Long-term survival of 57 premolars consecutively transplanted to premolar sites.

INTRODUCTION: The objective of this study was to report the long-term outcome of autotransplantation of premolars to other premolar recipient sites. METHODS: The sample was limited to adolescents seeking orthodontic treatment, and all had 1 or 2 premolars transplanted to a recipient site in which a premolar was congenitally missing. The transplantations were performed between 1980 and 2008, comprising 29 premolars in 22 males and 28 premolars in 22 females. Systematic clinical and radiographic follow-up varied from 1 year to 36.8 years, with a mean observation time of 18.9 years and a median of 19.2 years. Of the 57 transplanted teeth, 52 were subjected to orthodontic forces. RESULTS: A total of 9 of 57 teeth (15.8%) were lost during the observation period, and 8 of 9 lost teeth had been functional for at least 9 years posttransplantation. Of the 48 surviving transplants, 6 did not meet the criteria for success, giving an overall success rate of 73.7%. Complications were diagnosed within 5 years from the transplantation in 4 of 57 teeth (7.0%) and later in 11 of 57 (19.3%). The Kaplan-Meier survival curve shows that the complication-free proportion of transplants decreased at a constant rate over the observation time. The average survival time, taking censoring into account during follow-up of 36.8 years, was estimated as 28.5 years. The complications in the 15 teeth were classified into 4 categories: periapical lesions (6 teeth), inflammatory resorption (5 teeth), abrupt fracture (2 teeth), and ankylosis (2 teeth). CONCLUSIONS: Overall, premolar transplants in all stages of root formation have high success and survival rates. Transplants with complications may survive temporarily and preserve critical arch space and alveolar bone. Transplants with normal healing may have latent weaknesses that can eventually affect long-term survival.

History of childhood maltreatment associated with hospitalization or death due to COVID-19: a cohort study.

BACKGROUND: Childhood maltreatment (CM) has been indicated in adverse health outcomes across the lifespan, including severe infection-related outcomes. Yet, data are scarce on the potential role of CM in severe COVID-19-related outcomes as well as on mechanisms underlying this association. METHODS: We included 151,427 individuals in the UK Biobank who responded to questions on the history of CM in 2016 and 2017 and were alive on January 31, 2020. Binomial logistic regression models were performed to estimate the association between a history of CM and severe COVID-19 outcomes (i.e. hospitalization or death due to COVID-19), as well as COVID-19 diagnosis and vaccination as secondary outcomes. We then explored the potential mediating roles of socio-economic status, lifestyle and pre-pandemic comorbidities, and the effect modification by polygenic risk score for severe COVID-19 outcomes. RESULTS: The mean age of the study population at the start of the pandemic was 67.7 (SD = 7.72) years, and 56.5% were female. We found the number of CM types was associated with the risk of severe COVID-19 outcomes in a graded manner (pfor trend < 0.01). Compared to individuals with no history of CM, individuals exposed to any CM were more likely to be hospitalized or die due to COVID-19 (odds ratio [OR] = 1.54 [95%CI 1.31-1.81]), particularly after physical neglect (2.04 [1.57-2.62]). Largely comparable risk patterns were observed across groups of high vs. low genetic risks for severe COVID-19 outcomes (pfor difference > 0.05). Mediation analysis revealed that 50.9% of the association between CM and severe COVID-19 outcomes was explained by suboptimal socio-economic status, lifestyle, and pre-pandemic diagnosis of psychiatric disorders or other chronic medical conditions. In contrast, any CM exposure was only weakly associated with COVID-19 diagnosis (1.06 [1.01-1.12]) while significantly associated with not being vaccinated for COVID-19 (1.21 [1.13-1.29]). CONCLUSIONS: Our results add to the growing knowledge base indicating the role of childhood maltreatment in negative health outcomes across the lifespan, including severe COVID-19-related outcomes. The identified factors underlying this association represent potential intervention targets for mitigating the harmful effects of childhood maltreatment in COVID-19 and similar future pandemics.

Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer's disease.

A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.

Male-Female Spatio-Temporal Differences of Age-Related Bone Changes Show Faster Bone Deterioration in Older Women at Femoral Regions Associated with Incident Hip Fracture.

A better understanding of how age-related bone loss affects the fracture-prone regions of the proximal femur could lead to more informed fracture-prevention strategies. Therefore, the aim of this work was to assess the spatio-temporal distribution of bone deterioration in older men and women with aging. A subset of 305 men (74.87 ± 4.76 years; mean ± SD) and 371 age-matched women (74.84 ± 4.71 years) with no history of fracture were randomly selected from the Age, Gene/Environment Susceptibility-Reykjavik study. Quantitative computed tomography (QCT) scans of the left proximal femur obtained at baseline and at 5.2 ± 0.4 years follow-up were processed to assess local changes in volumetric bone mineral density (vBMD), cortical bone thickness (Ct.Th), and internal bone structure using voxel-based morphometry (VBM), surface-based statistical parametric mapping (surf-SPM), and tensor-based morphometry (TBM). Local parametric changes within each sex and sex differences in these changes were statistically assessed using linear mixed effects models allowing for baseline and time-varying covariates, yielding Student's t-test and P-value statistical maps of the proximal femur. The statistical maps indicated regions with significant parametric changes in each sex, and with significant different parametric changes between older men and older women with aging. Older women manifested significantly larger losses in vBMD, cortical bone thickness, and structure than older men, and they did so in regions where deficiency in these parameters has been associated with incident hip fracture. Using longitudinal QCT scans of the proximal femur and Computational Anatomy, we provided new insights into the higher fracture rates of the proximal femur in older women compared with men of similar age providing new information on the pathophysiology of osteoporosis.

Sexual violence in the workplace and associated health outcomes: a nationwide, cross-sectional analysis of women in Iceland.

BACKGROUND: Workplace sexual violence against women is a pressing global issue with scarce knowledge on its health implications. Existing research is largely limited to specific occupations, which calls for comprehensive, population-based studies. This study aimed to examine the associations between self-labelled workplace sexual violence and a variety of health outcomes in a nationally representative sample of Icelandic women aged 18-69 years. METHODS: Participants in this cross-sectional study were women in the Stress-And-Gene-Analysis (SAGA) cohort who answered the question regarding workplace sexual violence, defined in our study as encompassing all work sectors, academic settings, and other school environments. Eligible participants were women, aged 18-69 years, residing in Iceland, who spoke Icelandic and were listed in the Icelandic Population Register or had a contact number registered with the online 1819 service. Poisson and binomial regressions were used to assess the associations between workplace sexual violence and validated measures of current mental and physical health outcomes (eg, probable depression, general anxiety, and severe sleep problems). Multiple imputation was performed to account for missing values in the dataset. FINDINGS: The study was conducted from March 1, 2018, to July 1, 2019. Of the 113 814 women deemed eligible for study inclusion, 104 197 were invited to take part in the online survey. Of those invited, 30 403 women completed the survey and were included in the SAGA cohort. Among these participants, 15 812 provided answers to the question regarding exposure to workplace sexual harassment or violence. Exposure to sexual violence was associated with an increased prevalence of probable depression (prevalence ratio [PR] 1·50 [95% CI 1·41-1·60]), general anxiety (PR 1·49 [1·40-1·59]), social phobia (PR 1·62 [1·48-1·78]), self-harm (PR 1·86 [1·53-2·28]), suicidal ideation (PR 1·68 [1·44-1·68]), suicide attempts (PR 1·99 [1·62-2·44]), binge drinking (PR 1·10 [1·01-1·20]), sleep problems (PR 1·41 [1·48-1·91]), physical symptoms (PR 1·59 [1·48-1·70]), and sick leave (PR 1·20 [1·12-1·28]). The prevalence of the health outcomes among those exposed show age-related differences: younger women report anxiety or depression more frequently, while older women report sleep problems after experiencing workplace sexual violence. INTERPRETATION: In this cross-sectional study self-reported experiences of sexual violence in the workplace were associated with several self-reported health outcomes. The findings suggest a need for targeted interventions to promote workplace safety and to mitigate adverse health implications among people who have experienced workplace sexual violence. Future research should explore factors such as the frequency, duration, and relationship dynamics of workplace sexual violence, as well as the effect on different genders and sexual orientations, to deepen our understanding of these experiences and inform effective prevention strategies. FUNDING: Reykjavík Energy Research Fund, The Icelandic Gender Equality Fund, European Research Council, and Icelandic Center for Research.

Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Refracture and mortality risk in the elderly with osteoporotic fractures: the AGES-Reykjavik study.

There is imminent refracture risk in elderly individuals for up to six years, with a decline thereafter except in women below 75 who face a constant elevated risk. Elderly men with fractures face the highest mortality risk, particularly those with hip and vertebral fractures. Targeted monitoring and treatment strategies are recommended. PURPOSE: Current management and interventions for osteoporotic fractures typically focus on bone mineral density loss, resulting in suboptimal evaluation of fracture risk. The aim of the study is to understand the progression of fractures to refractures and mortality in the elderly using multi-state models to better target those at risk. METHODS: This prospective, observational study analysed data from the AGES-Reykjavik cohort of Icelandic elderly, using multi-state models to analyse the evolution of fractures into refractures and mortality, and to estimate the probability of future events in subjects based on prognostic factors. RESULTS: At baseline, 4778 older individuals aged 65 years and older were included. Elderly men, and elderly women above 80 years of age, had a distinct imminent refracture risk that lasted between 2-6 years, followed by a sharp decline. However, elderly women below 75 continued to maintain a nearly constant refracture risk profile for ten years. Hip (30-63%) and vertebral (24-55%) fractures carried the highest 5-year mortality burden for elderly men and women, regardless of age, and for elderly men over 80, lower leg fractures also posed a significant mortality risk. CONCLUSION: The risk of refracture significantly increases in the first six years following the initial fracture. Elderly women, who experience fractures at a younger age, should be closely monitored to address their long-term elevated refracture risk. Elderly men, especially those with hip and vertebral fractures, face substantial mortality risk and require prioritized monitoring and treatment.

Nocturnal gastro-oesophageal reflux and respiratory symptoms are increased in sleep apnoea: comparison with the general population.

AIM: To assess respiratory symptoms and nocturnal gastro-oesophageal reflux (nGER) among untreated obstructive sleep apnoea (OSA) patients, compared with the general population. Also, if nGER associates differently with respiratory symptoms among OSA patients. METHODS: 2 study cohorts were included: 822 newly diagnosed subjects with moderate-severe OSA and 738 Icelandic general population study participants. All participants answered the same questionnaires. Those reporting nGER symptoms at least once per week were defined as 'with nGER'; those without nGER symptoms and without nGER medication were defined as 'no nGER'; and other participants were defined as having 'possible nGER'. Propensity score-based weights were used to minimise confounding and selection bias and facilitate causal interpretations. RESULTS: The prevalence of nGER among OSA patients was 14.1%, compared with 5.8% in the general population. This increased prevalence in OSA was not explained by differences in age, gender, body mass index, smoking, hypertension and diabetes (adjusted OR (95% CI)=3.79 (2.24 to 6.43)). OSA patients 'with nGER' and with 'possible nGER' reported more wheezing (44% and 44% vs 25%, respectively) and productive cough (47% and 42% vs 29%, respectively), compared with OSA patients with 'no nGER'. The same pattern was seen in the general population, although with a generally lower prevalence. The effect of nGER on respiratory symptoms was similar between the two cohorts. CONCLUSION: nGER was more often reported among untreated moderate-severe OSA patients than in the general population. Participants with nGER had more wheezing and productive cough, both among untreated OSA patients and in the general population.

Plasma proteomic signature of human longevity.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

Adverse Childhood Experiences and Adult Mental Health Outcomes.

