Effects and safety of transcranial direct current stimulation on multiple health outcomes: an umbrella review of randomized clinical trials.

Transcranial direct current stimulation (tDCS), which delivers a direct current to the brain, emerged as a non-invasive potential therapeutic in treating a range of neurological and neuropsychiatric disorders. However, a comprehensive quantitative evidence synthesis on the effects of tDCS on a broad range of mental illnesses is lacking. Here, we systematically assess the certainty of the effects and safety of tDCS on several health outcomes using an umbrella review of randomized controlled trials (RCTs). The methodological quality of each included original meta-analysis was assessed by the A Measurement Tool for Assessing Systematic Reviews 2 (AMSTAR2), and the certainty of the evidence for each effect was evaluated with Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). We followed an a priori protocol (PROSPERO CRD42023458700). We identified 15 meta-analyses of RCTs (AMSTAR 2; high 3, moderate 3, and low 9) that included 282 original articles, covering 22 unique health endpoints across 22 countries and six continents. From meta-analyses of RCTs supported by very low to high certainty of evidence, it was found that tDCS improved symptoms related to post-stroke, including post-stroke depression scale score (equivalent standardized mean difference [eSMD], 1.61 [95% confidence level, 0.72-2.50]; GRADE=moderate), activities of daily living independence (7.04 [3.41-10.67]; GRADE=high), motor recovery of upper and lower extremity (upper extremity: 0.15 [0.06-0.24], GRADE=high; lower extremity: 0.10 [0.03-0.16], GRADE=high), swallowing performance (GRADE=low), and spasticity (GRADE=moderate). In addition, tDCS had treatment effects on symptoms of several neurological and neuropsychiatric disorders, including obsessive-compulsive disorder (0.81 [0.44-1.18]; GRADE=high), pain in fibromyalgia (GRADE=low), disease of consciousness (GRADE=low), insight score (GRADE=moderate) and working memory (0.34 [0.01-0.67]; GRADE=high) in schizophrenia, migraine-related pain (-1.52 [-2.91 to -0.13]; GRADE=high), attention-deficit/hyperactivity disorder (reduction in overall symptom severity: 0.24 [0.04-0.45], GRADE=low; reduction in inattention: 0.56 [0.02-1.11], GRADE=low; reduction in impulsivity: 0.28 [0.04-0.51], GRADE=low), depression (GRADE=low), cerebellar ataxia (GRADE=low), and pain (GRADE=very low). Importantly, tDCS induced an increased number of reported cases of treatment-emergent mania or hypomania (0.88 [0.62-1.13]; GRADE=moderate). We found varied levels of evidence for the effects of tDCS with multiple neurological and neuropsychiatric conditions, from very low to high certainty of evidence. tDCS was effective for people with stroke, obsessive-compulsive disorder, fibromyalgia, disease of consciousness, schizophrenia, migraine, attention-deficit/hyperactivity disorder, depression, cerebellar ataxia, and pain. Therefore, these findings suggest the benefit of tDCS for several neurological and neuropsychiatric disorders; however, further studies are needed to understand the underlying mechanism and optimize its therapeutic potential.

Evolutionary Design of Self-Templated Supramolecular Fibrils Using M13 Bacteriophage for Tissue Engineering.

Biomaterials in nature form hierarchical structures and functions across various length scales through binding and assembly processes. Inspired by nature, we developed hierarchically organized tissue engineering materials through evolutionary screening and self-templating assembly. Leveraging the M13 bacteriophage (phage), we employed an evolutionary selection process against hydroxyapatite (HA) to isolate HA-binding phage (HAPh). The newly discovered phage exhibits a bimodal length, comprising 950 nm and 240 nm, where the synergistic effect of these dual lengths promotes the formation of supramolecular fibrils with periodic banded structures. The assembled HAPh fibrils show the capability of HA mineralization and the directional growth of osteoblast cells. When applied to a dentin surface, it induces the regeneration of dentin-like tissue structures, showcasing its potential applications as a scaffold in tissue engineering. The integration of evolutionary screening and self-templating assembly holds promise for the future development of hierarchically organized tissue engineering materials.

Association between high levels of nitrogen dioxide and increased cumulative incidence of lung cancer in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. However, the association between individual exposure to air pollutants and lung cancer development in patients with IPF is unknown. This study aimed to assess the effect of individual exposure to nitrogen dioxide (NO2) on lung cancer development in patients with IPF. METHODS: We enrolled 1085 patients from an IPF cohort in the Republic of Korea (mean age 65.6 years, males 80.6%). We estimated individual-level long-term exposures to NO2 at the patients' residential addresses using a national-scale exposure prediction model based on data from air quality regulatory monitoring stations. To evaluate the association between NO2 levels and lung cancer development in IPF, we used an individual- and area-level covariates adjusted model as our primary model. RESULTS: The estimated average annual NO2 concentration was 23.1 ppb. During a median follow-up of 4.3 years, 86 patients (7.9%) developed lung cancer. NO2 concentration was associated with lung cancer development in an unadjusted model (HR 1.219; p=0.042), while a marginal association was found in the primary model (HR 1.280; p=0.084). When NO2 concentration was stratified by the median value (21.0 ppb), exposure to high NO2 levels (≥21.0 ppb) was associated with a 2.0-fold increase in the risk of lung cancer development (HR 2.023; p=0.047) in the primary model. CONCLUSION: Individual exposure to high NO2 levels may increase the risk of lung cancer development in patients with IPF.

National Trends in Allergic Rhinitis and Chronic Rhinosinusitis and COVID-19 Pandemic-Related Factors in South Korea, from 1998 to 2021.

INTRODUCTION: Existing studies provide insights into the prevalence and environmental factors associated with allergic rhinitis (AR) and chronic rhinosinusitis (CRS) globally. However, limitations still persist in these studies, particularly regarding cohort sizes and the duration of follow-up periods, indicating a need for more comprehensive and long-term research in these fields. Our study aimed to investigate the prevalence, long-term trends, and underlying factors of these conditions in the general population of adult participants (≥19 years) in Korea. METHOD: We analyzed data from adult participants (≥19 years) from the Korea National Health and Nutrition Examination Survey (KNHANES) study to determine the prevalence of AR and CRS from 1998 to 2021. To analyze prevalence trends before and during the COVID-19 pandemic, we employed a weighted linear regression model and obtained ß-coefficients with 95% confidence intervals (CI). RESULTS: Between 1998 and 2021, over a span of 24 years, the comprehensive KNHANES study included 146,264 adult participants (mean age: 47.80 years, standard deviation: 16.49 years; 66,177, 49.3% men). The prevalence of AR and CRS increased from 1998 to 2021, with AR prevalence rising from 5.84% (95% CI, 5.57-6.10) in 1998-2005 to 8.99% (8.09-9.91) in 2021 and CRS from 1.84% (1.70-1.97) in 1998-2005 to 3.70% (3.18-4.23) in 2021. However, the increasing trend has slowed down during the COVID-19 pandemic era. CONCLUSIONS: The significance of continuous monitoring and focused interventions for AR and CRS is underscored by this study. The observed deceleration in the rising prevalence of AR and CRS during the pandemic indicates the possibility of beneficial impacts from lifestyle modifications triggered by the pandemic. These findings call for additional research to explore potential protective effects in greater depth.

National Trends and Prevalence of Atopic Dermatitis and Pandemic-Related Factors among Korean Adults, 2007-2021.

INTRODUCTION: Previous studies have variably reported inconclusive trends in the prevalence of atopic dermatitis (AD) among adults, and there are limited data on the impact of the COVID-19 pandemic. We aimed to investigate the national trends and age-stratified prevalence of AD among adults from 2007 to 2021 in South Korea, focusing mainly on the impact of the COVID-19 pandemic-related factors. METHODS: A nationwide cross-sectional study was conducted using the Korea National Health and Nutrition Examination Survey data from 2007 to 2021. Overall and age-stratified prevalence for AD were assessed using weighted beta coefficients or odds ratios. RESULTS: A total of 83,566 adults over 20 years (male, 49.40%) were included. During the observation period, the prevalence of AD was stable in the overall population from 2.61% (95% CI, 2.29-2.93) in 2007-2009 to 2.15% (1.68-2.63) in 2020 and 2.38% (1.81-2.95) in 2021. However, the weighted prevalence of AD in adults aged 40-59 years old decreased during the pre-pandemic era, and the prevalence of AD in adults aged above 60 years significantly decreased during the pandemic, with a significant decline observed after the initial outbreak. From age-stratification analysis, the adults aged 40-59 years showed a significant increase after the pandemic outbreak which was evident in specific variables: individuals with rural residence, lower education, and lower household income quartiles. Adults aged above 60 years showed a significant decrease in the slope after the outbreak, evident in specific variables: individuals of female, rural residence, lower education, and lower household income quartiles. CONCLUSION: We observed a stable overall prevalence of AD throughout the 15-year observation period. However, the age-stratified analysis suggested significantly different trends according to age-stratified groups and the impact of the COVID-19 pandemic on the prevalence of AD.

