Structural covariance network activity in the medial prefrontal cortex is modulated by childhood abuse in adolescents with depression.

Aberrant structural covariance (SC) in the medial prefrontal cortex (mPFC) is believed to play a crucial role in adolescent-onset major depressive disorder (AO-MDD). However, the effect of childhood abuse (CA) on SC in AO-MDD patients is still unknown. Here, we measured anomalous SC in the mPFC of AO-MDD patients and assessed the potential modulation of this feature by CA. We acquired T1-weighted structural images of AO-MDD patients (n = 93) and healthy controls (HCs, n = 81). Using voxel-based morphometry analysis, we calculated gray matter volumes for each subject. Subsequently, we classified abnormal SC in the mPFC into three subtypes according to overall CA. Compared with HCs, AO-MDD patients showed alterations in the structural covariance network of the mPFC, which is a central region in the default mode network (DMN). We also found an anterior-posterior dissociation in the structural covariance connectivity of the DMN. A history of CA modulated bilateral mPFC SC. These changes were primarily focused on the SC between the mPFC and the limbic system, indicating a gap in the rate of neural maturation between these regions. In summary, the DMN and frontal-limbic system, which are involved in emotional processing, appear to play a significant role in the development of AO-MDD. These findings highlight the crucial effects of CA on neurophysiological alterations in individuals with AO-MDD.

The impact of the physical activity intervention on sleep in children and adolescents with neurodevelopmental disorders: a systematic review and meta-analysis.

Objective: The purpose of this review was to synthesize the current literature on the relationship between sleep and physical activity in children and adolescents with neurodevelopmental disorders. Methods: Articles were searched in PubMed, Web of Science, EBSCO, Cochrane, and Embase until April 2024. The meta-analysis was performed using Review Manager 5.3. Results: Our results show that measuring sleep parameters by means of different measuring tools yields different results. Most studies have found no association between sleep and physical activity in children with neurodevelopmental disorders, especially when measured subjectively, such as parent reports and sleep logs. Physical activity interventions had a significant effect on sleep efficiency, wake after sleep onset, and sleep duration when measured objectively using instruments such as wrist actigraphy. Meta-analysis showed that children and adolescents with neurodevelopmental disorders who participated in mind-body activities (SMD = -3.01, 95%CI = -4.15~-1.87, p < 0.001, I2 = 99%) showed significant improvements in sleep, which were sessions lasting more than 12 weeks (SMD = -1.01, p < 0.01, I2 = 97%), performed at least 3 times per week (SMD = -0.81, 95%CI = -1.53~-0.10, p = 0.03, I2 = 95%), and lasted for more than 60 min per session (SMD = -1.55, 95%CI = -2.67~-0.43, p = 0.007, I2 = 97%). However, the results of these subgroup analyses must be interpreted with caution because of the small number of studies included. Conclusion: Our results show that measuring sleep parameters by means of different measuring tools yields different results. There was difficulty in interpreting many of the studies included in this meta-analysis, in view of the non-standardization of protocol, especially the ability range of the cohort, duration of the study, recommended exercises, whether the caregivers or researchers supervised the exercise regime/activity, and the practicality of continuing the exercise long-term by caregivers. Systematic review registration: Identifier, CRD42024541300.

Regional variation and adaptive evolution in Bifidobacterium pseudocatenulatum: Insights into genomic and functional diversity in human gut.

Bifidobacterium pseudocatenulatum is a prevalent gut microbe in humans of all ages and plays a crucial role in host health. However, its adaptive evolutionary characteristics remain poorly understood. This study analyzed the genome of 247 B. pseudocatenulatum isolates from Chinese, Vietnamese, Japanese and other region populations using population genomics and functional genomics. Our findings revealed high genetic heterogeneity and regional clustering within B. pseudocatenulatum isolates. Significant differences were observed in genome characteristics, phylogeny, and functional genes. Specifically, Chinese and Vietnamese isolates exhibited a higher abundance of genes involved in the metabolism of plant-derived carbohydrates (GH13, GH43, and GH5 enzyme families), aligning with the predominantly vegetable-, wheat- and fruit-based diets of these populations. Additionally, we found widespread transmission of antibiotic resistance genes (tetO and tetW) through mobile genetic elements, such as genomic islands (GIs), resulting in substantial intra-regional differences. Our findings highlight distinct adaptive evolution in B. pseudocatenulatum driven by gene specialization, possibly in response to regional variations in diet and lifestyle. This study sheds light on bifidobacteria colonization mechanisms in the host gut. IMPORTANCE: Gut microbiota, as a key link in the gut-brain axis, helps to maintain the health of the organism, among which, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum) is an important constituent member of the gut microbiota, which plays an important role in maintaining the balance of gut microbiota. The probiotic properties of B. pseudocatenulatum have been widely elaborated, and in order to excavate its evolutionary features at the genomic level, here we focused on the genetic background and evolutionary mechanism of the B. pseudocatenulatum genomes isolated from the intestinal tracts of different populations. Ultimately, based on the phylogenetic tree, we found that B. pseudocatenulatum has high genetic diversity and regional clustering phenomenon, in which plant-derived carbohydrate metabolism genes (GH13, GH43, GH5) showed significant regional differences, and this genetic differentiation drove the adaptive evolution, which likely shaped by diet and lifestyle.

Influence of aerobic exercise on depression in young people: a meta-analysis.

OBJECTIVE: To investigate the influence of aerobic exercise on depression among the young people. DATA SOURCES: PubMed, Web of science, Embase, Cochrane, EBSCO were searched from inception to November 2023. STUDY SELECTION: RCT studies, assessing the use of aerobic exercise in young people aged 6-35 years and then determining the development of depression in young people (aged 6-35 years), were selected, and mean ± SD values adjusted for the presence of baseline depression were extracted. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Review manager 5.4.1 and Cochrane 5.1 item on risk of bias and precision of observational studies. Two reviewers conducted all review stages independently. Selected data were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: The included studies evaluated the relationship between aerobic exercise and depression at various time points among young individuals, and provided corresponding mean ± SD values. Depression diagnosis in the selected studies was conducted using the Depression Correlation Scale. RESULTS: After screening 2296 articles, 163 articles were selected for full-text review, and 8 of those were further reviewed. Ultimately, 12 studies, involving 658 individuals, were included in the meta-analysis. The results of the meta-analysis indicated that aerobic exercise could effectively improve depression in young people (d = -1.33, 95%CI: -1.78 ~ -0.87, P < 0.05). Subgroup analysis demonstrated that aerobic exercise was beneficial for both depression (d = -2.68, 95%CI: -3.87 ~ -1.48, P < 0.05) and non-depression (d = -0.85, 95%CI: -1.20 ~ -0.51, P < 0.05) conditions, as well as for low intensity (d = -0.93, 95%CI: -1.29 ~ 0.58, P < 0.05) and moderate intensity (d = -2.08,95%CI:-2.88 ~ -1.27, P < 0.05) exercises. Additionally, aerobic exercise was found to significantly alleviate depression in young people when performed for 40 min or less (d = -2.00,95%CI: -2.96 ~ -1.04, P < 0.05), whereas durations exceeding 40 min showed a lesser effect (d = -0.85,95%CI:-1.47 ~ -0.24, P < 0.05). Furthermore, the duration-based analysis revealed that aerobic exercise improved depression levels in young people regardless of duration, whether it was for less than 6 weeks (d = -1.27,95%CI: 2.12 ~ 0.14, P < 0.05), 6 to 11 weeks (d = 1.55, 95% CI: 2.16 ~ 0.94, P < 0.05), or more than 12 weeks (d = 1.00, 95% CI: -1.76 ~ -0.24,P < 0.05). Overall, these findings suggest that aerobic exercise is a promising intervention for alleviating depression in young individuals. CONCLUSIONS: Both short (less than 40 min) and long (more than 40 min) periods of aerobic exercise were effective in improving depressive symptoms. However, the optimal duration of aerobic exercise may vary depending on the specific population and individual factors studied, such as age, health status, and exercise tolerance. Therefore, this study concluded that the most effective exercise regimen, 40 min of moderate-intensity aerobic exercise three times a week for 6 to 11 weeks, showed more significant improvement in depression indicators in individuals with depressive symptoms.

Probio-M9, a breast milk-originated probiotic, alleviates mastitis and enhances antibiotic efficacy: Insights into the gut-mammary axis.

Breast milk naturally contains lactic acid bacteria, but their precise origin remains a subject of debate. In this study, we utilized a rat mastitis animal model to investigate the potential of a breast milk-derived probiotic strain, Lacticaseibacillus rhamnosus Probio-M9, in alleviating mastitis and enhancing the efficacy of antibiotic treatment. Through histopathological analysis of mammary tissue, we observed that Probio-M9 effectively relieved mastitis, mitigated inflammation, and improved the response to antibiotic treatment. Metagenomic analysis further revealed that Probio-M9 enhanced interactions among gut microbes, accompanied by an increase in the relative abundance of Ruminococcaceae and the regulation of specific genes and carbohydrate-active enzymes, subsequently impacting host immunity. Additionally, an intriguing finding was the translocation of live Probio-M9 from the gut to the mammary tissue only during bacterial mastitis and lactation, likely facilitated through lymphatic circulation. These findings advance our understanding of the intricate gut-mammary axis and provide valuable insights into the potential health benefits of probiotic interventions.

Dung Beetle Optimizer Algorithm and Machine Learning-Based Genome Analysis of Lactococcus lactis: Predicting Electronic Sensory Properties of Fermented Milk.

In the global food industry, fermented dairy products are valued for their unique flavors and nutrients. Lactococcus lactis is crucial in developing these flavors during fermentation. Meeting diverse consumer flavor preferences requires the careful selection of fermentation agents. Traditional assessment methods are slow, costly, and subjective. Although electronic-nose and -tongue technologies provide objective assessments, they are mostly limited to laboratory environments. Therefore, this study developed a model to predict the electronic sensory characteristics of fermented milk. This model is based on the genomic data of Lactococcus lactis, using the DBO (Dung Beetle Optimizer) optimization algorithm combined with 10 different machine learning methods. The research results show that the combination of the DBO optimization algorithm and multi-round feature selection with a ridge regression model significantly improved the performance of the model. In the 10-fold cross-validation, the R2 values of all the electronic sensory phenotypes exceeded 0.895, indicating an excellent performance. In addition, a deep analysis of the electronic sensory data revealed an important phenomenon: the correlation between the electronic sensory phenotypes is positively related to the number of features jointly selected. Generally, a higher correlation among the electronic sensory phenotypes corresponds to a greater number of features being jointly selected. Specifically, phenotypes with high correlations exhibit from 2 to 60 times more jointly selected features than those with low correlations. This suggests that our feature selection strategy effectively identifies the key features impacting multiple phenotypes, likely originating from their regulation by similar biological pathways or metabolic processes. Overall, this study proposes a more efficient and cost-effective method for predicting the electronic sensory characteristics of milk fermented by Lactococcus lactis. It helps to screen and optimize fermenting agents with desirable flavor characteristics, thereby driving innovation and development in the dairy industry and enhancing the product quality and market competitiveness.

Structural basis of nearest-neighbor cooperativity in the ring-shaped gene regulatory protein TRAP from protein engineering and cryo-EM.

Homotropic cooperativity is widespread in biological regulation. The homo-oligomeric ring-shaped trp RNA binding attenuation protein (TRAP) from bacillus binds multiple tryptophan ligands (Trp) and becomes activated to bind a specific sequence in the 5' leader region of the trp operon mRNA. Ligand-activated binding to this specific RNA sequence regulates downstream biosynthesis of Trp in a feedback loop. Characterized TRAP variants form 11- or 12-mer rings and bind Trp at the interface between adjacent subunits. Various studies have shown that a pair of loops that gate each Trp binding site is flexible in the absence of the ligand and become ordered upon ligand binding. Thermodynamic measurements of Trp binding have revealed a range of cooperative behavior for different TRAP variants, even if the averaged apparent affinities for Trp have been found to be similar. Proximity between the ligand binding sites, and the ligand-coupled disorder-to-order transition has implicated nearest-neighbor interactions in cooperativity. To establish a solid basis for describing nearest-neighbor cooperativity we engineered dodecameric (12-mer) TRAP variants constructed with two subunits connected by a flexible linker (dTRAP). We mutated one of the protomers such that only every other site was competent for Trp binding. Thermodynamic and structural studies using native mass spectrometry, NMR spectroscopy, and cryo-EM provided unprecedented detail into the thermodynamic and structural basis for the observed ligand binding cooperativity. Such insights can be useful for understanding allosteric control networks and for the development of new ones with defined ligand sensitivity and regulatory control.