Importance: Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders. Objective: To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding. Design, Setting, and Participants: This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023. Exposures: A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey. Main Outcomes and Measures: Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register. Results: Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11). Conclusions and relevance: This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.

Polysomnographic characteristics of excessive daytime sleepiness phenotypes in obstructive sleep apnea: results from the international sleep apnea global interdisciplinary consortium.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnea (OSA). Traditional polysomnographic (PSG) measures only partially explain EDS in OSA. This study analyzed traditional and novel PSG characteristics of two different measures of EDS among patients with OSA. METHODS: Sleepiness was assessed using the Epworth Sleepiness Scale (>10 points defined as "risk of dozing") and a measure of general sleepiness (feeling sleepy ≥ 3 times/week defined as "feeling sleepy"). Four sleepiness phenotypes were identified: "non-sleepy," "risk of dozing only," "feeling sleepy only," and "both at risk of dozing and feeling sleepy." RESULTS: Altogether, 2083 patients with OSA (69% male) with an apnea-hypopnea index (AHI) ≥ 5 events/hour were studied; 46% were "non-sleepy," 26% at "risk of dozing only," 7% were "feeling sleepy only," and 21% reported both. The two phenotypes at "risk of dozing" had higher AHI, more severe hypoxemia (as measured by oxygen desaturation index, minimum and average oxygen saturation [SpO2], time spent < 90% SpO2, and hypoxic impacts) and they spent less time awake, had shorter sleep latency, and higher heart rate response to arousals than "non-sleepy" and "feeling sleepy only" phenotypes. While statistically significant, effect sizes were small. Sleep stages, frequency of arousals, wake after sleep onset and limb movement did not differ between sleepiness phenotypes after adjusting for confounders. CONCLUSIONS: In a large international group of patients with OSA, PSG characteristics were weakly associated with EDS. The physiological measures differed among individuals characterized as "risk of dozing" or "non-sleepy," while "feeling sleepy only" did not differ from "non-sleepy" individuals.

Childhood maltreatment and risk of endocrine diseases: an exploration of mediating pathways using sequential mediation analysis.

BACKGROUND: Adverse childhood experiences (ACEs), including childhood maltreatment, have been linked with increased risk of diabetes and obesity during adulthood. A comprehensive assessment on the associations between childhood maltreatment and all major endocrine diseases, as well as the relative importance of different proposed mechanistic pathways on these associations, is currently lacking. METHODS: Based on the UK Biobank, we constructed a cohort including 151,659 participants with self-reported data on childhood maltreatment who were 30 years of age or older on/after January 1, 1985. All participants were followed from the index date (i.e., January 1, 1985, or their 30th birthday, whichever came later) until the first diagnosis of any or specific (12 individual diagnoses and 9 subtypes) endocrine diseases, death, or the end of follow-up (December 31, 2019), whichever occurred first. We used Cox models to examine the association of childhood maltreatment, treated as continuous (i.e., the cumulative number of experienced childhood maltreatment), ordinal (i.e., 0, 1 and ≥ 2), or binary (< 2 and ≥ 2) variable, with any and specific endocrine diseases, adjusted for multiple covariates. We further examined the risk of having multiple endocrine diseases using Linear or Logistic Regression models. Then, sequential mediation analyses were performed to assess the contribution of four possible mechanisms (i.e., suboptimal socioeconomic status (SES), psychological adversities, unfavorable lifestyle, and biological alterations) on the observed associations. RESULTS: During an average follow-up of 30.8 years, 20,885 participants received a diagnosis of endocrine diseases. We observed an association between the cumulative number of experienced childhood maltreatment and increased risk of being diagnosed with any endocrine disease (adjusted hazard ratio (HR) = 1.10, 95% confidence interval 1.09-1.12). The HR was 1.26 (1.22-1.30) when comparing individuals ≥ 2 with those with < 2 experienced childhood maltreatment. We further noted the most pronounced associations for type 2 diabetes (1.40 (1.33-1.48)) and hypothalamic-pituitary-adrenal (HPA)-axis-related endocrine diseases (1.38 (1.17-1.62)), and the association was stronger for having multiple endocrine diseases, compared to having one (odds ratio (95% CI) = 1.24 (1.19-1.30), 1.35 (1.27-1.44), and 1.52 (1.52-1.53) for 1, 2, and ≥ 3, respectively). Sequential mediation analyses showed that the association between childhood maltreatment and endocrine diseases was consistently and most distinctly mediated by psychological adversities (15.38 ~ 44.97%), while unfavorable lifestyle (10.86 ~ 25.32%) was additionally noted for type 2 diabetes whereas suboptimal SES (14.42 ~ 39.33%) for HPA-axis-related endocrine diseases. CONCLUSIONS: Our study demonstrates that adverse psychological sequel of childhood maltreatment constitutes the main pathway to multiple endocrine diseases, particularly type 2 diabetes and HPA-axis-related endocrine diseases. Therefore, increased access to evidence-based mental health services may also be pivotal in reducing the risk of endocrine diseases among childhood maltreatment-exposed individuals.

