How do probiotics alleviate constipation? A narrative review of mechanisms.

Constipation is a common gastrointestinal condition, which may occur at any age and affects countless people. The search for new treatments for constipation is ongoing as current drug treatments fail to provide fully satisfactory results. In recent years, probiotics have attracted much attention because of their demonstrated therapeutic efficacy and fewer side effects than pharmaceutical products. Many studies attempted to answer the question of how probiotics can alleviate constipation. It has been shown that different probiotic strains can alleviate constipation by different mechanisms. The mechanisms on probiotics in relieving constipation were associated with various aspects, including regulation of the gut microbiota composition, the level of short-chain fatty acids, aquaporin expression levels, neurotransmitters and hormone levels, inflammation, the intestinal environmental metabolic status, neurotrophic factor levels and the body's antioxidant levels. This paper summarizes the perception of the mechanisms on probiotics in relieving constipation and provides some suggestions on new research directions.

Longitudinal ultrasound-based AI model predicts axillary lymph node response to neoadjuvant chemotherapy in breast cancer: a multicenter study.

OBJECTIVES: Developing a deep learning radiomics model from longitudinal breast ultrasound and sonographer's axillary ultrasound diagnosis for predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) in breast cancer. METHODS: Breast cancer patients undergoing NAC followed by surgery were recruited from three centers between November 2016 and December 2022. We collected ultrasound images for extracting tumor-derived radiomics and deep learning features, selecting quantitative features through various methods. Two machine learning models based on random forest were developed using pre-NAC and post-NAC features. A support vector machine integrated these data into a fusion model, evaluated via the area under the curve (AUC), decision curve analysis, and calibration curves. We compared the fusion model's performance against sonographer's diagnosis from pre-NAC and post-NAC axillary ultrasonography, referencing histological outcomes from sentinel lymph node biopsy or axillary lymph node dissection. RESULTS: In the validation cohort, the fusion model outperformed both pre-NAC (AUC: 0.899 vs. 0.786, p < 0.001) and post-NAC models (AUC: 0.899 vs. 0.853, p = 0.014), as well as the sonographer's diagnosis of ALN status on pre-NAC and post-NAC axillary ultrasonography (AUC: 0.899 vs. 0.719, p < 0.001). Decision curve analysis revealed patient benefits from the fusion model across threshold probabilities from 0.02 to 0.98. The model also enhanced sonographer's diagnostic ability, increasing accuracy from 71.9% to 79.2%. CONCLUSION: The deep learning radiomics model accurately predicted the ALN response to NAC in breast cancer. Furthermore, the model will assist sonographers to improve their diagnostic ability on ALN status before surgery. CLINICAL RELEVANCE STATEMENT: Our AI model based on pre- and post-neoadjuvant chemotherapy ultrasound can accurately predict axillary lymph node metastasis and assist sonographer's axillary diagnosis. KEY POINTS: Axillary lymph node metastasis status affects the choice of surgical treatment, and currently relies on subjective ultrasound. Our AI model outperformed sonographer's visual diagnosis on axillary ultrasound. Our deep learning radiomics model can improve sonographers' diagnosis and might assist in surgical decision-making.

Single-Port Robotic Trans-Subxiphoid Surgery for Anterior Mediastinal Disease: A Pilot Trial.

OBJECTIVE: In recent years, there has been an increasing focus on minimally invasive mediastinal surgery using a trans-subxiphoid single-port thoracoscopic approach. Despite its potential advantages, the widespread adoption of this method has been hindered by the intricate surgical maneuvers required within the confined retrosternal space. Robotic surgery offers the potential to overcome the limitations inherent in the thoracoscopic technique. METHODS: This was a clinical trial (NCT05455840) to evaluate the feasibility and safety of utilizing the da Vinci® SP system (Intuitive Surgical, Sunnyvale, CA, USA) for trans-subxiphoid single-port surgery in patients with anterior mediastinal disease. The primary endpoints encompassed conversion rates and the secondary endpoints included the occurrence of perioperative complications. RESULTS: Between August 2022 and April 2023, a total of 15 patients (7 men and 8 women; median age = 56 years, interquartile range [IQR]: 49 to 65 years) underwent trans-subxiphoid robotic surgery using da Vinci SP platform for maximal thymectomy (n = 2) or removal of anterior mediastinal masses (n = 13). All surgical procedures were carried out with success, with no need for conversion to open surgery or the creation of additional ports. The median docking time was 2 min (IQR: 1 to 4 min), while the console time had a median of 152 min (IQR: 95 to 191 min). There were no postoperative complications and patients experienced a median postoperative hospital stay of 2 days with no unplanned 30-day readmission. CONCLUSIONS: This study shows that trans-subxiphoid single-port robotic surgery employing the da Vinci SP system in patients with anterior mediastinal disease is clinically viable with acceptable safety and short-term outcomes.