Association of Soda Drinks and Fast Food with Allergic Diseases in Korean Adolescents: A Nationwide Representative Study.

INTRODUCTION: A high consumption of carbonated soft drinks (i.e., soda drinks) and fast food is potentially associated with the observed global rise in adolescent allergic diseases. Thus, our study aimed to examine the potential associations between the consumption of soda drinks and fast food and allergic conditions, identifying specific relationships across subgroups and each allergic condition (asthma, allergic rhinitis, and atopic dermatitis). METHODS: This study uses large-scale data from the Korea Youth Risk Behavior Web-Based Survey (total n = 865,614). Soda drinks and fast food were defined by a self-reported questionnaire and allergic conditions by physician-diagnosed within 1 year. Multivariable logistic regression was used to analyze the weighted odds ratios (ORs), along with 95% confidence intervals (CIs), for allergic diseases associated with the intake of soda drinks and fast food. RESULTS: Among 865,614 adolescents in grades 7-12 (male, 51.40%), patients with asthma, allergic rhinitis, and atopic dermatitis were 18,568 (2.15%), 153,536 (17.74%), and 59,014 (6.82%), respectively. Current asthma was associated with soda drinks (OR, 1.07; 95% CI, 1.03-1.12) and fast food consumption (1.25; 1.17-1.33). Interestingly, stronger associations were observed for female high schoolers, compared to male high schoolers and middle schoolers, in relation to the consumption of soda drinks (1.31; 1.19-1.44) and fast food (1.46; 1.26-1.69) with asthma. Current allergic rhinitis and atopic dermatitis had no significant association with fast food consumption and soda drinks. CONCLUSION: This first large-scale study suggests that fast food and soda drinks consumption are potentially associated with current asthma, with stronger associations observed in females than males, underscoring the need for sex-specific allergy prevention programs.

Effects of Ambient Air Pollution on Brain Cortical Thickness and Subcortical Volume: A Longitudinal Neuroimaging Study.

INTRODUCTION: Several cross-sectional studies have shown that long-term exposures to air pollutants are associated with smaller brain cortical volume or thickness. Here, we investigated longitudinal associations of long-term air pollution exposures with cortical thickness and subcortical volume. METHODS: In this longitudinal study, we included a prospective cohort of 361 adults residing in four cities in the Republic of Korea. Long-term concentrations of particulate matter with aerodynamic diameters of ≤10 µm (PM10) and ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2) at residential addresses were estimated. Neuroimaging markers (cortical thickness and subcortical volume) were obtained from brain magnetic resonance images at baseline (August 2014 to March 2017) and at the 3-year follow-up (until September 2020). Linear mixed-effects models were used, adjusting for covariates. RESULTS: A 10-µg/m3 increase in PM10 was associated with reduced whole-brain mean (ß = -0.45, standard error [SE] = 0.10; p < 0.001), frontal (ß = -0.53, SE = 0.11; p < 0.001) and temporal thicknesses (ß = -0.37, SE = 0.12; p = 0.002). A 10-ppb increase in NO2 was associated with a decline in the whole-brain mean cortical thickness (ß = -0.23, SE = 0.05; p < 0.001), frontal (ß = -0.25, SE = 0.05; p < 0.001), parietal (ß = -0.12, SE = 0.05; p = 0.025), and temporal thicknesses (ß = -0.19, SE = 0.06; p = 0.001). Subcortical structures associated with air pollutants included the thalamus. CONCLUSIONS: Long-term exposures to PM10 and NO2 may lead to cortical thinning in adults.

Expectations Versus Fantasies and Vaccine Hesitancy: How Suffering From COVID-19 Versus Suffering From Vaccines Interact.

