Novel pleuromutilin derivatives conjugated with phenyl-sulfide and boron-containing moieties as potent antibacterial agents against antibiotic-resistant bacteria.

In response to the escalating threat of microbial resistance, a series of novel pleuromutilin derivatives, conjugated with phenyl-sulfide and boron-containing moieties, were designed and synthesized. Most derivatives, especially 14b and 16b, demonstrated significant efficacy against Gram-positive bacteria, including multidrug-resistant strains, as well as pleuromutilin-resistant strains. Compound 16b showed high stability in the liver microsomes of rats and humans, along with acceptable tolerance in vitro and in vivo. Additionally, compound 16b exhibited promising efficacy in MRSA-infected mouse models. Our data highlight the potential of conjugated pleuromutilin derivatives as valuable agents against drug-resistant bacteria.

La doped-Fe2(MoO4)3 with the synergistic effect between Fe2+/Fe3+ cycling and oxygen vacancies enhances the electrocatalytic synthesizing NH3.

The electrocatalytic nitrogen reduction reaction (NRR) is a crucial process in addressing energy shortages and environmental concerns by synthesizing the NH3. However, the difficulty of N2 activation and fewer NRR active sites limit the application of NRR. Therefore, the NRR performance can be improved by rapid electron transport paths to participate in multi-electron reactions and N2 activation. Doping with transition metal element is a viable strategy to provide electrons and electronic channels in the NRR. This study focuses on the synthesis of Fe2(MoO4)3 (FeMo) and x%La-doped FeMo (x = 3, 5, 7, and 10) using the hydrothermal method. La-doping creates electron transport channels Fe2+-O2--Fe3+ and oxygen vacancies, achieving an equal molar ratio of Fe2+/Fe3+. This strategy enables the super-exchange in Fe2+-O2--Fe3+, and then enhances electron transport speed for a rapid hydrogenation reaction. Therefore, the synergistic effect of Fe2+/Fe3+ cycling and oxygen vacancies improves the NRR performance. Notably, 5%La-FeMo demonstrates the superior NRR performance (NH3 yield rate: 29.6 µg h-1 mgcat-1, Faradaic efficiency: 5.8%) at -0.8 V (vs. RHE). This work analyzes the influence of the catalyst electronic environment on the NRR performance based on the effect on different valence states of ions on electron transport.

In a Canine Model of Septic Shock, Cardiomyopathy Occurs Independent of Catecholamine Surges and Cardiac Microvascular Ischemia.

BACKGROUND: High levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. METHODS AND RESULTS: Purpose-bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 µg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine-stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High-dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular-aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800-fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular-aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. CONCLUSIONS: Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.

Cardiac Magnetic Resonance Studies in a Large Animal Model That Simulates the Cardiac Abnormalities of Human Septic Shock.

BACKGROUND: Septic shock is associated with increases in end-diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown. METHODS AND RESULTS: Purpose-bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular-arterial coupling, and circumferential strain. Early during sepsis, (0-24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. CONCLUSIONS: The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.

Case Report and Literature Review: Orthostatic Hypotension Due to Multiple System Atrophy.

Objective: Multiple system atrophy (MSA) is a rare and fatal adult-onset neurodegenerative disease with multiple clinical and pathological variants. The etiology of MSA remains uncertain. Orthostatic hypotension (OH) is the main characteristic of MSA. An upright position can trigger a syncope attack, making it impossible for the patient to stand and walk briefly. Case Study: We report the case of a 67-year-old man with initial symptoms of recurrent syncope and this patient was hospitalized several times, despite multiple therapeutic interventions, his symptoms persisted. Eventually, this patient died at the age of 68 with a diagnosis of MSA. Conclusion: For those patients with neurogenic OH, an underlying neurodegenerative disease should always be considered. Prompt diagnosis, early aggressive treatment, and prediction of complications may have a huge impact on the prognosis of MSA. This article also reviews relevant reported cases to enrich the experience of treating MSA in the clinic.

Effects of exoskeleton-assisted walking on bowel function in motor-complete spinal cord injury patients: involvement of the brain-gut axis, a pilot study.

Evidence has demonstrated that exoskeleton robots can improve intestinal function in patients with spinal cord injury (SCI). However, the underlying mechanisms remain unelucidated. This study investigated the effects of exoskeleton-assisted walking (EAW) on intestinal function and intestinal flora structure in T2-L1 motor complete paraplegia patients. The results showed that five participants in the EAW group and three in the conventional group reported improvements in at least one bowel management index, including an increased frequency of bowel evacuations, less time spent on bowel management per day, and less external assistance (manual digital stimulation, medication, and enema usage). After 8 weeks of training, the amount of glycerol used in the EAW group decreased significantly (p <0.05). The EAW group showed an increasing trend in the neurogenic bowel dysfunction (NBD) score after 8 weeks of training, while the conventional group showed a worsening trend. Patients who received the EAW intervention exhibited a decreased abundance of Bacteroidetes and Verrucomicrobia, while Firmicutes, Proteobacteria, and Actinobacteria were upregulated. In addition, there were decreases in the abundances of Bacteroides, Prevotella, Parabacteroides, Akkermansia, Blautia, Ruminococcus 2, and Megamonas. In contrast, Ruminococcus 1, Ruminococcaceae UCG002, Faecalibacterium, Dialister, Ralstonia, Escherichia-Shigella, and Bifidobacterium showed upregulation among the top 15 genera. The abundance of Ralstonia was significantly higher in the EAW group than in the conventional group, and Dialister increased significantly in EAW individuals at 8 weeks. This study suggests that EAW can improve intestinal function of SCI patients in a limited way, and may be associated with changes in the abundance of intestinal flora, especially an increase in beneficial bacteria. In the future, we need to further understand the changes in microbial groups caused by EAW training and all related impact mechanisms, especially intestinal flora metabolites. Clinical trial registration: https://www.chictr.org.cn/.

Covalent Organic Frameworks for Electrocatalysis：Design, Applications, and Perspectives.

Covalent organic frameworks (COFs) are an innovative class of crystalline porous polymers composed of light elements such as C, N, O, etc., linked by covalent bonds. The distinctive properties of COFs, including designable building blocks, large specific surface area, tunable pore size, abundant active sites, and remarkable stability, have led their widespread applications in electrocatalysis. In recent years, COF-based electrocatalysts have made remarkable progress in various electrocatalytic fields, including the hydrogen evolution reaction, oxygen evolution reaction, oxygen reduction reaction, nitrogen reduction reaction, nitrate reduction reaction, and carbon dioxide reduction reaction. This review begins with an introduction to the design and synthesis strategies employed for COF-based electrocatalysts. These strategies include heteroatom doping, metalation of COF and building monomers, encapsulation of active sites within COF pores, and the development of COF-based derived materials. Subsequently, a systematic overview of the recent advancements in the application of COF-based catalysts in electrocatalysis is presented. Finally, the review discusses the main challenges and outlines possible avenues for the future development of COF-based electrocatalysts.

LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling.

Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4-mediated itch sensation remains unclear. Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4-knockout mice, suggesting LPS acted through a TLR4-dependent mechanism. Mechanistically, LPS enhanced GSK101-evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification.

Association between Whole-Grain Intake and Obesity Defined by Different Anthropometric Indicators and Dose-Response Relationship Analysis among U.S. Adults: A Population-Based Study.

Existing research shows an inconsistent correlation between whole-grain intake and obesity risk, with limited study on the dose-response relationship. Here, we aimed to examine this association and dose-response relationship among U.S. adults who participated in a NHANES (2003-2018). The intake of whole grain was collected and calculated from two rounds of 24 h dietary recall. Obesity was categorized based on body mass index (BMI) and waist circumference (WC). Weighted multivariable logistic regression models were used to calculate the odds of obesity according to whole-grain intake, and the dose-response relationship was modeled by restricted cubic spline regression. Among the 27,862 participants, 38.3% had general obesity, while 58.3% had abdominal obesity. After multivariate adjustment of potential confounders, the participants in the highest quintile of whole-grain intake had a lower prevalence of general obesity (OR 0.79; 95% CI 0.72-0.88) and abdominal obesity (OR 0.80; 95% CI 0.73-0.89) compared with those in the lowest category. Spline regression showed an inversely linear dose-response association between whole-grain intake and the prevalence of general obesity and abdominal obesity. In conclusion, a higher whole-grain intake was associated with lower odds of obesity, both general and abdominal. Our findings highlight the importance of increasing the whole-grain intake to prevent and manage obesity.

Effects of Cognitive Intervention and Rehabilitation Training on the Expression of miR-134-5p in Elderly Patients with Diabetes Mellitus and Cognitive Impairment.

OBJECTIVE: This study aimed to analyze the effect and potential mechanism of cognitive intervention and rehabilitation training in elderly patients with diabetes mellitus complicated with mild cognitive impairment. METHODS: In this study, 128 elderly patients with diabetes mellitus complicated with mild cognitive impairment were randomly divided into the control group and the training group. The effects of the two groups were compared before and after the cognitive intervention. The expression of miR-134-5p was assessed by qRT-PCR. The relationships between miR-134-5p and Mini-Mental State Examination Scale and Montreal Cognitive Assessment Scale were evaluated. RESULTS: After 3-month management, the Mini-Mental State Examination Scale, Montreal Cognitive Assessment Scale, the Chinese version of the diabetes self-efficacy rating scale, and WHO quality of life brief were improved in both control group and training group, and the training group showed better improvement. Cognitive intervention and rehabilitation training restricted the expression of miR-134-5p. The levels of miR-134-5p were pertinent to cognitive function. CONCLUSION: Cognitive intervention and rehabilitation training might prevent the development of diabetes mellitus complicated with mild cognitive impairment by inhibiting miR-134-5p.

Exploring Porous Flow Behavior of the Decomposed Gas from CH4 Hydrate in Clayey Sediments by Molecular Dynamics Simulation.

A fundamental understanding of the fluid flow mechanism during CH4 hydrate dissociation in nanoscale clayey sediments from the molecular perspective can provide invaluable information for macroscale natural gas hydrate (NGH) exploration. In this work, the fluid flow behaviors of the decomposed gas from CH4 hydrate within clayey nanopores under different temperature conditions are revealed by molecular dynamics (MD) simulation. The simulation results indicate that the key influencing factors of gas-water flow in nanoscale clayey sediments include the diffusion and the random migration of gas molecules. The influencing mechanisms of fluid flow in nanopores are closely related with the temperature conditions. Under a low temperature condition, the gas diffusion process is impeded by the secondary hydrate formation, leading to the decline in gas transport velocity within nanopores. However, it is still noteworthy that the gas-water fluid flow channels are not completely blocked by the occurrence of secondary hydrate. Under a high temperature condition, the significant phenomenon of water migration during gas flow is observed, which can be ascribed to the gas-liquid entrainment effect in nanopores of the clayey sediment. These results may provide valuable implications and fundamental evidence for improving gas production efficiency in future field tests of NGH exploitation in marine sediments.

Berberine as a novel ACSL4 inhibitor to suppress endothelial ferroptosis and atherosclerosis.

The discovery of an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein involved in the process of cell injury through ferroptosis, has the potential to ameliorate cell damage. In this study, we aimed to investigate the potential of berberine (BBR) as an inhibitor of ACSL4 in order to suppress endothelial ferroptosis and provide protection against atherosclerosis. An atherosclerosis model was created in ApoE-/- mice by feeding a high fat diet for 16 weeks. Additionally, a mouse model with endothelium-specific overexpression of ACSL4 was established. BBR was administered orally to assess its potential therapeutic effects on atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low density lipoprotein (ox-LDL) to simulate atherosclerotic endothelial damage in vitro. The interaction between ACSL4 and BBR has been confirmed, with BBR playing a role in inhibiting erastin-induced ferroptosis by regulating ACSL4. Additionally, BBR has been found to inhibit lipid deposition, plaque formation, and collagen deposition in the aorta, thereby delaying the progression of atherosclerosis. It also restored the abnormal expression of ferroptosis-related proteins in atherosclerotic vascular endothelial cells both in vivo and in vitro. In conclusion, BBR, acting as an ACSL4 inhibitor, can improve atherosclerosis by inhibiting ferroptosis in endothelial cells. This highlights the potential of targeted inhibition of vascular endothelial ACSL4 as a strategy for treating atherosclerosis, with BBR being a candidate for this purpose.

The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review.

Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988.

Exceptional figure of merit achieved in boron-dispersed GeTe-based thermoelectric composites.

GeTe is a promising p-type material with increasingly enhanced thermoelectric properties reported in recent years, demonstrating its superiority for mid-temperature applications. In this work, the thermoelectric performance of GeTe is improved by a facile composite approach. We find that incorporating a small amount of boron particles into the Bi-doped GeTe leads to significant enhancement in power factor and simultaneous reduction in thermal conductivity, through which the synergistic modulation of electrical and thermal transport properties is realized. The thermal mismatch between the boron particles and the matrix induces high-density dislocations that effectively scatter the mid-frequency phonons, accounting for a minimum lattice thermal conductivity of 0.43 Wm-1K-1 at 613 K. Furthermore, the presence of boron/GeTe interfaces modifies the interfacial potential barriers, resulting in increased Seebeck coefficient and hence enhanced power factor (25.4 µWcm-1K-2 at 300 K). Consequently, we obtain a maximum figure of merit Zmax of 4.0 × 10-3 K-1 at 613 K in the GeTe-based composites, which is the record-high value in GeTe-based thermoelectric materials and also superior to most of thermoelectric systems for mid-temperature applications. This work provides an effective way to further enhance the performance of GeTe-based thermoelectrics.

A Tight-Connection g-C3N4/BiOBr (001) S-Scheme Heterojunction Photocatalyst for Boosting Photocatalytic Degradation of Organic Pollutants.

The efficient separation of photogenerated charge carriers and strong oxidizing properties can improve photocatalytic performance. Here, we combine the construction of a tightly connected S-scheme heterojunction with the exposure of an active crystal plane to prepare g-C3N4/BiOBr for the degradation of high-concentration organic pollutants. This strategy effectively improves the separation efficiency of photogenerated carriers and the number of active sites. Notably, the synthesized g-C3N4/BiOBr displays excellent photocatalytic degradation activity towards various organic pollutants, including methylene blue (MB, 90.8%), congo red (CR, 99.2%), and tetracycline (TC, 89%). Furthermore, the photocatalytic degradation performance of g-C3N4/BiOBr for MB maintains 80% efficiency under natural water quality (tap water, lake water, river water), and a wide pH range (pH = 4-10). Its excellent photocatalytic activity is attributed to the tight connection between g-C3N4 and BiOBr in the S-scheme heterojunction interface, as well as the exposure of highly active (001) crystal planes. These improve the efficiency of the separation of photogenerated carriers, and maintain their strong oxidation capability. This work presents a simple approach to improving the separation of electrons and holes by tightly combining two components within a heterojunction.

A global view of altered ligand-receptor interactions in bone marrow aging based on single-cell sequencing.

Altered cell-cell communication is a hallmark of aging, but its impact on bone marrow aging remains poorly understood. Based on a common and effective pipeline and single-cell transcriptome sequencing, we detected 384,124 interactions including 2575 ligand-receptor pairs and 16 non-adherent bone marrow cell types in old and young mouse and identified a total of 5560 significantly different interactions, which were then verified by flow cytometry and quantitative real-time PCR. These differential ligand-receptor interactions exhibited enrichment for the senescence-associated secretory phenotypes. Further validation demonstrated supplementing specific extracellular ligands could modify the senescent signs of hematopoietic stem cells derived from old mouse. Our work provides an effective procedure to detect the ligand-receptor interactions based on single-cell sequencing, which contributes to understand mechanisms and provides a potential strategy for intervention of bone marrow aging.

Exploring optimal incubation conditions and characteristics of methane oxidizing organisms in deep-sea environments.

Anaerobic methanotrophic archaea (ANME) play key roles in buffering the methane budget in the deep-sea environment. This study aimed to explore the optimal environmental conditions for ANME enrichment. The result showed that the sample at 10.5 MPa contained the largest copy numbers of methyl-coenzyme M reductase alpha subunit (mcrA) gene (1.1 × 106 copies/g) compared to any other pressures and the sample at 4 °C contained higher mcrA gene (1.6 × 106 copies/g) than other temperatures. The optimal enrichment pressure for ANME-2c is 10.5 MPa at 4 °C, with an optimal subsequent incubation for ANME-2c less than 211days. Moreover, the beta nearest taxon index was significantly correlated with the incubation time (P<0.05). Total inorganic carbon and sulfate ion were key environmental factors driving community construction. This study offers insights into how ANME-2c was enriched and how species coexist in shared habitats during enrichment.

Sleep traits and breast cancer risk: a two-sample Mendelian randomization study.

Globally, breast cancer continues to be the leading cause of cancer-related incidence and mortality among females. Research has shown that sleep patterns significantly influence tumor onset and progression. In this research, the association was examined through the application of a two-sample Mendelian randomization (MR) approach. For the analysis of seven sleep patterns, genetic tools were sourced from both the UK Biobank and 23andMe, including morning/evening person (chronotype) n = 177,604, morning person (chronotype) n = 248,094, daytime dozing/sleepiness n = 193,472, getting up in the morning n = 193,717, and sleeplessness n = 193,987; sleep duration n = 192,810; and nap during the day n = 166,853. The Breast Cancer Association Consortium (BCAC) supplied genome-wide association studies (GWAS) data, including 133,384 breast cancer cases and 113,789 controls, alongside subtype-specific data with 106,278 cases and 91,477 controls. We discovered that chronotype encompasses both morning and evening types contributes to the risk of overall breast cancer. While daytime dozing and morning person (chronotype) are linked to a lower risk of breast cancer in general, In subtype-specific analyses, morning person (chronotype) was negatively associated with luminal B, HER2-negative-like, and daytime dozing was negatively correlated with luminal A-like, luminal B-like, and HER2-enriched-like. The study corroborates that chronotype is a danger element for breast cancer, aligning with previous observational findings. The association between being a morning person (chronotype) or having daytime dozing and a decreased risk of breast cancer underscores the significance of sleep patterns in formulating strategies for cancer prevention.

Performance of antisaccades in patients with cerebral small vessel disease accompanied by white matter hyperintensities.

OBJECTIVES: The antisaccades (AS) task is considered a reliable indicator of inhibitory control of eye movements in humans. Achieving good AS performance requires efficient cognitive processes that are sensitive to changes in brain structure. White matter hyperintensities (WMH) can cause subcortical-cortical dysconnectivity, affecting diverse cognitive domains. Thus, the AS task was investigated in patients with WMH in cerebral small vessel disease (CSVD). METHODS: In this retrospective study, 75 participants with WMH, determined by neuroimaging standards for CSVD research, were admitted to the Department of Neurology of Beijing Luhe Hospital, Capital Medical University from January 2021 to December 2022. All subjects underwent the AS task, Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and 3.0T brain MRI. Additionally, 61 healthy subjects were recruited to characterize WMH profiles. RESULTS: Compared to the control group, patients with WMH had a significantly increased AS error rate (49.81%, p = 0.001) and lower gain (76.00%, p = 0.042). The AS error rate was significantly higher in patients with WMH in the frontal lobe than in those without WMH (p = 0.004). After adjusting for confounders (age), a positive correlation was found between the AS error rate and MoCA scores for patients with WMH (coefficient = 0.262, p = 0.024). CONCLUSIONS: Patients with WMH due to CSVD exhibited abnormal AS performances, particularly in the frontal lobe. The eye movement paradigms, the new diagnostic forms in neurology, can be utilized to investigate the distributed cortical and subcortical systems involved in cognitive control processes, offering simple, well-tolerated and highly sensitive advantages over traditional measures.

The mediating effect of blood biomarkers in the associations between inflammatory bowel disease and incident psychiatric disorders: a prospective cohort study.

BACKGROUND: Despite the growing evidence of an association between inflammatory bowel disease (IBD) and psychiatric disorders, there has been limited research exploring the underlying mediating role of blood biomarkers on the gut-brain axis. This study aimed to examine the association between IBD and the risk of incident psychiatric disorders and investigate whether and how blood biomarkers mediate this association. METHODS: This prospective cohort study using data from the UK Biobank included participants without psychiatric diagnoses at baseline. The case cohort consisted of participants with a hospital-based diagnosis of IBD at baseline. The primary outcome was all psychiatric disorders. Secondary outcomes included 11 major psychiatric disorders. Cox regression models estimated adjusted hazard ratios (HRs) for psychiatric outcomes. Causal mediation models investigated the potential mediation effects of blood biomarkers. RESULTS: Among 491,131 participants, patients with IBD exhibited higher risks of overall psychiatric disorders (HR 1.23 [95% CI 1.13-1.33]), substance misuse (1.23 [1.09-1.38]), depression (1.36 [1.22-1.52]), anxiety (1.15 [1.01-1.30]) and post-traumatic stress disorder (1.87 [1.00-3.51]) compared with non-IBD participants. The association with incident substance misuse was only among patients with Crohn's disease (CD, 1.47 [1.23-1.76]), but not ulcerative colitis (UC, 1.01 [0.84-1.21]). Mediation analysis revealed 16, 14, 15, and 6 biomarkers partially mediated the associations for all psychiatric disorders, substance misuse, depression, and anxiety, respectively. Six blood markers showed the strongest mediating effects: neutrophil count (12.04%), C-reactive protein (10.29%), systemic immune-inflammatory index (8.94%), erythrocyte distribution width (16.51%), erythrocyte count (9.76%), and albumin (9.15%). Moreover, several blood mediators of CD identified in association with incident substance misuse may explain the risk discrepancy between IBD subtype. CONCLUSION: The blood biomarkers of inflammation, blood oxygen-carrying capacity, and metabolism mediate the effect of IBD on the risk of psychiatric outcomes and could be considered as a therapeutic target.