Unveiling the inhibition mechanism of Clostridioides difficile by Bifidobacterium longum via multiomics approach.

Antibiotic-induced gut microbiota disruption constitutes a major risk factor for Clostridioides difficile infection (CDI). Further, antibiotic therapy, which is the standard treatment option for CDI, exacerbates gut microbiota imbalance, thereby causing high recurrent CDI incidence. Consequently, probiotic-based CDI treatment has emerged as a long-term management and preventive option. However, the mechanisms underlying the therapeutic effects of probiotics for CDI remain uninvestigated, thereby creating a knowledge gap that needs to be addressed. To fill this gap, we used a multiomics approach to holistically investigate the mechanisms underlying the therapeutic effects of probiotics for CDI at a molecular level. We first screened Bifidobacterium longum owing to its inhibitory effect on C. difficile growth, then observed the physiological changes associated with the inhibition of C. difficile growth and toxin production via a multiomics approach. Regarding the mechanism underlying C. difficile growth inhibition, we detected a decrease in intracellular adenosine triphosphate (ATP) synthesis due to B. longum-produced lactate and a subsequent decrease in (deoxy)ribonucleoside triphosphate synthesis. Via the differential regulation of proteins involved in translation and protein quality control, we identified B. longum-induced proteinaceous stress. Finally, we found that B. longum suppressed the toxin production of C. difficile by replenishing proline consumed by it. Overall, the findings of the present study expand our understanding of the mechanisms by which probiotics inhibit C. difficile growth and contribute to the development of live biotherapeutic products based on molecular mechanisms for treating CDI.

Multiomics analysis reveals the biological effects of live Roseburia intestinalis as a high-butyrate-producing bacterium in human intestinal epithelial cells.

Butyrate-producing bacteria play a key role in human health, and recent studies have triggered interest in their development as next-generation probiotics. However, there remains limited knowledge not only on the identification of high-butyrate-producing bacteria in the human gut but also in the metabolic capacities for prebiotic carbohydrates and their interaction with the host. Herein, it was discovered that Roseburia intestinalis produces higher levels of butyrate and digests a wider variety of prebiotic polysaccharide structures compared with other human major butyrate-producing bacteria (Eubacterium rectale, Faecalibacterium prausnitzii, and Roseburia hominis). Moreover, R. intestinalis extracts upregulated the mRNA expression of tight junction proteins (TJP1, OCLN, and CLDN3) in human intestinal epithelial cells more than other butyrate-producing bacteria. R. intestinalis was cultured with human intestinal epithelial cells in the mimetic intestinal host-microbe interaction coculture system to explore the health-promoting effects using multiomics approaches. Consequently, it was discovered that live R. intestinalis only enhances purine metabolism and the oxidative pathway, increasing adenosine triphosphate levels in human intestinal epithelial cells, but that heat-killed bacteria had no effect. Therefore, this study proposes that R. intestinalis has potentially high value as a next-generation probiotic to promote host intestinal health.

Increased metabolic variability in Korean patients with new onset bipolar disorder: a nationwide cohort study.

Introduction: The aim of this study was to determine associations between changes of metabolic parameters and the development of BD using nationally representative data. Methods: We used health examination data provided by the South Korean National Health Insurance System (NHIS) (n = 8,326,953). The variability of each metabolic parameter including weight circumference, blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, and triglyceride levels was caculated using variability independent of mean (VIM) indices. The presence of metabolic syndrome was associated with new onset BD. Each metabolic parameter with high variability was associated with a higher risk of new onset BD compared to those with low variability after adjusting for age, sex, smoking, alcohol drinking, regular exercise, income status, baseline diabetes, hypertension, and dyslipidemia. Results: As the number of highly variable metabolic parameters increased, the risk for new onset depression also increased even after covariates adjustment. The associations between new onset BD and metabolic variability were greater in populations with age > 50 years. In addition, these associations remained significant after adjusting for the presence of depression prior to diagnoses of BD. Discussion: Our results suggest possibility of metabolic variability as an independent environmental risk factor for BD even after adjusting for the presence of metabolic syndrome.

