bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE USE OF ZOLPIDEM AND THE RISK OF ARRHYTHMIA: INSIGHTS FROM A NATIONAL SURVEY
Authors: Chen *Tien-Yu , Shen Jia-Ying , Chung Chi-Hsiang , Chien Wu-Chien 
Published: February 2025

Abstract

Background
Insomnia, a prevalent sleep disorder with significant health implications, is commonly treated with medications such as zolpidem. Zolpidem, a non-benzodiazepine medication, has advantages over traditional sedative-hypnotics, but its widespread use raises concerns about potential side effects.

Aims & Objectives
This study focuses on investigating the correlation between zolpidem use and cardiac arrhythmias, considering the increasing prevalence of zolpidem consumption and its association with comorbidities.

Method
This population-based, matched-cohort cohort study used Taiwan’ s National Health Insurance Research Database. Participants included those using zolpidem for at least 7 days between the years January 1, 2000, and December 31, 2015. The study focused on patients who used zolpidem and classified them as the exposed cohort. The exposed and unexposed groups were selected in a ratio of 1:2, matching for sex, age, and index year. We used a logistic regression model to investigate the association between zolpidem exposure and the risk of arrhythmia.

Results
We identified 152,652 zolpidem use cases and 305,304 matched controls. Participants with zolpidem use exhibited higher rates of comorbidities compared to the control group. Cox regression analysis revealed a significant association between zolpidem use and incident cardiac arrhythmia (adjusted hazard ratio [aHR] = 1.983, 95% CI: 1.149 – 2.76, P &lt;0.001). Subgroup analyses confirmed the elevated risk of arrhythmia in zolpidem users across various demographic and comorbidity subgroups. Specific cardiac arrhythmias, including paroxysmal ventricular tachycardia, atrial fibrillation, ventricular fibrillation, and cardiac arrest, showed higher adjusted hazard ratios than other types of arrhythmia in patients who used zolpidem.

Discussion & Conclusion
The study suggests a heightened risk of cardiac arrhythmias associated with zolpidem use. While acknowledging the limitations of observational studies, these findings emphasize the need for further research to elucidate underlying mechanisms and establish causality. Healthcare practitioners should consider these risks when prescribing zolpidem, particularly in individuals with predisposing comorbidities.
EFFECTS OF NEUROTICISM ON SUICIDE RISK IN MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER
Authors: Li *Tian , Xing Yujie , Bo Qijing , Wang Chuanyue 
Published: February 2025

Abstract

Background
Suicide is the primary cause of death in patients with major depressive disorder (MDD) or bipolar disorder (BD). However, the effects of personality traits on suicide risk in MDD or BD have not been examined sufficiently. This study characterized the personality traits of patients with MDD or BD, and analyzed the association between personality traits and suicide risk in these patients.

Methods
The study population comprised 88 MDD patients and 90 BD patients. We assessed lifetime suicide risk by using the SCID-I/P. Additionally, the current suicide risk was judged based on the third item (suicide) of the 17-item Hamilton Depression Rating Scale. Personality traits were determined by the Eysenck Personality Questionnaire.

Results
Lifetime suicide risk was present in 60.7% of the study population. In the entire sample, neuroticism was significantly associated with both lifetime and current suicide risk. Higher scores for neuroticism suggested an increased lifetime suicide risk in the whole cohort. Elevated scores for neuroticism increased the current suicide risk in the MDD group.

Conclusion
For patients with MDD or BD, a higher neuroticism score may indicate a higher lifetime risk of suicide. For patients with MDD, a high neuroticism score signaled an elevated current suicide risk.
ASSOCIATION BETWEEN AUTISTIC SPECTRUM DISORDER AND PRECOCIOUS PUBERTY: A NATIONWIDE COHORT STUDY
Authors: Liu *Yi-Chun , Liao Yin-To , Chen Vincent Chin-Hong , Chen Yi-Lung 
Published: February 2025

Abstract

Background
Limited knowledge is available about the association between autistic spectrum disorder (ASD) and precocious puberty.

Aims & Objectives
Our study examined the association between the two medical conditions, and the effect modification by sex and neuropsychiatric comorbidities in a nationwide population.

Method
To compare the risk of precocious puberty between ASD and non-ASD cases, we conducted Cox regression analysis with ASD as exposure and time-to-precocious puberty as outcomes adjusting for sex, attention-deficit/hyperactivity disorder (ADHD), tics disorder, obsessive– compulsive disorder (OCD), anxiety disorder, intellectual disability, and epilepsy. We performed a moderation analysis to examine the potential moderating effects by sex or comorbidities.

