Valproate-related neutropenia and lithium-related leukocytosis in patients treated with clozapine: a retrospective cohort study.

BACKGROUND: Neutropenia is a noteworthy side effect of clozapine, which might warrant this drugs' discontinuance for safety. Studies have revealed that the risk of neutropenia increases with concurrent administration of valproate, but the evidence was limited. Conversely, lithium may have an ameliorating effect on clozapine-induced neutropenia. This study explored the effects of valproate and lithium on white blood cell counts in patients treated with clozapine. METHODS: We retrospectively investigated the electronic medical records from one tertiary psychiatric hospital in Taiwan and enrolled patients discharged between January 1, 2006, and December 31, 2017, with clozapine prescriptions. We scrutinized their demographic data, medications, and hematological results at discharge and during follow-up outpatient clinic visits over the subsequent 3 years. Patients were classified into four groups: clozapine only (CLO), clozapine and valproate (CLO + VAL), clozapine and lithium (CLO + Li), and clozapine, valproate, and lithium (CLO + VAL + Li). We also identified hematological events (neutropenia or leukocytosis) of these patients during outpatient follow-ups. RESULTS: Of the included 1084 patients, 55(5.1%) developed neutropenia. Concurrent valproate use (odds ratio [OR] = 3.49) and older age (p = .007) were identified as risk factors. Moreover, 453 (41.79%) patients developed leukocytosis. Younger age; male sex; and concurrent use of lithium (OR = 3.39, p < .001), clozapine daily dosage, and benzodiazepines were the risk factors for leukocytosis. CONCLUSION: Concurrent valproate use and older age are associated with the development of neutropenia in patients treated with clozapine. Concurrent lithium usage, younger age, male sex, and concurrent benzodiazepine use might be related to leukocytosis.

Bilateral theta-burst stimulation on emotional processing in major depressive disorder: A functional neuroimaging study from a randomized, double-blind, sham-controlled trial.

AIM: Bilateral theta-burst stimulation (biTBS; intermittent TBS over the left dorsolateral prefrontal cortex [DLPFC] and continuous TBS over the right DLPFC) has demonstrated efficacy in improving symptoms in patients with major depressive disorder (MDD). However, the underlying brain mechanisms remain unknown. The authors aimed to investigate the antidepressant efficacy of biTBS monotherapy and its effects on the brain responses measured by functional magnetic resonance imaging (fMRI) during emotional processing in MDD. METHODS: The authors conducted a double-blind, randomized, sham-controlled trial of patients with MDD who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode. Recruited patients were randomly assigned to 10 biTBS monotherapy or sham stimulation sessions. The fMRI scans during performing emotional recognition task were obtained at baseline and after 10 sessions of treatment. Depressive symptoms were assessed using the 21-item Hamilton Rating Scale for Depression at baseline and the weeks 4, 8, 12, 16, 20, and 24 week. RESULTS: The biTBS group (n = 17) exhibited significant decreases in depression scores compared with the sham group (n = 11) at week 8 (70% vs 40%; P = 0.02), and the significant differences persisted during the 24-week follow-up periods. At week 4, when the treatment course was completed, patients in the biTBS group, but not in the sham group, exhibited increased brain activities over the left superior and middle frontal gyrus during negative emotional stimuli. CONCLUSION: The authors' findings provide the first evidence regarding the underlying neural mechanisms of biTBS therapy to improve clinical symptoms in patients with MDD.

Towards Accurate Identification of Antibiotic-Resistant Pathogens through the Ensemble of Multiple Preprocessing Methods Based on MALDI-TOF Spectra.