Proteomic associations with forced expiratory volume: a Mendelian randomisation study.

BACKGROUND: A decline in forced expiratory volume (FEV1) is a hallmark of respiratory diseases that are an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. METHODS: Data from the population-based AGES-Reykjavik study were used. Serum proteomic measurements were done using 4782 DNA aptamers (SOMAmers). Data from 1479 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional two-sample Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). RESULTS: In observational analyses, 530 SOMAmers were associated with FEV1 after multiple testing adjustment (FDR < 0.05). The most significant were Retinoic Acid Receptor Responder 2 (RARRES2), R-Spondin 4 (RSPO4) and Alkaline Phosphatase, Placental Like 2 (ALPPL2). Of the 257 SOMAmers with genetic instruments available, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta (ERO1B) and Apolipoprotein M (APOM). THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. CONCLUSIONS: In summary, this large scale proteogenomic analyses of FEV1 reveals circulating protein markers of FEV1, as well as several proteins with potential causality to lung function.

Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.

The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n = 719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Vascular Age Assessed From an Uncalibrated, Noninvasive Pressure Waveform by Using a Deep Learning Approach: The AI-VascularAge Model.

BACKGROUND: Aortic stiffness, assessed as carotid-femoral pulse wave velocity, provides a measure of vascular age and risk for adverse cardiovascular disease outcomes, but it is difficult to measure. The shape of arterial pressure waveforms conveys information regarding aortic stiffness; however, the best methods to extract and interpret waveform features remain controversial. METHODS: We trained a convolutional neural network with fixed-scale (time and amplitude) brachial, radial, and carotid tonometry waveforms as input and negative inverse carotid-femoral pulse wave velocity as label. Models were trained with data from 2 community-based Icelandic samples (N=10 452 participants with 31 126 waveforms) and validated in the community-based Framingham Heart Study (N=7208 participants, 21 624 waveforms). Linear regression rescaled predicted negative inverse carotid-femoral pulse wave velocity to equivalent artificial intelligence vascular age (AI-VA). RESULTS: The AI-VascularAge model predicted negative inverse carotid-femoral pulse wave velocity with R2=0.64 in a randomly reserved Icelandic test group (n=5061, 16%) and R2=0.60 in the Framingham Heart Study. In the Framingham Heart Study (up to 18 years of follow-up; 479 cardiovascular disease, 200 coronary heart disease, and 213 heart failure events), brachial AI-VA was associated with incident cardiovascular disease adjusted for age and sex (model 1; hazard ratio, 1.79 [95% CI, 1.50-2.40] per SD; P<0.0001) or adjusted for age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, prevalent diabetes, hypertension treatment, and current smoking (model 2; hazard ratio, 1.50 [95% CI, 1.24-1.82] per SD; P<0.0001). Similar hazard ratios were demonstrated for incident coronary heart disease and heart failure events and for AI-VA values estimated from carotid or radial waveforms. CONCLUSIONS: Our results demonstrate that convolutional neural network-derived AI-VA is a powerful indicator of vascular health and cardiovascular disease risk in a broad community-based sample.

Proteomic prediction of incident heart failure and its main subtypes.

AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables. METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study. CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.

Adverse childhood experiences and psychological functioning among women with schizophrenia or bipolar disorder: population-based study.

BACKGROUND: Adverse childhood experiences (ACEs) are well-known risk factors for schizophrenia and bipolar disorder. AIMS: The aim was to study the associations between specific ACEs and psychological functioning in women with schizophrenia or bipolar disorder. METHOD: Among 29 367 women (mean age 44 years) from the Icelandic Stress-And-Gene-Analysis (SAGA) study, 534 (1.8%, mean age 40) reported having been diagnosed with schizophrenia or bipolar disorder, which were combined to 'severe mental disorders'. Participants reported on 13 types of ACEs, childhood deprivation and psychological functioning (defined as coping ability and current symptoms of depression, anxiety and sleep disturbances). Adjusted Poisson regression calculated prevalence ratios (PRs) between ACEs and severe mental disorders. Linear regression assessed the association between ACEs and psychological functioning among women with a severe mental disorder. RESULTS: Women with a severe mental disorder reported more ACEs (mean 4.57, s.d. = 2.82) than women without (mean 2.51, s.d. = 2.34) in a dose-dependent manner (fully-adjusted PR = 1.23 per ACE, 95% CI 1.20-1.27). After mutual adjustment for other ACEs, emotional abuse, sexual abuse, mental illness of a household member, emotional neglect, bullying and collective violence were associated with severe mental disorders. Among women with severe mental disorders, a higher number of ACEs was associated with increased symptom burden of depression (ß = 2.79, 95% CI = 1.19-4.38) and anxiety (ß = 2.04, 95% CI = 0.99-3.09) including poorer sleep quality (ß = 0.83, 95% CI = 0.07-1.59). Findings were similar for schizophrenia and bipolar disorder separately. CONCLUSION: Women with schizophrenia or bipolar disorder show a strong history of ACEs, which may interfere with their psychological functioning and, therefore, need to be addressed as part of their treatment, for example, with trauma-focused psychotherapy.

Trends of perceived disruption in healthcare services during the pandemic: findings from the COVID-19 National Resilience Cohort in Iceland.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused major disruptions in healthcare services worldwide. Yet, little is known about the association between perceived disruption in healthcare services and socio-demographic factors, pre-existing health conditions as well as concurrent physical and psychological symptoms. METHODS: Leveraging data from the Icelandic COVID-19 National Resilience Cohort, we performed a repeated measure analysis among 15 754 participants who responded to the question on perceived disruption in healthcare services from December 2020 to July 2021, to explore its association with socio-demographic factors, health indicators and conditions. Furthermore, we performed a longitudinal analysis among 7848 participants with two repeated measures to explore the association between timing and duration of perceived disruption in healthcare services and changes in depression, anxiety, sleep quality and somatic symptoms. RESULTS: The prevalence of perceived disruption in healthcare services slightly decreased over time (P < 0.01). Perceived disruption in healthcare services was more prevalent among individuals with pre-existing health conditions, i.e. history of psychiatric disorders (prevalence ratio = 1.59, 95% confidence interval 1.48-1.72) and chronic somatic conditions [1.40 (1.30-1.52)]. However, no increase in the prevalence of perceived disruption in healthcare services was observed among individuals diagnosed with COVID-19 [0.99 (0.84-1.18)]. Moreover, we found that emerging perceived disruption in healthcare services was associated with an increase in symptoms of mental illness during the pandemic (ßs 0.06-0.68). CONCLUSIONS: A disruption in healthcare services during the COVID-19 pandemic was reported by vulnerable groups, while the Icelandic healthcare system managed to maintain accessible services to individuals with COVID-19.