bluuebunny/crossref_metadata_2025_split huggingface dataset:
MK2 Inhibition in CD4+ T Cells Protects Against IFNγ and IL-17A, Chronic Inflammation, and Fibrosis in Inflammatory Bowel Disease Models
Authors: Howe Cody S , Chulkina Marina , Syrcle Ryan , McAninch Christina , McAninch Steven , Pinchuk Irina V , Beswick Ellen J 
Published: February 2025

Abstract

Background
CD4+ T cells contribute to chronic inflammation and fibrosis in inflammatory bowel disease (IBD), but the cellular mechanisms remain elusive. We have found that the mitogen-activated protein kinase 2 (MK2) pathway plays a major role in inflammation and overall pathology in IBD. Thus, here, we examined the role of MK2 in regulating CD4+ T cell responses in IBD models.

Methods
Interleukin-10 (IL-10) knockout (KO) mice treated with MK2 inhibitors (MK2i) and CD4-specific MK2 knockdown mice treated with chronic dextran sodium sulfate (DSS) treatments were used to examine inflammation and fibrosis by multiplex array, gene expression, flow cytometry, and histology. Human tissues were treated with MK2i to examine Th1 and Th17 markers.

Results
IL-10 KO mice treated with MK2i therapeutically showed significantly reduced interferon gamma (IFNγ) and interleukin-17A (IL-17A) and a significantly reduced number of IFNγ+ and IL-17A+ producing CD4+ T cells by flow cytometry. To investigate the direct role of MK2 in CD4+ T cells during IBD, we utilized CD4-specific MK2 knockdown mice in chronic DSS colitis. A decrease in colonic inflammation, IFNγ and IL-17,
pro-fibrotic genes, and extracellular matrix deposition was observed in mice with MK2 knockdown in CD4+ T cells compared to control mice. Additionally, IL-17A and IFNγ directly regulated the expression of fibrosis genes in colon tissues.

Conclusions
The MK2 pathway regulates inflammatory CD4+ T cells and fibrosis in IBD models and is a potential therapeutic target.
Long-term outcome after repair of interrupted aortic arch in a single center
Authors: Kreuzer Michaela , Sames-Dolzer Eva , Tulzer Andreas , Klapper Melanie , Mair Roland , Gierlinger Gregor , Seeber Fabian , Mair Rudolf 
Published: February 2025

Abstract

OBJECTIVES
Mortality in patients with interrupted aortic arch rates among the highest in congenital heart surgery. Various techniques for aortic arch repair are described, reintervention rates remain substantially. The aim of this retrospective single center study: To evaluate the long-term outcome in a biventricular series with a preferably performed direct anastomosis and one-stage repair.

METHODS
At the Children’s Heart Center Linz 58 biventricular patients with interrupted aortic arch were operated between 1999 and 2023. Median age at operation was 10 [7; 15] days, weight 3.3 [3; 3.7] kg. In the 24 children with VSDs only, the arch was repaired by a direct anastomosis. 34 had complex concomitant heart defects, the arch reconstruction was performed by direct anastomosis (20), direct anastomosis + patch (10), reverse subclavian flap + patch (3), aortic autograft + patch (1).

RESULTS
Median cardiopulmonary bypass time was 222 [159; 315] min, aortic cross-clamp time 94 [75; 143] min. 2 patients died during the hospital stay (4%), 2 patients after discharge (4%), 4 (7%) required an arch reintervention during a follow-up period of median 9.3 [6.2; 17.2] years. There was no death or arch reintervention in the VSD group.

CONCLUSIONS
All-cause mortality in biventricular patients with interrupted aortic arch was 7%, arch reintervention rate 8%. Direct aortic anastomosis in patients with VSD only can be performed with excellent outcomes, with no deaths or arch reinterventions being observed after a follow-up up to 24 years.
SLOWER CLOZAPINE TITRATION THAN THE OFFICIAL JAPANESE PROTOCOL LED TO FEWER INFLAMMATORY ADVERSE EFFECTS
Authors: Kikuchi *Yuki , Komatsu Hiroshi , Otsuka Yuji , Ito Fumiaki , Kanahara Nobuhisa , Tanifuji Hiroaki , Tomita Hiroaki 
Published: February 2025

Abstract

Background
Higher frequencies of inflammatory adverse effects of clozapine have been reported in Japan (Kishi et al., 2013; Tsukahara et al., 2021). Tsukahara et al. reported 38 % (57/152) clozapine- induced fever, 5 % (7/152) myocarditis, 13 % (20/152) pleuritis, and 1 % interstitial nephritis (2/152) in 152 patients first introduced to clozapine. The international titration protocol for Asians has set slower dose titration than the Japanese package insert to prevent clozapine-induced inflammatory adverse effects (de Leon et al., 2022).

Aims & Objectives
We hypothesized that a dose titration speed slower than the recommendation of the guideline would be associated with fewer inflammatory-related adverse events. We aimed to investigate the relationship between the rate of clozapine dose titration and inflammatory adverse events in Japanese individuals.

Method
The medical records of all 272 patients who were first started on clozapine at seven hospitals between 2009 and 2023 were studied retrospectively. Of those, 241 were included in the analysis. The patients were divided into two groups regarding whether the titration speed was faster or slower than the guideline for Asians. The incidence of inflammatory adverse events with clozapine was compared between the groups.

Results
The frequency of inflammatory adverse events was 34 % (37/110) in the faster titration group and 13 % (17/131) in the slower titration group, and a significant difference was observed by Fisher exact test (odds ratio 3.38; 95 % confidence interval 1.71–6.91; p &lt;0.001). Serious adverse effects, fever for more than five days, and clozapine discontinuation were significantly more frequent in the faster titration group. Logistic regression analysis indicated significantly more inflammatory adverse events in the faster titration group (adjusted odds ratio 4.01; 95 % confidence interval 2.02–7.87; p &lt; 0.001) considering age, sex, body mass index, concomitant valproic acid, and smoking as confounding factors.

Discussion & Conclusion
Clozapine-induced inflammatory adverse events were less frequent in Japanese individuals when a titration rate was more gradual than the protocol recommended in the Japanese package insert.

References
1. Kishi, T. et al. (2013) Efficacy and tolerability of clozapine in Japanese patients with treatment- resistant schizophrenia: results from a 12-week, flexible dose study using raters masked to antipsychotic choice. Asian J. Psychiatr. 6 (3), 200–207.
2. Tsukahara, M. et al. (2021) Clinical utility and safety of slower-than-recommended titration of clozapine for treatment-resistant schizophrenia: a retrospective cohort study. Psychiatr. Q. 92 (2), 703–713.
3. de Leon, J. et al. (2022) An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 55 (2), 73–86.
CLINICALLY PREDICTIVE MODULATION OF COGNITIVE IMPAIRMENTS IN MOUSE TOUCHSCREEN TASKS
Authors: Spark *Daisy , Castelijn Juulke , Churilov Leonid , Pham Trang , Camerino Michelle , Langmead Christopher J , Stewart Gregory D , Nithianantharajah Jess 
Published: February 2025

Abstract

Background
Cognitive deficits in individuals with schizophrenia present a significant barrier to maintaining interpersonal relationships, employment, and independent living. Moderate to severe impairments have been found in cognitive domains including working memory, attention, learning and executive function. Despite the clear impact on functional outcomes, there are currently no approved treatments for cognitive impairments associated with schizophrenia (CIAS). Extensive efforts to develop pro-cognitive medicines, both for CIAS and other neuropsychiatric disorders, have repeatedly led to clinical trials that do not reflect the efficacy predicted in preclinical models.

Aims & Objectives
The rodent touchscreen platform has begun to bridge the translational gap between preclinical and clinical assessments of cognitive function. However, to date there has been no pharmacological validation of whether these tests are stringent enough to be clinically predictive and can therefore improve translation of CIAS treatments.

Method
Here, we use an NMDA receptor antagonist mouse model (acute low-dose administration) that we have validated for cognitive deficits in working memory performance on the rodent trial-unique delayed nonmatch-to-location touchscreen task. We then measured the effect of 1) current standard of care (aripiprazole and olanzapine), 2) failed investigational new drugs (IND) for CIAS (atomoxetine and encenicline), and 3) a current IND for schizophrenia (xanomeline) on working memory and attentional impairments.

Results
For the first time, we demonstrate a translational method for cognitive assessment in mice that can distinguish drugs with clinical efficacy from those without.

Discussion & Conclusion
These results provide critical insight into the predictive validity of our preclinical assay and cognitive deficit model, and have significant implications for the development and translation of novel pro-cognitive medicines.
VOLUMETRIC ASSESSMENT OF INDIVIDUAL THALAMIC NUCLEI IN PATIENTS WITH DRUG-NAÏ VE, FIRST-EPISODE MAJOR DEPRESSIVE DISORDER
Authors: Chibaatar *Enkhmurun , Watanabe Keita , Okamoto Naomichi , Orkhonselenge Nasanbadrakh , Natsuyama Tomoya , Hayakawa Gaku , Ikenouchi Atsuko , Kakeda Shingo , Yoshimura Reiji 
Published: February 2025

Abstract

Introduction
Despite the previous inconsistent findings of structural and functional abnormalities of the thalamus in patients with major depressive disorder (MDD), the disruption of the thalamic nuclei in the pathophysiology of this disorder has not yet been adequately studied. Therefore, we investigated the volumetric changes of thalamic subregions and their nuclei in drug-naï ve, first-episode MDD patients. We also investigated the association between HAM-D scores, a clinical scale frequently used to evaluate the severity of depression and thalamic nuclei volumes in MDD patients.

Methods
This study included 76 drug-naï ve MDD patients and an equal number of healthy subjects. Magnetic resonance imaging (MRI) data were obtained using a 3T MR system and thalamic nuclei volumes were evaluated using FreeSurfer ver.7.11. The volumetric differences were compared by one-way analysis of covariance (ANCOVA) and to ensure that effects were not accounted for by other factors, age, sex, and ETICV variables were included as covariates.

Results
We observed significant volume reductions of the left whole thalamus (p &lt;0.003) and several thalamic nuclei mostly on the left side in the MDD group compared with healthy controls (HCs). Furthermore, we have revealed weak negative correlations between several thalamic nuclei volumes and HAM-D total and subscale scores.

Discussion
This is the first research study to investigate alterations of the various thalamic nuclei volumes in MDD patients compared with HCs.
Moreover, we first analyzed the association between individual thalamic nuclei volumes and HAM-D subscale scores. Though our study may be restricted at certain levels, especially by the demographic difference between the two groups, they possibly contribute at a preliminary level to understanding the thalamic structural changes at its subregions in patients with drug-naï ve, first-episode MDD.
EFFICACY AND SAFETY OF DUAL-TARGET DEEP BRAIN STIMULATION FOR TREATMENT-RESISTANT ALCOHOL USE DISORDER: PROTOCOL FOR A MULTI-CENTER, SINGLE ARM, PROSPECTIVE STUDY
Authors: Jiang *Haifeng , Gan Hong , Zhao Min , Hao Wei 
Published: February 2025

Abstract

Background
Alcohol use disorder (AUD) is the most common, costly, and lethal substance use disorder worldwide, with a rising prevalence. Case reports and animal studies suggest deep brain stimulation (DBS) may be an effective harm-reduction treatment in AUD.

Aims & Objectives
The aim of this study is to explore whether deep stimulating the nucleus accumbens (NAc) and anterior limb of internal capsule (ALIC) simultaneously may have a synergistic effect against treatment-resistant AUD.

Method
Total of 12 subjects from two centers (Shanghai Mental Health Center and The Second Xiangya Hospital of Central South University) who fit inclusion and exclusion criteria are recruited to undergo neurosurgical implantation of dual-target DBS in bilateral NAc and ALIC on a certain date, the DBS system will be turned on for stimulation and parameters adjusted 10-14 days after implantation. Clinical observations will be follow-up during the 9-32 weeks after DBS system has been turned on. The primary outcome is the performance on alcohol use self-report which will be carried out regularly every three days during the study period. Safety assessments will include adverse event reporting, clinical laboratory tests, vital signs, and prior/concomitant medications.

Results
This study is recruiting subjects now, and all results will be reported after study completion.

Discussion & Conclusion
The study will provide evidence for the efficacy and safety of dual-target DBS for treatment-resistant AUD. This abstract describes the design and methodology of the study.

Trial Registration
ClinicalTrials.gov ID NCT05786872

References
None.
ALCOHOL INTAKE IS ASSOCIATED WITH EATING HABITS DURING DEVELOPMENT
Authors: Yamaguchi *Yasuharu , Kasai Shinya , Hasegawa Junko , Ikeda Kazutaka 
Published: February 2025

Abstract

Background & Objectives
There are individual differences in susceptibility to alcohol use disorders, and multiple factors including genetic and lifestyle factors would be involved in the susceptibility. The genetic contribution of alcohol use disorders is estimated from twin studies to be around 0.5. Many genetic factors, including single nucleotide variations, have been reported to be involved in alcohol use disorders, but most have low effect sizes and have not been reproducible in subsequent studies. Few analyses have been conducted on life and environmental factors related to alcohol use disorders. The present study focused on eating habits during the developmental period to identify lifestyle factors related to drinking and alcohol use disorders.

Method
This study included 628 patients who were treated at White Dental Clinic (Saitama, Japan). All of the patients provided written informed consent before participating in the study. Twenty patients were excluded because of incomplete data. The participants completed a questionnaire that consisted of various questions about drinking behaviors and eating habits. The associations between drinking-related traits and eating habits were statistically evaluated using the chi-square test. The study protocol was approved by the Institutional Review Board of the Tokyo Metropolitan Institute of Medical Science.

Result
Patients who ate more sweet and sour foods during their developmental years had lower rates of drinking (χ2 = 14.828; p &lt;0.001, χ2 = 6.499; p = 0.015, respectively). Conversely, patients who ate more salty foods had higher rates of drinking (χ2 = 7.150; p = 0.009).

Discussion & Conclusion
Sweet, sour, and salty tastes are sensations elicited via their unique receptors. Alcohol intake by drinking would act on the central nervous system via the taste buds in the mouth before being taken up into the bloodstream. The formation of neural circuits via taste receptors during the developmental period may influence the rewarding effects of alcohol in adulthood. This study suggests the possibility of developing a new drug for alcohol abstinence.
FUNCTIONAL NEAR-INFRARED SPECTROSCOPY: A POTENTIAL TOOL IN ASSISTING DIAGNOSTIC APPLICATIONS FOR PSYCHIATRIC DISORDERS
Authors: Kim *Yuna , Park Yun Seong , Kim Jaehyun , Jang Yoonjeong , Myung Woojae 
Published: February 2025

Abstract

Background
Psychiatric disorders such as mood disorders are increasingly common in modern society, carrying social and economic burdens, including the risk of suicide. Timely identification of these disorders and intervention is crucial, and ongoing research explores adjunctive diagnostic tools and biomarkers, alongside patient history, to aid early detection.

Aims & Objectives
The study seeks to utilize functional near-infrared spectroscopy (fNIRS) for its cost-effectiveness and ease of use, aiming to improve the diagnosis and differentiation of Major Depressive Disorder (MDD) and Bipolar Disorder (BP) from the healthy control (HC) group.

Method
Thirty participants each from MDD, BP, and HC groups, were diagnosed using DSM-IV criteria, Hamilton Depression Rating Scale, and Clinical Global Impression scores, and performed a verbal fluency task. They recited Korean vowels and produced words starting with specific consonants within the allotted times. The fNIRS system, NIRSIT, included 24 lasers, 32 photodetectors, and oxyhemoglobin waveforms were analyzed for integral and centroid values. One-way ANOVA and ANCOVA assessed differences and the impact of age, education, and task performance. Results
Figure 1 displays the average oxyhemoglobin waveforms in the frontal region (R1) and bilateral temporal regions (R2) for each group. The MDD participants were older than the BP and HC groups (F = 14.664, p&lt;0.005). Task performance was similar for MDD and HC, and better than BP (F = 5.622, p &lt;0.005). One- way ANOVA indicated significant differences in integral values across the groups and post-hoc analyses highlighted substantial distinctions between the healthy control (HC) and the psychiatric disorder groups (HC vs BP, HC vs MDD; P &lt;0.05). Although no significant differences were observed in centroid values between patient groups, each group exhibited unique patterns.

Discussion & Conclusion
Using fNIRS, the findings suggest that IV and CV, derived from changes in hemoglobin waveforms, hold promise in distinguishing individuals with mood disorders from healthy controls. While further research is needed to explore their applicability to other psychiatric conditions such as psychosis, there is potential for them to serve as auxiliary diagnostic tools in the future for personalized psychiatric treatment.
NEUROPHYSIOLOGICAL CHARACTERISTICS OF BIPOLAR DISORDER BY RESTING EEG MICROSTATE ANALYSIS
Authors: Taniguchi *Keita , Nakajima Shinichiro Luke , Moriyama Sotaro , Wada Masataka , Kaneko Naotsugu , Takano Mayuko , Honda Shiori , Mimura Masaru , Uchida Hiroyuki , Noda Yoshihiro 
Published: February 2025

Abstract

Background
Behind the difficulty in diagnosing bipolar disorder (BD) is the reality that it takes several years after the initial consultation before the diagnosis is confirmed. In this context, it is essential to establish biomarkers that contribute to the diagnosis of BD. In recent years, electroencephalography (EEG) microstates (MS) have garnered great attention as a useful tool to elucidate whole-brain neural network activity due to their high reproducibility. Therefore, EEG-MS is expected to be an aid in the diagnosis of psychiatric disorders, including BD. Specifically, MS-E is associated with the processing of internal and emotional information as well as cognitive functions.

Aims & Objectives
In this study, we aimed to identify EEG-MS biomarker of BD by comparison with that of healthy controls (HC).

Method
We included 36 individuals with BD (age: 47.7±15.7, %female: 38.9%) and 72 HC (age: 47.5±15.4, %female: 38.9%). Using a 64-channel high-density EEG system, we recorded resting-state EEG for 5 minutes with participants eyes closed. EEG-MS were classified into five states from A to E using the k- means clustering method. Then, three temporal indices were calculated for each MS: duration, occurrence, and coverage. Two-way repeated-measures analysis of variance (ANOVA) was conducted for the three temporal indices of each MS. MS classes and three indices served as within-subject factors while participant groups were treated as a between-subject factor. For MS indices for which the interaction was significant, an independent t-test was performed as a post-hoc analysis to test for differences between the BD and HC groups.

Results
The ANOVA showed significant interactions between the groups, MS classes, and temporal indices (F(1,8)=3.91, p&lt;0.001). Subsequent ANOVAs indicated significant interactions across the two groups in duration (F(1,4)=2.412, p=0.049), occurrence (F(1,4)=3.861, p=0.004), and coverage (F(1,4)=2.924, p=0.021), as well as in MS-D (F(1,2)=3.304, p=0.039) and MS-E (F(1,2)=6.759, p=0.001). Finally, post-hoc independent t-tests for MS-D and MS-E revealed that in MS-D, the BD group showed longer values in duration (t(106)=3.967, p&lt;0.001) and coverage (t(106)=2.904, p=0.004) compared to the HC group. In contrast, in MS-E, the BD group showed lower values in occurrence (t(106)=-2.600, p=0.011) and coverage (t(106)=-2.382, p=0.019) compared to the HC group.

Discussion & Conclusion
This study demonstrated that the BD group exhibited a higher occurrence and longer duration for MS-D compared to the HC group. Conversely, regarding MS-E, the BD group showed a lower occurrence and decreased coverage than the HC group. Based on the physiological significance of MS-E, there may be a potential decline in cognitive function in the BD group compared to the HC group.
APPETITE HORMONE DYSREGULATION AND EXECUTIVE DYSFUNCTION AMONG ADOLESCENTS WITH BIPOLAR DISORDER AND DISRUPTIVE MOOD DYSREGULATION DISORDER
Authors: Da Huang Guan- , Chen *Mu-Hong , Hsu Ju-Wei 
Published: February 2025

Abstract

Background
Appetite hormone dysregulation may play a role in the pathomechanisms of bipolar disorder and chronic irritability. However, its association with executive dysfunction in adolescents with bipolar disorder and those with disruptive mood dysregulation disorder (DMDD) remains unclear.

Methods
We included 20 adolescents with bipolar disorder, 20 adolescents with DMDD, and 47 healthy controls. Fasting serum levels of appetite hormones, including leptin, ghrelin, insulin, and adiponectin were examined. All participants completed the Wisconsin Card Sorting Test.

Results
Generalized linear models with adjustments for age, sex, body mass index, and clinical symptoms revealed that patients with DMDD had elevated fasting log-transformed insulin levels (p =.023) compared with the control group. Adolescents with DMDD performed worse in terms of the number of tries required to complete tasks associated with the first category (p =.035), and adolescents with bipolar disorder performed worse in terms of the number of categories completed (p =.035). A positive correlation was observed between log-transformed insulin levels and the number of tries required for the first category (β = 1.847, p = 032).

Discussion
Adolescents with DMDD, but not those with bipolar disorder, were more likely to exhibit appetite hormone dysregulation compared with healthy controls. Increased insulin levels were also related to executive dysfunction in these patients. Prospective studies should elucidate the temporal association between appetite hormone dysregulation, executive dysfunction, and emotional dysregulation.

References
1.Hsu et al. Eur Child Adolesc Psychiatry. 2023 May 26
2.Chen et al. World J Biol Psychiatry. 2021 Jul;22(6):428-434