Surgical treatment of graft infection combined with aortoesophageal fistula after TEVAR: a retrospective single-center, single-arm study.

OBJECTIVE: Aortoesophageal fistula (AEF) secondary to thoracic aortic endovascular repair (TEVAR) is rare and fatal. The author reports the treatment methods and outcomes of 10 patients with a TEVAR graft infection and an aortoesophageal fistula. METHOD: A retrospective analysis was conducted on the clinical data of 10 patients who developed a secondary AEF and a graft infection after TEVAR from March 2018 to March 2024. RESULT: The perioperative mortality rate was 70%. Two patients had TEVAR only and all died of bleeding and infection. Eight patients underwent open surgery, five died within 30 days, four of them died due to massive bleeding, the one patient died of a serious infection after surgery. Three patients recovered well and were discharged. One patient died of severe pneumonia 3 months after discharge, and two patients survived for 6 years and 3 months, respectively. CONCLUSION: Extra-anatomical bypass reconstruction is feasible for treating graft infection combined with aortoesophageal fistula after TEVAR but related to bad outcomes in most of the patients. It is reserved for highly select patients and is performed at centers with experience with this procedure.

Abernethy Malformation and Gastrointestinal Bleeding: A Case Report and Literature Review.

Background: Congenital extrahepatic portosystemic shunt (CEPS), also termed Abernethy malformation (AF) is a rare anomaly of the splanchnic venous system. Several approaches, including shunt closures through surgical or radiological interventions and liver transplantations, have been proposed, but clear comparisons among different treatment strategies are still unavailable. Purpose: We report a case in which an unusual portosystemic shunt was present between the dilated inferior mesenteric vein (IMV) to the right ovarian vein. A mini literature review of AF patients presented with gastrointestinal (GI) tract bleeding. Research design: Case report and literature review. Data Collection: An electronic search of PubMed was performed from inception to December 2023. Results: 34 AF patients presented with GI tract bleeding were identified published in the literature. The proportion of type II AF patients presenting with GI bleeding is greater (79%). Conclusions: We regard that both surgical ligation and endovascular closure of the shunt are effective and safe treatments for these patients, but coils embolization alone may not be sufficient to completely close the shunt when the shunt flow is high.

The genetic link between thyroid dysfunction and alopecia areata: a bidirectional two-sample Mendelian randomization study.

Background: Although descriptive studies have found an association between thyroid dysfunction (TD) and alopecia areata (AA), however, the causal relationship between TD and AA remains unclear. The purpose of this study is to investigate the causal relationship between the two and the specific directions. Methods: We performed large-scale, two-sample Mendelian randomization (MR) analyses to examine whether there was an association between TD (such as Graves' disease (GD), Hashimoto's thyroiditis (HT), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), etc.) and AA. Genome-wide association study (GWAS) summary statistics for TD and AA were from the IEU OpenGwas project. The inverse variance-weighted (IVW) method was used as the primary analysis method to evaluate the causality between TD and AA, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. In addition, sensitivity analyses were performed to assess the reliability of the study results. Results: Our study found that single nucleotide polymorphisms (SNPs) in HT (IVW OR = 1.396, 95% CI 1.030-1.892, P=0.031) and hypothyroidism (IVW OR = 1.431, 95% CI 1.138-1.799, P=0.002) significantly increased the risk of AA. Reverse MR analysis indicated that genetic susceptibility to AA (ß=-0.029, 95%CI=-0.051 to -0.007, P=0.009) may be a risk for TRH. Positive MR analysis observed no statistically significant causal relationship between other TD and AA (IVW P>0.05). Reverse MR analysis also showed no statistically significant association between AA and other TD (IVW P>0.05) other than TRH. Furthermore, additional sensitivity analyses were performed, including a leave-one-out test, a heterogeneity test, and a pleiotropy test to assess the robustness of the results. Conclusions: This study provides a very comprehensive analysis of the causal relationship between TD and AA, providing convincing genetic evidence to support the causal relationship between TD and alopecia areata. It reveals some causes of AA patients, which is of great significance for the management and treatment of AA patients.

Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Mycobacterium Infection of Abscess with Hemoptysis as the Initial Manifestation.