Streptococcus hohhotensis sp. nov., isolated from the breast milk of a healthy woman.

Human breast milk contains lactic acid bacteria (LAB), which have an important influence on the composition of the intestinal microbia of infants. In this study, one strain of an α-hemolytic species of the genus Streptococcus, IMAU99199T, isolated from the breast milk of a healthy nursing mother in Hohhot city PR China, was studied to characterise its taxonomic status using phenotypic and molecular taxonomic methods. The results indicated that it represented a member of the mitis-suis clade, pneumoniae subclade of the genus Streptococcus. It is a Gram-stain-positive, catalase-negative and oxidase-negative bacterium, and the cells are globular, paired or arranged in short chains. The results of a phylogenetic analysis of its 16S rRNA gene and two housekeeping genes (gyrB and rpoB) placed it in the genus Streptococcus. A phylogenetic tree based on 135 single-copy genes sequences indicated that IMAU99199T formed a closely related branch well separated from 'Streptococcus humanilactis' IMAU99125, 'Streptococcus bouchesdurhonensis' Marseille Q6994, Streptococcus mitis NCTC 12261T, 'Streptococcus vulneris' DM3B3, Streptococcus toyakuensis TP1632T, Streptococcus pseudopneumoniae ATCC BAA-960T and Streptococcus pneumoniae NCTC 7465T. IMAU99199T and 'S. humanilactis' IMAU99125 had the highest average nucleotide identity (93.7 %) and digital DNA-DNA hybridisation (55.3 %) values, which were below the accepted thresholds for novel species. The DNA G+C content of the draft genome of IMAU99199T was 39.8 %. The main cellular fatty acids components of IMAU99199T were C16 : 0 and C16 : 1ω7. It grew at a temperature range of 25-45 °C (the optimum growth temperature was 37 °C) and a pH range of 5.0-8.0 (the optimum growth pH was 7.0). These data indicate that strain IMAU99199T represents a novel species in the genus Streptococcus, for which the name Streptococcus hohhotensis sp. nov. is proposed. The type strain is IMAU99199T (=GDMCC 1.1874T=KCTC 21155T).

Functional connectivity of the amygdala subregions and the antidepressant effects of repeated ketamine infusions in major depressive disorder.

BACKGROUND: Amygdala subregion-based network dysfunction has been determined to be centrally implicated in major depressive disorder (MDD). Little is known about whether ketamine modulates amygdala subarea-related networks. We aimed to investigate the relationships between changes in the resting-state functional connectivity (RSFC) of amygdala subregions and ketamine treatment and to identify important neuroimaging predictors of treatment outcomes. METHODS: Thirty-nine MDD patients received six doses of ketamine (0.5 mg/kg). Depressive symptoms were assessed, and magnetic resonance imaging (MRI) scans were performed before and after treatment. Forty-five healthy controls underwent one MRI scan. Seed-to-voxel RSFC analyses were performed on the amygdala subregions, including the centromedial amygdala (CMA), laterobasal amygdala (LBA), and superficial amygdala subregions. RESULTS: Abnormal RSFC between the left LBA and the left precuneus in MDD patients is related to the therapeutic efficacy of ketamine. There were significant differences in changes in bilateral CMA RSFC with the left orbital part superior frontal gyrus and in changes in the left LBA with the right middle frontal gyrus between responders and nonresponders following ketamine treatment. Moreover, there was a difference in the RSFC of left LBA and the right superior temporal gyrus/middle temporal gyrus (STG/MTG) between responders and nonresponders at baseline, which could predict the antidepressant effect of ketamine on Day 13. CONCLUSIONS: The mechanism by which ketamine improves depressive symptoms may be related to its regulation of RSFC in the amygdala subregion. The RSFC between the left LBA and right STG/MTG may predict the response to the antidepressant effect of ketamine.

Research on Performance Improvement of Emulsified Asphalt Mixture Based on Innovative Forming Process.

Bulk density and porosity have great influence on the technical performance of an emulsified asphalt mixture, so in order to enhance the strength of the asphalt mixture, bulk density should be improved and porosity should be reduced. Considering the forming process of the emulsified asphalt mixture, the decrease in porosity can ensure the state of the mixture. In order to reduce the porosity of the emulsified asphalt mixture, an innovative forming process is proposed to improve the performance of the emulsified asphalt mixture, and its strength formation mechanism is explored in this paper. Three groups of emulsified asphalt mixtures (ARC-8 + SBR, SMA-5 + EVA, SMA-5 + SBR) were prepared by a conventional mixing process and novel mixing process. Marshall test of the emulsified asphalt mixture, CT scanning test of the emulsified asphalt mixture, workability test and analysis were manufactured and tested. The results show that, compared with conventional methods, the innovative forming method can increase the bulk density of the mixture and reduce the porosity, and thus improve its technical performance. The reason is that most of the water in the mixture of the innovative forming method sticks to the outer surface of the fine aggregate, and the water is more easily discharged. Secondly, the fine aggregate of the innovative forming method is directly mixed with the emulsion, and the volume is smaller. The emulsion wraps the fine aggregate in it due to the surface tension, which enhances the adhesion effect, thus improving the strength of the mixture.

Mediating effect of inflammation on the relationship between sleep disruption and suicidal ideation in major depressive disorder.

BACKGROUND: Sleep disruption, particularly insomnia, is a notable characteristic of depression and is associated with an increased risk of suicide in patients diagnosed with major depressive disorder (MDD). Moreover, the pathophysiology of depression and suicide has been linked to inflammation, specifically proinflammatory cytokines. However, the complex interplay among these factors in individuals with MDD remains poorly understood. This study investigated the mediating role of inflammatory cytokines in the relationship between sleep disruption and suicidal ideation (SI), with a particular emphasis on gender differences. METHODS: This study used a cross-sectional design in which 281 individuals diagnosed with MDD were recruited from psychiatric clinics. The main assessments included the evaluation of sleep disruption, inflammatory markers, and SI. The Beck Scale for Suicide Ideation (SSI) scores was employed to quantify SI, whereas HAMD-SLD, a component of the Hamilton Rating Scale (HAMD-17), was used to evaluate sleep disruption. Blood analysis was performed to measure inflammatory markers. RESULT: For females diagnosed with MDD, significant associations between sleep disruption and the levels of IL-6 (B = 0.994, p = 0.013) and TNF-α (B = 1.986, p = 0.016) were found when IL-6 or TNF-α were considered as mediators in the regression model. In addition, IL-6 (B = 5.689, p < 0.001) and TNF-α (B = 9.916, p = 0.006) exhibited strong correlation with SSI scores. CONCLUSIONS: The primary results of this study indicate that IL-6 and TNF-α could function as potential mediators in the relationship between sleep disruption and SI among female patients diagnosed with MDD. CLINICAL TRIAL: Name of the registry: Zhejiang University Trial registration number: ChiCTR1800017626 Date of registration: 2018-08-07, 'Retrospectively registered' URL of trial registry record: https://www.chictr.org.cn/showproj.html?proj=27321.

Basketball specific agility: A narrative review of execution plans and implementation effects.

This systematic review and evaluation aim to comprehensively overview current international advanced basketball specialized agility training methods. The primary objective is to analyze and synthesize existing literature, offering insights and guidance to enhance agility training levels specifically tailored for basketball players. Methods involved a systematic literature search using keywords like "Basketball," "Agility," and "Training" in major databases (PubMed, Web of Science, and EBSCO), covering studies from 2010 to 2022. Inclusion criteria focused on studies addressing advanced agility training methods for basketball players. Data extraction and analysis were conducted to identify key trends and outcomes. A total of 563 articles were initially identified, and after reviewing titles, abstracts, and full texts, 20 articles were ultimately selected, excluding those with inconsistent outcome measures or unavailable full texts. The findings suggest that plyometric training, comprehensive speed training, and equipment-assisted training methods (SSG, TRX, Bulgarian ball, etc) have demonstrated effectiveness in improving agility indicators in basketball players.