BACKGROUND: Previous research on COVID-19 vaccination highlights future thoughts associated with possible Coronavirus infection and vaccine side effects as key predictors of vaccine hesitancy. Yet, research has focused on independent contributions of such future thoughts, neglecting their interactive aspects. PURPOSE: We examined whether thoughts about two possible COVID-related futures (suffering from COVID-19 and vaccine side effects) interactively predict vaccine hesitancy and vaccination behavior among unvaccinated and vaccinated people. Importantly, we compared two forms of future thinking: beliefs or expectations (likelihood judgments) versus fantasies (free thoughts and images describing future events). METHODS: In Study 1, we conducted a longitudinal study with an unvaccinated group (N = 210). We assessed expectations versus fantasies about the two COVID-related futures as predictors. As outcome variables, we measured vaccine hesitancy, and 9 weeks later we assessed information seeking and vaccine uptake. Study 2 was a cross-sectional study comparing vaccine hesitancy of an unvaccinated group (N = 307) to that of a vaccinated group (N = 311). RESULTS: Study 1 found that more negative fantasies about COVID-19 impact and less negative fantasies about vaccine side effects interactively predicted lower vaccine hesitancy and more vaccine-related behaviors among unvaccinated people; no such interaction was observed between respective expectations. Study 2 replicated these results of Study 1. Additionally, for vaccinated people, low expectations of negative COVID-19 impact and high expectations of negative vaccine impact interactively predicted higher vaccine hesitancy, whereas no such interaction was observed for respective fantasies. CONCLUSIONS: Research on vaccine hesitancy should explore interactions between future thinking about disease and about vaccine side effects. Importantly, there is much to be gained by distinguishing expectations versus fantasies: vaccination interventions aiming to boost vaccine uptake among unvaccinated people should tap into their negative future fantasies regarding both disease and vaccine side effects.

In two correlational studies, we investigated the relationship between future thoughts about two possible COVID-related futures­suffering from COVID-19 and vaccine side effects­and vaccine hesitancy. Prior research has emphasized thoughts about these potential risks as significant predictors of vaccine hesitancy but has focused on their independent contributions, neglecting their interactive nature. Our research examined the interaction between the thoughts about disease and those about vaccine side effects, highlighting the two forms of future thinking: expectations (likelihood judgments) and fantasies (free-flowing thoughts and images describing a future event). In a longitudinal study (Study 1) with an unvaccinated group, we found that more negative fantasies about COVID-19 disease and less negative fantasies about vaccine side effects interactively predicted lower vaccine hesitancy and more vaccination behavior. There was no interaction between the expectations. Study 2, a cross-sectional study comparing another unvaccinated sample to a vaccinated sample, revealed a divergent pattern in the two groups; negative fantasies, not expectations, interactively predicted vaccine hesitancy among unvaccinated people while expectations, not fantasies, did so among vaccinated people. The research suggests the importance of considering interactions between future thoughts about disease and vaccine side effects in understanding vaccine hesitancy and distinguishing expectations and fantasies.

Clinical and laboratory findings in scrub typhus associated Guillain-Barré syndrome in South Korea.

BACKGROUND AND AIMS: Scrub typhus is an endemic disease in the fall season that occurs in a limited number of places known as the Tsutsugamushi Triangle. Peripheral neuropathy is a common complication of scrub typhus. Herein, we encountered several patients with ascending paralysis after scrub typhus infection, who were diagnosed with Guillain-Barré syndrome (GBS). We aimed to investigate the clinical and laboratory characteristics of patients who developed GBS after scrub typhus. METHODS: Patients were retrospectively recruited from six nationwide tertiary centers in South Korea from January 2017 to December 2021. Patients who had been clinically diagnosed with GBS and confirmed to have scrub typhus via laboratory examination and/or the presence of an eschar before the onset of acute limb paralysis were included. The GBS-associated clinical and electrophysiological characteristics, outcomes, and scrub typhus-associated features were collected. RESULTS: Of the seven enrolled patients, six were female and one was male. The median time from scrub typhus infection to the onset of limb weakness was 6 (range: 2-14) days. All patients had eschar on their bodies. Four patients (57.1%) were admitted to the intensive care unit and received artificial ventilation for respiratory distress. At 6 months, the median GBS disability score was 2 (range, 1-4) points. INTERPRETATION: Patients with scrub typhus-associated GBS have a severe clinical presentation and require intensive treatment with additional immunotherapies. Therefore, GBS should be included in the differential diagnosis when peripheral neuropathies develop during scrub typhus treatment. Notably, scrub typhus is associated to GBS.

Exposure to ambient air pollution mixture and senescence-associated secretory phenotype proteins among middle-aged and older women.

Our study aimed to investigate the impact of environmental exposures, such as ambient air pollutants, on systemic inflammation and cellular senescence in middle-aged and older women. We utilized epidemiological data linked with exposure data of six air pollutants (particulate matters [PM10, PM2.5], sulphur dioxide [SO2], nitrogen dioxide [NO2], carbon monoxide [CO], and ozone [O3]) and blood samples of 380 peri- and postmenopausal women participants of the Korean Genome and Epidemiology Study. We measured blood high-sensitivity C-reactive protein (hsCRP) and age-related 27 circulatory senescence-associated secretory phenotypes (SASP) produced by senescent cells. We employed single exposure models to explore the general pattern of association between air pollution exposure and proteomic markers. Using quantile g-computation models, we assessed the association of six air pollutant mixtures with hsCRP and SASP proteins. In single-exposure, single-period models, nine out of the 27 SASP proteins including IFN-γ (ß = 0.04, 95% CI: 0.01, 0.07 per interquartile range-increase), IL-8 (0.15, 95% CI: 0.09, 0.20), and MIP1α (0.11, 95% CI: 0.04, 0.18) were positively associated with the average level of O3 over one week. Among the age-related SASP proteins, IFN-γ (0.11, 95% CI: 0.03, 0.20) and IL-8 (0.22, 95% CI: 0.05, 0.39) were positively associated with exposure to air pollutant mixture over one week. The MIP1ß was higher with an increasing one-month average concentration of the air pollutant mixture (0.11, 95% CI: 0.00, 0.21). The IL-8 showed consistently positive association with the ambient air pollutant mixture for the exposure periods ranging from one week to one year. O3 predominantly showed positive weights in the associations between air pollutant mixtures and IL-8. These findings underscore the potential of proteomic indicators as markers for biological aging attributed to short-term air pollution exposure.

Global association of secondhand smoke exposure locations and smoking behaviour among adolescents in 99 countries.

AIM: This study classified 99 countries into four income groups and then analysed the impact of secondhand smoke (SHS) exposure at home, in public places and at school, on current cigarette smoking prevalence. METHODS: We utilised data from the WHO Global Youth Tobacco Survey and a meta-analysis was conducted to evaluate the prevalence and weighted odds ratios (wORs) of adolescent smoking behaviour and SHS exposure locations. RESULTS: Both smoking behaviours increased with higher national income levels. Smoking behaviours in high and upper-middle-income countries (HICs and UMICs) exhibited an association with SHS exposure in public places (HIC: wOR, 3.50 [95% CI, 2.85-4.31]; UMIC: wOR, 2.90 [2.60-3.23]) compared to home. Low- and lower-middle-income countries (LICs and LMICs) showed an association with SHS exposure in the home (LIC: wOR, 5.33 [3.59-7.93]; LMIC: wOR, 2.71 [2.33-3.17]) than public places. The association between current cigarette smoking and SHS exposure at home increased with lower income levels, while anticipated future use of any form of tobacco with SHS exposure in public places rose in lower income countries. CONCLUSIONS: Targeted interventions based on income levels are essential, emphasising home strategies in lower income countries and public place efforts in higher income countries.

Effects of Hormone Replacement Therapy on Bone Mineral Density in Korean Adults With Turner Syndrome.

BACKGROUND: Turner syndrome (TS) is a common chromosomal abnormality, which is caused by loss of all or part of one X chromosome. Hormone replacement therapy in TS is important in terms of puberty, growth and prevention of osteoporosis however, such a study has never been conducted in Korea. Therefore, the purpose of our study was to determine relationship between the starting age, duration of estrogen replacement therapy (ERT) in TS and develop a hormone replacement protocol suitable for the situation in Korea. METHODS: This is retrospective study analyzed the medical records in TS patients treated at the Severance hospital, Yonsei University College of Medicine, Seoul, Korea from 1997 to 2019. Total of 188 subjects who had received a bone density test at least once were included in the study. Korean National Health and Nutrition Examination Survey (KNHANES) was used for achieving bone mineral density (BMD) of normal control group. Student's t-test, Mann-Whitney U test, ANOVA and correlation analysis were performed using SPSS 18.0. RESULTS: Each BMD measurement was significantly lower in women with TS than in healthy Korean women. Early start and longer duration of ERT is associated with higher lumbar spine BMD but not femur neck BMD. Femur neck BMD, but not lumbar spine BMD was significantly higher in women with mosaicism than 45XO group. CONCLUSION: Early onset and appropriate duration of hormone replacement therapy is important for increasing bone mineral density in patients with Turner syndrome. Also, ERT affects differently to TS patients according to mosaicism.

