h glucose.KEY MESSAGESIn addition to conventional CV risk factors,1-h but not fasting or 2-h post-load glucoses seems to be an independent predictor of cardiovascular events and seems to improve the predictive ability of the traditional cardiovascular risk model.Elevated 1-hpost-load glucose finds a large number (slightly over 50%)of cardiovascular endpoints that were not recognized by fasting or 2-h post-load glucose levels.One-hour glucose seems to be a better long-term predictor of cardiovascular morbidity and mortality than fasting or 2-h post-load glucose.
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http://dx.doi.org/10.1080/07853890.2021.1902557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993377PMC
December 2021

Incidence and remission of aeroallergen sensitization in adults in Northern Finland: 15 years longitudinal study.

Sci Rep 2021 Feb 19;11(1):4249. Epub 2021 Feb 19.

PEDEGO Research Unit, PEDEGO Research Group, Department of Dermatology, University Hospital of Oulu and Medical Research Center, University of Oulu, Aapistie 5A, 90029, Oulu, Finland.

Studies on the longitudinal changes in sensitization to aeroallergens in adult populations are sparse. The aim was to evaluate changes in sensitization to aeroallergens [birch, timothy, cat and house dust mite (HDM)] in an unselected adult population aged from 31 to 46 years. Data were gathered from a cohort of adults (Northern Finland Birth Cohort 1966) who had been skin prick tested (SPT) with birch, timothy, cat and HDM allergens at the age of 31 years and at age 46 (n = 5484 and 5373 respectively). Data from both time points were available for 3409 participants, who made up the cohort of the longitudinal study. The overall prevalence of sensitization to any of the selected allergens was 30.3% (n = 1661) in 31-year-olds and 30.7% (n = 1649) in 46-year-olds. In general, men were more sensitized (P < 0.001) and also had more polysensitization (P < 0.001) compared to women. In longitudinal sub-population incidence of sensitization was 7.1%. Birch was the most prevalent new sensitizer, however, the difference was not statistically significant when compared to cat. We conclude that new sensitization, demonstrated by positive findings in SPT, can still occur in middle age and this should be taken into account when managing allergic manifestations in adults as sensitization can be considered the first step in developing clinical allergy.
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http://dx.doi.org/10.1038/s41598-021-83326-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895822PMC
February 2021

Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women.

Eur J Endocrinol 2020 Dec;183(6):619-626

Department of Obstetrics and Gynecology, Oulu University Hospital, University of Oulu and Medical Research Center, and PEDEGO Research Unit (Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology), Oulu, Finland.

Objective: The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial.

Design: The study is a prospective longitudinal population-based cohort study.

Methods: The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884).

Results: In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status.

Conclusions: CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.
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http://dx.doi.org/10.1530/EJE-20-0406DOI Listing
December 2020

Association of glucose metabolism and retinopathy signs in non-diabetic individuals in midlife-The Northern Finland Birth Cohort 1966 study.

PLoS One 2020 22;15(10):e0240983. Epub 2020 Oct 22.

Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Diabetic retinopathy is a microvascular complication of hyperglycaemia. Little is known about the association of glucose metabolism and retinopathy signs in the non-diabetic middle-aged population. We studied prevalence of retinopathy in a subsample of Northern Finland Birth Cohort study (NFBC1966) of 1809 subjects, at 47 years of age, without previously diagnosed type 2 diabetes and/or blood pressure-lowering medication. All participants underwent clinical evaluations including an oral glucose tolerance test (glucose and insulin values measured at 0, 30, 60 and 120 min) and HbA1c. The retinopathy signs were diagnosed by fundus photographs and classified according to the Eurodiab classification scheme. The overall prevalence of newly diagnosed retinopathy was 1.4%. The retinopathy signs were significantly associated with increased 30 min, 1-h and 2-h glucose levels and 2-h insulin level in an OGTT. After adjustment with systolic blood pressure, only 30 min glucose, 1-h glucose and 2-h insulin levels were associated with retinopathy signs. Our findings show the potential role of 30 min and 1-h post-load glucose and 2-h insulin levels as risk factors for retinopathy lesions among the participants without previously diagnosed diabetes or hypertensive medication.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240983PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580974PMC
December 2020

Association of hyperglycaemia with periodontal status: Results of the Northern Finland Birth Cohort 1966 study.

