Thromboembolic Risk in Patients With Pneumonia and New-Onset Atrial Fibrillation Not Receiving Anticoagulation Therapy

IMPORTANCE: New-onset atrial fibrillation (AF) is commonly reported in patients with severe infections. However, the absolute risk of thromboembolic events without anticoagulation remains unknown. OBJECTIVE: To investigate the thromboembolic risks associated with AF in patients with pneumonia, assess the risk of recurrent AF, and examine the association of initiation of anticoagulation therapy with new-onset AF. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used linked Danish nationwide registries. Participants included patients hospitalized with incident community-acquired pneumonia in Denmark from 1998 to 2018. Statistical analysis was performed from August 15, 2021, to March 12, 2022. EXPOSURES: New-onset AF. MAIN OUTCOMES AND MEASURES: Thromboembolic events, recurrent AF, and all-cause death. Estimated risks were calculated for thromboembolism without anticoagulation therapy, new hospital or outpatient clinic contact with AF, initiation of anticoagulation therapy, and all-cause death at 1 and 3 years of follow-up. Death was treated as a competing risk, and inverse probability of censoring weights was used to account for patient censoring if they initiated anticoagulation therapy conditioned on AF. RESULTS: Among 274 196 patients hospitalized for community-acquired pneumonia, 6553 patients (mean age [SD], 79.1 [11.0] years; 3405 women [52.0%]) developed new-onset AF. The 1-year risk of thromboembolism was 0.8% (95% CI, 0.8%-0.8%) in patients without AF vs 2.1% (95% CI, 1.8%-2.5%) in patients with new-onset AF without anticoagulation; this risk was 1.4% (95% CI, 1.0%-2.0%) among patients with AF with intermediate stroke risk and 2.8% (95% CI, 2.3%-3.4%) in patients with AF with high stroke risk. Three-year risks were 3.5% (95% CI, 2.8%-4.3%) among patients with intermediate stroke risk and 5.3% (95% CI, 4.4%-6.5%) among patients with high stroke risk. Among patients with new-onset AF, 32.9% (95% CI, 31.8%-34.1%) had a new hospital contact with AF, and 14.0% (95% CI, 13.2%-14.9%) initiated anticoagulation therapy during the 3 years after incident AF diagnosis. At 3 years, the all-cause mortality rate was 25.7% (95% CI, 25.6%-25.9%) in patients with pneumonia without AF vs 49.8% (95% CI, 48.6%-51.1%) in patients with new-onset AF. CONCLUSIONS AND RELEVANCE: This cohort study found that new-onset AF after community-acquired pneumonia was associated with an increased risk of thromboembolism, which may warrant anticoagulation therapy. Approximately one-third of patients had a new hospital or outpatient clinic contact for AF during the 3-year follow-up, suggesting that AF triggered by acute infections is not a transient, self-terminating condition that reverses with resolution of the infection

Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

Background and aims Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT

Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

Virally suppressed HIV-positive individuals on combination antiretroviral therapy who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality. The increased mortality was seen across different patient groups and for all causes of deat

The Incidence of AIDS-Defining Illnesses at a Current CD4 Count ≥200 Cells/µL in the Post-Combination Antiretroviral Therapy Era

The incidence of AIDS was higher in patients with a current CD4 count of 500-749 cells/µL compared to 750-999 cells/µL, but did not decrease further at higher CD4 levels. Results were similar in those virologically suppressed on combination antiretroviral therapy, suggesting immune reconstitution is incomplete until CD4 >750/µ

Genome-wide association for major depression through age at onset stratification:Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Background Major depressive disorder (MDD) is a disabling mood disorder and, despite a known heritable component, a large meta-analysis of GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease. Results We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. Conclusions We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of \ue2\u89\ua55 consecutive viral loads (VL) \ue2\u89\ua4500 copies/mL over \ue2\u89\ua51 year whilst ART-naive, with the last VL \ue2\u89\ua4500 copies/mL measured \ue2\u89\ua55 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe