Towards complete and error-free genome assemblies of all vertebrate species.

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1-4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.

Optimal surgical management of unifocal vs. multifocal NF-PNETs: a respective cohort study.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) represent 1-2% of pancreatic tumors, with recent guidelines recommending active surveillance for non-functioning PNETs (NF-PNETs) smaller than 2 cm. However, the management of multiple NF-PNETs, as well as the influence of tumor number on prognosis, remains under-researched. METHODS: This retrospective study analyzed NF-PNET patients who underwent pancreatic resection at Severance Hospital between February 1993 and August 2023, comparing the characteristics of patients diagnosed with multifocal tumors and those with unifocal tumors. A subgroup analysis of overall survival (OS) and recurrence-free survival (RFS) was performed based on multifocality employing the Kaplan-Meier method and the log-rank test. RESULTS: Of 187 patients, 169 (90.4%) had unifocal and 18 (9.6%) had multifocal tumors. Multifocal tumors were more likely to be diffusely spread, necessitating more total pancreatectomies (diffuse tumor location: 4.7% in unifocal vs. 38.9% in multifocal cases, p < 0.001; total pancreatectomy: 4.1% in unifocal vs. 33.3% in multifocal cases, p < 0.001). In patients with NF-PNET who underwent the same extent of pancreatic resection, no significant difference in the incidence of complication was observed regardless of multifocality. Moreover, no significant difference in OS was seen between the unifocal and multifocal groups (log-rank test: p = 0.93). However, the multifocal group exhibited a poorer prognosis in terms of RFS compared to the unifocal group (log-rank test: p = 0.004) Hereditary syndrome, tumor grade, size, lymphovascular invasion, and lymph node metastasis were key factors in the recurrence. CONCLUSION: This study's findings suggest that the presence of multiple tumors was associated with poorer recurrence-free survival but did not affect long-term survival following surgery. Given the long-term oncologic outcome and quality of life following surgery, resection of tumors over 2 cm is advisable in patients with multifocal PNETs, while a cautious "wait-and-see" approach for smaller tumors (under 2 cm) can minimize the extent of resection and improve the quality of life. In cases with only small multifocal NF-PNETs (< 2 cm), immediate resection may not be crucial, but the higher recurrence rate than that in solitary NF-PNET necessitates intensified surveillance.

Serum cortisol and neuroticism for post-traumatic stress disorder over 2 years in patients with physical injuries.

AIM: This study aimed to explore the relationships between serum cortisol levels, personality traits, and the development of Post-Traumatic Stress Disorder (PTSD) over 2 years among individuals with physical injuries. METHODS: Participants were consecutively recruited from a trauma center and followed prospectively for 2 years. At baseline, serum cortisol levels were measured, and personality traits were categorized into five dimensions (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness), using the Big Five Inventory-10. The diagnosis of PTSD during follow-up (at 3, 6, 12, and 24 months post-injury) was determined using the Clinician-Administered PTSD Scale for DSM-5. Binary and multinomial logistic regression analyses were conducted to examine the interactions between cortisol levels, personality traits, and PTSD development. RESULTS: Among 923 patients analyzed, 112 (12.1%) were diagnosed with PTSD at some point during the study period, with prevalence rates decreasing from 8.8% at 3 months to 3.7% at 24 months post-injury. Direct associations between cortisol levels or personality traits and PTSD were not observed. However, a significant interaction between lower cortisol levels and higher Neuroticism in relation to PTSD risk was identified, especially during the early follow-up periods (3 to 6 months), but this association waned from the 12-month follow-up onward. CONCLUSION: Our findings reveal Neuroticism-dependent associations between serum cortisol levels and PTSD development, exhibiting temporal variations. These results suggest that PTSD development may be influenced by a complex, time-sensitive interplay of biological and psychosocial factors, underscoring the importance of considering individual differences in stress reactivity and personality in PTSD research and treatment.

Hierarchically Plied Mechano-Electrochemical Energy Harvesting Using a Scalable Kinematic Sensing Textile Woven from a Graphene-Coated Commercial Cotton Yarn.

Wearable sensing systems are suitable for monitoring human motion. To realize a cost-effective and self-powered strain-sensing fiber, we developed a mechano-electrochemical harvesting yarn and textile using hierarchically arranged plied yarns composed of meter-long graphene-coated cotton yarns. Such a fiber relies on the principle of electrochemical capacity change to convert mechanical energy to electric energy. Further, this harvester can be used as a self-powered strain sensor because its output depends on mechanical stimuli. Additionally, the yarn can be woven into a kinematic sensing textile that measures the strength and direction of the applied force. The textile-type harvester can successfully detect various human movements such as pressing, bending, and stretching. The proposed sensing fiber will pave the way for the development of advanced wearable systems for ubiquitous healthcare in the future.

Multiple serum biomarkers for predicting suicidal behaviours in depressive patients receiving pharmacotherapy.

BACKGROUND: Predictive values of multiple serum biomarkers for suicidal behaviours (SBs) have rarely been tested. This study sought to evaluate and develop a panel of multiple serum biomarkers for predicting SBs in outpatients receiving a 12-month pharmacotherapy programme for depressive disorders. METHODS: At baseline, 14 serum biomarkers and socio-demographic/clinical characteristics including previous suicidal attempt and present suicidal severity were evaluated in 1094 patients with depressive disorders without a bipolar diagnosis. Of these, 884 were followed for increased suicidal severity and fatal/non-fatal suicide attempt outcomes over a 12-month treatment period. Individual and combined effects of serum biomarkers on these two prospective SBs were estimated using logistic regression analysis after adjustment for relevant covariates. RESULTS: Increased suicidal severity and fatal/non-fatal suicide attempt during the 12-month pharmacotherapy were present in 155 (17.5%) and 38 (4.3%) participants, respectively. Combined cortisol, total cholesterol, and folate serum biomarkers predicted fatal/non-fatal suicide attempt, and these with interleukin-1 beta and homocysteine additionally predicted increased suicidal severity, with clear gradients robust to adjustment (p values < 0.001). CONCLUSIONS: Application of multiple serum biomarkers could considerably improve the predictability of SBs during the outpatient treatment of depressive disorders, potentially highlighting the need for more frequent monitoring and risk appraisal.

Psychological and Personality Characteristics Associated With COVID-19 Vaccination Behavior in Korean General Population.

BACKGROUND: This study characterized coronavirus disease 2019 (COVID-19) vaccination behavior in the Korean general population using cluster analysis and explored related psychological factors. METHODS: We categorized 1,500 individuals based on their attitudes toward COVID-19 vaccination using hierarchical clustering and identified their level of vaccine acceptance. We examined the associations between vaccine acceptance and behavioral and psychological characteristics. RESULTS: Clustering revealed three groups according to vaccine acceptance: 'totally accepting' (n = 354, 23.6%), 'somewhat accepting' (n = 523, 34.9%), and 'reluctant' (n = 623, 41.5%). Approximately 60% of all participants who belonged to the 'totally accepting' and 'somewhat accepting' groups were willing to receive a COVID-19 vaccine despite concerns about its side effects. High vaccine acceptance was associated with older age, regular influenza vaccination, and trust in formal sources of information. Participants with high vaccine acceptance had higher levels of gratitude, extraversion, agreeableness, and conscientiousness, and lower levels of depression, anxiety, and neuroticism. CONCLUSIONS: People weighed the benefits of COVID-19 vaccination against the risk of side effects when deciding to receive the COVID-19 vaccine. Our findings also indicate that this vaccination behavior may be affected by coping mechanisms and psychological factors.

High-Performance Biscrolled Ni-Fe Yarn Battery with Outer Buffer Layer.

The increasing demand for portable and wearable electronics has promoted the development of safe and flexible yarn-based batteries with outstanding electrochemical properties. However, achieving superior energy storage performance with a high active material (AM) load and long cycle life with this device format remains a challenge. In this study, a stable and rechargeable high-performance aqueous Ni-Fe yarn battery was constructed via biscrolling to embed AMs within helical carbon nanotube (CNT) yarn corridors. Owing to the high load of charge storage nanoparticles (NPs; above 97 wt%) and the outer neat CNT layer, the buffered biscrolled Ni-Fe yarn battery demonstrates excellent linear capacity (0.053 mAh/cm) and cycling stability (60.1% retention after 300 charge/discharge cycles) in an aqueous electrolyte. Moreover, our flexible yarn battery exhibits maximum energy/power densities of 422 mWh/cm3 and 7535 mW/cm3 based on the total volume of the cathode and anode, respectively, which exceed those reported for many flexible Ni-Fe batteries. Thus, biscrolled Ni-Fe yarn batteries are promising candidates for next-generation conformal energy solutions.

Prospective associations of multimodal serum biomarkers with 12-week and 12-month remission in patients with depressive disorders receiving stepwise psychopharmacotherapy.

Prognostic biomarkers for depression treatment outcomes have yet to be elucidated. This study sought to evaluate whether a multi-modal serum biomarker panel was prospectively associated with 12-week and 12-month remission in outpatients with depressive disorders receiving stepwise psychopharmacotherapy. At baseline, 14 serum biomarkers and socio-demographic/clinical characteristics were evaluated in 1094 patients. They received initial antidepressant monotherapy followed, as required by a protocol of successive alternative pharmacological strategies administered in 3-week steps during the acute (3-12 week) phase (N = 1086), and in 3-month steps during the continuation (6-12 month) phase (N = 884). Remission was defined as a Hamilton Depression Rating Scale score of ≤ 7. Remission was achieved in 490 (45.1%) over the 12-week, and in 625 (70.7%) over the 12-month, treatment periods. Combination scores of four serum biomarkers (high-sensitivity C-reactive protein, interleukin-1 beta, interleukin-6, and leptin) were prospectively associated with 12-week remission; and four (high-sensitivity C-reactive protein, tumor necrosis factor-alpha, interleukin-1 beta, and brain-derived neurotrophic factor) were prospectively associated with 12-month remission in a clear gradient manner (P-values < 0.001) and after adjustment for relevant covariates. These associations were evident after the Step 1 treatment monotherapy but weakened with increasing treatment steps, falling below statistical significance after 4 + treatment steps. Application of combined multiple serum biomarkers, particularly on inflammatory markers, could improve predictability of remission at acute and continuation treatment phases for depressive disorders. Patients with unfavourable biomarkers might require alternative treatment regimes for better outcomes.

Interaction effect between childhood abuse and interleukin-1ß levels on suicidality in depressed patients.

INTRODUCTION: The roles of childhood abuse and interleukin (IL)-1ß levels, a representative pro-inflammatory cytokine, in suicidal behavior are unclear. This study investigated the main and interactive effects of childhood abuse and IL-1ß levels on suicidal behavior in patients with a depressive disorder before and after pharmacological treatment. METHODS: At baseline, exposure to self-reported childhood abuse, including emotional, physical, and sexual abuse, before the age of 16 years, and IL-1ß levels, were measured in 1,094 outpatients with a depressive disorder, 884 of whom were followed for 1 year. Suicidal behavior was evaluated, including previous suicide attempts (at baseline), suicidal ideation (at baseline and follow-up), and fatal/non-fatal suicide attempts (at follow-up). The main and interaction effects of self-reported childhood abuse and IL-1ß level on the four types of suicidal behavior were analyzed using logistic regression after adjusting for covariates. RESULTS: Individual associations of self-reported childhood abuse were significant only with previous suicidal attempt but not with other suicidal behaviors. There was no significant association of plasma IL-1ß level with any suicidal behavior. There were significant interactive associations of self-reported childhood abuse and a high IL-1ß level on previous suicide attempts, baseline suicidal ideation, and fatal/non-fatal suicidal attempts during follow-up. CONCLUSION: Suicidal behavior in patients with a depressive disorder could be influenced by considering the interactive effect of childhood abuse and IL-1ß levels. Our study suggests that childhood trauma and biochemical factors play roles in the pathology of suicide in depressed patients.

Modifying Effect of the Interleukin-18 Level on the Association between BDNF Methylation and Long-Term Cardiovascular Outcomes in Patients with Acute Coronary Syndrome.

This study investigated the potential modifying effects of the level of the serum interleukin-18 (IL-18) on the association between BDNF methylation status and long-term cardiovascular outcomes in patients with acute coronary syndrome (ACS). Hospitalized ACS patients were recruited sequentially from 2006 to 2012. At baseline, the IL-18 level and BDNF methylation status were evaluated in 969 patients who were followed for major adverse cardiac events (MACEs) for 5-12 years, until 2017 or death. The time to first composite or individual MACE was compared between individuals with lower and higher average BDNF methylation levels (in the low- and high-IL-18 groups, respectively) using a Cox proportional hazards model. After adjusting for potential covariates, the modifying effects of IL-18 and average BDNF methylation levels on the initial composite and individual MACEs were examined. In the high-IL-18 group, but not in the low-IL-18 group, a higher average BDNF methylation level was associated with increases in composite MACEs (HR (95% CI) = 2.15 (1.42-3.26)), all-cause mortality (HR (95% CI) = 1.89 (1.11-3.22)), myocardial infarction (HR (95% CI) = 1.98 (1.07-3.67)), and percutaneous coronary intervention (HR (95% CI) = 1.81 (1.01-3.23)), independent of confounding variables. The interaction effect between the IL-18 and average BDNF methylation levels on composite MACEs (p = 0.019) and myocardial infarction (p = 0.027) was significant after adjusting for covariates. Analysis of BDNF methylation status and IL-18 levels may help identify ACS patients who are most likely to have adverse clinical outcomes.

Investigating associations of childhood abuse and serum brain-derived neurotrophic factor levels with suicidal behaviours in patients with depressive disorders.

BACKGROUND: The role of childhood abuse and serum brain-derived neurotrophic factor (BDNF) levels in suicidal behaviour is controversial. AIMS: We aimed to investigate the individual and interactive effects of the childhood abuse and serum BDNF on suicidal behaviour before and after pharmacologic treatment in patients with depressive disorders. METHOD: At baseline, reported childhood emotional, physical and sexual abuse were ascertained and serum BDNF levels were measured in 1094 patients with depressive disorder, 884 of whom were followed during a 1-year period of stepwise pharmacotherapy. Suicidal behaviours evaluated at baseline were previous suicide attempt and baseline suicide severity, and suicidal behaviours evaluated at follow-up were increased suicide severity and fatal/non-fatal suicide attempt. Individual and interactive associations of any childhood abuse and serum BDNF levels with four types of suicidal behaviours were analysed using logistic regression models, after adjusting relevant covariates. RESULTS: Individual associations of childhood abuse were significant only with previous suicide attempt, and no significant individual associations were found for serum BDNF with any suicide outcome. However, the presence of both childhood abuse and lower serum BDNF levels was associated with the highest prevalence/incidence of all four suicidal behaviours, with significant interactions for baseline suicide severity and fatal/non-fatal suicide attempt during follow-up. CONCLUSIONS: Synergistic interactive effects of child abuse and serum BDNF levels on suicidal behaviours were found before and after pharmacologic treatment in patients with depressive disorders. Information combining childhood abuse and serum BDNF levels could improve predictions of suicidal behaviour in patients with depressive disorders.

Long-term cardiac outcomes of depression screening, diagnosis and treatment in patients with acute coronary syndrome: the DEPACS study.

BACKGROUND: To investigate the impacts of depression screening, diagnosis and treatment on major adverse cardiac events (MACEs) in acute coronary syndrome (ACS). METHODS: Prospective cohort study including a nested 24-week randomised clinical trial for treating depression was performed with 5-12 years after the index ACS. A total of 1152 patients recently hospitalised with ACS were recruited from 2006 to 2012, and were divided by depression screening and diagnosis at baseline and 24-week treatment allocation into five groups: 651 screening negative (N), 55 screening positive but no depressive disorder (S), 149 depressive disorder randomised to escitalopram (E), 151 depressive disorder randomised to placebo (P) and 146 depressive disorder receiving medical treatment only (M). RESULTS: Cumulative MACE incidences over a median 8.4-year follow-up period were 29.6% in N, 43.6% in S, 40.9% in E, 53.6% in P and 59.6% in M. Compared to N, screening positive was associated with higher incidence of MACE [adjusted hazards ratio 2.15 (95% confidence interval 1.63-2.83)]. No differences were found between screening positive with and without a formal depressive disorder diagnosis. Of those screening positive, E was associated with a lower incidence of MACE than P and M. M had the worst outcomes even compared to P, despite significantly milder depressive symptoms at baseline. CONCLUSIONS: Routine depression screening in patients with recent ACS and subsequent appropriate treatment of depression could improve long-term cardiac outcomes.

Interactive effects of systemic inflammation and life stressors on treatment response of depressive disorders.

Inflammation is an important contributor in the pathophysiology of depression and recent evidence suggests that systemic inflammation and life stressors have interactive roles in depression onset. The aim of the present study was to investigate the individual and interactive effects of systemic inflammation and life stressors with short- and long-term treatment responses in outpatients with depressive disorders in a naturalistic one-year prospective design. Serum high-sensitivity C-reactive protein (hsCRP) levels were measured and number of stressful life events (SLEs) during the last 3 months were ascertained from 1094 patients at baseline. These patients received initial antidepressant monotherapy, then, for patients with an insufficient response or uncomfortable side effects, next treatment with alternative strategies were administered at every 3 weeks in the acute treatment phase (3, 6, 9, and 12 weeks) and at every 3 months in the continuation treatment phase (6, 9, and 12 months). 12-week and 12-month remission was estimated, defined as a Hamilton Depression Rating Scale score of ≤ 7. In multivariable logistic regression analyses, individual effects were found only between higher baseline serum hsCRP levels (≥1.0 vs. < 1.0 mg/L) and 12-week non-remission. Significant interactive effects between higher hsCRP levels and higher number of SLEs (≥2 vs. < 2) on both 12-week and 12-month non-remission were observed. Combining serum hsCRP levels and number of SLEs might therefore be a useful predictor for short- and long-term treatment responses in patients with depressive disorders receiving pharmacotherapy.

Effects of acute and chronic depression on 12-year long-term outcomes after stroke.

OBJECTIVES: This study aimed to investigate whether acute and chronic poststroke depression (PSD) were associated with cardio-cerebrovascular events (CVEs). METHODS: A total of 423 patients with recent stroke were recruited from 2006 to 2009. They were diagnosed with major or minor depressive disorder during the acute phase (within 2 weeks) after stroke. Of these, 284 completed the same diagnostic evaluation during the chronic phase (1 year) after stroke. An average 12-year (range 8.7-14.1 years) follow-up was conducted to assess composite CVEs including recurrent stroke, myocardial infarction, and vascular death after the index stroke. During the follow-up, Kaplan-Meier event rates for outcomes were calculated, and hazard ratios were estimated using Cox regression models after adjusting for a range of covariates. RESULTS: The composite CVE incidence was higher in patients with acute or chronic PSD than in those without. Composite event incidence was highest in patients with PSD during both the acute and chronic phases. CONCLUSIONS: The presence of depression at acute and chronic phase of stroke predicted worse long-term cardio-cerebrovascular outcomes. Evaluation of PSD during both the acute and chronic phases is recommended.

Risk and protective factors of depression in the general population during the COVID-19 epidemic in Korea.

BACKGROUND: The risk of depression has risen in the general population during the COVID-19 epidemic. This study was conducted to explore risk and protective factors associated with depression among the general population uninfected by COVID-19. METHODS: A cross-sectional study was conducted with 1,500 representative South Korean citizens aged 19-65 years through an anonymous online survey. Depression was defined as a Patient Health Questionnaire-9 score of 10 or higher. Other questionnaires included one measuring psycho-behavioural and social changes, and stress, due to COVID-19, a six-item version of the Gratitude Questionnaire (GQ-6), and a three-item version of the UCLA loneliness scale. RESULTS: Of the 1492 participants not infected by COVID-19, 312 (20.9%) exhibited depression. Multiple logistic regression analysis revealed that depression was positively associated with COVID-19-related stress and psycho-behavioural variables such as disturbances in eating and sleeping, younger age, smoking, underlying mental illness, and loneliness scale scores. In contrast, exercise three or more times per week and GQ-6 scale scores were inversely associated with depression. CONCLUSION: During the COVID-19 pandemic, maintaining daily routines including eating, sleeping, and regular exercise and focusing on gratitude may be important for the prevention of depression. In addition, more attention should be paid to vulnerable populations, including young people, those with mental illnesses, and smokers, who might be more susceptible to depression.

TRBP maintains mammalian embryonic neural stem cell properties by acting as a novel transcriptional coactivator of the Notch signaling pathway.

Transactivation response element RNA-binding protein (TRBP; TARBP2) is known to play important roles in human immunodeficiency virus (HIV) replication and microRNA biogenesis. However, recent studies implicate TRBP in a variety of biological processes as a mediator of cross-talk between signal transduction pathways. Here, we provide the first evidence that TRBP is required for efficient neurosphere formation and for the expression of neural stem cell markers and Notch target genes in primary neural progenitor cells in vitro Consistent with this, introduction of TRBP into the mouse embryonic brain in utero increased the fraction of cells expressing Sox2 in the ventricular zone. We also show that TRBP physically interacts with the Notch transcriptional coactivation complex through C promoter-binding factor 1 (CBF1; RBPJ) and strengthens the association between the Notch intracellular domain (NICD) and CBF1, resulting in increased NICD recruitment to the promoter region of a Notch target gene. Our data indicate that TRBP is a novel transcriptional coactivator of the Notch signaling pathway, playing an important role in neural stem cell regulation during mammalian brain development.

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway.

Despite growing evidence linking Drosophila melanogaster tweety-homologue 1 (Ttyh1) to normal mammalian brain development and cell proliferation, its exact role has not yet been determined. Here, we show that Ttyh1 is required for the maintenance of neural stem cell (NSC) properties as assessed by neurosphere formation and in vivo analyses of cell localization after in utero electroporation. We find that enhanced Ttyh1-dependent stemness of NSCs is caused by enhanced γ-secretase activity resulting in increased levels of Notch intracellular domain (NICD) production and activation of Notch targets. This is a unique function of Ttyh1 among all other Ttyh family members. Molecular analyses revealed that Ttyh1 binds to the regulator of γ-secretase activity Rer1 in the endoplasmic reticulum and thereby destabilizes Rer1 protein levels. This is the key step for Ttyh1-dependent enhancement of γ-secretase activity, as Rer1 overexpression completely abolishes the effects of Ttyh1 on NSC maintenance. Taken together, these findings indicate that Ttyh1 plays an important role during mammalian brain development by positively regulating the Notch signaling pathway through the downregulation of Rer1.

Genetic Markers for Later Remission in Response to Early Improvement of Antidepressants.

Planning subsequent treatment strategies based on early responses rather than waiting for delayed antidepressant action can be helpful. We identified genetic markers for later non-remission in patients exhibiting poor early improvement using whole-exome sequencing data of depressive patients treated in a naturalistic manner. Among 1000 patients, early improvement at 2 weeks (reduction in Hamilton Depression Rating Scale [HAM-D] score ≥ 20%) and remission at 12 weeks (HAM-D score ≤ 7) were evaluated. Gene- and variant-level analyses were conducted to compare patients who did not exhibit early improvement and did not eventually achieve remission (n = 126) with those who exhibited early improvement and achieved remission (n = 385). Genes predicting final non-remission in patients who exhibited poor early improvement (COMT, PRNP, BRPF3, SLC25A40, and CGREF1 in males; PPFIBPI, LZTS3, MEPCE, MAP1A, and PFAS in females; ST3GAL5 in the total population) were determined. Among the significant genes, variants in the PRNP (rs1800014), COMT (rs6267), BRPF3 (rs200565609), and SLC25A40 genes (rs3213633) were identified. However, interpretations should be made cautiously, as complex pharmacotherapy involves various genes and pathways. Early detection of poor early improvement and final non-remission based on genetic risk would be helpful for decision-making in a clinical setting.

Modifying effects of depression on the association between BDNF methylation and prognosis of acute coronary syndrome.

AIMS: Brain-derived neurotrophic factor (BDNF) plays important roles in angiogenesis, inflammation, and neuronal plasticity. BDNF methylation has been extensively investigated in depression, but not in cardiac diseases. We asked whether BDNF methylation status is associated with a major adverse cardiac event (MACE), inflammation, and the association with depression comorbidity and its treatment in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: A cross-sectional baseline study and nested 24 week double-blind escitalopram placebo-controlled trial (ClinicalTrial.gov identifier NCT00419471) were performed from 2006 to 2012, with 5-12 year follow-up for MACE. Patients with recent ACS (969 total) were divided into four groups according to depression comorbidity at baseline and treatment allocation: 591, absent depression; 127, depression on escitalopram; 128, depression on placebo; 123, depression on care as usual (CAU). BDNF methylation was measured in leucocyte DNA, and multiple demographic and clinical characteristics including interleukin 6 were evaluated as covariates at baseline. The primary outcome, time to first MACE (a composite of all-cause mortality, myocardial infarction and percutaneous coronary intervention), was investigated using Cox regression models after adjustment for covariates. Interleukin 6 level was significantly higher in patients with higher BDNF methylation values. Higher BDNF methylation was associated with increased MACE independent of confounding factors [HR (95% CI) = 1.45 (1.17-1.78)]. This association was significant in patients without depression [HR (95% CI) = 1.39 (1.01-1.90)] and depressive patients on placebo [HR (95% CI) = 1.72 (1.02-3.02)] or CAU [HR (95% CI) = 1.53 (1.01-2.61)], but not in those treated with escitalopram [HR (95% CI) = 1.00 (0.51-1.95)]. CONCLUSION: BDNF methylation was significantly associated with prognosis of ACS. Escitalopram may mitigate the deleterious effect of higher BDNF methylation in depressive patients with ACS. Further research is needed to elucidate the mechanistics and to assess the generalisability of these findings.

Associations of white matter hyperintensities with poststroke depression: A 1-year longitudinal study.

BACKGROUND: Depression is common in stroke survivors and may lead to a poor prognosis and more severe functional impairment. Although subcortical white matter hyperintensities (WMHs) are associated with late-life depression, few studies have examined the association between depression and WMHs after a stroke. We investigated the associations of periventricular (PVWMH) and deep (DWMH) WMHs with poststroke depression (PSD) at two time points after stroke. METHODS: A total of 408 patients were evaluated 2 weeks after stroke (baseline), and of those, 284 (70%) were followed up 1 year later. Magnetic resonance images were obtained in all subjects at baseline. PVWMHs and DWMHs were rated using the four-point modified Fazekas scale and categorized as mild (grades 0 and 1) or severe (grades 2 and 3). Depression was diagnosed according to DSM-IV criteria, and subjects were divided into without PSD, any PSD, and major PSD groups at baseline, and follow-up examinations were conducted according to the severity of depression. Associations of PSD with PVWMHs and DWMHs were assessed using multivariate logistic regression analyses after adjusting for various demographic and clinical characteristics. RESULTS: The adjusted analyses revealed that severe PVWMHs were significantly associated with any PSD at baseline and severe DWMHs were significantly associated with major PSD at follow-up. CONCLUSION: The association between WMH and PSD varies according to type of WMH, and time after stroke, such that early depressive symptoms are associated with PVWMHs, and delayed severe depression is associated with DWMHs.