Heterogeneous early illness courses of Korean patients with bipolar disorders: replication of the staging model.

BACKGROUND: Clinical staging of bipolar disorder (BD) requires application of real-world data, as the next step in hypothesis. This study used the staging model to analyze the long-term course of BD in Korean patients based on clinical features and treatment responses to map the progression of bipolar illness from its early phase after the onset of illness. METHODS: A total of 136 patients diagnosed with BD-I (n = 62) or BD-II (n = 74) were recruited. Their progressive stages were retrospectively evaluated. A multi-state model was used to calculate the probability of progression to each stage. Hazard ratios of covariates expected to influence different courses of BD were calculated. Using the Alda score, long-term responses to mood stabilizers depending on the current stage were compared. RESULTS: Several sub-populations showed varied courses during the first five years after the onset of illness, with 41.5% remaining in stage 2 and 53% progressing to higher stages with shortened time for transition. Profiles of patients with BD-I and BD-II were different, suggesting biologically distinct groups. Comorbid psychiatric disorders, such as obsessive-compulsive disorder (OCD) and bulimia nervosa (BN) were associated with a recurrent course (stage 3a or 3b) or a malignant course (stage 3c or 4). Early age of onset, shorter duration of illness, older age at the start of medication, and poor response to lithium affected the illness progression. CONCLUSION: We were able to apply the stage model based on episode recurrence patterns in early illness courses of Korean patients with BD. The stage progression pattern differed from the early phase in BD-I and BD-II patients. Psychotic comorbidity, age at onset, age at starting psychiatric treatment showed associations with the illness progression.

Changes in working status after cancer diagnosis and socio-demographic, clinical, work-related, and psychological factors associated with it.

BACKGROUND: While many studies investigated changes in working status in cancer survivors, most studies have been performed in survivors of breast cancer and few studies evaluated factors associated with changes in the working status of cancer survivors comprehensively. We aimed to evaluate the changes in the working status of cancer survivors after diagnosis and socio-demographic, clinical, work-related and psychological factors associated with it. METHODS: We conducted a cross-sectional survey of adult patients with cancer who were working at the time of diagnosis. A trained interviewer inquired about participants' current working status, including leave of absence, discontinuing, continuing, and changing work. Sociodemographic, clinical, work-related and psychological factors were measured. Multinomial logistic regression was used to identify factors associated with changes in the working status. RESULTS: Among the 730 patients, 29%, 18% and 6% were currently on a discontinued working, leave of absence and had changed jobs, respectively. Patients who discontinued working after cancer diagnosis were more likely to be female, have ≥ $3,000 of monthly family income, not be the principal wage earners for their families and be blue-collar workers. In clinical characteristics, advanced-stage cancer and experienced cancer recurrence was associated with leave of absence and discontinued working. In work-related and psychological factors, stress due to insufficient job control (relative risk ratio [RRR] = 2.26), interpersonal conflict (RRR = 1.86), job insecurity (RRR = 2.63), organizational system (RRR = 3.49), and lack of reward (RRR = 11.76), and less meaning to work were more likely to discontinue working after a cancer diagnosis. CONCLUSION: Occupational health care professionals and other stakeholders need to openly communicate with patients with cancer about potential barriers during the return-to-work trajectory.

Estimated glomerular filtration rate in Korean patients exposed to long-term lithium maintenance therapy.