Highly specific intracellular ubiquitination of a small molecule.

Ubiquitin is a small, highly conserved protein that acts as a posttranslational modification in eukaryotes. Ubiquitination of proteins frequently serves as a degradation signal, marking them for disposal by the proteasome. Here, we report a novel small molecule from a diversity-oriented synthesis library, BRD1732, that is directly ubiquitinated in cells, resulting in dramatic accumulation of inactive ubiquitin monomers and polyubiquitin chains causing broad inhibition of the ubiquitin-proteasome system. Ubiquitination of BRD1732 and its associated cytotoxicity are stereospecific and dependent upon two homologous E3 ubiquitin ligases, RNF19A and RNF19B. Our finding opens the possibility for indirect ubiquitination of a target through a ubiquitinated bifunctional small molecule, and more broadly raises the potential for posttranslational modification in trans.

Effect of different isolation sources of Lactococcus lactis subsp. lactis on volatile metabolites in fermented milk.

Lactococcus lactis subsp. lactis (L. lactis subsp. lactis) is a commonly used starter cultures in fermented dairy products, contributing distinct flavor and texture characteristics with high application value. However, the strains from different isolates have different contributions to milk fermentation. Therefore, this study aimed to investigate the influence of L. lactis subsp. lactis isolated from various sources on the volatile metabolites present in fermented milk. In this study, L. lactis subsp. lactis from different isolation sources (yogurt, koumiss and goat yogurt) was utilized as a starter culture for fermentation. The volatile metabolites of fermented milk were subsequently analyzed by headspace solid phase microextraction gas chromatography-mass spectrography (HS-SPME-GC-MS). The results indicated significant differences in the structure and abundance of volatile metabolites in fermented milk produced with different isolates (R2Y = 0.96, Q2 = 0.88). Notably, the strains isolated from goat yogurt appeared to enhance the accumulation of ketones (goat yogurt vs yogurt milk: 50 %; goat yogur vs koumiss: 27.3 %)and aldehydes (goat yogurt vs yogurt milk: 21.4 %; goat yogurt vs koumiss: 54.5 %) in fermented milk than strains isolated from koumiss and yogurt milk. It significantly promoted the production of 8 flavor substances (1 substance with OAV ≥ 1 and 6 substances with OAV > 0.1) and enhanced the biosynthesis of valine, leucine, and isoleucine. This study provides valuable insights for the application of Lactococcus lactis subsp. lactis isolated from different sources in fermented dairy production and screening of potential starter cultures.

Efficacy and safety of intermittent theta burst stimulation on adolescents and young adults with major depressive disorder: A randomized, double blinded, controlled trial.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a newer form of Repetitive Transcranial Magnetic Stimulation (rTMS) for depression. However, its efficacy and safety in adolescents and young adults with major depressive disorder (AYA-MDD) have not been well studied, especially when applied with a strategy that combines neuronavigation targeting and accelerated iTBS. METHODS: In this study, ninety patients were randomly assigned to twice-daily (two 600-pulse sessions spaced out by 10 min, n = 31), once-daily (one 600-pulse session, n = 29) or sham iTBS (no pulses, n = 30) groups for 10 treatment days. The primary outcome measure was the change in depression scores on the Hamilton Rating Scale for Depression (HAMD-17). Other clinical symptoms, such as anxiety, were also evaluated. RESULTS: Linear mixed model analysis found that scores on the HAMD-17 and its factors improved in all three groups, but these improvements did not significantly differ among groups. Other clinical symptoms such as anxiety also improved. Response and remission rates were relatively low and did not differ among groups at any time point. The most common adverse event was headache, and the proportion of participants who reported headache in the twice-daily and once-daily groups was significantly higher than that in the sham group. CONCLUSIONS: The current results indicated that twice-daily and once-daily iTBS under neuronavigation are safe and well tolerated in AYA-MDD, but the overall efficacy was not superior to that of sham treatment. We speculated several possible reasons such as the high placebo response of the young population, inadequate iTBS pulses and so on.

Long-term quality of life after repeated ketamine infusions in anxious and nonanxious patients with depression.