J Clin Periodontol 2021 01 4;48(1):24-36. Epub 2020 Nov 4.

Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.

Aim: To investigate the association of hyperglycaemia and changes in glycaemic control with periodontal status in non-diabetic individuals.

Materials And Methods: A sub-population (n = 647) of the Northern Finland Birth Cohort 1966 was studied. We categorized long-term glucose balance based on fasting plasma glucose (FPG) at ages 31 and 46: FPG <5.0 mmol/l (strict normoglycaemia), FPG 5.0-5.59 mmol/l (slightly elevated FPG) and FPG 5.6-6.9 mmol/l (prediabetes). Probing pocket depth (PPD) and alveolar bone level (BL) data were collected at age 46. Relative risks (RR, 95% CI) were estimated using Poisson regression models.

Results: Periodontal status was poorer in individuals whose glucose balance worsened from age 31 to 46 years than in those with a stable glucose balance. In the case of strict normoglycaemia at age 31 and slightly elevated FPG or prediabetes at age 46, the RRs for PPD ≥4 mm were 1.8 (95% CI 1.4-2.2) and 2.8 (95% CI 2.0-3.8) and for BL ≥5 mm 1.1 (95% CI 0.8-1.4) and 1.8 (95% CI 1.2-2.8), respectively.

Conclusion: The results of this population-based cohort study suggest that impairment in glucose control in non-diabetic individuals is associated with periodontal pocketing and alveolar bone loss.
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http://dx.doi.org/10.1111/jcpe.13388DOI Listing
January 2021

Onset of the climacteric phase by the mid-forties associated with impaired insulin sensitivity: a birth cohort study.

Menopause 2020 09 21;28(1):70-79. Epub 2020 Sep 21.

Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Oulu University Hospital and University of Oulu, Oulu, Finland.

Objective: To investigate whether the early-onset menopausal transition is associated with deteriorated glucose tolerance in women in their mid-forties.

Methods: A cross-sectional analysis of a cohort study including 2,632 women of the Northern Finland Birth Cohort 1966. The participants were divided into two groups by their menstrual history and follicle-stimulating hormone values at age 46: climacteric and preclimacteric women. Glucose and insulin parameters, as well as mathematical indices derived from them to evaluate insulin sensitivity, were compared between the groups. The results were adjusted for measured body mass index and smoking. The possible effect of hormone therapy was investigated in subanalyses excluding hormone therapy users.

Results: Climacteric women (n = 379) were more often current smokers at age 46 (P = 0.008), and their body mass indices increased more from 31 to 46 years (P = 0.013), compared to preclimacteric women (n = 2,253). In a multivariable generalized linear model, being climacteric at age 46 was associated with several findings suggesting decreased insulin sensitivity: increased glycated hemoglobin (P < 0.001), 2-hour oral glucose tolerance test 30- and 60-minute insulin (P = 0.040 and 0.006, respectively), and area under the insulin curve (P = 0.005). Being climacteric also was associated with a decreased the McAuley (P = 0.024) and Belfiore indices (P = 0.027) and glucose tolerance test 60-minute glucose (P = 0.015). In subanalyses excluding hormone therapy users (n = 94), the results did not change significantly.

Conclusions: Earlier onset of climacteric transition is associated with impaired insulin sensitivity in middle-aged women.
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http://dx.doi.org/10.1097/GME.0000000000001658DOI Listing
September 2020

The association between diabetes and cognitive changes during aging.

Scand J Prim Health Care 2020 Sep 10;38(3):281-290. Epub 2020 Aug 10.

Centre for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.

Background: Worldwide, we are observing a rising prevalence of dementia and mild cognitive impairments that often co-occur with the heightened incidence of non-communicable diseases in the elderly. It is suggested that type 2 diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and more rapid decline in old age.

Methods: to address existing knowledge gaps in this area, we systematically reviewed the literature to identify whether patients with type 2 diabetes (T2DM) and pre-diabetes are at a higher risk of poorer cognitive performance, and whether the risk (if any) might affect specific cognitive abilities. We concentrated the review on elderly individuals (65 years or older) at intake. In total, 3251 original articles were retrieved, of which 17 met our inclusion and quality control criteria, which comprised 12 structured questions used to define the articles.

Results: 11 of 17 studies found a statistically significant decline in cognition among individuals who had T2DM or pre-diabetes compared to their non-diabetic counterparts. The association between diabetes and cognitive decline was not always clear, and the extent of the cognitive tests used seemed to have the greatest effect on the results.

Conclusion: Focusing on a population age 65 years and over, we found insufficient evidence to support an association between pre-diabetes stages and mild cognitive impairment. However, there is consistent evidence to support diabetes as an independent risk factor for low cognitive ability in the elderly. Finally, we found insufficient evidence to support effect of T2DM on distinct cognitive ability due to the scarcity of comparable findings.
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http://dx.doi.org/10.1080/02813432.2020.1802140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470088PMC
September 2020

Type 1 and type 2 diabetes after gestational diabetes: a 23 year cohort study.

Diabetologia 2020 10 29;63(10):2123-2128. Epub 2020 Jul 29.

Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland.

Aims/hypothesis: The aim of this work was to examine the progression to type 1 and type 2 diabetes after gestational diabetes mellitus (GDM) in a 23 year follow-up study.

Methods: We carried out a cohort study of 391 women with GDM diagnosed by an OGTT or the use of insulin treatment during pregnancy, and 391 age- and parity-matched control participants, who delivered in 1984-1994 at the Oulu University Hospital, Finland. Diagnostic cut-off levels for glucose were as follows: fasting, ≥4.8 mmol/l; 1 h, ≥10.0 mmol/l; and 2 h, ≥8.7 mmol/l. Two follow-up questionnaires were sent (in 1995-1996 and 2012-2013) to assess the progression to type 1 and type 2 diabetes. Mean follow-up time was 23.1 (range 18.7-28.8) years.

Results: Type 1 diabetes developed (5.7%) during the first 7 years after GDM pregnancy and was predictable at a 2 h OGTT value of 11.9 mmol/l during pregnancy (receiver operating characteristic analysis: AUC 0.91, sensitivity 76.5%, specificity 96.0%). Type 2 diabetes increased linearly to 50.4% by the end of the follow-up period and was moderately predictable with fasting glucose (AUC 0.69, sensitivity 63.5%, specificity 68.2%) at a level of 5.1 mmol/l (identical to the fasting glucose cut-off recommended by the International Association of Diabetes and Pregnancy Study Groups [IADPSG) and WHO]).

Conclusions/interpretation: All women with GDM should be intensively monitored for a decade, after which the risk for type 1 diabetes is minimal. However, the incidence of type 2 diabetes remains linear, and therefore individualised lifelong follow-up is recommended.
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http://dx.doi.org/10.1007/s00125-020-05215-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476985PMC
October 2020

Alcohol consumption is associated with a later need for ICU admission: a Northern Finland Birth Cohort 1966-study.

J Public Health (Oxf) 2021 09;43(3):551-557

Oulu University Hospital, Department of Anesthesiology, 90029 Oulu, Finland.

Background: Alcohol-related problems are common in intensive care unit (ICU) admitted patients. The aim of the present study is to assess the impact of alcohol consumption on the need of intensive care in 19 years follow-up period.

Methods: The study population consists of Northern Finland Birth Cohort 1966 participants, who responded alcohol-related questions at 31 years of age and Intensive Care Unit (ICU admissions from 1997 to 2016.