BACKGROUND: Mycobacterium abscessus is a new pathogen in recent years, which belongs to non-tuberculosis mycobacterium. Mycobacterium abscessus is widely involved in many nosocomial infections and secondary aggravation of genetic respiratory diseases. Mycobacterium abscessus is naturally resistant to most antibiotics and is difficult to treat. We report a case of mycobacterium abscessus infection with hemoptysis as the first manifestation. METHODS: Bronchoscopy, next-generation sequencing (NGS). RESULTS: Acid-fast staining of bronchoscopic lavage fluid showed that a small amount of acid-fast bacilli could be seen. NGS test showed the presence of Mycobacterium abscess, sequence number 137 (reference range ≥ 0), and symptomatic treatment against non-tuberculosis mycobacteria. CONCLUSIONS: For the follow-up infection of patients with hemoptysis, the treatment effect of antibiotics is not good, so the pathological tissue should be obtained by bronchoscopy or percutaneous lung biopsy in time, and the diagnosis should be confirmed by NGS if necessary.

Circulating white blood cell traits and prolonged night shifts: a cross-sectional study based on nurses in Guangxi.

This study aimed to elucidate the effects of long day and night shifts on immune cells in a population of nurses. This cross-sectional study in December 2019 was based on a group of nurses. 1568 physically healthy caregivers were included, including 1540 women and 28 men. 1093 nurses had long-term shift work (working in a rotating system for > 1 year). The receiver operating characteristic curve, Ensemble Learning, and Logistic regression analyses were used to evaluate factors related to long-term shift work. The night shift group nurses had significantly higher MPV, PLCR, and WBC and significantly lower BASO%, ELR, MCHC, PLR, RDW-CV, and RDW-SD (P < 0.01). ROC curves showed that WBC, PLR, ELR, RDW_CV, and BASO% were more related to the night shift. Ensemble Learning, combined with the LASSO model, finally filtered out three indicators of night shifts related to ELR, WBC, and RDW_SD. Finally, logistic regression analysis showed that the nurses' night shift situation greatly influenced two peripheral blood ELR and WBC indicators (ELR: log (OR) = - 3.9, 95% CI: - 5.8- - 2.0; WBC: log (OR) = 0.25, 95% CI: 0.18-0.32). Finally, we showed that, unlike WBC, the relative riskiness of ELR showed opposite results among junior nurses and middle-senior nurses (log (OR) 6.5 (95% CI: 1.2, 13) and - 7.1 (95% CI: - 10, - 3.8), respectively). Our study found that prolonged night shifts were associated with abnormal WBC and ELR, but after strict age matching, WBC remained significantly different. These findings help to confirm that COVID-19 and tumorigenesis (e.g., breast cancer) are significantly associated with circadian rhythm disruption. However, more detailed studies are needed to confirm this.

Knowledge-guided learning methods for integrative analysis of multi-omics data.

Integrative analysis of multi-omics data has the potential to yield valuable and comprehensive insights into the molecular mechanisms underlying complex diseases such as cancer and Alzheimer's disease. However, a number of analytical challenges complicate multi-omics data integration. For instance, -omics data are usually high-dimensional, and sample sizes in multi-omics studies tend to be modest. Furthermore, when genes in an important pathway have relatively weak signal, it can be difficult to detect them individually. There is a growing body of literature on knowledge-guided learning methods that can address these challenges by incorporating biological knowledge such as functional genomics and functional proteomics into multi-omics data analysis. These methods have been shown to outperform their counterparts that do not utilize biological knowledge in tasks including prediction, feature selection, clustering, and dimension reduction. In this review, we survey recently developed methods and applications of knowledge-guided multi-omics data integration methods and discuss future research directions.

The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas.

ABSTRACT: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Treatment outcomes in patients with acute thromboembolic occlusion of the superior mesenteric artery.

OBJECTIVES: The goals of this study were to investigate the treatment outcomes of acute thromboembolic occlusion of the superior mesenteric artery (ATOS) and identify prognostic factors after treatment. METHODS: The clinical data of 62 patients with ATOS between 2013 and 2021 were retrospectively reviewed. Patients were stratified by the treatment strategy, complications and mortality were compared in different group. RESULTS: Sixty-two consecutive patients were identified with ATOS. The median patient age was 69 years (interquartile range 58-79 years). Endovascular therapy was initiated in 21 patients, and 4 patients received conservative treatment. Open surgery was performed first in the remaining 37 patients. The technical success rates of the endovascular first group and open surgery group were 90.5% and 97.3%, respectively. One patient in the conservative treatment group had progression of ischemia to extensive bowel necrosis. There was no difference in 30-day mortality between these groups. Predictors of 30-day mortality included initial neutrophil count > 12* 103/dL, age over 60 years old and history of chronic renal insufficiency. CONCLUSIONS: Endovascular treatment or conservative treatment may be adopted in selected patients who do not exhibit signs and symptoms of bowel necrosis, and close monitoring for bowel necrosis is important. The increase in preoperative neutrophil count, age over 60 years old and history of chronic renal insufficiency were poor prognostic factors.