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has been used to identify microorganisms and predict antibiotic resistance. The preprocessing method for the MS spectrum is key to extracting critical information from complicated MS spectral data. Different preprocessing methods yield different data, and the optimal approach is unclear. In this study, we adopted an ensemble of multiple preprocessing methods--FlexAnalysis, MALDIquant, and continuous wavelet transform-based methods--to detect peaks and build machine learning classifiers, including logistic regressions, naïve Bayes classifiers, random forests, and a support vector machine. The aim was to identify antibiotic resistance in Acinetobacter baumannii, Acinetobacter nosocomialis, Enterococcus faecium, and Group B Streptococci (GBS) based on MALDI-TOF MS spectra collected from two branches of a referral tertiary medical center. The ensemble method was compared with the individual methods. Random forest models built with the data preprocessed by the ensemble method outperformed individual preprocessing methods and achieved the highest accuracy, with values of 84.37% (A. baumannii), 90.96% (A. nosocomialis), 78.54% (E. faecium), and 70.12% (GBS) on independent testing datasets. Through feature selection, important peaks related to antibiotic resistance could be detected from integrated information. The prediction model can provide an opinion for clinicians. The discriminative peaks enabling better prediction performance can provide a reference for further investigation of the resistance mechanism.

Antidepressant efficacy and immune effects of bilateral theta burst stimulation monotherapy in major depression: A randomized, double-blind, sham-controlled study.

Inflammation theory has been consolidated by accumulating evidence, and many studies have suggested that the peripheral cytokine levels could be biomarkers for disease status and treatment outcome in major depressive disorder (MDD). Theta burst stimulation (TBS), a new form of repetitive transcranial magnetic stimulation (TMS) for MDD, has been demonstrated to improve depression via modulating dysfunctional neural network or hypothalamic­pituitary­adrenal axis hyperactivities in MDD. However, there is lack of exploratory studies investigating its effect on serum inflammatory cytokines. Here, we aimed to investigate the antidepressant efficacy of bilateral TBS monotherapy and its effects on the serum cytokine levels in MDD. We conducted a double-blind, randomized, sham-controlled trial, with 53 MDD patients who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode assigned randomly to one of two groups: bilateral TBS monotherapy (n = 27) or sham stimulation (n = 26). The TBS treatment period was 22 days. Blood samples from 31 study subjects were obtained for analyses. The bilateral TBS group exhibited significantly greater decreases in depression scores than the sham group at week 4 (56.5% vs. 33.1%; p < 0.001 [effect size (Cohen ' s d) = 1.00]) and during the 20-week follow-up periods. Significantly more responders were also found at week 4 (70.3% vs. 23.1%, p = 0.001) and during the 20-week follow-up periods. However, we did not detect any significant effects of TBS on the cytokine panels or any correlations between improvement in depressive symptoms and changes in serum inflammatory markers. Our findings provided the first evidence that the antidepressant efficacy of bilateral TBS monotherapy might not work via immune-modulating mechanisms.

Alcohol-Related Dementia: A Systemic Review of Epidemiological Studies.

BACKGROUND: Alcohol-related dementia (ARD) is a heterogeneous long-term cognitive problem that can develop in the course of alcoholism. Current understanding of ARD remains limited. METHODS: We conducted a systematic review to synthesize available data on the epidemiology of ARD, through searching the relevant studies in the PubMed, PsycINFO, and ALOIS. "Alcohol" and "dementia" were used as keywords. RESULTS: We included articles published between January 1, 1991 and February 29, 2016, where language was not limited. Of the 9 identified articles, the prevalence of ARD ranged from 1.19/1000 in multiday admission patients residing in the United Kingdom to 25.6% in elderly clinic alcoholics from the United States. The proportion of ARD in early-onset dementia taken from 3 studies was approximately 10%, whereas only 1.28% in late-onset dementia taken from 1 study. CONCLUSIONS: Considering the relatively high proportion of ARD in early-onset dementia and its potentially reversible course, future investigation into ARD is necessary.

Secondary mania due to AIDS and cryptococcal meningitis in a 78-year-old patient.

We report a 78-year-old man without past psychiatric history who experienced his first manic episode successfully treated with quetiapine and lorazepam, but was ultimately found to have AIDS and Cryptococcus neoformans meningitis. Our presented case highlights the importance of comprehensive differential diagnoses to rule out secondary causes of psychiatric symptoms presenting for the first time in elderly patients.

Proton-Pump Inhibitor Exposure Aggravates Clostridium difficile-Associated Colitis: Evidence From a Mouse Model.

BACKGROUND: Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients. In addition to the infection due to toxigenic C. difficile in the gastrointestinal tract of susceptible hosts, other predisposing factors for C. difficile infection (CDI) are identified, including advanced age, a prolonged hospital stay, and use of acid-suppressive drugs. Of note, exposure to gastric acid-reducing agents, such as H2 blockers and proton pump inhibitors (PPIs), remains a controversial risk factor, and has been associated with CDI in some studies but not in others. A mouse model of antibiotic-associated clostridial colitis was established to examine the role of PPIs for CDI. MATERIALS AND METHODS: A mouse model of antibiotic-associated clostridial colitis was set up. NF-κB reporter mice were used to address the in vivo spatial and temporal inflammatory patterns of C. difficile-associated colitis. Serum levels of lipopolysaccharide and dextran-FITC were measured to reflect the barrier permeability of affected intestines. RESULTS: Mice with CDI that were exposed to PPI exhibited greater losses of stool consistency and body and cecal weights than those that were not exposed to PPI. Further, more neutrophilic infiltrations, epithelial damage, and inflammatory cytokine expression were noted in colon specimens of the mice with PPI exposure. More-evident inflammatory responses were detected by in vivo imaging of NF-κB reporter mice with CDI that were exposed to PPI. Gut barrier permeability was increased to a greater extent, as reflected by higher serum levels of lipopolysaccharide and dextran-FITC in mice with CDI that were exposed to PPI. CONCLUSIONS: Our mouse model demonstrates that PPI exposure increases the severity of intestinal inflammation in mice with C. difficile-associated colitis.

Season of birth in obsessive-compulsive disorder.

BACKGROUND: Effects of season of birth (SOB) have been documented in numerous neuropsychiatric disorders. To date, few studies have evaluated this issue in obsessive-compulsive disorder (OCD). The aim of this study was to investigate the birth seasonality in OCD. METHODS: This study was based on Taiwan National Health Insurance Research Database. Data for the birth-year period 1956-1991 were extracted for analysis (273,837 males and 292,207 females). The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), code 300.3 was used as the diagnosis of OCD. Birth seasonality was compared between the OCD patients (519 males and 528 females) and the general population. RESULTS: The birth distributions across the 12 months were significantly different between the OCD patients and the general population (P-value for the Walter & Elwood's test = .04). A significant decrease of births from March to July and an excess from August to November in OCD patients as compared to the general population was noted (the relative risk of these months vs. the rest months of the year: 0.85 (95% CI 0.74-0.96) and 1.19 (95% CI 1.05-1.36). Effects of SOB in OCD were present in males (P-value for the Walter & Elwood's test = .03) but not in females. CONCLUSION: The findings support an effect of SOB in people with OCD, especially for men.

Asthma in patients with attention-deficit/hyperactivity disorder: a nationwide population-based study.

BACKGROUND: Asthma symptoms can interrupt daily activities, disturb sleep, and increase the risk of a child having an attention deficit or irritability, which also are symptoms of attention-deficit/hyperactivity disorder (ADHD). Previous studies have shown conflicting results regarding the association between ADHD and asthma. This study investigates the possible correlation between asthma and ADHD. METHODS: We retrieved data on 221,068 pediatric patients from Taiwan's National Health Insurance Research Database in 2005, and calculated the prevalence and risk factors of allergic diseases among ADHD patients. RESULTS: The prevalence of asthma in the ADHD group, compared with the control group, was 4.3 fold higher in the age 12 to 17 subgroup (95% CI, 1.71 to 10.6), 1.5-fold higher in males (95% CI, 1.05 to 2.03), and 1.6-fold higher for children living in urban areas (95% CI, 1.12 to 2.28). Multivariate logistic regression models showed the odds ratio of asthma for children with ADHD was 1.43 (95% CI, 1.05 to 1.95) as compared with children without ADHD. CONCLUSIONS: Pediatric ADHD was associated positively with asthma, but the underlying mechanisms require further clarification.

Prevalence of gastroesophageal reflux disease in major depressive disorder: a population-based study.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common physical disease among psychiatric patients. OBJECTIVE: We conducted this study to investigate the prevalence and risk of GERD in patients with major depressive disorder (MDD) in Taiwan. METHODS: We conducted a cross-sectional study using the National Health Insurance Research Database in Taiwan. The study subjects included 4790 patients with MDD and 728,749 people in the general population during 2005. Distributions of GERD as well as age, gender, income, region of residence, and medical comorbidities, such as diabetes mellitus, hypertension, renal disease, hyperlipidemia, and ischemic heart disease, in the 2 groups were examined by χ(2)-tests. Multivariate logistic regression models were used to analyze the associations between MDD and GERD. RESULTS: The 1-year prevalence rates of GERD in patients with MDD and the general population were 3.75% and 1.05%, respectively. The prevalence rate of GERD was significantly higher in patients with MDD in all age, sex, insurance amount, region, and urbanicity subgroups (all p < 0.001). The multivariate logistic regression analysis showed that patients with MDD were significantly associated with an increased rate for GERD ([Odds Ratio] = 3.16; 95% Confidence Interval = 2.71-3.68; p < 0.001). CONCLUSION: The prevalence of GERD was significantly higher in patients with MDD. In clinical practice, psychiatrists should pay attention to the possibility of GERD symptoms, such as heartburn, regurgitation, or dysphagia, and should consider consulting Gastroenterology specialists when clinically indicated.

Comparing different non-invasive brain stimulation interventions for bipolar depression treatment: A network meta-analysis of randomized controlled trials.

Non-invasive brain stimulation (NIBS) is a promising treatment for bipolar depression. We systematically searched for randomized controlled trials on NIBS for treating bipolar depression (INPLASY No: 202340019). Eighteen articles (N = 617) were eligible for network meta-analysis. Effect sizes were reported as standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs). Anodal transcranial direct current stimulation over F3 plus cathodal transcranial direct current stimulation over F4 (a-tDCS-F3 +c-tDCS-F4; SMD = -1.18, 95%CIs = -1.66 to -0.69, N = 77), high-definition tDCS over F3 (HD-tDCS-F3; -1.17, -2.00 to -0.35, 25), high frequency deep transcranial magnetic stimulation (HF-dTMS; -0.81, -1.62 to -0.001, 25), and high frequency repetitive TMS over F3 plus low frequency repetitive TMS over F4 (HF-rTMS-F3 +LF-rTMS-F4; -0.77, -1.43 to -0.11, 38) significantly improved depressive symptoms compared to sham controls. Only a-tDCS-F3 +c-tDCS-F4 (OR = 4.53, 95%CIs = 1.51-13.65) and HF-rTMS-F3 +LF-rTMS-F4 (4.69, 1.02-21.56) showed higher response rates. No active NIBS interventions exhibited significant differences in dropout or side effect rates, compared with sham controls.

Prevalence of allergic rhinitis in patients with attention-deficit/hyperactivity disorder: a population-based study.

Allergic rhinitis (AR) is common in children. Characteristic symptoms of AR may result in daytime inattention, irritability, and hyperactivity, which are also components of ADHD. Conflicting data in previous studies exist regarding the relationship between ADHD and AR. The aim of this study was to examine the prevalence and risk of AR in ADHD patients in Taiwan. We conducted a cross-sectional study using the National Health Insurance Research Database in Taiwan. The study subjects included 469 patients who received psychiatric care for ADHD in 2005 and the general population (n = 220,599). Distributions of age, gender, and living areas as well as allergic diseases in the general population and in the ADHD group were examined by χ2 tests. Multivariate logistic regression models were used to analyze the risk factors of AR. The prevalence of AR in ADHD group and the general population was 28.4 and 15.2%, respectively. The prevalence of asthma was 9.6% in ADHD group and 6.4% in the general population. Both the prevalence of AR (p < 0.001) and asthma (p = 0.008) was significantly higher in ADHD group than the general population. The multivariate logistic regression analysis showed that ADHD patients had an increased rate of AR than general population (OR = 1.83; 95% CI = 1.48-2.27; p < 0.0001), and asthma was strongly associated with AR (OR = 9.28; 95% CI = 8.95-9.63; p < 0.0001). Our data showed that ADHD patients had an increased rate of AR. Therefore, psychiatrists should be more aware of the comorbidity of AR when treating ADHD patients.

The effects of treatment via telemedicine interventions for patients with depression on depressive symptoms and quality of life: a systematic review and meta-ranalysis.

Aim: The aim of this systematic review and meta-analysis was to identify, evaluate, and synthesize the evidence from studies that have investigated the treatment effect via telemedicine interventions on depressive symptoms, quality of life, and work and social functioning in patients with depression.Methods: Six electronic databases (MEDLINE [1916-2021], PubMED [1950-2021], PsycINFO [1971-2021], Scopus [2004-2021], Embase [1972-2021], and CINAHL [1937-2021]) were systematically searched in March 2021. Reference lists of identified articles were hand searched. Randomized controlled trials were included if they investigated the treatment effects via telemedicine interventions in patients who had a depression diagnosis. Quality assessment was evaluated using the critical appraisal checklists developed by the Joanna Briggs Institute.Results: Seventeen (17) trials (n = 2,394) met eligibility criteria and were included in the analysis. Eleven (11) randomized controlled trials shared common outcome measures, allowing meta-analysis. The results provided evidence that treatment via telemedicine interventions were beneficial for depressive symptoms (standardized mean difference= -0.44; 95% CI= -0.64 to -0.25; p < .001) and quality of life (standardized mean difference= 0.25, 95% CI -0.01 to 0.49, p = .04) in patients of depression. There were insufficient data for meta-analysis of work and social functioning.Conclusion: This study showed the positive effects of treatment via telemedicine interventions on depressive symptoms and quality of life in patients with depression and supported the idea for clinical practice to establish a well-organized telepsychiatry system.KEY MESSAGESTelemedicine is effective at reducing symptoms of depression.Telemedicine can improve quality of life in persons with depression.

Trauma-related guilt as a mediator between post-traumatic stress disorder and suicidal ideation.

Background: As a mental health issue, suicide is a growing global concern, with patients who have post-traumatic stress disorder (PTSD) being at particularly high risk. This study aimed to investigate whether the link between PTSD and suicidal ideation is mediated by trauma-related guilt. Methods: Data were obtained from Wave 1, Time 1 (November 2016), and Time 2 (March 2017) of the National Survey for Stress and Health (NSSH) in Japan. The NSSH is an online longitudinal survey conducted on Japan's national population aged 18 years and older. The cumulative response rate of the survey was 66.7% at Time 2. A total of 1,005 patients with PTSD were included for analyses. The severity of PTSD symptoms was assessed with PTSD DSM-5 Checklist, and the trauma-related guilt were assessed using the two subscales (hindsight-bias/responsibility and global guilt scale) of the trauma-related guilt inventory (TRGI). Suicidal ideation was evaluated using the suicidal ideation attributes scale (SIDAS). Pearson's correlation was used to investigate the associations among PTSD symptoms, TRGI scores, and SIDAS scores. Causal mediation analysis was applied to evaluate the causal relationship between PTSD, trauma-related guilt, and suicidal ideation. Results: Pearson's correlation did not show patients' age, gender, and household income significantly associated with SIDAS scores. On the other hand, severities of PTSD symptoms (r = 0.361, p < 0.001) and trauma-related guilt (r = 0.235, p < 0.001) were positively associated with SIDAS scores. After adjusting for age, gender, and household income, the mediation analysis revealed that trauma-related guilt significantly mediates the effects of PTSD symptoms on suicidal ideation. Conclusion: Our results implied that trauma-related guilt may represent a critical link between PTSD and suicidal ideation, which may be a noteworthy target for therapeutic intervention.

Associations between frontal lobe activity and depressive symptoms in patients with major depressive disorder receiving rTMS treatment: a near-infrared spectroscopy study.

Introduction: The effects of repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC) in patients with major depressive disorder (MDD) have been proved to have antidepressant effects. However, the absence of biomarkers to assess treatment response remains a challenge. This research aims to explore the relationship between frontal lobe activity, measured using near infrared spectroscopy (NIRS), and changes in symptoms among MDD patients following rTMS treatment. Methods: A total of 26 MDD patients underwent 20 sessions of 10 Hz rTMS targeting the left DLPFC. NIRS was used to measure frontal lobe activity during a verbal fluency test at baseline, after 10 rTMS sessions, and after 20 rTMS sessions. Responders were defined as individuals with more than a 50% reduction in symptoms based on the 21-item Hamilton Depression Rating Scale after 20 rTMS sessions. Results: Among the 14 responders, an increase in frontal lobe activity was significantly correlated with improvements in depressive symptoms following 10 (p = 0.0001) and 20 rTMS sessions (p = 0.007). Additionally, frontal lobe activity after 10 rTMS sessions was significantly associated with symptom improvement after 20 sessions (p = 0.001). These associations were not observed among non-responders. Conclusion: The findings from this study indicate distinct patterns of frontal lobe activity between responders and non-responders to rTMS treatment, suggesting that NIRS has the potential to serve as a biomarker for monitoring treatment response in MDD patients undergoing rTMS.

Safety of Supplementation of Omega-3 Polyunsaturated Fatty Acids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is no comprehensive review of the evidence to support omega-3 polyunsaturated fatty acids (PUFAs) as a relatively safe and tolerable intervention. This study aimed to provide a meta-analytic and comprehensive review on the adverse effects of all kinds of ω-3 PUFA supplementation reported in randomized controlled trials (RCTs) in human subjects. A systematic review of RCTs published between 1987 and 2023 was carried out based on searches of 8 electronic databases. All RCTs that compared the adverse effects of ω-3 PUFAs containing eicosapentaenoic acid, docosahexaenoic acid, or both compared with controls (a placebo or a standard treatment) were included. The primary outcome was the adverse effects related to ω-3 PUFA prescription. A total of 90 RCTs showed that the ω-3 PUFA group, when compared with the placebo, had significantly higher odds of occurrence of diarrhea (odds ratio [OR] = 1.257, P = 0.010), dysgeusia (OR = 3.478, P < 0.001), and bleeding tendency (OR = 1.260, P = 0.025) but lower rates of back pain (OR = 0.727, P < 0.001). The subgroup analysis showed that the prescription ω-3 PUFA products (RxOME3FAs) had higher ω-3 PUFA dosages than generic ω-3 PUFAs (OME3FAs) (3056.38 ± 1113.28 mg/d compared with 2315.92 ± 1725.61 mg/d), and studies on RxOME3FAs performed more standard assessments than OME3FAs on adverse effects (63% compared with 36%). There was no report of definite ω-3 PUFA-related serious adverse events. The subjects taking ω-3 PUFAs were at higher odds of experiencing adverse effects; hence, comprehensive assessments of the adverse effects may help to detect minor/subtle adverse effects associated with ω-3 PUFAs. This study was registered at PROSPERO as CRD42023401169.

NIRS-aided differential diagnosis among patients with major depressive disorder, bipolar disorder, and schizophrenia.

BACKGROUND: To establish a clinically applicable neuroimaging-guided diagnostic support system that uses near-infrared spectroscopy (NIRS) for differential diagnosis at the individual level among major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SZ). METHODS: A total of 192 participants were recruited, including 40 patients with MDD, 38 patients with BPD, 65 patients with SZ, and 49 healthy individuals. We analyzed the spatiotemporal characteristics of hemodynamic responses in the frontotemporal cortex during a verbal fluency test (VFT) measured by NIRS to assess the accuracy of single-subject classification for differential diagnosis among the three psychiatric disorders. The optimal threshold of the frontal centroid value (54 seconds) was utilized on the basis of the findings of the Japanese study. RESULTS: The application of the optimal threshold of the frontal centroid value (54 seconds) allowed for the accurate differentiation of patients with unipolar MDD (72.5%) from BPD (78.9%) or SZ (84.6%). CONCLUSION: These results suggest that the NIRS-aided differential diagnosis of major psychiatric disorders can be a promising biomarker in Taiwan. Future multi-site studies are needed to validate our findings.

Efficacy of Non-Invasive Brain Stimulation for Treating Depression in Patients with Traumatic Brain Injury: A Meta-Analysis and Meta-Regression of Randomized Controlled Trials.

OBJECTIVE: This meta-analysis aimed to ascertain the efficacy of non-invasive brain stimulation (NIBS)-comprising repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)-for depression in traumatic brain injury (TBI) patients. METHODS: Comprehensive searches were conducted in PubMed, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials up to 28 January 2023. Random-effects models assessed the treatment effects, and heterogeneity was evaluated through I2 statistics and funnel plot inspection. RESULTS: From 10 trials (234 participants; 8 rTMS, 2 tDCS), NIBS was found significantly more effective than sham in alleviating depressive symptoms (SMD: 0.588, 95% CI: 0.264-0.912; p < 0.001). rTMS, specifically, showed higher efficacy (SMD: 0.707, 95% CI: 0.306-1.108; p = 0.001) compared to sham, whereas tDCS outcomes were inconclusive (SMD: 0.271, 95% CI: -0.230 to 0.771; p = 0.289). Meta-regression found no correlation with the number of sessions, treatment intensity, or total dose. Notably, while post-treatment effects were significant, they diminished 1-2 months post intervention. Adverse events associated with NIBS were minimal, with no severe outcomes like seizures and suicide reported. CONCLUSIONS: rTMS emerged as a potent short-term intervention for depression in TBI patients, while tDCS findings remained equivocal. The long-term efficacy of NIBS is yet to be established, warranting further studies. The low adverse event rate reaffirms NIBS's potential safety.

Five inhibitory receptors display distinct vesicular distributions in T cells.

T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3 and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and a biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation.

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects.

BACKGROUND: The follow-up effect after acute repetitive transcranial magnetic stimulation (rTMS) for major depressive episodes remains unclear. Furthermore, the benefits of maintenance rTMS are poorly understood. AIM: To investigate the trajectory of changes in depressive symptoms after acute rTMS and effects of maintenance rTMS during this period. METHOD: This meta-analysis (PROSPERO: CRD42022374077) searched major databases up to October 1, 2022. Treatment outcome was depressive scores collected at least 3 months after the end of an acute rTMS course for depression. We extracted data at different time points after acute rTMS and categorized by whether maintenance rTMS was performed. A single-stage random-effects dose-response meta-analysis was undertaken to model the nonlinear relationships. Effect sizes were calculated as standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: 24 eligible studies comprising 911 total patients-225 of whom received maintenance rTMS-were included. Maintenance rTMS contributed to relative stability in patients' mood symptoms during the first 5 months (SMD [95% CI]: 3rd month, -0.10 [-0.30 to 0.10]; 5th month, 0.00 [-0.55 to 0.55]), with heterogeneity characterized as low to moderate. Further analysis revealed that maintenance rTMS performed monthly or more frequently provided sustained benefits for up to 6-12 months. Conversely, patients without maintenance rTMS had moderate to high heterogeneity, although the change in mean mood symptom scores during the 12-month follow-up was also minor (6th month, 0.03 [-0.51 to 0.56]; 12th month, 0.10 [-0.59 to 0.79]). CONCLUSION: Maintenance rTMS might keep patients' mood relatively stable for up to 5 months after acute rTMS. Monthly or more frequent maintenance rTMS offers greater benefits.