Erratum: Correction of Text in the Article "Effects of Hormone Replacement Therapy on Bone Mineral Density in Korean Adults With Turner Syndrome".

This corrects the article on p. e9 in vol. 39, PMID: 38193328.

Cervical enamel projections from a periodontal perspective: A scoping review.

Cervical enamel projections (CEPs) represent a unique developmental and anatomical anomaly wherein the enamel structure extends apically beyond the cemento-enamel junction of the tooth. In this scoping review, the existing literature on CEPs was evaluated to delineate their characteristics, prevalence, predilection for specific teeth and surfaces, clinical significance, and management approaches. Searches were conducted on MEDLINE (PubMed), Cochrane Library, and Embase databases using the keywords "enamel projection(s)" or "ectopic enamel." In total, 24 studies meeting inclusion criteria were included in the review. The prevalence of CEPs varied widely (8.3%-85.1%), predominantly manifesting as grade I or grade III. Mandibular first and second molars exhibited a higher incidence of CEPs, with a notable predilection for buccal surfaces. The consensus in most studies was that CEPs are associated with localized periodontal diseases. Recommendations inclined toward the removal of ectopic enamel during periodontal surgery to enhance periodontal attachment formation. However, decision-making should involve careful consideration of the benefits and drawbacks based on individual circumstances.

Successful interventional occlusion of muscular ventricular septal defect in a dog.

Ventricular septal defect (VSD) is a rare congenital heart disease in dogs. Hemodynamically important interventricular defects must be closed to improve the prognosis. This case report describes successful interventional transcatheter closure of a muscular VSD in a young Maltese and poodle mixed-breed dog with a large muscular interventricular defect (~5 mm in diameter) with a high rate of left-to-right shunt flow. The VSD was closed with a customized Amplatzer-type VSD occluder via a percutaneous transvenous (jugular) approach. We concluded that interventional occlusion of a muscular VSD with an Amplatzer-type occluder is a viable treatment option for dogs. A regular follow-up study for this dog is ongoing and has not detected complications. Key clinical message: Interventional occlusion of a muscular VSD with an Amplatzer-type occluder is a viable treatment option for dogs.

Occlusion interventionnelle réussie d'une communication interventriculaire musculaire chez un chien. La communication interventriculaire (VSD) est une maladie cardiaque congénitale rare chez le chien. Les anomalies interventriculaires hémodynamiquement importantes doivent être fermées pour améliorer le pronostic. Ce rapport de cas décrit la fermeture interventionnelle réussie par cathéter d'un VSD musculaire chez un jeune chien de race mixte (maltais et caniche) présentant un défaut interventriculaire musculaire important (~5 mm de diamètre) avec un débit de shunt élevé de gauche à droite. Le VSD a été fermé avec un obturateur VSD personnalisé de type Amplatzer via une approche trans-veineuse percutanée (jugulaire). Nous avons conclu que l'occlusion interventionnelle d'un VSD musculaire avec un obturateur de type Amplatzer est une option de traitement viable pour les chiens. Une étude de suivi régulière de ce chien est en cours et aucune complication n'a été détectée.Message clinique clé :L'occlusion interventionnelle d'un VSD musculaire avec un obturateur de type Amplatzer est une option de traitement viable pour les chiens.(Traduit par Dr Serge Messier).

Novel rAAV vector mediated intrathecal HGF delivery has an impact on neuroimmune modulation in the ALS motor cortex with TDP-43 pathology.

Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF's role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.

Export of Diverse and Bioactive Small Proteins through a Type I Secretion System.

Small proteins perform a diverse array of functions, from microbial competition, to endocrine signaling, to building biomaterials. Microbial systems that can produce recombinant small proteins enable discovery of new effectors, exploration of sequence activity relationships, and have the potential for in vivo delivery. However, we lack simple systems for controlling small-protein secretion from Gram-negative bacteria. Microcins are small-protein antibiotics secreted by Gram-negative bacteria that inhibit the growth of neighboring microbes. They are exported from the cytosol to the environment in a one-step process through a specific class of type I secretion systems (T1SSs). However, relatively little is known about substrate requirements for small proteins exported through microcin T1SSs. Here, we investigate the prototypic microcin V T1SS from Escherichia coli and show that it can export a remarkably wide range of natural and synthetic small proteins. We demonstrate that secretion is largely independent of the cargo protein's chemical properties and appears to be constrained only by protein length. We show that a varied range of bioactive sequences, including an antibacterial protein, a microbial signaling factor, a protease inhibitor, and a human hormone, can all be secreted and elicit their intended biological effect. Secretion through this system is not limited to E. coli, and we demonstrate its function in additional Gram-negative species that can inhabit the gastrointestinal tract. Our findings uncover the highly promiscuous nature of small-protein export through the microcin V T1SS, which has implications for native-cargo capacity and the use of this system in Gram-negative bacteria for small-protein research and delivery. IMPORTANCE Type I secretion systems for microcin export in Gram-negative bacteria transport small antibacterial proteins from the cytoplasm to the extracellular environment in a single step. In nature, each secretion system is generally paired with a specific small protein. We know little about the export capacity of these transporters and how cargo sequence influences secretion. Here, we investigate the microcin V type I system. Remarkably, our studies show that this system can export small proteins of diverse sequence composition and is only limited by protein length. Furthermore, we demonstrate that a wide range of bioactive small proteins can be secreted and that this system can be used in Gram-negative species that colonize the gastrointestinal tract. These findings expand our understanding of secretion through type I systems and their potential uses in a variety of small-protein applications.

Comparison of clinical manifestations in mpox patients living with HIV versus without HIV: A systematic review and meta-analysis.

Currently, many cases of mpox patients living with the human immunodeficiency virus (HIV) have been reported. Immunocompromised mpox patients, including those living with HIV are noted for an increased risk for severe symptoms; however, existing studies did not focus on the statistical comparison of mpox outcomes associated with HIV. Thus, we conducted a systematic review and meta-analysis to evaluate and compare the clinical manifestations of mpox in people living with HIV (PLWH) and people without HIV. In this systematic review and meta-analysis, PubMed/MEDLINE, Embase, and Google Scholar were searched up to March 7, 2023. A random effects model was used to calculate the pooled prevalence along with the 95% confidence intervals (CI), and the odds ratio and its corresponding 95% CIs were calculated to elucidate the significance of each clinical feature for mpox patients with and without HIV. In this study, we included 99 published papers with 2413 patients with mpox (median age, 35.5 years; PLWH n = 1151) from 27 countries across six continents. The odds ratio of the mpox outcomes with PLWH in comparison to patients without HIV was found to be significant for skin rash (1.24, 95% CI: 1.01-1.53), proctitis (2.03, 95% CI: 1.36-3.04), cough (0.57, 95% CI: 0.33-0.98), and diarrhea (3.85, 95% CI: 1.24-11.98). The odds ratio of mpox patients with HIV for historical infections of syphilis was 2.14 (95% CI: 1.38-3.32), compared with those without HIV. This is the first international and comprehensive study that performed a systematic review and meta-analysis to statistically measure mpox manifestations according to HIV status. As clinical features related to mucosal contact were characteristically pronounced in PLWH, our systematic review provides insight that the primary invasion site of infection strongly relates to the outcomes of mpox.

ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Early rituximab treatment reduces long-term disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses, we hypothesised that earlier initiation of rituximab can also reduce long-term disability of patients with NMOSD. METHODS: This multicentre retrospective study involving 19 South Korean referral centres included patients with NMOSD with aquaporin-4 antibodies receiving rituximab treatment. Factors associated with the long-term Expanded Disability Status Scale (EDSS) were assessed using multivariable regression analysis. RESULTS: In total, 145 patients with rituximab treatment (mean age of onset, 39.5 years; 88.3% female; 98.6% on immunosuppressants/oral steroids before rituximab treatment; mean disease duration of 121 months) were included. Multivariable analysis revealed that the EDSS at the last follow-up was associated with time to rituximab initiation (interval from first symptom onset to initiation of rituximab treatment). EDSS at the last follow-up was also associated with maximum EDSS before rituximab treatment. In subgroup analysis, the time to initiation of rituximab was associated with EDSS at last follow-up in patients aged less than 50 years, female and those with a maximum EDSS score ≥6 before rituximab treatment. CONCLUSIONS: Earlier initiation of rituximab treatment may prevent long-term disability worsening in patients with NMOSD, especially among those with early to middle-age onset, female sex and severe attacks.