Results
Patients with ASD have a higher risk of precocious puberty compared with non-ASD individuals, with an adjusted hazard ratio (aHR) of 1.80 (95% CI: 1.61-2.01). For the effect modification, sex, specifically female, moderated the association between ASD and precocious puberty, with relative excess risk due to interaction (RERI) 7.35 (95% CI 4.90-9.80). No significant effect modification was found for any of the comorbidities within the scope of additive effect modification.

Discussion & Conclusion
We found that patients with ASD had a higher risk of precocious puberty, regardless of sex or comorbid neuropsychiatric disorders. Girls with ASD are at particularly high risk to develop precocious puberty.
PSYCHOPHARMACOTHERAPY FOR CHILDREN WITH AUTISM SPECTRUM DISORDER CAN IMPROVE THEIR ADAPTIVE FUNCTIONING
Authors: Jung *Hanyong , Lee Jeewon 
Published: February 2025

Abstract

Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder which shows deficits in social interaction and communication, as well as repetitive and restricted patterns of behaviors and interests. Although there is currently no medication that can treat the core symptoms of ASD, there are many pharmacological treatment options that can help diminish the associated symptoms.

Aims & Objectives
The purpose of the present study was to examine the pharmacological treatment of children with ASD. We investigated how the pharmacological treatment of children with ASD improved their adaptive functioning.

Method
The present study was a cross-sectional study of 112 school-aged children who were diagnosed with ASD (mean age= 8.65±1.66 years, female=17.79%). Demographic information and information about current medications were collected. Parents completed the Parent/Caregiver Form of Vineland Adaptive Behavior Scales, 3rd Edition (Vineland-3).

Results
Among the 112 children diagnosed with ASD, 88 children (78.57%) had received psychopharmacotherapy. The medication that the children with ASD were most treated with was antipsychotics such as aripiprazole and risperidone, followed by ADHD medications such as atomoxetine and methylphenidate. SSRIs such as fluoxetine and sertraline, as well as buspirone were also prescribed. Results of VAPS-3 showed that pharmacological treatment improved child’ s communication skills, daily living skills and socialization.

Discussion & Conclusion
The current study showed that majority of children with ASD received pharmacological treatment which were beneficial for their adaptive functioning. Many parents recognize that there is no cure for ASD and eliminate pharmacological treatment options for their children. It should be emphasized that psychopharmacological treatment can alleviate symptoms of irritability, ADHD, and anxiety in children with ASD which improve their adaptive functioning.
EXPRESSION PATTERNS OF IL-17 RECEPTORS IN THE CEREBRAL CORTEX DURING POSTNATAL DEVELOPMENT AND ITS ALTERATION BY MATERNAL IMMUNE ACTIVATION
Authors: Sasaki *Tetsuya , Kamiya Sara , Kishi Kyoko , Iwata Suguru , Takei Yosuke 
Published: February 2025

Abstract

Background
T-helper 17 (Th17) cells are a subset of CD4+ T cells that produce interleukin (IL)-17A. Recent studies showed that an increase in circulating IL-17A causes cognitive dysfunction, although it is unknown how increased systemic IL-17A affects brain function.

Aims & Objectives
Using transgenic mice overexpressing RORγ t, a transcription factor essential for differentiation of Th17 cells (RORγ t Tg mice), we examined changes in the brain caused by chronically increased IL-17A resulting from excessive activation of Th17 cells.

Methods
To investigate the effect of IL-17 on neuronal and glial cells in the brain, we made use of mutant mice overexpressing RORγ t (RORγ t Tg mice).

Results
RORγ t Tg mice exhibited elevated Rorc and IL-17A mRNA expression in the colon, as well as a chronic increase in circulating IL-17A. We found that the immunoreactivity of Iba1 and density of microglia were lower in the dentate gyrus of RORγ t Tg mice compared with wild-type mice. However, GFAP+ astrocytes were unchanged in the hippocampi of RORγ t Tg mice. Levels of synaptic proteins were not significantly different between RORγ t Tg and wild-type mouse brains. In addition, novel object location test results indicated no difference in preference between these mice.

Discussion & Conclusion
Our findings indicate that a continuous increase of IL-17A in response to RORγ t overexpression resulted in decreased microglia activity in the dentate gyrus, but had only a subtle effect on murine hippocampal functions.

References
Sasaki T, Nagata R, Takahashi S, Takei Y. Effects of RORγ t overexpression on the murine central nervous system. Neuropsychopharmacology Reports. 2021. 41(1): 102-110.
Sasaki T, Tome S, Takei Y. Intraventricular IL-17A Administration Activates Microglia and Alters Their Localization in the Mouse Embryo Cerebral Cortex. Mol Brain. 13:93. 2020.
Tome S, Sasaki T, Takahashi S, Takei Y. Elevated maternal retinoic acid-related orphan receptor-γ t enhances the effect of polyinosinic-polycytidylic acid in inducing fetal loss. Exp Animals. 2019. Jun 10.
THE EFFECTS OF REDUCED ENDOGENOUS OXYTOCIN RELEASE ON COGNITIVE FUNCTION IN CAPS2 CKO MICE
Authors: Nagano *Wakana , Takahashi Junpei , Yamada Daisuke , Sano Yoshitake , Furuichi Teiichi , Saitoh Akiyoshi 
Published: February 2025

Abstract

Background & Objectives
Recently, we found that the mice treated with oxytocin (OXT) improved the amyloid-β induced memory dysfunction. In addition, plasma OXT levels have been reported to be lower in Alzheimer’ s disease (AD) patients than in healthy individuals, proposing that decreasing the secretion of OXT could be a risk factor for the development of AD. However, it is unknown whether decreased OXT levels affect cognitive functions. We previously developed mice with OXT neuron-specific deficiency of the Ca2+-dependent activator protein for secretion (CAPS) (Caps2 conditional KO (cKO) mice) and found that plasma OXT level was decreased in these mice. In this study, we examined the effects of reduced OXT release on cognitive function in Caps2 cKO mice.

Results
We firstly investigated the OXT receptors mRNA in hippocampus. OXT receptors mRNA was significantly increased in Caps2 cKO mice compared to Caps2flox/flox mice. In Caps2 cKO mice, object memory in the novel object recognition (NOR) test and fear memory in the passive avoidance (PA) test were impaired, respectively, but short-term spatial memory in the Y-maze test was not. The cognitive dysfunction observed in Caps2 cKO mice observed in the NOR and PA tests was reversed by intracerebroventricular administration of OXT. In addition, hippocampal long-term potentiation (LTP) was reduced in Caps2 cKO mice compared to Caps2flox/flox mice without affecting the paired-pulse ratio or input-output curve. Further, the expression of phosphorylated ERK (pERK) in the ventral hippocampus was reduced in the Caps2 cKO mice compared to Caps2flox/flox mice.

Discussion & Conclusion
These results indicate that deletion of CAPS2 in OXT neurons impairs synaptic plasticity via the ERK signaling pathway in the hippocampus, which may result in impairment of cognitive functions such as object recognition and fear memory. This study is expected to provide insight into the relationship between the activity of the oxytocin nervous system in the brain and cognitive function.
ANALYSIS OF MIXED EPISODES IN BIPOLAR DISORDER AND INFLUENCING FACTORS
Authors: Wang *Hong-Li , Lu Ya-Zhou , Shi Xiao-Ning , Zhao Ying-Ying , Dun Wen-Wen , Zhu Xue-Quan , Zhang Ling 
Published: February 2025

Abstract

Background
Mixed episodes of bipolar disorder typically develop at an earlier age, have more severe symptoms, higher rate of suicide, comorbidities and poorer clinical outcomes[1, 2]. Therefore, it is an urgent clinical problem to explore the risk factors of mixed episodes and reduce the recurrence rate.

Aims & Objectives
To explore the mixed episodes of bipolar disorder and analyze its influencing factors.

Methods
During February 2013 to June 2014, 520 patients with bipolar disorder were selected from 7 hospitals in China by continuous sampling method. The demographic data, medical history information, disease characteristics, treatment and other clinical data were collected. We investigated the number of mixed episodes of bipolar disorder and analyzed the influencing factors by Poisson regression model.

Results
Among 520 patients with bipolar disorder, 75 cases (14.42%) were mixed episodes, including 72 cases type I and 3 cases type II. Poisson regression model analysis showed that the risk factors of mixed episodes included: Type I patients had more episodes than type II (IRR = 0.068, p &lt;0.001). Patients with family history of mental illness had more mixed episodes (IRR = 1.435, p = 0.037). Patients with non- manic polarity at first episode had more mixed episodes than manic patients (IRR = 9.988, p &lt;0.001). Non-depressed patients at first episode had more episodes than depressed patients (IRR = 6.241, p &lt;0.001). Patients taking mood stabilizers had more mixed episodes (IRR = 0.561, p = 0.001).

Discussion & Conclusion
Mixed episodes of bipolar disorder are closely related to the type of bipolar disorder, family history of mental illness, polarity of first episode and use of mood stabilizers.

References
1.Chakrabarty, T., K. Keramatian, and L.N. Yatham, Treatment of Mixed Features in Bipolar Disorder: an Updated View. Curr Psychiatry Rep, 2020. 22(3): p. 15.
2.Isometsä, E., et al., Dangerously mixed. Bipolar Disord, 2017. 19(4): p. 314-315.
CATHEPSIN B MODULATES MICROGLIAL MIGRATION AND PHAGOCYTOSIS OF AMYLOID β THROUGH PI3K-AKT SIGNALS IN ALZHEIMER’ S DISEASE
Authors: Ni *Junjun 
Published: February 2025

Abstract
The approval of anti-Amyloid β (Aβ) monoclonal antibodies (lecanemab) in the treatment of patients with early Alzheimer’ s disease by FDA, suggests the reliability and importance of clearance of brain Aβ in AD therapy. Microglia are the main phagocytes in the brain to clean up Aβ, but the regulatory mechanism has not been fully clarified. Here, we investigated the critical role of cathepsin B (CatB) in modulating microglial clearance of Aβ in the mouse brain. We stereotaxically injected Aβ into the hippocampus of mice to assess the effect of CatB on Aβ clearance. CatB deficiency significantly reduced the Aβ clearance efficiency and aggravated the cognitive decline in mice after Aβ administration for 3 weeks.
Exogenous Aβ increase CatB expression majorly in activated microglia. Transcriptomic analysis indicated that CatB is associated with gene clusters of migration, phagocytosis, and inflammation, which were validated by in vitro cell culture experiments. In addition, KEGG analysis and immunoblotting suggested that CatB modulates microglial Aβ clearance depending on PI3K-AKT activation. These findings indicate that CatB regulated microglial Aβ clearance activity, highlighting CatB as a therapeutic target for AD targeting Aβ clearance.
EVALUATION OF ADOLESCENT SMOKERS WHO CALLED TAIWAN SMOKERS’ HELPLINE
Authors: Chiu *Nan-Ying 
Published: February 2025

Abstract

Background
In 1997, the Legislative Yuan of Taiwan passed the “Tobacco Harm Control Act”, which restricts the intake of addictive substances by smokers. On January 3, 2003, the Department of Health and Welfare established Asia's first smoking cessation hotline - "Taiwan Smokers’ Helpline Service Center". On April 30, 2021, Changhua Christian Hospital took charge the Smokers’ Helpline Service. Objectives The aims of the study were to realize the effectiveness of this smokers’ helpline for young smokers, and explore related factors.

Methods
The author collected the data of adolescent smokers aged under 18 years old who called Taiwan Smokers’ Helpline from May1 to November 30, 2021, and analyzed related data, discussed the factors influencing rate of successfully quit smoking.

Results
The data was compared according to whether the adolescent case had successfully quit smoking (consistent non-smoking for more than 6 months). Totally 312 teenage smokers were enrolled, 83.7% were male, average age was 15.8 (SD 1.3) year-old, 88.8% were student, 31.7% smoked for 2-3 years, 69.2% were daily smoker, 38.8% smoked less than 10 cigarettes per day, 35.6% had experience of using electronic cigarette, 27.6% experienced withdrawal syndrome, 71.2% were low tobacco dependence (according to FTND), 69.6% had quitted smoking for at least 24 hours in the past year. 26.0% successfully quit smoking (continuous smoking cessation rate). The author found relating factors for successfully smoking cessation were gender, area of residence, daily smoker, amount of daily tobacco use, family request for quit tobacco smoking, appearance of physical withdrawal syndrome during quitting smoking or reduce smoking amount, total score of FTND, and whether there had been an attempt not to smoke for at least 24 hour in the past year. The accuracy rate of our prediction model for successfully quit tobacco smoking due to related factors is 70.0 %.

Discussion & Conclusion
The Smokers’ Helpline is helpful for adolescent smokers to quit tobacco smoking, the continuous smoking cessation rate was 26.0% of this study. Some significant relating factors were found, the accuracy of prediction rate is acceptable.

References
W.H.C. Li, S.S.C. Chan, M.P. Wang, K.Y. Ho, Y.T.Y. Cheung, V.W.F. Chan, T.H. Lam. An Evaluation of the Youth Quitline Service Young Hong Kong Smokers. J Adolesc Health. 2017 May; 60(5):584-591.
α6GABAAR POSITIVE ALLOSTERIC MODULATOR AS A NOVEL THERAPY FOR ALCOHOL WITHDRAWAL SYNDROME
Authors: Hung *Hao-Yuan , You Ya-Wun , Chiou Lih-Chu 
Published: February 2025

Abstract

Background
Alcohol use disorder (AUD) is a disease manifested by compulsive use of alcohol, the inability to control intake, and characterized by repeated cycles of intoxication, withdrawal, craving, and relapse. Alcohol withdrawal syndrome (AWS), like anxiety, tremor, and hyperthermia, is the leading cause of the high relapse rate in heavy drinkers. Alcohol can facilitate GABA action and down-regulate GABA receptors after long-term use.

Aims & Objectives
Clinically AWS is usually treated with GABAAR positive allosteric modulators (PAMs), like benzodiazepines and barbiturates. However, the combination of benzodiazepines and alcohol is hazardous, leading to life-threatening consequences. Therefore, developing a safer and more efficient therapy is crucial for treating AWS/AUD, mainly focusing on the GABAergic system.

Method
Here, we employed an AUD animal model well-established previously by giving rats intermittent (every other day) access to ethanol (20%) in a 2-bottle choice (IA2BC) procedure (Fig. 1A). After the eight-week IA2BC test, we performed different behavioral tests to evaluate the AWS in our animal model. The light-dark box, open field test, and marble-burying test were used to assess anxiety-related behaviors in rats. Our international collaborating team identified a series of pyrazoloquinolinones (PQs) as the first α6GABAAR-selective PAMs. Hence, we evaluated whether these PQs could be used as a potential novel therapy for treating AWS/AUD. Statistical significance was determined using a two-way ANOVA followed by a Bonferroni post hoc test on raw data.

Results
The rats exposing to alcohol under the IA2BC procedure for eight weeks gradually increased the intake of alcohol, but not water, with a significant ethanol preference from four weeks (Fig. 1B). In these alcohol- dependent rats after 7 days’ abstinence, we observed significant anxiety-like behaviors in the marble- burying (Fig. 1C) and light-dark box (Fig. 1D). In the open field test (Fig. 1E), the alcohol-dependent rats showed less exploration and hypo-locomotion after alcohol withdrawal. We speculate that the decreased locomotion activity is probably related to depression or stress. In contrast, DK-I-56-1 (one of PQs) significantly alleviated the anxiety-related behaviors in both marble-burying and light/dark box tests (Fig. 1C-D), especially on the first withdrawal day.

Discussion & Conclusion
Our preliminary results showed that DK-I-56-1 could significantly improve AWS. Since the AWS period brings great discomfort and intense cravings to the patient, the patient turned to use alcohol, presumably for symptom relief.
Hence, we believe α6GABAARs may be a therapeutic target of AUD/AWS.
ASSOCIATION BETWEEN PROOPIOMELANOCORTIN GENE VARIATION AND ALCOHOL DEPENDENCE IN JAPANESE
Authors: Kasai *Shinya , Nishizawa Daisuke , Higuchi Susumu , Ikeda Kazutaka 
Published: February 2025

Abstract

Background & Objectives
The contribution of genetic factors in alcohol dependence is approximately 0.4- 0.6, indicating that genetic variations can be markers for individual vulnerability to alcohol dependence. Racial and ethnic differences in genetic backgrounds lead to different effect sizes of each genetic variation in the analyses and would be expected to affect the results of association studies. The endogenous opioid system has been reportedly implicated in addiction including alcohol dependence. In the present study, we focused on the Proopiomeranocortin (POMC) gene which encodes an endogenous opioid, β-Endorphin and examined the effects of genetic variations on alcohol dependence in Japanese.

Method
This study included 425 Japanese patients diagnosed with alcohol abuse/dependence by DSM-III- R and 339 control subjects matched to alcoholic patients on gender and age. The statistical significance of associations between genetic variations in alcohol-dependent patients and control subjects was evaluated with non-parametric analyses. Linkage disequilibrium (LD) was examined with the SNVs identified by direct sequencing around the POMC gene.

Result
The POMC C-1802T variation was significantly different between patients with alcohol dependence and control subjects. The significant difference in the recessive model was confirmed after correction by ALDH2 rs672 variation. Three LD blocks were constructed around the POMC gene, but no one including the variation was identified in Japanese.

Discussion & Conclusion
A genetic variation in 5 flanking region of the POMC gene appears to be associated with alcohol dependence in Japanese. This genetic variation may alter the expression of the POMC gene and affect vulnerability to alcohol dependence. Nalmefene, an inverse agonist of the μ-opioid receptor and a partial agonist of the κ-opioid receptor, is used in the treatment of alcohol dependence in Japan. The frequency of this genetic variation varies widely among racial groups around the world and is expected to influence the efficacy of alcoholism medications such as naltrexone and nalmefene.