BACKGROUND: There have been many studies on the benefits of repeated ketamine infusions on patients' depression but few on the impact of ketamine on patients' long-term quality of life (QoL). This study investigated long-term QoL in individuals with depression, both anxious and nonanxious. METHODS: A total of 107 individuals with a diagnosis of depression were included in the study. The patients were evaluated on Days 0, 13 and 26 and Months 6 and 9, and they received six ketamine infusions over the course of two weeks. The World Health Organization Quality of Life-BREF (WHOQOL-BREF) Scale and the Patient Health Questionnaire-9 (PHQ-9) Scale were used to measure depressive symptoms and QoL. Linear mixed models were used to evaluate depressive symptoms and QoL during ketamine treatment. RESULTS: A total of 67.2 % of patients were diagnosed with anxious depression. In the long term, there were no significant differences in the time-by-group interactions for general QoL (F = 0.510; P = 0.676), physical QoL (F = 2.092; P = 0.102), psychological QoL (F = 0.102; P = 0.959), social QoL (F = 2.180; P = 0.091), or environmental QoL (F = 1.849; P = 0.139) between the two groups. LIMITATIONS: The main limitation of this study is its open-label design. CONCLUSION: The improvement in depression symptoms and QoL following ketamine treatment was not impacted by the presence or absence of anxiety in patients who were depressed prior to treatment. Only occasionally did depressed individuals with anxiety experience a worsening of their quality of life compared to those without anxiety.

Sex differences in the effects of repeated ketamine infusions on bone markers in patients with unipolar and bipolar depression.

BACKGROUND: Patients with depression, especially women, are associated with low bone mineral density (BMD). Traditional antidepressants are associated with negative effects on BMD. Few studies have examined the effect of ketamine on BMD, and it remains unclear whether there are sex differences in the effects of ketamine on BMD in patients with depression. METHODS: A total of 102 patients with unipolar and bipolar depression were administered six infusions of intravenous ketamine over a 12-day period. Plasma levels of eight bone markers were examined at baseline, 24 h after the sixth infusion and again 2 weeks (Days 13 and 26). RESULTS: Linear mixed models showed all bone markers had significant time main effect (all p < 0.05). Compared with baseline, the whole sample showed increased levels of leptin and osteoprotegerin at Days 13 and 26, as well as Dickkopf-related protein 1 at Day 13, and decreased levels of osteocalcin, sclerostin, osteopontin, parathyroid hormone and fibroblast growth factor 23 at Days 13 and 26 (all p < 0.05). Females had a higher level of leptin at Days 13 and 26, and lower levels of osteocalcin and sclerostin at Day 13 than males (all p < 0.05). Increases of leptin were associated with depressive symptom improvements at Day 13 and Day 26 in females (both p < 0.05). In males, higher baseline osteocalcin levels were associated with greater depressive symptom improvement at Day 26 (ß = 0.414, p = 0.009). CONCLUSIONS: Our results suggest that repeated ketamine infusions may be associated with modulation of bone markers in patients with depression and present sex differences. Baseline osteocalcin level may be served as a predictor for the antidepressant effects of ketamine in males. Trial registration Data were derived from an open label clinical trial, which was registered at Chinese Clinical Trial Registry (ChiCTR-OOC-17012239). Registered 26 May 2017. http://www.chictr.org.cn.

Depression and low bone mineral density (BMD) are epidemiologically linked and traditional antidepressants may act as a risk factor for BMD. However, it is unclear whether the novel antidepressant, ketamine, has effects on bone markers in patients with depression and whether there are sex differences on these effects. Ketamine infusions may be associated with modulation of bone markers and may exert a positive effect on BMD in patients with depression, which present sex differences. The study results may inform potential strategies for prevention of low BMD during the treatment of depression. Clinicians should be aware of the bone markers because some of them may be associated antidepressant response.

Altered regional brain activity moderating the relationship between childhood trauma and depression severity.

