Integrative analysis of clinical and epigenetic biomarkers of mortality.

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

Postoperative drainage for 6, 12, or 24 h after burr-hole evacuation of chronic subdural hematoma in symptomatic patients (DRAIN-TIME 2): study protocol for a nationwide randomized controlled trial.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common acute or subacute neurosurgical condition, typically treated by burr-hole evacuation and drainage. Recurrent CSDH occurs in 5-20% of cases and requires reoperation in symptomatic patients, sometimes repeatedly. Postoperative subdural drainage of maximal 48 h is effective in reducing recurrent hematomas. However, the shortest possible drainage time without increasing the recurrence rate is unknown. METHODS: DRAIN-TIME 2 is a Danish multi-center, randomized controlled trial of postoperative drainage time including all four neurosurgical departments in Denmark. Both incapacitated and mentally competent patients are enrolled. Patients older than 18 years, free of other intracranial pathologies or history of previous brain surgery, are recruited at the time of admission or no later than 6 h after surgery. Each patient is randomized to either 6, 12, or 24 h of passive subdural drainage following single burr-hole evacuation of a CSDH. Mentally competent patients are asked to complete the SF-36 questionnaire. The primary endpoint is CSDH recurrence rate at 90 days. Secondary outcome measures include SF-36 at 90 days, length of hospital stay, drain-related complications, and complications related to immobilization and mortality. DISCUSSION: This multi-center trial will provide evidence regarding the shortest possible drainage time without increasing the recurrence rate. The potential impact of this study is significant as we believe that a shorter drainage period may be associated with fewer drain-related complications, fewer complications related to immobilization, and shorter hospital stays-thus reducing the overall health service burden from this condition. The expected benefits for patients' lives and health costs will increase as the CSDH patient population grows. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15186366 . Registered in December 2020 and updated in October 2021. This protocol was developed in accordance with the SPIRIT Checklist and by use of the structured study protocol template provided by BMC Trials.

Embolization of the middle meningeal artery in patients with chronic subdural hematoma-a systematic review and meta-analysis.

BACKGROUND: Chronic subdural hematoma (CSDH) remains a neurosurgical condition with high recurrence rate after surgical treatment. The primary pathological mechanism is considered to be repeated microbleedings from fragile neo-vessels within the outer hematoma membrane. The neo-vessels are supplied from peripheral branches of the middle meningeal artery, and embolization of MMA (eMMA) has been performed to prevent re-bleeding episodes and thereby CSDH recurrence. OBJECTIVE: To evaluate the published evidence for the effect of eMMA in patients with recurrent CSDH. Secondarily, to investigate the effect of eMMA as an alternative to surgery for primary treatment of CSDH. METHOD: A systematic review of the literature on eMMA in patients with recurrent CSDH was conducted. PubMed, Embase, and Cochrane databases were reviewed using the search terms: Embolization, Medial Meningeal Artery, Chronic Subdural Haematoma, and Recurrence. Furthermore, the following mesh terms were used: Chronic Subdural Haematoma AND embolization AND medial meningeal artery AND recurrence. Eighteen papers were found and included. No papers were excluded. The number of patients with primary CSDH and the number of patients with recurrent CSDH treated with eMMA were listed. Furthermore, the number of recurrences in both categories was registered. RESULTS: Eighteen papers with a total of 191 included patients diagnosed with CSDH treated with eMMA for primary and recurrent CSDH were identified. Recurrence rate for patients treated with eMMA for recurrent CSDH was found to be 2.4%, 95% CI (0.5%; 11.0%), whereas the recurrence rate for patients treated with eMMA for primary CSDH was 4.1%, 95% CI (1.4%; 11.4%). CONCLUSION: eMMA is a minimally invasive procedure for treatment of CSDH. Although this study is limited by publication bias, it seems that this procedure may reduce recurrence rates compared with burr hole craniostomy for both primary and recurrent hematomas. A controlled study is warranted.

Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength.

Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55-90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73-90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the COL6A1 and CACNA1B genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, CEBPD, ID2 and BRCA1. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.

Early Dynamics of P-selectin and Interleukin 6 Predicts Outcomes in Ischemic Stroke.

BACKGROUND: Thromboinflammatory molecules connect the prothrombotic state, endothelial dysfunction, and systemic/local inflammation in the acute phase of ischemic stroke. METHODS: We prospectively investigated (1) serial changes in the levels of thromboinflammatory biomarkers in 76 patients with acute ischemic stroke (6, 24, and 72 hours after onset); (2) compared with 44 patients with asymptomatic severe (≥70%) carotid stenosis and 66 patients with Parkinson disease; and (3) we applied multiple regression methods, relating biological biomarkers combined with demographic data and comorbidities to poststroke infection, death, and functional outcome, and assessed the ability of the models to predict each outcome. RESULTS: Interleukin 6 (IL-6) levels and change of IL-6 concentrations by 72 hours correlated with the size of tissue damage indicated by S100B titers. Levels of IL-6 and P-selectin at 72 hours were higher in patients with large-artery versus lacunar stroke. High concentration of IL-6, monocyte chemotactic protein 1, and S100B at 6 hours were associated with poststroke infections; high concentration of IL-6, S100B, and high-sensitivity C-reactive protein (hsCRP) correlated with death. Change of P-selectin from 6 to 72 hours by 1 unit increased the incidence of poststroke infections with an odds ratio of 22.7; each 100 units of IL-6 at baseline increased the odds of death by 9‰, and at 72 hours, the odds of poststroke infections by 4‰. Each unit of baseline hsCRP elevated the odds of death by 7%. CONCLUSIONS: In regression models, in which biological, demographic, and comorbid factors were combined, those biological biomarkers predicted poor outcome with high accuracy, which were characterized by an increasing concentration by 72 hours. Two particular biomarkers emerged to predict outcomes besides hsCRP: early dynamic changes in the systemic levels of P-selectin and IL-6.

Does selenium supplementation affect thyroid function? Results from a randomized, controlled, double-blinded trial in a Danish population.

OBJECTIVE: Selenium is present in the active site of proteins important for thyroid hormone synthesis and metabolism. The objective of this study is to investigate the effect of selenium supplementation in different doses on thyroid function, under conditions of suboptimal dietary selenium intake. DESIGN: The Danish PREvention of Cancer by Intervention with SElenium pilot study (DK-PRECISE) is a randomized, double-blinded, placebo-controlled trial. A total of 491 males and females aged 60-74 years were randomized to 100 µg (n=124), 200 µg (n=122), or 300 µg (n=119) selenium-enriched yeast or matching yeast-based placebo tablets (n=126). A total of 361 participants, equally distributed across treatment groups, completed the 5-year intervention period. METHODS: Plasma samples were analyzed for selenium and serum samples for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) at baseline, and after 6 months, and 5 years of supplementation. RESULTS: Plasma selenium concentrations increased significantly and dose-dependently in treatment groups receiving selenium (P<0.001). Serum TSH and FT4 concentrations decreased significantly and dose-dependently by 0.066 mIU/l (P=0.010) and 0.11 pmol/l (P=0.015), respectively, per 100 µg/day increase, with insignificant differences between 6 months and 5 years. No significant effects were found for FT3 and FT3:FT4 ratio. CONCLUSIONS: In euthyroid subjects, selenium supplementation minutely and dose-dependently affects thyroid function, when compared with placebo, by decreasing serum TSH and FT4 concentrations. Based on these findings, selenium supplementation is not warranted under conditions of marginal selenium deficiency. However, a role for selenium supplementation in the treatment of autoimmune thyroid diseases is still unresolved.