Results: There were a total of 8379 assessed people and 136 (1.6%) of them were later admitted to ICU. A total of 44 (32.4%) of the ICU-admitted persons had their alcohol consumption at the highest quartile of the cohort (P = 0.047). These patients had a lower number of malignancy-related admissions (3.6% versus 14.0%, P = 0.027), neurological admissions (14.3 versus 30.6%, P = 0.021), and were more often admitted due to poisonings (12.5% versus 5.0%, P = 0.07). There were no differences in 28-day post-ICU mortality but long-term mortality of ICU-admitted patients with lower alcohol consumption was higher than non-ICU-admitted population.

Conclusion: Among ICU-admitted population, there was higher alcohol consumption at age of 31 years. People in the lower alcohol consumption quartiles were more often admitted to ICU due to malignancy-related causes and they had higher long-term mortality.
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http://dx.doi.org/10.1093/pubmed/fdaa085DOI Listing
September 2021

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study.

BMC Pulm Med 2020 Jun 16;20(1):171. Epub 2020 Jun 16.

National Heart and Lung Institute, Imperial College London, London, UK.

Background: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.

Methods: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV, FVC, and FEV/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.

Results: In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.

Conclusions: To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI.
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http://dx.doi.org/10.1186/s12890-020-01212-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298775PMC
June 2020

Accumulated unhealthy behaviors and psychosocial problems in adolescence are associated with labor market exclusion in early adulthood - a northern Finland birth cohort 1986 study.

BMC Public Health 2020 Jun 5;20(1):869. Epub 2020 Jun 5.

Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014, Oulu, Finland.

Background: The relevance of health-related behaviors to exclusion from the labor market in early adulthood remains poorly studied in relation to the magnitude of the problem. We explored whether adolescents' accumulated unhealthy behaviors and psychosocial problems are associated with later labor market exclusion, and whether multisite musculoskeletal pain (MMSP) impacts these relations.

Methods: We gathered questionnaire data on unhealthy behaviors and psychosocial problems and MMSP among adolescents aged 15 to 16 belonging to the Northern Finland Birth Cohort 1986. The findings were combined with registry data on unemployment, employment and permanent work disability during a five-year follow-up between the ages of 25 and 29 (n = 6692). In the statistical modeling we used education, family leave and socioeconomic status of childhood family as potential confounders, as well as latent class and logistic regression analyses.

Results: The Externalizing behavior cluster associated with over one year of unemployment (RR 1.64, CI 1.25-2.14) and permanent work disability (OR 2.49, CI 1.07-5.78) in the follow-up among the men. The Sedentary cluster also associated with over one year (RR 1.41, CI 1.13-1.75) and under one year of unemployment (RR 1.25, CI 1.02-1.52) and no employment days (RR 1.93, CI 1.26-2.95) among the men. Obese male participants were at risk of over one year of unemployment (RR 1.50, CI 1.08-2.09) and no employment days (RR 1.93, CI 1.07-3.50). Among the women, the Multiple risk behavior cluster related significantly to over one year of unemployment (RR 1.77, CI 1.37-2.28). MMSP had no influence on the associations.

Conclusions: Unhealthy behavior patterns and psychosocial problems in adolescence have long-term consequences for exclusion from the labor market in early adulthood, especially among men. Simultaneously supporting psychological well-being and healthy behaviors in adolescence may reduce labor market inclusion difficulties in the early phase of working life.
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http://dx.doi.org/10.1186/s12889-020-08995-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275307PMC
June 2020

Maternal alcohol consumption during pregnancy associates with bone fractures in early childhood. A birth-cohort study of 6718 participants.

Bone 2020 08 30;137:115462. Epub 2020 May 30.

Department of Pediatric Surgery and Orthopaedics, Oulu University Hospital, PEDEGO-research unit and Medical Research Center, University of Oulu, Oulu, Finland.

Fractures are common injuries in children, but their underlying biological and environmental risk factors are not well known. Maternal alcohol consumption during pregnancy is a known risk factor for bone malformations and impaired growth, in connection with Fetal Alcohol Spectrum Disorders (FASD). There is evidence that even lower doses of alcohol than what is needed for FASD can cause changes in the developing bone. Birth weight and length may also associate to childhood fractures. The aim of this study was to find out whether there exist associations between maternal alcohol use during pregnancy, birth weight or length and fractures of the long bones in childhood. A prospective birth cohort was performed, including all women in Northern Finland with an expected date of delivery between July 1985 and June 1986, and their offspring (N = 9432). The National Hospital Discharge Register (NHDR) provided the information on inpatient treated fractures. The subjects who declined participation or were treated as outpatient were excluded. The final study population consisted of 6718 children (71.2%). 98 (1.5%) of them suffered from inpatient treated fracture of a long bone (N = 105). Maternal alcohol consumption during pregnancy was inquired by questionnaires during late pregnancy or shortly after parturition. The birth length and weight were recorded immediately after birth. Binomial regression analysis was used to determine the association between the potential explanatory variables and bone fractures. Gender, socioeconomic status of the family, maternal age, premature birth, body mass index (BMI) of the children and maternal smoking during pregnancy were taken as possible confounders. In this study, the maternal alcohol consumption during pregnancy was associated to 2.22-fold (CI 1.09-4.12, p < 0.02) increased risk of a long bone fracture before the age of eight. Birth weight or length did not associate to childhood fractures. Bone fractures are an important cause of morbidity in childhood. Their prevention should start from the prenatal period by protecting the fetus from the alcohol exposure.
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http://dx.doi.org/10.1016/j.bone.2020.115462DOI Listing
August 2020

Early Growth Patterns and Cardiac Structure and Function at Midlife: Northern Finland 1966 Birth Cohort Study.

J Pediatr 2020 06;221:151-158.e1

Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

Objectives: To evaluate the influence of early growth patterns that have previously been associated with later cardiometabolic risk on cardiac left ventricular (LV) structure and function in midlife.

Study Design: A subpopulation of the Northern Finland Birth Cohort 1966 took part in follow-up, including echocardiography (n = 1155) at the age of 46 years. Body mass index (BMI) growth curves were modeled based on frequent anthropometric measurements in childhood. Age and BMI at adiposity peak (n = 482, mean age 9.0 months) and at adiposity rebound (n = 586, mean age 5.8 years) were determined. Results are reported as unstandardized beta (β) or OR with 95% CIs for 1 SD increase in early growth variable.

Results: Earlier adiposity rebound was associated with increased LV mass index (β = -4.10 g/m (-6.9, -1.3); P = .004) and LV end-diastolic volume index (β = -2.36 mL/m (-3.9, -0.84); P = .002) as well as with eccentric LV hypertrophy (OR 0.54 [0.38, 0.77]; P = .001) in adulthood in males. BMI at adiposity rebound was directly associated with LV mass index (β = 2.33 g/m [0.80, 3.9]; P = .003). Higher BMI at both adiposity peak and at adiposity rebound were associated with greater LV end-diastolic volume index (β = 1.47 mL/m; [0.51, 2.4], β = 1.28 mL/m [0.41, 2.2], respectively) and also with eccentric LV hypertrophy (OR 1.41 [1.10, 1.82], OR 1.53 [1.23, 1.91], respectively) and LV concentric remodeling (OR 1.38 [1.02, 1.87], OR 1.40 [1.06, 1.83], respectively) in adulthood (P < .05 for all). These relationships were only partly mediated by adult BMI.

Conclusions: Early growth patterns in infancy and childhood contribute to cardiac structure at midlife.
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http://dx.doi.org/10.1016/j.jpeds.2020.03.007DOI Listing
June 2020

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

Lancet Diabetes Endocrinol 2020 06;8(6):501-510

ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.

Background: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight.

Methods: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496.

Findings: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (p=0·10). Each 1 SD increase in FT concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second.

Interpretation: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy.

Funding: Netherlands Organization for Scientific Research (grant 401.16.020).
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http://dx.doi.org/10.1016/S2213-8587(20)30061-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168324PMC
June 2020

Association Between Modic Changes and Low Back Pain in Middle Age: A Northern Finland Birth Cohort Study.

Spine (Phila Pa 1976) 2020 Oct;45(19):1360-1367

Medical Research Center Oulu, Faculty of Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland.