Bacillus subtilis SOM8 isolated from sesame oil meal for potential probiotic application in inhibiting human enteropathogens.

BACKGROUND: While particular strains within the Bacillus species, such as Bacillus subtilis, have been commercially utilised as probiotics, it is critical to implement screening assays and evaluate the safety to identify potential Bacillus probiotic strains before clinical trials. This is because some Bacillus species, including B. cereus and B. anthracis, can produce toxins that are harmful to humans. RESULTS: In this study, we implemented a funnel-shaped approach to isolate and evaluate prospective probiotics from homogenised food waste - sesame oil meal (SOM). Of nine isolated strains with antipathogenic properties, B. subtilis SOM8 displayed the most promising activities against five listed human enteropathogens and was selected for further comprehensive assessment. B. subtilis SOM8 exhibited good tolerance when exposed to adverse stressors including acidity, bile salts, simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and heat treatment. Additionally, B. subtilis SOM8 possesses host-associated benefits such as antioxidant and bile salt hydrolase (BSH) activity. Furthermore, B. subtilis SOM8 contains only haemolysin toxin genes but has been proved to display partial haemolysis in the test and low cytotoxicity in Caco-2 cell models for in vitro evaluation. Moreover, B. subtilis SOM8 intrinsically resists only streptomycin and lacks plasmids or other mobile genetic elements. Bioinformatic analyses also predicted B. subtilis SOM8 encodes various bioactives compound like fengycin and lichendicin that could enable further biomedical applications. CONCLUSIONS: Our comprehensive evaluation revealed the substantial potential of B. subtilis SOM8 as a probiotic for targeting human enteropathogens, attributable to its exceptional performance across selection assays. Furthermore, our safety assessment, encompassing both phenotypic and genotypic analyses, showed B. subtilis SOM8 has a favourable preclinical safety profile, without significant threats to human health. Collectively, these findings highlight the promising prospects of B. subtilis SOM8 as a potent probiotic candidate for additional clinical development.

The Below-the-Knee Approach to Percutaneous Mechanical Thrombectomy for Lower Extremity Deep Venous Thrombosis: A Retrospective Single-Centre, Single-Arm Study.

PURPOSE: The objective of this study was to evaluate the safety, efficacy, and feasibility of percutaneous mechanical thrombectomy (PMT) through a below-the-knee (BTK) approach for acute lower extremity deep venous thrombosis (DVT). METHODS: A retrospective review of DVT patients treated with PMT by the BTK approach at our center from April 2022 to August 2023 was performed. Their preoperative demographics, intraoperative data, and postoperative outpatient outcomes were analyzed. RESULTS: A total of 12 patients (67% men; mean age, 63 years) met the inclusion criteria. The BTK approach was successfully achieved in all patients through the posterior tibial vein (n = 1), anterior tibial vein (n = 2), and peroneal vein (n = 9). PMTs were achieved in 11 (92%) patients. Successful lysis (grade II and grade III lysis) was achieved in all patients with PMT. Four (33%) patients had residual venous occlusion over the popliteal vein. No intraoperative complications or bleeding events occurred in any of the patients. CONCLUSION: PMT via BTK puncture seems to be a safe and effective approach for treating lower extremity DVT. It is reserved for highly select patients with a low risk of bleeding and is performed at centers that have experience with this procedure.

Enzyme-Assisted Endogenous Guide DNA Generation-Mediated Pyrococcus furiosus Argonaute for Alicyclobacillus acidoterrestris Detection.

Pyrococcus furiosusArgonaute (PfAgo) emerged as a novel endonuclease for the nucleic acid test recently. However, the input of exogenous guide DNA (gDNA) to activate PfAgo has reduced its flexibility. In this work, an enzyme-assisted endogenous gDNA generation-mediated PfAgo for the target detection strategy, termed EGG-PAD, was proposed. With the aid of EcoR Ι, the target double-strand DNA was cut, producing a phosphate group at the 5' end, functioning as gDNA to activate PfAgo for nucleic acid detection. The applicability of this assay was tested in the detection ofAlicyclobacillus acidoterrestris, a bacterium causing the spoilage of fruit juice, showing excellent sensitivity and specificity, ascribed to the "duplex amplification and triple insurance" mechanism. Moreover, EGG-PAD exhibited superior versatility in the identification of common foodborne pathogens. This powerful platform could also be an on-site test tool for detecting nucleic acid-containing organisms such as tumor cell, pathogen, and virus in the future.

Microbial gene expression analysis of healthy and cancerous esophagus uncovers bacterial biomarkers of clinical outcomes.

Local microbiome shifts are implicated in the development and progression of gastrointestinal cancers, and in particular, esophageal carcinoma (ESCA), which is among the most aggressive malignancies. Short-read RNA sequencing (RNAseq) is currently the leading technology to study gene expression changes in cancer. However, using RNAseq to study microbial gene expression is challenging. Here, we establish a new tool to efficiently detect viral and bacterial expression in human tissues through RNAseq. This approach employs a neural network to predict reads of likely microbial origin, which are targeted for assembly into longer contigs, improving identification of microbial species and genes. This approach is applied to perform a systematic comparison of bacterial expression in ESCA and healthy esophagi. We uncover bacterial genera that are over or underabundant in ESCA vs healthy esophagi both before and after correction for possible covariates, including patient metadata. However, we find that bacterial taxonomies are not significantly associated with clinical outcomes. Strikingly, in contrast, dozens of microbial proteins were significantly associated with poor patient outcomes and in particular, proteins that perform mitochondrial functions and iron-sulfur coordination. We further demonstrate associations between these microbial proteins and dysregulated host pathways in ESCA patients. Overall, these results suggest possible influences of bacteria on the development of ESCA and uncover new prognostic biomarkers based on microbial genes. In addition, this study provides a framework for the analysis of other human malignancies whose development may be driven by pathogens.

Diverse prenylated C6-C3 derivatives from the stems and branches of Illicium ternstroemioides A. C. Smith with anti-inflammatory and antiviral activities.

Fifteen unreported prenylated C6-C3 derivatives (1-15) were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith, including one bis-prenylated C6-C3 derivative (1), three prenylated C6-C3 derivative-shikimic acid ester hybrids (2-4) and 11 prenylated C6-C3 monomers (5-15). The structures of compounds 1-15 were elucidated by spectroscopic analysis (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of the compounds were determined using electronic circular dichroism (ECD), induced circular dichroism (ICD), and the modified Mosher's method. Among the isolates, compounds 11, 12, and 15 exhibited significant anti-inflammatory activities by inhibiting the nitric oxide with IC50 values ranging from 1.89 to 24.83 µM in lipopolysaccharide-stimulated murine RAW 264.7 macrophages and murine BV2 microglial cells; compounds 2, 3, and 7 exhibited antiviral activitives against Coxsackievirus B3 with an IC50 value of 33.3, 25.9, and 27.8 µM, respectively.

Influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene in acute unprovoked deep vein thrombosis and residual vein thrombosis.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of plasminogen activator, but the role of the PAI-1 4G/5G polymorphism in deep vein thrombosis (DVT) has been contradictory. In this study, we investigated the distribution of the PAI-1 4G/5G genotype in Chinese patients with DVT compared with healthy controls and the association between the PAI-1 4G/5G genotype and the persistence of residual venous occlusion (RVO) after different treatments. METHODS: The PAI-1 4G/5G genotype was determined by fluorescence in situ hybridization in 108 patients with unprovoked DVT and 108 healthy controls. The patients with DVT were treated with catheter-based therapy or anticoagulation only. RVO was assessed by duplex sonography during the follow-up. RESULTS: Thirty-two patients (29.6%) were homozygous for 4G (4G/4G), 62 patients (57.4%) were heterozygous for 4G/5G, and 14 patients (13%) were homozygous for 5G (5G/5G). No significant difference in genotype frequency was found between patients with DVT and controls. A total of 86 patients completed follow-up of ultrasound examination with a mean follow-up of 13.4 ±7.2 months. The results of patients with RVO were significantly different between homozygous 4G carriers (76.9%), heterozygous 4G/5G (58.3%), and homozygous carriers of 5G (33.3%) (P <.05) at the end of follow-up. Catheter-based therapy showed a better result in patients who were noncarriers of 4G (P = .045). CONCLUSIONS: The PAI-1 4G/5G genotype was not a relevant predictor for DVT in Chinese patients, but is a risk factor for persistent RVO after idiopathic DVT.

Molecular identification and physiological functional analysis of NtNRT1.1B that mediated nitrate long-distance transport and improved plant growth when overexpressed in tobacco.

Although recent physiological studies demonstrate that flue-cured tobacco preferentially utilizes nitrate ( NO 3 - ) or ammonium nitrate (NH4NO3), and possesses both high- and low-affinity uptake systems for NO 3 - , little is known about the molecular component(s) responsible for acquisition and translocation in this crop. Here we provide experimental data showing that NtNRT1.1B with a 1,785-bp coding sequence exhibited a function in mediating NO 3 - transport associated with tobacco growth on NO 3 - nutrition. Heterologous expression of NtNRT1.1B in the NO 3 - uptake-defective yeast Hp△ynt1 enabled a growth recovery of the mutant on 0.5 mM NO 3 - , suggesting a possible molecular function of NtNRT1.1B in the import of NO 3 - into cells. Transient expression of NtNRT1.1B::green fluorescent protein (GFP) in tobacco leaf cells revealed that NtNRT1.1B targeted mainly the plasma membrane, indicating the possibility of NO 3 - permeation across cell membranes via NtNRT1.1B. Furthermore, promoter activity assays using a GFP marker clearly indicated that NtNRT1.1B transcription in roots may be down-regulated by N starvation and induced by N resupply, including NO 3 - , after 3 days' N depletion. Significantly, constitutive overexpression of NtNRT1.1B could remarkably enhance tobacco growth by showing a higher accumulation of biomass and total N, NO 3 - , and even NH 4 + in plants supplied with NO 3 - ; this NtNRT1.1B-facilitated N acquisition/accumulation could be strengthened by short-term 15N- NO 3 - root influx assays, which showed 15%-20% higher NO 3 - deposition in NtNRT1.1B-overexpressors as well as a high affinity of NtNRT1.1B for NO 3 - at a K m of around 30-45 µM. Together with the detection of NtNRT1.1B promoter activity in the root stele and shoot-stem vascular tissues, and higher NO 3 - in both xylem exudate and the apoplastic washing fluid of NtNRT1.1B-transgenic lines, NtNRT1.1B could be considered as a valuable molecular breeding target aiming at improving crop N-use efficiency by manipulating the absorption and long-distance distribution/transport of nitrate, thus adding a new functional homolog as a nitrate permease to the plant NRT1 family.

The evaluation of different types fecal bacteria products for the treatment of recurrent Clostridium difficile associated diarrhea: A systematic review and network meta-analysis.

Purpose: To determine the efficacy of different types of fecal microbiota transplantation for the treatment of recurrent clostridium difficile associated diarrhea (RCDAD). Methods: We searched PubMed, Embase, The Cochrane Library, Web of Science, China Biomedical Medicine (CBM), China National Knowledge Infrastructure (CNKI) and WanFang database. We also tracked the references found in systematic reviews of RCDAD treated with fecal microbiota transplantation. We included randomized controlled trials (RCTs) comparing different types of fecal microbiota transplantation with other methods for the treatment of RCDAD. The search period was from the date of inception of this treatment method to January 16, 2022. Two reviewers independently screened the published literature, extracted the data and assessed the risk of bias. Systematic review and network meta-analysis were conducted using RevMan 5.4, Stata 16.0 and R 4.1.2 software. Results: Ten RCTs involving 765 patients were included in this network meta-analysis. The results showed that treatment with fresh fecal bacteria and frozen fecal bacteria were better than vancomycin, fresh vs. vancomycin [odds ratio, (OR) = 8.98, 95% confidence interval (95% CI) (1.84, 43.92)], frozen vs. vancomycin [OR = 7.44, 95% CI (1.39, 39.75)]. However, there were no statistically significant differences in cure rate [fresh vs. frozen: OR = 1.21, 95% CI (0.22, 6.77); fresh vs. lyophilized, OR = 1.95, 95% CI (0.20, 19.44); frozen vs. lyophilized, OR = 1.62, 95% CI (0.30, 8.85)]. The Surface Under the Cumulative Ranking (SUCRA) indicated that fresh fecal bacteria were the best treatment for RCDAD. Conclusions: Fresh fecal bacteria are the best treatment of RCDAD, frozen fecal bacteria and lyophilized fecal bacteria can achieve the same effect. Fecal microbiota transplantation is worthy of clinical and commercial application.

Current approaches and strategies to identify Hedgehog signaling pathway inhibitors for cancer therapy.