BACKGROUND: Lithium-induced nephrotoxicity has long been debated. However, it has been rarely explored in Asian populations. The aim of the present study was to assess the effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in Korean patients diagnosed with a psychiatric illness. METHODS: This was a single-centered, retrospective study that included patients treated with lithium or comparator drug (valproate) in Samsung Seoul Medical Center between November 1994 and July 2020. Patients diagnosed with ICD codes F20-33 who had ≥ 6 months of exposure to lithium or valproate were included. Patients had to have ≥ 1 baseline and ≥ 2 post-baseline eGFR data with post-baseline data having an interval of at least 30 days. Chronic kidney disease (CKD) was defined as CKD stage 3 (eGFR < 60 mL/min/1.732). To be considered as CKD, the threshold had to be met at two consecutive post-baseline measurements. Those treated with both lithium and valproate, diagnosed with CKD stages 3-5, diagnosed with a renal disease, or received kidney transplantation were excluded. RESULTS: A total of 766 patients were included (242 treated with lithium and 524 with valproate). Two (0.8%) in the lithium group and 8 (1.5%) in the valproate group developed CKD stage 3. None developed CKD stages 4-5. Median yearly eGFR change was - 1.3 mL/min/1.732 (IQR: - 6.8, 1.7) for the lithium group and - 1.1 mL/min/1.732 (IQR: - 4.5, 1.5) for the valproate group, showing no significant difference between the two groups (p = 0.389). The rate of decline was more rapid for those with CKD in both groups. eGFR values of lithium and valproate groups did not show significant differences during a follow-up duration of 15 years or more. A significant negative correlation between baseline eGFR and yearly eGFR change was identified in a linear regression analysis. CONCLUSIONS: In Korean patients, treatment with lithium did not increase the risk of developing CKD compared to treatment with valproate. Prevalence of CKD was lower than those previously reported in western populations. Low baseline eGFR showed significant correlation with changes in renal function.

Machine-learning-based diagnosis of drug-naive adult patients with attention-deficit hyperactivity disorder using mismatch negativity.

Relatively little is investigated regarding the neurophysiology of adult attention-deficit/hyperactivity disorder (ADHD). Mismatch negativity (MMN) is an event-related potential component representing pre-attentive auditory processing, which is closely associated with cognitive status. We investigated MMN features as biomarkers to classify drug-naive adult patients with ADHD and healthy controls (HCs). Sensor-level features (amplitude and latency) and source-level features (source activation) of MMN were investigated and compared between the electroencephalograms of 34 patients with ADHD and 45 HCs using a passive auditory oddball paradigm. Correlations between MMN features and ADHD symptoms were analyzed. Finally, we applied machine learning to differentiate the two groups using sensor- and source-level features of MMN. Adult patients with ADHD showed significantly lower MMN amplitudes at the frontocentral electrodes and reduced MMN source activation in the frontal, temporal, and limbic lobes, which were closely associated with MMN generators and ADHD pathophysiology. Source activities were significantly correlated with ADHD symptoms. The best classification performance for adult ADHD patients and HCs showed an 81.01% accuracy, 82.35% sensitivity, and 80.00% specificity based on MMN source activity features. Our results suggest that abnormal MMN reflects the adult ADHD patients' pathophysiological characteristics and might serve clinically as a neuromarker of adult ADHD.

Increased metabolic variability is associated with newly diagnosed depression: A nationwide cohort study.

BACKGROUND: The effect of dynamic changes in metabolic parameters over time on the development of depression has yet to be examined. In this study, we aimed to determine the association between the variability of metabolic parameters and the development of depression using nationally representative data. METHODS: We used health examination data provided by the South Korean National Health Insurance System (NHIS) and included those who underwent the examination ≥ 3 times within five years of enrollment, without a previous history of depression (n = 9,058,424). The variability of each metabolic parameter including weight circumference, blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, and triglyceride levels was estimated using variability independent of mean (VIM) indices. High variability was defined as the highest quartile (Q4) of variability. RESULTS: Each metabolic parameter with high variability was associated with a higher risk of newly diagnosed depression compared to those with low variability, after adjusting for age, sex, smoking, alcohol drinking, regular exercise, income status, baseline diabetes, hypertension, and dyslipidemia. As the number of highly variable metabolic parameters increased, the risk for newly diagnosed depression increased even after adjusting for the aforementioned covariates (hazard ratio (HR) = 1.4, 95% confidence interval (CI): 1.3 - 1.4 in those with five highly variable parameters compared to those with no highly variable parameter). LIMITATIONS: relatively short observation period; no systematic measure of depression severity. CONCLUSIONS: Our results suggest that the variability of metabolic parameters is an independent risk factor for depression.

Exploratory Analysis of Behavioral Impulsivity, Pro-inflammatory Cytokines, and Resting-State Frontal EEG Activity Associated With Non-suicidal Self-Injury in Patients With Mood Disorder.

Introduction: Non-suicidal self-injury (NSSI) is a rapidly increasing mental health problem that requires more clinical attention. In this study, we aimed to explore the biobehavioral markers of NSSI in participants with mood disorders. Methods: A total of 45 participants with mood disorders (bipolar I, II, and major depressive disorder) were included in the study. Behavioral impulsivity was measured using the immediate memory task (IMT)/delayed memory task (DMT) and the go-no-go (GNG) tests. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1 ß), and interleukin 6 (IL-6) and resting-state quantitative electroencephalography (qEEG) were measured. Results: The NSSI group had shorter GNG reaction time (GNG-RT) and higher TNF-α levels compared to the non-NSSI group. TNF-α was positively correlated with frontal theta power. In addition, GNG-RT showed a significant positive association with frontal alpha activity. Conclusion: NSSI in mood disorders was associated with increased behavioral impulsivity and greater inflammation. Increased pro-inflammatory cytokines were associated with frontal theta power. Increased inflammation might change major neurotransmitter metabolism, which eventually affects frontal function and decreases response inhibition. Further studies to explore their causal relationship are warranted.

Effects of genetic variants of ST8SIA2 and NCAM1 genes on seasonal mood changes and circadian preference in the general population.

ST8SIA2 and NCAM1 are functionally related genes forming polysialic acid (PSA) - neural cell adhesion molecule (NCAM) complex in suprachiasmatic nucleus (SCN), the regulating site of circadian biological rhythm. In this study, the relationship of ST8SIA2 and NCAM1 with circadian and seasonal rhythms of human behavior was explored. Subjects were 261 healthy Korean adults who were free of any history of clinically significant psychiatric symptoms. The phenotypes were circadian preference and seasonal change of mood and behavior (seasonality) measured by the Composite Scale of Morningness and the Seasonal Pattern Assessment Questionnaire, respectively. Thirty-four single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and 15 SNPs of NCAM1 were analyzed. A nominally significant association with seasonality and circadian preference was observed in 21 variants of both genes. After corrections for multiple testing, associations of 8 SNPs of ST8SIA2 and 2 SNPs of NCAM1 with seasonality remained significant. Some of these SNPs were also associated with psychiatric disorders in previous studies. This study demonstrated a meaningful and/or suggestive evidence of association between behavioral phenotypes reflecting human biological rhythm and two interplaying genes involved in the plasticity of SCN's neuronal network.

Long-term response to mood stabilizer treatment and its clinical correlates in patients with bipolar disorders: a retrospective observational study.

BACKGROUND: The efficacy and utility of long-term prophylactic treatment in patients with bipolar disorders (BDs) have not been fully explored. This study aims to estimate the long-term clinical response of patients with BDs to mood stabilizer treatment and to identify the clinical factors associated with that response. METHODS: The study subjects consisted of 80 patients with bipolar I or bipolar II disorder who had been receiving treatment with lithium and/or valproate for more than 2 years at a single bipolar disorder clinic. The long-term response to the best treatment option based on treatment algorithms was evaluated using the Alda scale. Clinical characteristics were evaluated on a lifetime basis. Patients were classified into two response groups based on frequentist mixture analysis using the total Alda scale score. RESULTS: Thirty-four percent of the patients were good responders, with a total Alda score of 5 or higher. The treatment response rate did not differ between the lithium and valproate groups, but lithium and valproate combination therapy was associated with poorer response. The number of previous mixed episodes was associated with a worse response (p = 0.026). Of individual symptoms, delusions during manic episodes (p = 0.008) and increased appetite (p = 0.035) during depressive episodes were more common in moderate/poor responders than in good responders. Co-morbid anxiety disorders were more frequently observed in the moderate/poor response group (p = 0.008). CONCLUSIONS: Psychotic, mixed, and atypical features of BDs were found to be correlated with long-term treatment outcomes. Lithium and valproate showed similar efficacy but moderate/poor responders preferred to use polypharmacy.

Pattern of pharmacotherapy by episode types for patients with bipolar disorders and its concordance with treatment guidelines.

This study aimed to investigate the overall prescription pattern for patients with bipolar disorders in Korea and its relevance to the practice guidelines. Prescription records from all patients with bipolar I and II disorders who have been admitted or who started the outpatient treatment during the year of 2009 in 10 academic setting hospitals were reviewed. A total of 1447 patients with bipolar I and II disorders were included in this study. Longitudinal prescription patterns of inpatients and outpatients were analyzed by episode types and compared with the clinical practice guideline algorithms. In all phases, polypharmacy was chosen as an initial treatment strategy (>80%). The combination of mood stabilizer and atypical antipsychotics was the most favored. Antipsychotics were prescribed in more than 80% of subjects across all phases. The rate of antidepressant use ranged from 15% to 40%, and it was more frequently used in acute treatment and bipolar II subjects. The concordance rate of prescriptions for manic inpatients to the guidelines was higher and relatively more consistent (43.8%-48.7%) compared with that for depressive inpatients (18.6%-46.9%). Polypharmacy was the most common reason for nonconcordance. In Korean psychiatric academic setting, polypharmacy and atypical antipsychotics were prominently favored in the treatment of bipolar disorder, even with the lack of evidence of its superiority. More evidence is needed to establish suitable treatment strategies. In particular, the treatment strategy for acute bipolar depression awaits more consensuses.

Magnetic resonance imaging spectrum of solid pseudopapillary neoplasm of the pancreas.

OBJECTIVE: To describe the magnetic resonance imaging spectrum of solid pseudopapillary tumors (SPTs), with an emphasis on solid SPTs. METHODS: Thirty-two patients with proven SPTs with preoperative magnetic resonance were included. The SPTs were classified into 3 types: solid, cystic, and mixed; and 2 radiologists analyzed the images regarding the morphologic features and enhancement pattern. RESULTS: Of 11 solid SPTs, 9 SPTs (81.8%) were less than 3 cm. Alternatively, of the 18 mixed SPTs and 3 cystic SPTs, 15 SPTs (71.4%) were larger than 3 cm. The predominant imaging features were homogeneous hypoenhancement with a gradually incremental enhancement pattern showing a sharp margin without hemorrhage, whereas those of the mixed SPTs were heterogeneous enhancement showing a sharp margin with internal hemorrhage. CONCLUSION: Solid SPTs frequently present as small, well-defined tumors with a gradual enhancement and without hemorrhage or necrosis, and with features that differ from those of mixed or cystic SPTs.

Smoking and suicidality in subjects with major depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

BACKGROUND: Detailed characteristics of depressive smokers and its association with suicidality were still less investigated. The aim of this study was to delineate characteristics of smokers with major depressive disorder (MDD) and examine the relationship between these characteristics and suicidality using an epidemiologic database, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). METHODS: A total of 5695 subjects with MDD, defined by the DSM-IV criteria, were included in our analysis. Current smokers, former smokers, and lifetime nonsmokers were compared in terms of demographic, clinical characteristics, and functional level. Suicidality, evaluated by history of suicide ideation and attempts while in a low mood was evaluated and compared among the groups. RESULTS: Current smokers with MDD showed a greater number of DSM-IV symptoms while in acute episodes, a higher rate of alcohol and drug-use disorders, and poorer functional levels than nonsmokers. Previous smokers displayed intermediate characteristics between current smokers and nonsmokers. The logistic regression analysis revealed that both current and former smoking status predicted the risk of having a history of attempted suicide (current smokers: odds ratio 1.62, 95% C.I. 1.42-1.86; former smokers: odds ratio 1.37, 95% C.I. 1.13-1.66) after adjusting for demographic data, a history of subthreshold hypomania, and a lifetime axis II/anxiety/alcohol use/substance-use disorder. LIMITATIONS: Retrospective, cross-sectional evaluation; suicidality assessed only in the most severe depressive episode. CONCLUSIONS: The present study corroborates that smokers with MDD showed distinct clinical characteristics, and cigarette smoking can predict attempted suicide in a community representative sample of people with MDD.

Smoking and suicidality in subjects with bipolar disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

BACKGROUND: Smoking in patients with bipolar disorder is known to be related to suicidality. This link has not been investigated, however, in community-based samples. The aim of this study is to delineate the sociodemographic and clinical characteristics of bipolar smokers and examine the relationship between these characteristics and suicidal ideation or attempts in an epidemiologic database, the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). METHODS: Subjects (n = 1,643) with bipolar disorder I and II, defined by the DSM-IV criteria, who had a history of low moods lasting more than 2 weeks were included in our analysis. Current smokers, former smokers, and lifetime nonsmokers were compared in terms of demographic, clinical characteristics, and functional level. Suicidality, evaluated by a history of suicide ideation and attempts while in low mood were compared. RESULTS: Current smokers with bipolar disorder showed a greater number of DSM-IV symptoms while in acute episodes, higher rate of alcohol, and drug use disorders, as well as poorer functional levels than nonsmokers. Previous smokers displayed intermediate characteristics between current smokers and nonsmokers. The logistic regression analysis revealed that current smoking status predicted the risk of having a history of attempted suicide (Odds ratio 1.35, 95% CI: 1.05-1.76) after adjusting for age, sex, race, bipolar subtype, lifetime axis II/anxiety/alcohol use/substance use disorder; however, lifetime smoking status did not. CONCLUSIONS: The present study confirms that current cigarette smoking can predict attempted suicide in a community representative sample of people with bipolar disorder.

Radiofrequency ablation for treating liver metastases from a non-colorectal origin.

OBJECTIVE: We wanted to assess the safety and efficacy of performing radiofrequency ablation (RFA) in patients with non-colorectal liver metastases. MATERIALS AND METHODS: In this retrospective study, 25 patients with 40 hepatic metastases (M:F = 17:8; mean age, 57 years; tumor size, 0.5-5.0 cm) from a non-colorectal origin (stomach, biliary, breast, pancreas, kidney and skin) were treated with RFA. The RFA procedures were performed using either an internally cooled electrode or a clustered electrode under ultrasound or CT guidance. Contrast-enhanced CT scans were obtained immediately after RFA and follow-up CT scans were performed within three months after ablation and subsequently at least every six months. The intrahepatic disease-free interval was estimated and the overall survival from the time of the initial RFA was analyzed using the Kaplan-Meier method. RESULTS: No intraprocedural deaths occurred, but four major complications developed, including abscesses (n = 3) and pneumothorax (n = 1). Technical effectiveness was determined on the initial follow-up images. During the follow-up period (range, 5.9-68.6 months; median time, 18.8 months) for 37 tumors in 22 patients where technical effectiveness was achieved, 12 lesions (32%, 12 of 37) showed local tumor progression and new intrahepatic metastases occurred in 13 patients (59%, 13 of 22). The median intrahepatic disease-free interval was 10.1 months. The 1-year, 3-year and 5-year overall survival rates after RFA were 86%, 39% and 19%, respectively. CONCLUSION: RFA showed intermediate therapeutic effectiveness for the treatment of non-colorectal origin liver metastases.