Study Design: A cross-sectional study of the Northern Finland Birth Cohort 1966 (NFBC1966).

Objective: The aim of this study was to evaluate the association between the type, size, and location of lumbar Modic changes (MC), and prolonged disabling low back pain (LBP).

Summary Of Background Data: LBP is the leading cause of disability worldwide and it affects all age- and socioeconomical groups. Only a small proportion of LBP patients are diagnosed with a specific cause: In most cases no single nociceptive cause for the pain can be identified. MC are visualized in magnetic resonance imaging (MRI) as a signal intensity change in vertebral bone marrow and have been proposed to represent a specific degenerative imaging phenotype associated with LBP. MC can be classified into several subtypes, of which inflammatory Type 1 (MC1) is suggested as being more likely to be associated with LBP.

Methods: We assessed lumbar MRI (n = 1512) for the presence, type, and size of MC. The associations of MC characteristics with prolonged (≥30 days during the past year) and disabling (bothersomeness of LBP at least 6 on a 0-10 Numeric Rating Scale) LBP, evaluated at the time of imaging at 47 years, were analyzed using binary logistic regression, adjusted for sex, BMI, smoking, educational status, lumbar disc degeneration, and disc herniations.

Results: Any MC and MC1 were associated with prolonged disabling LBP (odds ratio [OR] after full adjustments 1.50 [95% confidence interval, CI 1.05-2.15] and 1.50 [95% CI 1.10-2.05], respectively). Furthermore, MC covering the whole anterior-posterior direction or the whole endplate, as well as the height of MC, were significantly associated with prolonged disabling LBP (OR after full adjustments 1.59 [95% CI 1.14-2.20], 1.67 [95% CI 1.13-2.46] and 1.26 [95% CI 1.13-1.42], respectively).

Conclusion: Our study showed a significant and independent association between MC and clinically relevant LBP.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000003529DOI Listing
October 2020

Maternal smoking during pregnancy affects adult onset of asthma in offspring: a follow up from birth to age 46 years.

Eur Respir J 2020 06 11;55(6). Epub 2020 Jun 11.

Environment Health Unit, National Institute for Health and Welfare, Kuopio, Finland.

Rationale: Environmental tobacco smoke (ETS) exposure increases asthma risk in children. There is limited knowledge of prenatal ETS for adult-onset asthma.

Objectives: To determine the association between prenatal ETS and adult onset asthma.

Measurements And Main Results: The questionnaire and clinical data of 5200 people, free of physician-diagnosed asthma by 31 years of age, who were included in the Northern Finland Birth Cohort 1966 Study was used. The association of maternal smoking during the last 3 months of pregnancy with onset of physician-diagnosed asthma and with lung function in adult offspring was studied using adjusted multivariate regression analyses. The cumulative incidence of physician-diagnosed asthma between the ages of 31 and 46 years was 5.1% among men and 8.8% among women. Gestational smoke exposure was associated with adult-onset asthma among offspring (adjusted OR 1.54, 95% CI 1.04-2.29), namely among offspring who reported either past non-diagnosed asthma (OR 9.63, 95% CI 2.28-40.67) or past cough with wheeze (3.21, 95% CI 1.71-6.05). A significant association was detected between gestational smoke exposure and the offspring's forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) ratio at 31 years of age. In offspring with the haplotype rs11702779-AA of , gestational smoke exposure was associated with adult-onset asthma (5.53, 95% CI 2.11-14.52, adjusted p-value for interaction 0.10).

Conclusion: Maternal smoking during pregnancy is associated with the cumulative incidence of asthma in offspring between the ages of 31 and 46 years. The association was accentuated in offspring who at age 31, reported having past respiratory problems and/or who had haplotype rs11702779-AA. A reduction in FEV/FVC ratio was also observed at age 31 years in offspring with gestational smoke exposure. These results could reflect the early vulnerability of offspring's airways to ETS and its putative long-term effects.
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http://dx.doi.org/10.1183/13993003.01857-2019DOI Listing
June 2020
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