The Hedgehog signaling pathway plays a vital role in embryonic development and tissue patterning. Aberrant regulation of this pathway is commonly associated with the occurrence, development and progression of various types of malignancies. The development of inhibitors targeting Hedgehog pathway has attracted significant interests in cancer therapy and led to the discovery of three drugs Vismodegib, Sonidegib and Glasdegib. However, their clinical application has been hampered due to adverse effects and resistance issues, highlighting the urgent need for new inhibitors. Herein we give a systematic overview of the current status and characteristics of various approaches to developing the Hedgehog pathway inhibitors, including library screening, natural product-oriented approach, analogue approach, drug repositioning, in silico tools and others. The future prospects are also discussed for the discovery and development of next-generation inhibitors.

An Accuracy Comparison of Minimally Invasive Transclavicular-Transcortical Drilling with Free-Hand, C-Shape and Assembly-Type Guide Device: An In Vitro Study.

OBJECTIVES: Ensuring the accuracy of transclavicular-transcoracoid drilling in the anatomical reconstruction of the coracoclavicular ligament complex with minimally invasive incisions remains a major problem for inexperienced surgeons. The purpose of this study was to design an assembly guide device for transclavicular-transcoracoid drilling with minimally invasive incisions, to manufacture the finished product, and to compare its feasibility and accuracy with the existing C-shape guide devices and free-hand techniques. METHODS: An assembly-type guide device was designed and produced using computer-aided design and three-dimensional printing. The specimen data of 54 human shoulders from 27 gross specimen (14 males and 13 females) treated by free-hand drilling, C-shape device drilling, and assembly-type guide device drilling from October 2018 to January 2021 were analyzed in a controlled laboratory study. Fifty-four human shoulder specimens were randomly assigned into free-hand (n = 18), C-shape (n = 18), and assembly (n = 18) groups by drawing lots for transclavicular-transcoracoid drilling by three inexperienced surgeons. After the drilling procedure was completed and the devices were removed, the operation outcomes were assessed and evaluated. Distances from the tunnel edge to the coracoid's medial (dm ) and lateral (dl ) edges, operation time, and tunnel location zones on the coracoid's inferior surface of all specimens in the three groups were measured to evaluate the surgical accuracy and efficiency. RESULTS: All specimens in the three groups completed the drilling operation successfully and were correctly measured. The distance differences (dd ) between dm and dl in the free-hand, C-shape, and assembly groups were 3.2 ± 1.8 mm, 1.8 ± 1.0 mm, 1.0 ± 0.8 mm, respectively. The dd of the free-hand group was higher than that of the other two groups (p < 0.001). The tunnel exit points on the inferior coracoid surface located in undesired zones were six (33%), one (6%), and zero in the free-hand group, C-shape group, and assembly-type group, respectively (p = 0.012). The operation time in the free-hand, C-shape, and assembly groups were 198 ± 36 s, 256 ± 64 s, and 353 ± 88 s, respectively. The operation time of each group significantly differed from that of the others (p < 0.001). CONCLUSION: The assembly-type devices may be the first choice for inexperienced surgeons while both the C shape devices and assembly-type guide devices achieved higher accuracy than free-hand techniques.

Ortner's syndrome secondary to thoracic aortic aneurysm: a case series.

BACKGROUND: Ortner's syndrome refers to vocal cord paralysis resulting from compression of the left recurrent laryngeal nerve by abnormal mediastinal vascular structures. This retrospective case series details our experience with Ortner's syndrome due to thoracic aortic aneurysm. METHODS: This study was a retrospective analysis of a case series. A total of 4 patients (mean age, 65.5 years) with Ortner's syndrome due to thoracic aortic aneurysm underwent thoracic endovascular aortic repair from July 2014 to May 2020. The patients' demographics, comorbidities, initial symptoms, time from hoarseness to treatment, aneurysm shape and size, surgical procedures and outcome are summarized. RESULTS: A total of 4 patients with Ortner's syndrome due to thoracic aortic aneurysm were analyzed. All the patients underwent thoracic endovascular aortic repair with no complications during the hospitalization period. At a mean follow-up of 26.8 (8-77) months, hoarseness in 3 patients had completely resolved or improved, and the symptoms in 1 patient had not progressed. CONCLUSIONS: Hoarseness due to left recurrent laryngeal nerve palsy can be the presenting symptom of thoracic aortic aneurysm. Early diagnosis leads to timely treatment of these patients which may be helpful in the functional recovery of symptoms.