CaSTH2 disables CaWRKY40 from activating pepper thermotolerance and immunity against Ralstonia solanacearum via physical interaction.

CaWRKY40 coordinately activates pepper immunity against Ralstonia solanacearum infection (RSI) and high temperature stress (HTS), forms positive feedback loops with other positive regulators and is promoted by CaWRKY27b/CaWRKY28 through physical interactions; however, whether and how it is regulated by negative regulators to function appropriately remain unclear. Herein, we provide evidence that CaWRKY40 is repressed by a SALT TOLERANCE HOMOLOG2 in pepper (CaSTH2). Our data from gene silencing and transient overexpression in pepper and epoptic overexpression in Nicotiana benthamiana plants showed that CaSTH2 acted as negative regulator in immunity against RSI and thermotolerance. Our data from BiFC, CoIP, pull down, and MST indicate that CaSTH2 interacted with CaWRKY40, by which CaWRKY40 was prevented from activating immunity or thermotolerance-related genes. It was also found that CaSTH2 repressed CaWRKY40 at least partially through blocking interaction of CaWRKY40 with CaWRKY27b/CaWRKY28, but not through directly repressing binding of CaWRKY40 to its target genes. The results of study provide new insight into the mechanisms underlying the coordination of pepper immunity and thermotolerance.

Tea Consumption, Milk or Sweeteners Addition, Genetic Variation in Caffeine Metabolism, and Incident Venous Thromboembolism.

OBJECTIVE: The association between tea consumption and venous thromboembolism (VTE) remains unknown. We aimed to evaluate the association between tea consumption with different additives (milk and/or sweeteners) and incident VTE, and the modifying effects of genetic variation in caffeine metabolism on the association. METHODS: A total of 190,189 participants with complete dietary information and free of VTE at baseline in the UK Biobank were included. The primary outcome was incident VTE, including incident deep vein thrombosis and pulmonary embolism. RESULTS: During a median follow-up of 12.1 years, 4,485 (2.4%) participants developed incident VTE. Compared with non-tea drinkers, tea drinkers who added neither milk nor sweeteners (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.76-0.94), only milk (HR: 0.86; 95% CI: 0.80-0.93), and both milk and sweeteners to their tea (HR: 0.90; 95% CI: 0.81-0.99) had a lower risk of VTE, while those who added only sweeteners to their tea did not (HR: 0.94; 95% CI: 0.75-1.17). Moreover, there was an L-shaped relationship between tea consumption and incident VTE among tea drinkers who added neither milk nor sweeteners, only milk, and both milk and sweeteners to their tea, respectively. However, a nonsignificant association was found among tea drinkers who added only sweeteners to their tea. Genetic variation in caffeine metabolism did not significantly modify the association (p-interaction = 0.659). CONCLUSION: Drinking unsweetened tea, with or without added milk, was associated with a lower risk of VTE. However, there was no significant association between drinking tea with sweeteners and incident VTE.

Diagnostic performance of computed tomography-digital subtraction angiography and conventional magnetic resonance imaging for evaluating the vascularity of osseous spinal tumors.

BACKGROUND AND PURPOSE: Patients with hypervascular spinal tumors may have severe blood loss during tumor resection, which increases the risks of perioperative morbidity and mortality. However, the preoperative evaluation of tumor vascularity may be challenging; moreover, the reliability of the data obtained in conventional preoperative noninvasive imaging is debatable. In this study, we compared conventional magnetic resonance imaging (MRI) and subtraction computed tomography angiography (CTA) in terms of their performance in vascularity evaluation. The catheter digital subtraction angiography (DSA) technique was used as a reference standard. METHODS: This study included 123 consecutive patients with spinal tumor who underwent subtraction CTA, catheter DSA, and subsequent surgery between October 2015 and October 2021. Data regarding qualitative and semiquantitative subtraction CTA parameters and conventional MRI signs were collected for comparison with tumor vascularity graded through catheter DSA. The diagnostic performance of qualitative CTA, quantitative CTA, and conventional MRI in assessing spinal tumor vascularity was analyzed. RESULTS: Qualitative subtraction CTA was the best noninvasive imaging modality in terms of diagnostic performance (area under the receiver operating characteristic curve [AUROC], 0.95). Quantitative CTA was relatively inferior (AUROC, 0.87). MRI results had low reliability (AUROC, 0.51 to 0.59). Intratumoral hemorrhage and prominent foraminal venous plexus were found to be the specific signs for hypervascularity (specificity 93.2%). CONCLUSIONS: Qualitative subtraction CTA offers the highest diagnostic value in evaluating spinal tumor vascularity, compared to quantitative CTA and MRI. Although conventional MRI may not be a reliable approach, certain MRI signs may have high specificity, which may be crucial for assessing spinal tumor vascularity.

Enhanced Co-adsorption of Alcohols and Amines for Visible Light Driven Oxidative Condensation Using Iron-based MOF.

Imines are essential intermediates in organic transformations, and is generally produced by dehydrogenative condensation of alcohols and amines with the assist of specialized catalysts and additives. Heterogeneous photocatalysis provides a sustainable platform for such process without the using of toxic oxidants, yet a functionalized photocatalyst with optimized co-adsorption of reactants needs to be developed to promote the stoichiometric oxidative condensation under ambient conditions. Here, we show that benzyl alcohol and aniline adsorb non-interferingly on the Fe node and the linker sites of the MIL-53(Fe) metal organic frameworks (MOFs), respectively. The co-adsorption of both reactants barely influences the reduction of molecular oxygen to generate oxygen radicals, resulting in efficient formation of benzaldehyde under visible light. Additionally, the weak adsorption of water together with surface acidity of the MIL-53(Fe) promote a rapid condensation of benzaldehyde with aniline and the depletion of generated water, achieving an efficient C-N bond creation for a wide range of substrates.

Characterization of therapeutic antibody charge heterogeneity under stress conditions by microfluidic capillary electrophoresis coupled with mass spectrometry.

Therapeutic antibodies are a major class of biopharmaceutics that are applied in disease treatment because of their many advantages, including high specificity and high affinity to molecular targets. Between their production and administration, therapeutic antibodies are exposed to multiple stress conditions. Forced degradation and stress stability studies are conducted to simulate the risk of degradation and the effects of these stresses, thereby enhancing understanding of the drug product to support strategies to mitigate the impact from stressed conditions. These types of studies are also routinely conducted to evaluate product comparability when major process changes are implemented during the production. Charge variant analysis helps understand the changes in the electrostatic environment of biotherapeutics and can uncover underlying molecular level alterations associated with charge variants. Herein, we used ZipChip native capillary electrophoresis-mass spectrometry (nCE-MS) to elucidate the changes in charge variant profiles at the molecular level. In two case studies under thermal stress conditions, we observed that charge variants arose from both post-translational modifications (including deamidation, oxidation, and pyroglutamate formation) and sequence truncations at the hinge regions. Under oxidative stress conditions, oxidation was found to be the major contributor to the changes in the charge variant profiles. Under pH stress conditions, the changes in the charge variant profile were due to increased deamidation, oxidation, and pyroglutamate formation. ZipChip nCE-MS analysis enables identification of charge variant species under various stress conditions, thus supporting process and formulation development of biotherapeutics.

Hippocampal proteome comparison of infant and adult Fmr1 deficiency mice reveals adult-related changes associated with postsynaptic density.

Deficiency in fragile X mental retardation 1 (Fmr1) leads to loss of its encoded protein FMRP and causes fragile X syndrome (FXS) by dysregulating its target gene expression in an age-related fashion. Using comparative proteomic analysis, this study identified 105 differentially expressed proteins (DEPs) in the hippocampus of postnatal day 7 (P7) Fmr1-/y mice and 306 DEPs of P90 Fmr1-/y mice. We found that most DEPs in P90 hippocampus were not changed in P7 hippocampus upon FMRP absence, and some P90 DEPs exhibited diverse proteophenotypes with abnormal expression of protein isoform or allele variants. Bioinformatic analyses showed that the P7 DEPs were mainly enriched in fatty acid metabolism and oxidoreductase activity and nutrient responses; whereas the P90 PEPs (especially down-regulated DEPs) were primarily enriched in postsynaptic density (PSD), neuronal projection development and synaptic plasticity. Interestingly, 25 of 30 down-regulated PSD proteins present in the most enriched protein to protein interaction network, and 6 of them (ANK3, ATP2B2, DST, GRIN1, SHANK2 and SYNGAP1) are both FMRP targets and autism candidates. Therefore, this study suggests age-dependent alterations in hippocampal proteomes upon loss of FMRP that may be associated with the pathogenesis of FXS and its related disorders. SIGNIFICANCE: It is well known that loss of FMRP resulted from Fmr1 deficiency leads to fragile X syndrome (FXS), a common neurodevelopmental disorder accompanied by intellectual disability and autism spectrum disorder (ASD). FMRP exhibits distinctly spatiotemporal patterns in the hippocampus between early development and adulthood, which lead to distinct dysregulations of gene expression upon loss of FMRP at the two age stages potentially linked to age-related phenotypes. Therefore, comparison of hippocampal proteomes between infancy and adulthood is valuable to provide insights into the early causations and adult-dependent consequences for FXS and ASD. Using a comparative proteomic analysis, this study identified 105 and 306 differentially expressed proteins (DEPs) in the hippocampi of postnatal day 7 (P7) and P90 Fmr1-/y mice, respectively. Few overlapping DEPs were identified between P7 and P90 stages, and the P7 DEPs were mainly enriched in the regulation of fatty acid metabolism and oxidoreduction, whereas the P90 DEPs were preferentially enriched in the regulation of synaptic formation and plasticity. Particularly, the up-regulated P90 proteins are primarily involved in immune responses and neurodegeneration, and the down-regulated P90 proteins are associated with postsynaptic density, neuron projection and synaptic plasticity. Our findings suggest that distinctly changed proteins in FMRP-absence hippocampus between infancy and adulthood may contribute to age-dependent pathogenesis of FXS and ASD.

A machine learning-based diagnosis modeling of IgG4 Hashimoto's thyroiditis.

PURPOSE: This study aims to develop a non-invasive diagnosis model using machine learning (ML) for identifying high-risk IgG4 Hashimoto's thyroiditis (HT) patients. METHODS: A retrospective cohort of 93 HT patients and a prospective cohort of 179 HT patients were collected. According to the immunohistochemical and pathological results, the patients were divided into IgG4 HT group and non-IgG4 HT group. Serum TgAb IgG4 and TPOAb IgG4 were detected by ELISAs. A logistic regression model, support vector machine (SVM) and random forest (RF) were used to establish a clinical diagnosis model for IgG4 HT. RESULTS: Among these 272 patients, 40 (14.7%) were diagnosed with IgG4 HT. Patients with IgG4 HT were younger than those with non-IgG4 HT (P < 0.05). Serum levels of TgAb IgG4 and TPOAb IgG4 in IgG4 HT group were significantly higher than those in non-IgG4 HT group (P < 0.05). There were no significant differences in gender, disease duration, goiter, preoperative thyroid function status, preoperative TgAb or TPOAb levels, and thyroid ultrasound characteristics between the two groups (all P > 0.05). The accuracy, sensitivity, and specificity were 57%, 78%, and 79% for logistic regression model of IgG4 HT, 80 ± 7%, 84.7% ± 2.6%, and 75.4% ± 9.6% for the RF model and 78 ± 5%, 89.8% ± 5.7%, and 64.7% ± 5.7% for the SVM model. The RF model works better than SVM. The area under the ROC curve of RF ranged 0.87 to 0.92. CONCLUSION: A clinical diagnosis model for IgG4 HT established by RF model might help the early recognition of the high-risk patients of IgG4 HT.

Synthesis, DNA binding of bis-naphthyl ferrocene derivatives and the application as new electroactive indicators for DNA biosensor.

A series of bis-naphthyl ferrocene derivatives were synthesized and characterized. Based on the results obtained from UV-visible absorption titration and ethidium bromide (EB) displacement experiments, it was observed that the synthesized compounds exhibited a strong binding ability to dsDNA. In comparison to the viscosity curve of EB, the tested compounds demonstrated a bisintercalation binding mode when interacting with CT-DNA. Differential pulse voltammetry (DPV) was employed to assess the binding specificity of these indicators towards ssDNA and dsDNA. All tested indicators displayed more pronounced signal differences before and after hybridization between probe nucleic acids and target nucleic acids compared to Methylene Blue (MB). Among the evaluated compounds, compound 3j containing an ether chain showed superior performance as an indicator, making it suitable for constructing DNA-based biosensors. Under optimized conditions including probe ssDNA concentration and indicator concentration, this biosensor exhibited good sensitivity, reproducibility, stability, and selectivity. The limit of detection was calculated as 4.53 × 10-11 mol/L. Furthermore, when utilizing 3j as the indicator in serum samples, the biosensor achieved satisfactory recovery rates for detecting the BRCA1 gene.