OBJECTIVE: Childhood trauma (CT) is a major environmental risk factor for an adverse course and treatment outcome of major depressive disorder (MDD). Evidence suggests that an altered regional brain activity may play a crucial role in the relationship between CT and MDD. This study aimed to clarify the relationship between CT, regional brain activity, and depression severity. METHODS: In this study, 96 patients with MDD and 82 healthy controls (HCs) participated. Regional brain activity was measured using the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). These measures were compared between the MDD and HC groups, and the values of different brain regions were extracted as moderators. RESULTS: Increased fALFF and ReHo values were observed in the left middle temporal gyrus in the MDD group compared with the HC group (p < 0.001). Furthermore, the fALFF and ReHo values moderated the positive correlation between the Childhood Trauma Questionnaire (CTQ) score, 17-item Hamilton Depression Rating Scale (HAMD-17) total score, and retardation factor score in the MDD group (all, p < 0.05). Finally, as the fALFF and ReHo values increased, the positive correlations between CTQ, HAMD-17 total, and retardation dimension scores became stronger. CONCLUSION: Our study highlighted the crucial role of altered brain function in connecting childhood maltreatment with depressive symptoms. Our findings indicate that an altered regional brain activity could explain the potential neurobiological mechanisms of MDD symptoms, offering the opportunity to function as a powerful diagnostic biomarker.

The core inflammatory factors in patients with major depressive disorder: a network analysis.

Introduction: The symptoms of major depressive disorder (MDD) vary widely. Psycho-neuro-inflammation has shown that MDD's inflammatory factors can accelerate or slow disease progression. This network analysis study examined the complex interactions between depressed symptoms and inflammatory factors in MDD prevention and treatment. Measures: We gathered participants' inflammatory factor levels, used the Hamilton Depression Scale (HAMD-17), and network analysis was used to analyzed the data. Network analysis revealed the core inflammatory (nodes) and their interactions (edges). Stability and accuracy tests assessed these centrality measures' network robustness. Cluster analysis was used to group persons with similar dimension depressive symptoms and examine their networks. Results: Interleukin-1ß (IL-1ß) is the core inflammatory factor in the overall sample, and IL-1ß-interleukin-4 (IL-4) is the strongest correlation. Network precision and stability passed. Network analysis showed significant differences between Cluster 1 (with more severe anxiety/somatization and sleep disruption) and Cluster 3 (with more severe retardation and cognitive disorders), as well as between Cluster 2 (with more severe anxiety/somatization, sleep disruption and body weight) and Cluster 3. IL-1ß is the core inflammatory factor in Cluster 1 and Cluster 2, while tumor necrosis factor alpha (TNF-α) in Cluster 3. Conclusion: IL-1ß is the central inflammatory factor in the network, and there is heterogeneity in the core inflammatory factor of MDD with specific depressive dimension symptoms as the main manifestation. In conclusion, inflammatory factors and their links should be prioritized in future theoretical models of MDD and may provide new research targets for MDD intervention and treatment.

Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial.

BACKGROUND: Ketamine and its enantiomer have rapid and robust effects on depressive symptom and suicidal ideation. Little is known about their cognitive effects in adolescents. We aimed to evaluate the short-term effect of esketamine on cognition in adolescents with major depressive disorder (MDD) and suicidal ideation. METHOD: In this randomized-controlled trial, 51 participants aged 13-18 with MDD and suicidal ideation received three intravenous infusions of either esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg). Four dimensions of the MATRICS Consensus Cognitive Battery (MCCB), including processing speed, working memory, verbal learning and visual learning, were assessed at Days 0, 6 and 12. RESULTS: In the linear mixed model, a significant time main effect (F = 12.803, P < 0.001), drug main effect (F = 6.607, P = 0.013), and interaction effect (F = 3.315, P = 0.041) was found in processing speed. Other dimensions including working memory and verbal learning showed significant time main effect (all P < 0.05), but no significant drug or interaction effect (all P > 0.05). Esketamine group showed improvement in processing speed from baseline to Days 6 and 12, and working memory from baseline to Day 12 (all P < 0.05). The generalized estimation equation showed no significant association between baseline cognition and antidepressant or antisuicidal effect (both P > 0.05). CONCLUSIONS: The present study suggested that three-dose subanesthetic esketamine infusions did not harm cognition among adolescents with MDD and suicidal ideation. Instead, esketamine may be associated with improvement in processing speed. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trials Registry ( http://www.chictr.org.cn , ChiCTR2000041232).