Fabrication of controlled porous and ultrafast dissolution porous microneedles by organic-solvent-free ice templating method.

Porous Microneedles (PMNs) have been widely used in drug delivery and medical diagnosis owing to their abundant interconnected pores. However, the mechanical strength, the use of organic solvent, and drug loading capacity have long been challenging. Herein, a novel strategy of PMNs fabrication based on the Ice Templating Method is proposed that is suitable for insoluble, soluble, and nanosystem drug loading. The preparation process simplifies the traditional microneedle preparation process with a shorter preparation time. It endows the highly tunable porous morphology, enhanced mechanical strength, and rapid dissolution performance. Micro-CT three-dimensional reconstruction was used to better quantify the internal structures of PMNs, and we further established the equivalent pore network model to statistically analyze the internal pore structure parameters of PMNs. In particular, the mechanical strength is mainly negatively correlated with the surface porosity, while the dissolution velocity is mainly positively correlated with the permeability coefficient by the correlation heatmap. The poorly water-soluble Asiatic acid was encapsulated in PMNs in nanostructured lipid carriers, showing prominent hypertrophic scar healing trends. This work offers a quick and easy way of preparation that may be used to expand PMNs function and be introduced in industrial manufacturing development.

Genetic evidence strengthens the bidirectional connection between gut microbiota and Shigella infection: insights from a two-sample Mendelian randomization study.

Background: In recent investigations, substantial strides have been made in the precise modulation of the gut microbiota to prevent and treat a myriad of diseases. Simultaneously, the pressing issue of widespread antibiotic resistance and multidrug resistance resulting from Shigella infections demands urgent attention. Several studies suggest that the antagonistic influence of the gut microbiota could serve as a novel avenue for impeding the colonization of pathogenic microorganisms or treating Shigella infections. However, conventional research methodologies encounter inherent challenges in identifying antagonistic microbial agents against Shigella, necessitating a comprehensive and in-depth analysis of the causal relationship between Shigella infections and the gut microbiota. Materials and methods: Utilizing the aggregated summary statistics from Genome-Wide Association Studies (GWAS), we conducted Mendelian Randomization (MR) analyses encompassing 18,340 participants to explore the interplay between the gut microbiota and Shigella infections. This investigation also involved 83 cases of Shigella infection patients and 336,396 control subjects. In the positive strand of our findings, we initially performed a preliminary analysis using the Inverse Variance Weighting (IVW) method. Subsequently, we undertook sensitivity analyses to assess the robustness of the results, addressing confounding factors' influence. This involved employing the Leave-One-Out method and scrutinizing funnel plots to ensure the reliability of the MR analysis outcomes. Conclusively, a reverse MR analysis was carried out, employing the Wald ratio method due to the exposure of individual Single Nucleotide Polymorphisms (SNPs). This was undertaken to explore the plausible associations between Shigella infections and genetically predicted compositions of the gut microbiota. Results: In this study, we employed 2,818 SNPs associated with 211 species of gut microbiota as instrumental variables (IVs). Through IVW analysis, our positive MR findings revealed a significant negative correlation between the occurrence of Shigella infections and the phylum Tenericutes (OR: 0.18, 95% CI: 0.04-0.74, p = 0.02), class Mollicutes (OR: 0.18, 95% CI: 0.04-0.74, p = 0.02), genus Intestinimonas (OR: 0.16, 95% CI: 0.04-0.63, p = 0.01), genus Gordonibacter (OR: 0.39, 95% CI: 0.16-0.93, p = 0.03), and genus Butyrivibrio (OR: 0.44, 95% CI: 0.23-0.87, p = 0.02). Conversely, a positive correlation was observed between the occurrence of Shigella infections and genus Sutterella (OR: 10.16, 95% CI: 1.87-55.13, p = 0.01) and genus Alistipes (OR: 12.24, 95% CI: 1.71-87.34, p = 0.01). In sensitivity analyses, utilizing MR-Egger regression analysis and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) detection, all outcomes demonstrated robust stability. Simultaneously, in the reverse MR analysis, Shigella infections resulted in an upregulation of four bacterial genera and a downregulation of three bacterial genera. Conclusion: In summation, the MR analysis outcomes corroborate the presence of bidirectional causal relationships between the gut microbiota and Shigella infections. This study not only unveils novel perspectives for the prevention and treatment of Shigella infections but also furnishes fresh insights into the mechanistic underpinnings of how the gut microbiota contributes to the pathogenesis of Shigella infections. Consequently, the established dual causal association holds promise for advancing our understanding and addressing the complexities inherent in the interplay between the gut microbiota and Shigella infections, thereby paving the way for innovative therapeutic interventions and preventive strategies in the realm of Shigella-related diseases.

Three cancers in the renal pelvis, bladder, and colon: A case report.

BACKGROUND: Multiple primary cancers are rare occurrences that can involve either metachronous or synchronous development. It is particularly rare for an individual to have more than two primary cancers. In this report, we present a case study of an elderly man who was diagnosed with three heterochronous cancers in the renal pelvis, bladder, and colon. CASE SUMMARY: On December 30, 2014, a 51-year-old Chinese man was admitted to our hospital with complaints of intermittent painless gross hematuria for the preceding week. A computed tomography (CT) scan revealed wall thickening in the left ureter's upper segment, while a CT urography revealed a left renal pelvis tumor. A successful laparoscopic radical resection of the left renal pelvis tumor was subsequently performed at Shanghai Zhongshan Hospital in January 2015. The pathological findings after the surgery revealed a low-grade papillary urothelial carcinoma of the renal pelvis. The final pathological tumor stage was pT1N0M0. After surgery, this patient received 6 cycles of intravenous chemotherapy with gemcitabine and carboplatin, as well as bladder infusion therapy with gemcitabine. On December 18, 2017, the patient was admitted once again to our hospital with a one-day history of painless gross hematuria. A CT scan showed the presence of a space-occupying lesion on the posterior wall of bladder. Cystoscopic examination revealed multiple tumors in the bladder and right cutaneous ureterostomy was performed under general anesthesia on December 29, 2017. The postoperative pathological findings disclosed multifocal papillary urothelial carcinoma of the bladder (maximum size 3.7 cm × 2.6 cm). The bladder cancer was considered a metastasis of the renal pelvis cancer after surgery. The pathological tumor stage was pT1N0M1. The patient refused chemotherapy after surgery. After another six years, the patient returned on February 28, 2023, complaining of periumbilical pain that had lasted six days. This time, a CT scan of the abdomen showed a tumor in the ascending colon, but a subsequent colonoscopy examination indicated a tumor in the descending colon. On March 12, 2023, a subtotal colectomy and an ileosigmoidal anastomosis were carried out under general anesthesia. Postoperative pathological findings revealed that all three tumors were adenocarcinomas. The final pathological tumor stage was pT3N0M0. The patient had an uneventful postoperative recovery and was discharged without complications. CONCLUSION: The case of this elderly man presents a rare occurrence of metachronous primary cancers in the renal pelvis and colon. Bladder cancer is considered a metastasis of renal pelvis cancer after surgery. Optimal treatment can be implemented by evaluating the patient's histological features, clinical history, and tumor distribution correctly.

Deep learning assessment of left ventricular hypertrophy based on electrocardiogram.

Background: Current electrocardiogram (ECG) criteria of left ventricular hypertrophy (LVH) have low sensitivity. Deep learning (DL) techniques have been widely used to detect cardiac diseases due to its ability of automatic feature extraction of ECG. However, DL was rarely applied in LVH diagnosis. Our study aimed to construct a DL model for rapid and effective detection of LVH using 12-lead ECG. Methods: We built a DL model based on convolutional neural network-long short-term memory (CNN-LSTM) to detect LVH using 12-lead ECG. The echocardiogram and ECG of 1,863 patients obtained within 1 week after hospital admission were analyzed. Patients were evenly allocated into 3 sets at 3:1:1 ratio: the training set (n = 1,120), the validation set (n = 371) and the test set 1 (n = 372). In addition, we recruited 453 hospitalized patients into the internal test set 2. Different DL model of each subgroup was developed according to gender and relative wall thickness (RWT). Results: The LVH was predicted by the CNN-LSTM model with an area under the curve (AUC) of 0.62 (sensitivity 68%, specificity 57%) in the test set 1, which outperformed Cornell voltage criteria (AUC: 0.57, sensitivity 48%, specificity 72%) and Sokolow-Lyon voltage (AUC: 0.51, sensitivity 14%, specificity 96%). In the internal test set 2, the CNN-LSTM model had a stable performance in predicting LVH with an AUC of 0.59 (sensitivity 65%, specificity 57%). In the subgroup analysis, the CNN-LSTM model predicted LVH by 12-lead ECG with an AUC of 0.66 (sensitivity 72%, specificity 60%) for male patients, which performed better than that for female patients (AUC: 0.59, sensitivity 50%, specificity 71%). Conclusion: Our study established a CNN-LSTM model to diagnose LVH by 12-lead ECG with higher sensitivity than current ECG diagnostic criteria. This CNN-LSTM model may be a simple and effective screening tool of LVH.

A new panel of pancreatic cancer biomarkers discovered using a mass spectrometry-based pipeline.

This corrects the article DOI: 10.1038/bjc.2017.85.

A new panel of pancreatic cancer biomarkers discovered using a mass spectrometry-based pipeline.

BACKGROUND: Pancreatic carcinoma (PC) is an aggressive malignancy that lacks strategies for early detection. This study aimed to develop a coherent, high-throughput and non-discriminatory pipeline for the novel clinical biomarker discovery of PC. METHODS: We combined mass spectrometry (MS)-intensive methods such as isobaric tags for relative and absolute quantitation with two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS), 1D-targeted LC-MS/MS, prime MRM (P-MRM) and stable isotope dilution-based MRM (SID-MRM) to analyse serum samples from healthy people (normal control, NC), patients with benign diseases (BD) and PC patients to identify novel biomarkers of PC. RESULTS: On the basis of the newly developed pipeline, we identified >1000 proteins, verified 142 differentially expressed proteins and finally targeted four proteins for absolute quantitation in 100 serum samples. The novel biomarker panel of apolipoprotein E (APOE), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), apolipoprotein A-I (APOA1), apolipoprotein L1 (APOL1), combining with CA19-9, statistically-significantly improved the sensitivity (95%) and specificity (94.1%), outperforming CA19-9 alone, for the diagnosis of PC. CONCLUSIONS: We developed a highly efficient pipeline for biomarker discovery, verification and validation, with each step systematically informing the next. A panel of proteins that might be clinically relevant biomarkers for PC was found.

The efficacy of TACE combined sorafenib in advanced stages hepatocellullar carcinoma.

BACKGROUND: The long-term survival in hepatocellullar carcinoma (HCC) patients after transarterial chemoembolization (TACE) remains dismal due to local and/or regional recurrence as well as distant metastasis. The efficacy of sorafenib in advanced HCC has been demonstrated and brought great hope. Recently, the use of sorafenib in combination with TACE for BCLC stage B and C HCC patients was recommended. However, data on this dual-modality treatment is little, and its advantage over TACE alone has not been addressed. The present study sought to understand the efficacy of the combination of TACE and sorafenib in the treatment of advanced HCC. METHODS: Between June 2008 and Feb 2011, 45 patients with advanced HCC were enrolled and treated with sorafenib in combination with TACE according to an institutional protocol of the Zhongshan hospital, Fudan University. The control group of 45 other HCC patients with similar characteristics treated with TACE alone in the same period of time in our institute were selected for retrospective comparison of the treatment outcomes especially overall survival time. Adverse reactions induced by sorafenib were observed and recorded. RESULTS: The median overall survival time of the combined treatment group was 27 (95% Confidence Interval: 21.9-32.1) months, and that of TACE alone group was 17 months (95% Confidence Interval: 8.9-25.0) months (P = 0.001). Patients required significantly less frequent TACE for their symptomatic treatment after the initiation of sorafenib therapy. The most common adverse events associated with sorafenib were hand-foot skin reaction, rash and diarrhea. Of CTCAE grade IV or V toxicity was observed. CONCLUSION: TACE combined sorafenib significantly prolonged median overall survival time of patients with advanced HCC.