MicroRNA-146a Signature in Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Psoriasis is a chronic, inflammatory, T-cell-mediated disease with a multifactorial pathogenesis. MicroRNA (miRNA) alteration in psoriasis has been identified within the last few years. In particular, miR-146a levels were altered. However, previous studies have equivocal or even contradictory findings. OBJECTIVE: The current study aimed to perform a systematic review and meta-analysis to evaluate the miRNA expression profile in different tissues in patients with psoriasis. Further, the correlation between miR-146a levels and psoriasis severity as well as the specific expression patterns of the miR-146a profile in patients with psoriasis after treatment were evaluated. METHODS: To retrieve studies investigating the correlation between miRNA and psoriasis, a comprehensive search of databases including PubMed, Cochrane Library, and Embase was performed from inception to 30 June 2023. Relevant journals and references of the included studies were also reviewed. A meta-analysis was conducted using the comprehensive meta-analysis version 3. RESULTS: The correlation between the miR-146a expression levels and psoriasis susceptibility in 14 studies was assessed. Results showed that the miR-146a expression level was upregulated in psoriasis samples [P = 0.001, standardized mean difference (SMD) = 1.489, 95% confidence interval (CI) = 0.618-2.360]. In a subgroup analysis based on sample type, the correlation between the peripheral blood mononuclear cell, blood, and tissue miR-146a expression level and psoriasis was significant (SMD = 1.293, 95% CI 0.310-2.276, P = 0.01; SMD = 2.526, 95% CI 1.710-3.342, P = 0.000; SMD = 3.153, 95% CI 1.432-4.874, P = 0.00, respectively). A positive correlation was observed between the miR-146a expression levels and Psoriasis Area and Severity Index (PASI) score. However, the result was not statistically significant (correlation coefficient = 0.29, 95% CI - 0.038 to 0.575, P = 0.081). Further, the miR-146a levels decreased after treatment (SMD = - 1.592, 95% CI - 2.067 to - 1.117, P = 0.000, I2 = 74.104). CONCLUSIONS: The miR-146a expression level is positively correlated with and can contribute to the pathobiology of psoriasis.

Transfer learning for anatomical structure segmentation in otorhinolaryngology microsurgery.

BACKGROUND: Reducing the annotation burden is an active and meaningful area of artificial intelligence (AI) research. METHODS: Multiple datasets for the segmentation of two landmarks were constructed based on 41 257 labelled images and 6 different microsurgical scenarios. These datasets were trained using the multi-stage transfer learning (TL) methodology. RESULTS: The multi-stage TL enhanced segmentation performance over baseline (mIOU 0.6892 vs. 0.8869). Besides, Convolutional Neural Networks (CNNs) achieved a robust performance (mIOU 0.8917 vs. 0.8603) even when the training dataset size was reduced from 90% (30 078 images) to 10% (3342 images). When directly applying the weight from one certain surgical scenario to recognise the same target in images of other scenarios without training, CNNs still obtained an optimal mIOU of 0.6190 ± 0.0789. CONCLUSIONS: Model performance can be improved with TL in datasets with reduced size and increased complexity. It is feasible for data-based domain adaptation among different microsurgical fields.

Mycoplasma genitalium infection and resistance-associated mutations to macrolides and fluoroquinolones among high-risk patients in Taiwan.

