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PURPOSE: Systemizer Profile Questionnaire (SPQ), which has not been used before, investigates difficulties in mentalisation, sensory- and/or social sensitivity and social cognition (MSSSC) in subjects with Autism-Spectrum-Disorders (ASD) with and without Attention-Deficit-Hyperactivity-Disorder (ADHD). The aim of this study was to evaluate the reliability and validity of the SPQ domains, and to assess the predictive validity of the SPQ against the Ritvo Autism Asperger Diagnostic Scale (RAADS). METHODS: Three-hundred-fifty-four study subjects with ICD-10 verified ASD confirmed by RAADS and 354 controls matched on age group and gender were recruited and evaluated systematically with SPQ, standardized questions about demographic and clinical data. Hypothesized SPQ subscales formed from 85 items were evaluated using confirmatory factor analysis (CFA). Resulting revised sub-scales were confirmed using item response theory (IRT) and the predictive validity of the SPQ scores was evaluated using RAADS scores above 64 as the standard. RESULTS: Twenty-two of the original 85 items were removed, resulting in an instrument with 63 items across nine psychometrically valid domains. These domains had high sensitivity (range: 0.64 to 0.84), and high specificity (range: 0.73 to 0.90). Positive predictive values (range: 0.76 to 0.89) and negative predictive values (range: 0.69 to 0.90) were also high. For the total SPQ score the sensitivity was 0.95, the specificity was 0.87, the positive predictive value was 0.88 and the negative predictive value was 0.95. CONCLUSION: SPQ domains are valid descriptions/profiles of MSSSC given that ASD is confirmed by RAADS, though irrelevant if not, as SPQ is not a diagnostic instrument.
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AIMS/HYPOTHESIS: Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes. METHODS: We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose. RESULTS: We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone. CONCLUSIONS/INTERPRETATION: Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.
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Background: Although the persistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, evidence from large observational studies beyond one year post diagnosis remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19. Methods: This multinational study included 64,880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis. Findings: During up to 27 months of follow-up, 34.5% participants (22,382/64,880) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25 [1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis. Interpretation: These data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness, highlighting the importance of continued monitoring and alleviation of these targeted core symptoms. Funding: This work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon 2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.
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BACKGROUND: The healthy donor effect (HDE) is a selection bias caused by the health criteria blood donors must meet. It obscures investigations of beneficial/adverse health effects of blood donation and complicates the generalizability of findings from blood donor cohorts. To further characterize the HDE we investigated how self-reported health and lifestyle are associated with becoming a blood donor, lapsing, and donation intensity. Furthermore, we examined differences in mortality based on donor status. STUDY DESIGN AND METHODS: The Danish National Health Survey was linked to the Scandinavian Donations and Transfusions (SCANDAT) database and Danish register data. Logistic- and normal regression was used to compare baseline characteristics and participation. Poisson regression was used to investigate future donation choices. Donation intensity was explored by the Anderson-Gill model and Poisson regression. Mortality was investigated using Poisson regression. RESULTS: Blood donors were more likely to participate in the surveys, OR = 2.45 95% confidence interval (2.40-2.49) than non-donors. Among survey participants, better self-reported health and healthier lifestyle were associated with being or becoming a blood donor, donor retention, and to some extent donation intensity, for example, current smoking conveyed lower likelihood of becoming a donor, OR = 0.70 (0.66-0.75). We observed lower mortality for donors and survey participants, respectively, compared with non-participating non-donors. CONCLUSION: We provide evidence that blood donation is associated with increased likelihood to participate in health surveys, possibly a manifestation of the HDE. Furthermore, becoming a blood donor, donor retention, and donation intensity was associated with better self-reported health and healthier lifestyles.
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Donantes de Sangre , Estado de Salud , Humanos , Encuestas y Cuestionarios , Estilo de Vida , Donación de SangreRESUMEN
A novel risk locus at 4q32.2, located between the Nuclear Assembly Factor 1 (NAF1) and Follistatin Like 5 (FSTL5) genes, was associated with increased risk of developing colorectal cancer (CRC), with SNP rs17042479 being the most associated. However, the link between CRC development and the risk locus at 4q32.2 is unknown. We investigated the promoter activity of NAF1 and FSTL5 and analyzed the risk locus at 4q32.2 as gene regulatory region. Our results showed that the activity of the FSTL5 promoter was low compared to the NAF1 promoter. Analyses of the NAF1 promoter in conjunction with the region containing the risk locus at 4q32.2 showed that the region functions as gene regulatory region with repressor activity on NAF1 promoter activity. The SNP rs17042479(G) increased the repressor effect of the region. CRC patients' biopsies were genotyped for SNP rs17042479(A/G), and NAF1 expression profiles were examined. We found an association between SNP rs17042479(G), cancer stage and tumor location. Additionally, patients with SNP rs17042479(G) showed lower NAF1 expression in comparison to patients with SNP rs17042479(A) in tumor tissue and the NAF1 expression in tumor tissue was lower compared to healthy tissue. The results in the study imply that reduced NAF1 expression in the tumor contribute to a more aggressive phenotype. Furthermore, this study suggests that the SNP rs17042479(G) change the expression of NAF1 and thereby increases the risk of developing CRC.
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Neoplasias Colorrectales , Factores de Transcripción NFI , Neoplasias Colorrectales/genética , Genotipo , Humanos , Factores de Transcripción NFI/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Ribonucleoproteínas/genéticaRESUMEN
BACKGROUND: Long-term mental and physical health consequences of COVID-19 (long COVID) are a persistent public health concern. Little is still known about the long-term mental health of non-hospitalised patients with COVID-19 with varying illness severities. Our aim was to assess the prevalence of adverse mental health symptoms among individuals diagnosed with COVID-19 in the general population by acute infection severity up to 16 months after diagnosis. METHODS: This observational follow-up study included seven prospectively planned cohorts across six countries (Denmark, Estonia, Iceland, Norway, Sweden, and the UK). Participants were recruited from March 27, 2020, to Aug 13, 2021. Individuals aged 18 years or older were eligible to participate. In a cross-sectional analysis, we contrasted symptom prevalence of depression, anxiety, COVID-19-related distress, and poor sleep quality (screened with validated mental health instruments) among individuals with and without a diagnosis of COVID-19 at entry, 0-16 months from diagnosis. In a cohort analysis, we further used repeated measures to estimate the change in mental health symptoms before and after COVID-19 diagnosis. FINDINGS: The analytical cohort consisted of 247â249 individuals, 9979 (4·0%) of whom were diagnosed with COVID-19 during the study period. Mean follow-up was 5·65 months (SD 4·26). Participants diagnosed with COVID-19 presented overall with a higher prevalence of symptoms of depression (prevalence ratio [PR] 1·18 [95% CI 1·03-1·36]) and poorer sleep quality (1·13 [1·03-1·24]) but not symptoms of anxiety (0·97 [0·91-1·03]) or COVID-19-related distress (1·05 [0·93-1·20]) compared with individuals without a COVID-19 diagnosis. Although the prevalence of depression and COVID-19-related distress attenuated with time, individuals diagnosed with COVID-19 but never bedridden due to their illness were consistently at lower risk of depression (PR 0·83 [95% CI 0·75-0·91]) and anxiety (0·77 [0·63-0·94]) than those not diagnosed with COVID-19, whereas patients who were bedridden for more than 7 days were persistently at higher risk of symptoms of depression (PR 1·61 [95% CI 1·27-2·05]) and anxiety (1·43 [1·26-1·63]) than those not diagnosed throughout the study period. INTERPRETATION: Severe acute COVID-19 illness-indicated by extended time bedridden-is associated with long-term mental morbidity among recovering individuals in the general population. These findings call for increased vigilance of adverse mental health development among patients with a severe acute disease phase of COVID-19. FUNDING: Nordforsk, Horizon2020, Wellcome Trust, and Estonian Research Council.
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COVID-19 , COVID-19/complicaciones , COVID-19/epidemiología , Prueba de COVID-19 , Estudios Transversales , Estudios de Seguimiento , Humanos , Salud Mental , Morbilidad , Síndrome Post Agudo de COVID-19RESUMEN
The mammalian Caudal-related homeobox transcription factor 2 (CDX2) plays a key role in the homeobox regulatory network and is essential in regulating the expression of several homeobox (HOX) genes during embryonic development, particularly in the gut. Genome-wide CDX2 chromatin immunoprecipitation analysis and expression data from Caco2 cells also suggests a role for CDX2 in the regulation of HOXB4 gene expression in the intestinal epithelium. Thus, the aim of this study was to investigate whether HOXB4 gene expression is regulated by CDX2 in the intestinal epithelium. We demonstrated binding of CDX2 to four different CDX2 binding sites in an enhancer region located upstream of the HOXB4 transcription start site. Mutations in the CDX2 binding sites reduced HOXB4 gene activity, and knock down of endogenous CDX2 expression by shRNA reduced HOXB4 gene expression. This is the first report demonstrating the CDX2 regulation of HOXB4 gene expression in the developed intestinal epithelium, indicating a possible role for HOXB4 in intestinal homeostasis.
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Factor de Transcripción CDX2/metabolismo , Proteínas de Homeodominio/metabolismo , Factores de Transcripción/metabolismo , Secuencia de Bases , Sitios de Unión , Factor de Transcripción CDX2/antagonistas & inhibidores , Factor de Transcripción CDX2/genética , Células CACO-2 , Línea Celular , Inmunoprecipitación de Cromatina , Ensayo de Cambio de Movilidad Electroforética , Elementos de Facilitación Genéticos , Células Epiteliales/citología , Células Epiteliales/metabolismo , Expresión Génica , Genes Reporteros , Proteínas de Homeodominio/genética , Humanos , Intestinos/citología , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factores de Transcripción/genética , Sitio de Iniciación de la TranscripciónRESUMEN
INTRODUCTION: The associations between ABO blood group and cancer risk have been studied repeatedly, but results have been variable. Consistent associations have only been reported for pancreatic and gastric cancers. MATERIALS AND METHODS: We estimated associations between different ABO blood groups and site-specific cancer risk in a large cohort of healthy blood donors from Sweden and Denmark. RESULTS: A total of 1.6 million donors were followed over 27 million person-years (20 million in Sweden and 7 million in Denmark). We observed 119,584 cancer cases. Blood groups A, AB and B were associated either with increased or decreased risk of cancer at 13 anatomical sites (p≤0.05), compared to blood group O. Consistent with assessment using a false discovery rate approach, significant associations with ABO blood group were observed for cancer of the pancreas, breast, and upper gastrointestinal tract (mouth, salivary glands, pharynx, esophageal adenocarcinoma and stomach). DISCUSSION: Our study reconfirms the association between ABO blood group and cancer risk and exact underlying mechanisms involved needs further research.
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Sistema del Grupo Sanguíneo ABO/genética , Neoplasias/etiología , Sistema del Grupo Sanguíneo ABO/efectos adversos , Adulto , Donantes de Sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Riesgo , Adulto JovenRESUMEN
BACKGROUND: ABO blood groups have been shown to be associated with increased risks of venous thromboembolic and arterial disease. However, the reported magnitude of this association is inconsistent and is based on evidence from small-scale studies. METHODS AND RESULTS: We used the SCANDAT2 (Scandinavian Donations and Transfusions) database of blood donors linked with other nationwide health data registers to investigate the association between ABO blood groups and the incidence of first and recurrent venous thromboembolic and arterial events. Blood donors in Denmark and Sweden between 1987 and 2012 were followed up for diagnosis of thromboembolism and arterial events. Poisson regression models were used to estimate incidence rate ratios as measures of relative risk. A total of 9170 venous and 24 653 arterial events occurred in 1 112 072 individuals during 13.6 million person-years of follow-up. Compared with blood group O, non-O blood groups were associated with higher incidence of both venous and arterial thromboembolic events. The highest rate ratios were observed for pregnancy-related venous thromboembolism (incidence rate ratio, 2.22; 95% confidence interval, 1.77-2.79), deep vein thrombosis (incidence rate ratio, 1.92; 95% confidence interval, 1.80-2.05), and pulmonary embolism (incidence rate ratio, 1.80; 95% confidence interval, 1.71-1.88). CONCLUSIONS: In this healthy population of blood donors, non-O blood groups explain >30% of venous thromboembolic events. Although ABO blood groups may potentially be used with available prediction systems for identifying at-risk individuals, its clinical utility requires further comparison with other risk markers.
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Sistema del Grupo Sanguíneo ABO/análisis , Arteriopatías Oclusivas/epidemiología , Donantes de Sangre/estadística & datos numéricos , Tromboembolia/epidemiología , Sistema del Grupo Sanguíneo ABO/genética , Adulto , Arteriopatías Oclusivas/genética , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Embarazo , Complicaciones Cardiovasculares del Embarazo/epidemiología , Complicaciones Cardiovasculares del Embarazo/genética , Embolia Pulmonar/epidemiología , Embolia Pulmonar/genética , Recurrencia , Análisis de Regresión , Riesgo , Suecia/epidemiología , Tromboembolia/genética , Trombofilia/genética , Trombosis de la Vena/epidemiología , Trombosis de la Vena/genética , Adulto JovenRESUMEN
BACKGROUND: It has been suggested that blood donors could have an increased risk of polycythemia vera (PV). However, no study has assessed whether frequent donors have a higher PV risk than less frequent donors. STUDY DESIGN AND METHODS: From the Scandinavian Donations and Transfusions (SCANDAT2) database, we established a cohort of blood donors who had donated whole blood at least once between 1980 and 2012. Within this cohort we first assessed the risk of PV, comparing the donors to the general population using standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs). To assess the association between frequency of blood donation and risk of PV we then conducted a case-control study nested within the cohort, where we compared prior donation activity among donors who were diagnosed with PV and matched controls. Here odds ratios (ORs) were used as measures of relative risk comparing donors with different donation frequency. RESULTS: Among 1.4 million donors in the cohort a total of 271 donors developed PV, yielding a SIR of 1.00 (95% CI, 0.89-1.13) compared to the general population. The nested case-control study showed no association between donation frequency and risk of PV. The OR of PV comparing donors who had made at least 33 donations in the period from 3 to 22 years before diagnosis of the case, to donors with one to eight donations in the same period was 1.01 (95% CI, 0.51-1.97). CONCLUSIONS: We find no evidence of excess risk of PV among blood donors or of an association between donation frequency and PV risk.
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Donantes de Sangre , Policitemia Vera/etiología , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Policitemia Vera/epidemiología , Riesgo , Países Escandinavos y Nórdicos/epidemiologíaRESUMEN
Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL occurrence among 7413 recipients of blood from 796 donors diagnosed with CLL after donation cessation, and among 80, 431 recipients of blood from 7477 matched CLL-free donors. During follow-up, 12 and 107 cases of CLL occurred among the exposed and unexposed recipients, respectively, yielding a relative risk of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized transfusion experience over more than 30 years indicate that MBL/CLL transmission does not contribute importantly to recipient CLL risk.