Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.

BACKGROUND: Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown. METHODS: Drpitor1a's ability to inhibit recombinant and endogenous Drp1-GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in normal and monocrotaline-PAH females. RESULTS: Drp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity. CONCLUSIONS: Drpitor1a is a specific Drp1-GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH-hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.

Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products.

Autophagy is a vital cellular process responsible for digesting various cytoplasmic organelles. This process plays a crucial role in maintaining cell survival and homeostasis, especially under conditions that cause nutrient deficiency, cellular damage, and oxidative stress. Neuroangiostrongyliasis is an infection caused by the parasitic nematode Angiostrongylus cantonensis and is considered as an emerging disease in many parts of the world. However, effective therapeutic strategies for neuroangiostrongyliasis still need to be further developed. In this study, we investigated the effects of benzaldehyde treatment on autophagy and sonic hedgehog (Shh) signaling in A. cantonensis-infected mice and its mechanisms. First, we found autophagosome generation in the central nervous system after A. cantonensis infection. Next, benzaldehyde combined with albendazole treatment reduced eosinophilic meningitis and upregulated the expression of Shh signaling- and autophagy-related molecules in A. cantonensis-infected mouse brains. In vitro experiments demonstrated that benzaldehyde could induce autophagy via the Shh signaling pathway in A. cantonensis excretory-secretory products (ESPs)-treated mouse astrocytes. Finally, benzaldehyde treatment also decreased lipid droplet accumulation and increased cholesterol production by activating the Shh pathway after ESPs treatment. In conclusion, these findings suggested that benzaldehyde treatment could alleviate brain damage by stimulating autophagy generation through the Shh signaling pathway.

Hydrogen Gas Inhalation Treatment for Coronary Artery Lesions in a Kawasaki Disease Mouse Model.

BACKGROUND: Kawasaki disease (KD) is a syndrome primarily affecting young children, typically under the age of five, and is characterized by the development of acute vasculitis. Through extensive research conducted on both murine and human subjects, it has been demonstrated that heightened levels of reactive oxygen species (ROS) play a pivotal role in the development of KD, especial coronary artery lesions (CALs). Hydrogen gas exhibits potent antioxidant properties that effectively regulate ROS production and the inflammatory response. METHODS: We used Lactobacillus casei cell wall extract (LCWE)-induced vasculitis in mice as an animal model of KD and treated the mice with hydrogen gas inhalation. RESULTS: We observed significant dilatation and higher Z scores in the left coronary artery (LCA) in D21 and D28 in mice after LCWE treatment compared to the control group (p < 0.001) and a significant resolution of LCA diameters (p < 0.01) and Z scores (p < 0.01) after treatment with inhaled hydrogen gas. We further demonstrated that serum IL-6 expression was higher in mice after LCWE treatment (p < 0.01) and IL-6 significantly decreased after inhaled hydrogen gas therapy (p < 0.001). CONCLUSION: According to our literature review, this is the first report where hydrogen gas inhalation has been demonstrated to be effective for the treatment of coronary artery dilatation in a KD murine model.

An inclusive study to elucidation the heavy metals-derived ecological risk nexus with antibiotic resistome functional shape of niche microbial community and their carbon substrate utilization ability in serpentine soil.

Heavy metals (HMs) contained terrestrial ecosystems are often significantly display the antibiotic resistome in the pristine area due to increasing pressure from anthropogenic activity, is complex and emerging research interest. This study investigated that impact of chromium (Cr), nickel (Ni), cobalt (Co) concentrations in serpentine soil on the induction of antibiotic resistance genes and antimicrobial resistance within the native bacterial community as well as demonstrated their metabolic fingerprint. The full-length 16S-rRNA amplicon sequencing observed an increased abundance of Firmicutes, Actinobacteriota, and Acidobacteriota in serpentine soil. The microbial community in serpentine soil displayed varying preferences for different carbon sources, with some, such as carbohydrates and carboxylic acids, being consistently favored. Notably, 27 potential antibiotic resistance opportunistic bacterial genera have been identified in different serpentine soils. Among these, Lapillicoccus, Rubrobacter, Lacibacter, Chloroplast, Nitrospira, Rokubacteriales, Acinetobacter, Pseudomonas were significantly enriched in high and medium HMs concentrated serpentine soil samples. Functional profiling results illustrated that vancomycin resistance pathways were prevalent across all groups. Additionally, beta-lactamase, aminoglycoside, tetracycline, and vancomycin resistance involving specific bio-maker genes (ampC, penP, OXA, aacA, strB, hyg, aph, tet(A/B), otr(C), tet(M/O/Q), van(A/B/D), and vanJ) were the most abundant and enriched in the HMs-contaminated serpentine soil. Overall, this study highlighted that heavy-metal enriched serpentine soil is potential to support the proliferation of bacterial antibiotic resistance in native microbiome, and might able to spread antibiotic resistance to surrounding environment.

Interspecific Differences in Carbon and Nitrogen Metabolism and Leaf Epiphytic Bacteria among Three Submerged Macrophytes in Response to Elevated Ammonia Nitrogen Concentrations.

Submerged macrophytes in eutrophic aquatic environments adapt to changes in ammonia nitrogen (NH4-N) levels by modifying their levels of free amino acids (FAAs) and soluble carbohydrates (SCs). As symbionts of submerged macrophytes, epiphytic bacteria have obvious host specificity. In the present study, the interspecific differences in the FAA and SC contents of Hydrilla verticillata (Linn. f.) Roylep, Vallisneria natans Hara and Chara braunii Gmelin and their leaf epiphytic bacterial communities were assessed in response to increased NH4-N concentrations. The results revealed that the response of the three submerged macrophytes to NH4-N stress involved the consumption of SCs and the production of FAAs. The NH4-N concentration had a greater impact on the variation in the FAA content, whereas the variation in the SC content was primarily influenced by the species. At the phylum level, the relative abundance of Nitrospirota on the leaves exhibited specific differences, with the order H. verticillata > V. natans > C. braunii. The dominant genera of epiphytic bacteria with denitrification effects on V. natans, H. verticillata and C. braunii leaves were Halomonas, Acinetobacter and Bacillus, respectively. When faced with NH4-N stress, the variation in epiphytic bacterial populations associated with ammonia oxidation and denitrification among submerged macrophytes could contribute to their divergent responses to heightened nitrogen levels.

Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-ß signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-ß signaling. Interestingly, blocking SOCE had little effect on TGF-ß-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-ß signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-ß-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-ß signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.

Understanding the human conflict processing network: A review of the literature on direct neural recordings during performance of a modified stroop task.

The Stroop Task is a well-known neuropsychological task developed to investigate conflict processing in the human brain. Our group has utilized direct intracranial neural recordings in various brain regions during performance of a modified color-word Stroop Task to gain a mechanistic understanding of non-emotional human conflict processing. The purpose of this review article is to: 1) synthesize our own studies into a model of human conflict processing, 2) review the current literature on the Stroop Task and other conflict tasks to put our research in context, and 3) describe how these studies define a network in conflict processing. The figures presented are reprinted from our prior publications and key publications referenced in the manuscript. We summarize all studies to date that employ invasive intracranial recordings in humans during performance of conflict-inducing tasks. For our own studies, we analyzed local field potentials (LFPs) from patients with implanted stereotactic electroencephalography (SEEG) electrodes, and we observed intracortical oscillation patterns as well as intercortical temporal relationships in the hippocampus, amygdala, and orbitofrontal cortex (OFC) during the cue-processing phase of a modified Stroop Task. Our findings suggest that non-emotional human conflict processing involves modulation across multiple frequency bands within and between brain structures.

Doxycycline cotherapy with albendazole relieves neural function damage in C57BL/6 and BALB/c mice infected with Angiostrongylus cantonensis.

BACKGROUND: We investigated the effects of combination therapy albendazole and doxycycline in Angiostrongylus cantonensis-infected mice during early and late treatment. MATERIALS AND METHODS: C57BL/6 and BALB/c mice were divided into five groups: (i) uninfected, (ii) infected with A. cantonensis, (iii) infected + 10 mg/kg albendazole, (iv) infected + 25mg/kg doxycycline, and (v) infected + 10 mg/kg albendazole + 25 mg/kg doxycycline. We administered drugs in both early treatments started at 7-day post infections (dpi) and late treatments (14 dpi) to A. cantonensis-infected C57BL/6 and BALB/c mice. To assess the impact of these treatments, we employed the Morris water maze test to evaluate spatial learning and memory abilities, and the rotarod test to measure motor coordination and balance in C57BL/6 mice. Additionally, we monitored the expression of the cytokine IL-33 and GFAP in the brain of these mice using western blot analysis. RESULTS: In this study, A. cantonensis infection was observed to cause extensive cerebral angiostrongyliasis in C57BL/6 mice. This condition significantly affected their spatial learning and memory abilities, as assessed by the Morris water maze test, as well as their motor coordination, which was evaluated using the rotarod test. Early treatment with albendazole led to favorable recovery outcomes. Both C57BL/6 and BALB/c mice express IL-33 and GFAP after co-therapy. The differences of levels and patterns of IL-33 and GFAP expression in mice may be influenced by the balance between pro-inflammatory and anti-inflammatory signals within the immune system. CONCLUSIONS: Combination therapy with anthelmintics and antibiotics in the early stage of A. cantonensis infection, in C57BL/6 and BALB/c mice resulted in the death of parasites in the brain and reduced the subsequent neural function damage and slowed brain damage and neurobehavior impairment. This study suggests a more effective and novel treatment, and drug delivery method for brain lesions that can decrease the neurological damage of angiostrongyliasis patients.

The Causality between Gut Microbiota and Hypertension and Hypertension-related Complications: A Bidirectional Two-Sample Mendelian Randomization Analysis.

BACKGROUND: Recent studies have highlighted a connection between gut microbiota and hypertension, yet the precise nature of this relationship remains unclear. OBJECTIVE: This research aims to analyze the causal link between gut microbiota and hypertension, along with associated complications, utilizing two-sample bidirectional Mendelian randomization (MR). MATERIALS AND METHODS: Summary data from genome-wide association studies (GWAS) meta-analyses, including gut microbiota GWAS data from 24 cohorts, and the latest GWAS data for hypertension-related conditions were acquired. Employing various MR methods, including Inverse-variance weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode, we investigated the association between gut microbiota and hypertension-related conditions. Sensitivity analyses were conducted for result stability, and reverse MR analysis assessed the potential for reverse causality. RESULTS: The Mendelian randomization analysis involving 199 microbial taxa and four phenotypes identified 46 microbial taxa with potential causal links to hypertension and its complications. Following Bonferroni correction, genus.Victivallis showed a robust causal relationship with hypertension (OR = 1.08, 95% CI = 1.04-1.12, P = 9.82e-5). This suggests an 8% increased risk of hypertension with each unit rise in genus.Victivallis abundance. CONCLUSION: In conclusion, this study establishes a causal connection between gut microbiota and hypertension, along with common associated complications. The findings unveil potential targets and evidence for future hypertension and complication treatment through gut microbiota interventions, offering a novel avenue for therapeutic exploration.

Positive Echocardiographic Association between Carotid Artery and Coronary Artery Diameter and Z-Score in a Mouse Model of Kawasaki Disease.

Kawasaki disease (KD) occurs in young children, has an unknown etiology, and can cause such life-threatening complications as coronary artery aneurysm. A mouse model using Lactobacillus casei cell wall extract (LCWE) with intraperitoneal injection was established for KD years ago. Histological examination of coronary artery lesions indicated features similar to those of vascular lesions of patients with KD. Since animals must be sacrificed during histological examination, the longitudinal survey of coronary artery lesions (CALs) is difficult. The aim of this study was to survey the vasculitis status of the coronary artery and the carotid artery in a KD mouse model. METHOD: LCWE was intraperitoneally injected into 5-week-old male C57BL/6 mice to induce CALs. We studied the longitudinal status of the carotid and coronary arteries and analyzed the Z-score of coronary artery diameter. RESULTS: Carotid artery wall thickness (day 7) and diameter (day 14) significantly increased in the LCWE group with a dose-dependent effect (p < 0.05). Aortic diameter and wall thickness demonstrated significant increases on day 28 and day 7, respectively (p < 0.05). Carotid artery outer diameter and wall thickness were positively associated with coronary artery diameter on day 28 (p < 0.01). Coronary artery diameter significantly increased in the LCWE group after day 7 (p < 0.05). The percentage of Z > 3.0 indicated was more than 80% in the high-dose LCWE group and 0% in the control group. CONCLUSIONS: This report is the first to use coronary artery Z-score in a mouse model of KD by echocardiography and to find a positive association between carotid artery and coronary artery diameter.

Impulse oscillometry and its independent role in the diagnosis of chronic obstructive pulmonary disease.

Background: Pulmonary function test, particularly in patients with COVID-19, is problematic because it involves forced expiration. Impulse oscillometry (IOS) reduces the potential exposure of health-care staff to infectious droplets. In this study, we investigated the correlation between IOS and spirometry and whether IOS can precisely predict spirometry-based diagnoses of chronic obstructive pulmonary disease (COPD). Methods: We retrospectively analyzed the data (January 1 to December 31, 2021) of patients who underwent both spirometry and IOS on the same date. One-way analysis of variance was performed to evaluate the IOS results of patients stratified into two (COPD and non-COPD) groups by spirometry results. IOS results were also analyzed using receiver operator characteristics curves to diagnose advanced COPD, which was indicated by a postbronchodilator (BD) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio of <0.6. We further evaluated the accuracy of oscillometry as a predictor of spirometry-based COPD diagnosis. Results: A total of 115 patients were included in the analysis. The best parameters assessed for spirometry-based COPD diagnosis were area under reactance (AX) and airway resistance (predicted R5% × resonant frequency) in relation to body mass index (BMI). However, when the post-BD FEV1/FVC ratio was <0.6, BMI-adjusted airway resistance had an area under curve (0.782; 95 % confidence interval: 0.620-0.945) value larger than the corresponding AX. A BMI-adjusted airway resistance value of >160 moderately predicted spirometry-based COPD diagnosis. Conclusions: BMI-adjusted airway resistance is a potential predictor of spirometry-based COPD diagnosis; the cutoff values of this parameter differ between individuals with and without obesity.

The influence of prior use of inhaled corticosteroids on COVID-19 outcomes: A systematic review and meta-analysis.

The influence of inhaled corticosteroids (ICS) on COVID-19 outcomes remains uncertain. To address this, we conducted a systematic review and meta-analysis, analyzing 30 studies, to investigate the impact of ICS on patients with COVID-19. Our study focused on various outcomes, including mortality risk, hospitalization, admission to the intensive care unit (ICU), mechanical ventilation (MV) utilization, and length of hospital stay. Additionally, we conducted a subgroup analysis to assess the effect of ICS on patients with chronic obstructive pulmonary disease (COPD) and asthma. Our findings suggest that the prior use of ICS did not lead to significant differences in mortality risk, ICU admission, hospitalization, or MV utilization between individuals who had used ICS previously and those who had not. However, in the subgroup analysis of patients with COPD, prior ICS use was associated with a lower risk of mortality compared to non-users (OR, 0.95; 95% CI, 0.90-1.00). Overall, while the use of ICS did not significantly affect COVID-19 outcomes in general, it may have beneficial effects specifically for patients with COPD. Nevertheless, more research is needed to establish a definitive conclusion on the role of ICS in COVID-19 treatment. PROSPERO registration number: CRD42021279429.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Changing the standardised obstetric care by expanded carrier screening and counselling: a multicentre prospective cohort study.

BACKGROUND: Expanded genetic screening before conception or during prenatal care can provide a more comprehensive evaluation of heritable fetal diseases. This study aimed to provide a large cohort to evaluate the significance of expanded carrier screening and to consolidate the role of expanded genetic screening in prenatal care. METHODS: This multicentre, retrospective cohort study was conducted between 31 December 2019 and 21 July 2022. A screening panel containing 302 genes and next-generation sequencing were used for the evaluation. The patients were referred from obstetric clinics, infertility centres and medical centres. Genetic counsellors conducted consultation for at least 15 min before and after screening. RESULTS: A total of 1587 patients were screened, and 653 pairs were identified. Among the couples who underwent the screening, 62 (9.49%) had pathogenic variants detected on the same genes. In total, 212 pathogenic genes were identified in this study. A total of 1173 participants carried at least one mutated gene, with a positive screening rate of 73.91%. Among the pathogenic variants that were screened, the gene encoding gap junction beta-2 (GJB2) exhibited the highest prevalence, amounting to 19.85%. CONCLUSION: Next-generation sequencing carrier screening provided additional information that may alter prenatal obstetric care by 9.49%. Pan-ethnic genetic screening and counselling should be suggested for couples of fertile age.

Endoscopic Versus Microscopic Type I Tympanoplasty: An Updated Systematic Review and Meta-analysis.

OBJECTIVE: Our objective was to perform a systematic review and meta-analysis comparing the clinical outcomes after endoscopic and microscopic type I tympanoplasty. STUDY DESIGN: Randomized controlled trials, two-arm prospective studies, and retrospective studies were included. SETTING: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until March 1, 2022 using the combinations of search terms: "endoscopic," "microscopic," and "tympanoplasty." METHODS: Two independent reviewers utilized the abovementioned search strategy to identify eligible studies. If any uncertainty existed regarding eligibility, a third reviewer was consulted. Primary outcome measures were graft success rate, air-bone gap (ABG) improvement, and operative time. Secondary outcomes were the rate of need for canalplasty, the proportion of self-rated excellent cosmetic results, and pain visual analog scale (VAS). RESULTS: Forty-three studies enrolled a total of 3712 patients who were undergoing type I tympanoplasty and were finally included. The pooled result showed endoscopic approach was significantly associated with shorter operative time (difference in means: -20.021, 95% confidence interval [CI]: -31.431 to -8.611), less need for canalplasty (odds ratio [OR]: 0.065, 95% CI: 0.026-0.164), more self-rated excellent cosmetic results (OR: 87.323, 95% CI: 26.750-285.063), and lower pain VAS (difference in means: -2.513, 95% CI: -4.737 to -0.228). No significant differences in graft success rate or ABG were observed between the two procedures. CONCLUSION: Endoscopic type I tympanoplasty provides a similar graft success rate, improvement in ABG, and reperforation rate to microscopic tympanoplasty with a shorter operative time, better self-rated cosmetic results, and less pain. Unless contraindicated, the endoscopic approach should be the procedure of choice in type I tympanoplasty.

Persistent Halogenated Organic Pollutants in Deep-Water-Deposited Particulates from South China Sea.

POP data are limited in the marine environment; thus, this study aimed to investigate background persistent organic pollutant (POP) levels in oceanic deep-water-deposited particulates in the South China Sea (SCS). Six POPs, including polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (DL-PCBs), polybrominated diphenyl ethers (PBDEs), polybrominated dibenzo-p-dioxins/dibenzofurans (PBDD/Fs), polychlorinated diphenyl ethers (PCDEs), and polybrominated biphenyls (PBBs), were investigated in eight pooled samples from the SCS from 20 September 2013 to 23 March 2014 and 15 April 2014 to 24 October 2014 at depths of 2000 m and 3500 m. PBDEs were the most predominant compounds, with the highest mean Σ14PBDE of 125 ± 114 ng/g dry weight (d.w.), followed by Σ17PCDD/F, Σ12PBDD/F, and Σ12DL-PCB (275 ± 1930, 253 ± 216, and 116 ± 166 pg/g d.w., respectively). Most PBDD/F, PBB, and PCDE congeners were below the detection limits. PCDDs had the highest toxic equivalency (TEQ), followed by PBDDs and DL-PCBs. Among the six POPs, PBDEs were the major components of the marine-deposited particles, regarding both concentrations and mass fluxes. Compared to 3500 m, PBDE levels were higher at a depth of 2000 m. PBDE mass fluxes were 20.9 and 14.2 ng/m2/day or 68.2 and 75.9 ng/m2/year at deep-water 2000 and 3500 m, respectively. This study first investigated POP levels in oceanic deep-water-deposited particles from existing global data.

Real-World Evidence of Intra-institutional Performance Variation in Indefinite Diagnosis of Pleural Effusion Cytology.

CONTEXT.­: Pleural effusion cytology has been widely used in the investigation of pathologic fluid accumulation in pleural spaces. However, up to one-tenth of the cases were not given a definitive diagnosis. These cases have largely been neglected in the bulk of the literature. OBJECTIVE.­: To provide real-world data on indefinite diagnoses including "atypia of uncertain significance" (AUS) and "suspicious for malignancy" (SFM) in pleural effusion cytology and to investigate pathologists' practice patterns on using these diagnostic categories. DESIGN.­: We reported the diagnoses of 51 675 cases. Descriptive statistics and correlation coefficients were used to analyze the relationships between different diagnostic categories and pathologists' practice patterns and possible explanatory variables. RESULTS.­: The diagnoses AUS and SFM were reported in 4060 cases (7.86%) and 1554 cases (3.01%) in the cohort, respectively. The mean rates for these indefinite diagnoses varied up to 3-fold between pathologists. Correlations were found between AUS and SFM, as well as between indefinite diagnoses and negative for malignancy (NFM). No correlations were found between pathologists' years of experience or case volume and the rates of indefinite diagnosis or diagnostic certainty. CONCLUSIONS.­: A real-world baseline for the rates of indefinite diagnoses in pleural effusion cytology is provided in this large retrospective study. Pathologists show significant variation in their use of indefinite diagnostic categories, and the tendency to use these ambiguous terms was not correlated with individuals' experience or case volume. How to untangle the intertwined relationship between the uncertainty of indefinite diagnoses and that of NFM requires future prospective studies.

Molecular Hydrogen: Emerging Treatment for Stroke Management.

Ischemic stroke is a major cause of death and disability worldwide. However, only intravenous thrombolysis using mechanical thrombectomy or tissue plasminogen activator is considered an effective and approved treatment. Molecular hydrogen is an emerging therapeutic agent and has recently become a research focus. Molecular hydrogen is involved in antioxidative, anti-inflammatory, and antiapoptotic functions in normal physical processes and may play an important role in stroke management; it has been evaluated in numerous preclinical and clinical studies in several administration formats, including inhalation of hydrogen gas, intravenous or intraperitoneal injection of hydrogen-enriched solution, or drinking of hydrogen-enriched water. In addition to investigation of the underlying mechanisms, the safety and efficacy of using molecular hydrogen have been carefully evaluated, and favorable outcomes have been achieved. All available evidence indicates that molecular hydrogen may be a promising treatment option for stroke management in the future. This review aimed to provide an overview of the role of molecular hydrogen in the management of stroke and possible further modifications of treatment conditions and procedures in terms of dose, duration, and administration route.

Circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis: a two-step bidirectional Mendelian randomization study.

Background: The relationship between gut microbiota and the occurrence of cholecystitis remains unclear. Existing research lacks a clear understanding of how circulating vitamin levels modulate this relationship. Therefore, our study aims to investigate whether circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis using a two-step bidirectional Mendelian randomization approach. Methods: In this study, we initially employed Linkage Disequilibrium Score Regression (LDSC) analysis to assess the genetic correlation of five circulating vitamin level genome-wide association study (GWAS) summary datasets, thereby avoiding potential sample overlap. Subsequently, we conducted a two-step analysis to investigate the causal effects between gut microbiota and cholecystitis. In the second step, we explored the causal relationship between circulating vitamin levels and cholecystitis and identified the mediating role of vitamin D. The primary method used for causal analysis was the inverse variance-weighted approach. We performed additional sensitivity analyses to ensure result robustness, including the cML-MA method and reverse Mendelian randomization (MR) analysis. Results: An increment of one standard deviation in RuminococcaceaeUCG003 was associated with a 25% increased risk of cholecystitis (OR = 1.25, 95%CI = 1.01-1.54, p = 0.04), along with a 3% decrease in 25-hydroxyvitamin D levels (OR = 0.97, 95%CI = 0.944-0.998, p = 0.04). However, following the rigorous Bonferroni correction, every one standard deviation decrease in circulating vitamin D levels was associated with a 33% increased risk of cholecystitis (OR = 0.67, 95%CI = 0.49-0.90, p = 0.008, Padjust = 0.04). Thus, the potential link between gut microbiota and cholecystitis risk might be mediated by circulating vitamin D levels (proportion mediated = 5.5%). Sensitivity analyses provided no evidence of pleiotropy. Conclusion: Our study results suggest that an elevated abundance of specific gut microbiota is associated with an increased susceptibility to cholecystitis, with the causal relationship being mediated by circulating vitamin D levels. Further large-scale randomized controlled trials are necessary to validate the causal effects of gut microbiota on cholecystitis risk. This study provides novel insights into cholecystitis prevention through the regulation of gut microbiota.

Dipeptidyl peptidase IV inhibitors and the risk of mycobacterial pulmonary infections in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (DM) is a risk factor for mycobacterial pulmonary infections (MPI), including tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD). Dipeptidyl peptidase IV inhibitor (DPP4i), a common DM medication, has an immune-modulation effect that raises concerns about developing MPI. However, there is scarce research on the topic. METHODS: This retrospective study was conducted in a tertiary-referral center in Taiwan from 2009 to 2016. Patients with type 2 DM who were receiving any DM medication were enrolled. TB and NTM-LD were defined by microbiological criteria. We analyzed the risk of MPI in DPP4i users using Cox proportional hazard regression with adjusted inverse probability of treatment weighting. RESULTS: A total of 9963 patients were included. Among them, 3931 were classified as DPP4i users, and 6032 patients were DPP4i nonusers. DPP4i users had no increase in incidences of MPI (604 vs. 768 per 100,000 person-years, p = 0.776), NTM-LD (174 vs. 255 per 100,000 person-years, p = 0.228), and TB (542 vs. 449 per 100,000 person-years, p = 0.663) relative to those of DPP4i nonusers. After adjustment, the adjusted hazard ratios for MPI (aHR: 1.07, 95% CI: 0.79-1.45), TB (aHR: 1.15, 95% CI: 0.81-1.64) and NTM-LD (aHR: 0.85, 95% CI: 0.49-1.47) were not significantly increased relative to those of nonusers. The subgroup analysis also showed that DPP4i use did not increase the risk of MPI in different DM severities and comorbidities. CONCLUSIONS: According to our large cohort study, DPP4i use is safe for patients with type 2 DM and might not increase the risk of MPI.