BACKGROUND: Mycoplasma genitalium is an emerging etiology of sexually transmitted infections (STIs) with increasing resistance to antimicrobials. Surveillance on the epidemiology of M. genitalium infection and antimicrobial resistance is warranted. METHODS: Between September 2021 and August 2023, people with HIV (PWH) and people without HIV (PWoH) at risk of STIs were screened for M. genitalium infection using a multiplex polymerase-chain-reaction assay of specimens collected from the rectum, urethra, oral cavity, and vagina. The prevalences of resistance-associated mutations (RAMs) of M. genitalium to fluoroquinolones, macrolides, and tetracycline were investigated. RESULTS: During the 2-year study period, 1021 participants were enrolled, including 531 PWH and 490 PWoH. Overall, 83 (8.1%) and 34 (7.6%) participants had M. genitalium infection at baseline and during follow-up, respectively, with the rectum being the most common site of detection (61.5%). With the first course of antimicrobial treatment, 27 of 63 (42.9%) participants with M. genitalium infection were cured during follow-up, including 24 of 58 (41.4%) who received doxycycline monotherapy. The prevalence of RAMs to macrolides, fluoroquinolones, and tetracyclines at baseline were 24.3%, 22.4%, and 7.9%, respectively. Though PWH had more M. genitalium infection (10.2% vs 5.9%, p = 0.01), a higher rate of RAMs to macrolides (41.0% vs 14.7%, p < 0.01) was found in PWoH. CONCLUSIONS: Among high-risk populations, the prevalence of M. genitalium infection was 8.1%. The overall genotypic resistance of M. genitalium to macrolides and fluoroquinolones was moderately high in Taiwan. Detection of M. genitalium infection and antimicrobial resistance is warranted to ensure resistance-guided antimicrobial treatments to be administered.

Identification and analysis of differently expressed transcription factors in aristolochic acid nephropathy.

BACKGROUND: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy caused by Aristolochic acid (AA). AAN is associated with the development of nephropathy and urothelial carcinoma. It is estimated that more than 100 million people worldwide are at risk of developing AAN. However, the underlying mechanisms driving renal deterioration in AAN remain poorly understood, and the treatment options are limited. METHODS: We obtained GSE27168 and GSE136276 series matrix data from the Gene Expression Omnibus (GEO) related to AAN. Using the R Studio environment, we applied the limma package and WGCNA package to identify co-differently expressed genes (co-DEGs). By GO/KEGG/GSVA analysis, we revealed common biological pathways. Subsequently, co-DEGs were subjected to the String database to construct a protein-protein interaction (PPI) network. The MCC algorithms implemented in the Cytohubba plugin were employed to identify hub genes. The hub genes were cross-referenced with the transcription factor (TF) database to identify hub TFs. Immune infiltration analysis was performed to identify key immune cell groups by utilizing CIBERSORT. The expressions of AAN-associated hub TFs were verified in vivo and in vitro. Finally, siRNA intervention was performed on the two TFs to verify their regulatory effect in AAN. RESULTS: Our analysis identified 88 co-DEGs through the "limma" and "WGCNA" R packages. A PPI network comprising 53 nodes and 34 edges was constructed with a confidence level >0.4. ATF3 and c-JUN were identified as hub TFs potentially linked to AAN. Additionally, expressions of ATF3 and c-JUN positively correlated with monocytes, basophils, and vessels, and negatively correlated with eosinophils and endothelial cells. We observed a significant increase in protein and mRNA levels of these two hub TFs. Furthermore, it was found that siRNA intervention targeting ATF3, but not c-JUN, alleviated cell damage induced by AA. The knockdown of ATF3 protects against oxidative stress and inflammation in the AAN cell model. CONCLUSION: This study provides novel insights into the role of ATF3 in AAN. The comprehensive analysis sheds light on the molecular mechanisms and identifies potential biomarkers and drug targets for AAN treatment.

Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

Robust, Reproducible, and Scalable Synthesis of Silver Nanocubes.

It remains a challenge to accomplish colloidal synthesis of noble-metal nanocrystals marked by high quality, large quantity, and batch-to-batch consistency. Here we report a self-airtight setup for achieving robust, reproducible, and scalable production of Ag nanocubes with uniform and controlled sizes from 18-60 nm. Different from the conventional open-to-air setup, the self-airtight system makes it practical to stabilize the reaction condition by minimizing the loss of volatile reagents. The new setup also allows us to easily optimize the amount of O2 (from air) trapped in the system, ensuring burst nucleation of single-crystal seeds, followed by their slow growth into nanocubes. Most significantly, the new setup allows for the production of Ag nanocubes at gram quantities without sacrificing uniformity, corner/edge sharpness, controlled size, and high purity across different batches. The availability of high-quality Ag nanocubes in such a large quantity is anticipated to substantially boost their use in applications related to plasmonics, catalysis, and biomedicine.

Signal-averaged electrocardiography as a noninvasive tool for evaluating the ventricular substrate in patients with nonischemic cardiomyopathy: reassessment of an old tool.

Introduction: Signal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM. Methods and results: This retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 (p = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence. Conclusion: In our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract.