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This study assessed the potential of large language models (OpenAI’s ChatGPT 3.5 and 4.0, Google Bard, Meta Llama2, and Anthropic Claude2) in addressing 30 common migraine-related queries, providing a foundation to advance artificial intelligence–assisted patient education and insights for a holistic approach to migraine management.

[This corrects the article DOI: 10.1371/journal.pone.0251578.].

BackgroundEthyl ferulate (EF) is a derivative of ferulic acid (FA), which is a monomeric component purified from the traditional medicinal herb Ferula, but its effects have not been clear yet. The purpose of this study was to evaluate whether EF can reduce inflammation levels in macrophages by regulating the Nrf2-HO-1 and NF-кB pathway.MethodsThe LPS-induced raw 264.7 macrophage cells model was used to determine the anti-inflammatory and anti-oxidative stress effects of EF. The levels of IL-1β, IL-6, TNF-α and PGE2 were analyzed by ELISA. The mRNA and protein of COX-2, iNOS, TNF-α, IL-6, HO-1 and Nrf2 were identified by RT-PCR analysis and western blotting. Intracellular ROS levels were assessed with DCFH oxidation staining. The expressions of NF-кB p-p65 and Nrf2 were analyzed by immunofluorescence assay. The inhibitory effect of Nrf2 inhibitor ML385 (2μM) on mediatation of antioxidant activity by raw 264.7 macrophage cells was evaluated. The effect of EF was confirmed in acute lung injury mice model.ResultsIn our research, EF reduced the expression of iNOS, COX2 and the production of PGE2. EF could inhibit the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in lipopolysaccharide (LPS) stimulated macrophages and decreased expression of IL-6 and TNF-α in LPS stimulated macrophages. Furthermore, EF inhibited NF-кB p65 from transporting to the nucleus, decreased the expression of p-IкBα, significantly decreased the level of intracellular reactive oxygen species (ROS) and activated Nrf2/HO-1 pathways. EF could attenuate the degree of leukocyte infiltration, reduced MPO activity, mRNA levels and secretion of TNF-α and IL-6 in vivo. EF exhibited potent protective effects against LPS-induced acute lung injury in mice.ConclusionsCollectively, our data showed that EF relieved LPS-induced inflammatory responses by inhibiting NF-κB pathway and activating Nrf2/HO-1 pathway, known to be involved in the regulation of inflammatory responses by Nrf2.

Abstract Background In the era of intensity-modulated radiotherapy (IMRT), the role of additional concurrent chemotherapy (CC) to radiotherapy (RT) after induction chemotherapy (IC) compared to IC followed by RT alone remains unclear for stage II-IVB nasopharyngeal carcinoma (NPC) patients. The aim of this study was to evaluate the efficacy and toxicities of IC/RT and IC/CCRT in the treatment of NPC with volumetric modulated arc therapy (VMAT). Methods From January 2012 to March 2016, a total of 217 NPC patients were retrospectively assessed. Of the 217 patients, 139 patients received IC followed by VMAT alone and 78 patients received IC plus CCRT. Overall survival (OS), progression-free survival (PFS) and toxicities were assessed. Results The 5-year OS, PFS rates were 57.5%, 41.8% and 47.8%, 38.4% for the IC/RT and IC/CCRT arms, respectively, without significant difference in survival between the two groups (both p > 0.05). Multivariate analysis indicated that treatment modality (IC/RT vs. IC/CCRT) was not an independent prognostic factor for OS or PFS. Grade 3–4 leukopenia/neutropenia (3.60% vs. 20.51%, p

Objective The purpose of this study was to investigate and characterize in vitro the post-β-lactamase inhibitor effect (PLIE) of clavulanic acid against two β-lactamase-producing species of bacteria. Methods The PLIE was investigated against one strain of Klebsiella pneumoniae and one strain of Haemophilus infiuenzae. A stationary-phase inoculum of about 10[sup 7] colony-forming units per mL of each bacterium was pre-exposed for 2 h to clavulanic acid, either alone or in combination with amoxicillin at various concentrations. After pre-exposure, the dilution required to remove the β-lactamase inhibitor was 1:100 or 1:1000 according to the bacterial species and their susceptibilities to clavulanic acid. Bacteria were counted hourly after drug removal, on solid agar medium. Results Control cultures exposed to amoxicillin alone after dilution, showed a delay in growth, which may be inherent to the time required to synthesize sufficient β-lactamase after the dilution steps. Control experiments clearly distinguished the post-antibiotic effect and the growth delay from the PLIE. Conclusion The PLIE could be one of several factors explaining why β-lactam/β-lactamase inhibitor combinations remain effective throughout the dosing interval, even if a few hours after in vivo administration, serum concentrations of β-lactamase inhibitor fall below levels that are active in vitro. [ABSTRACT FROM AUTHOR]

Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases. Radiopharmaceutical therapy, which directly causes systematic and irreparable damage to targeted cells, has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies. As the Food and Drug Administration (FDA) approvals of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617 and their complementary diagnostic agents, namely, [ 68 Ga]Ga-DOTA-TATE and [ 68 Ga]Ga-PSMA-11, targeted radiopharmaceutical-based theranostics (radiotheranostics) are being increasingly implemented in clinical practice in oncology, which lead to a new era of radiopharmaceuticals. The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition, making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy. Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets, demonstrating remarkable in vivo performance. These include high tumor uptake, prolonged retention time, and favorable pharmacokinetic properties that align with clinical standards. While radiotheranostics have been widely applied in tumor diagnosis and therapy, their applications are now expanding to neurodegenerative diseases, cardiovascular diseases, and inflammation. Furthermore, radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm. Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning, leading to improved therapeutic outcomes in targeted radionuclide therapy. This review offers a comprehensive overview of the evolution of radiopharmaceuticals, including both FDA-approved and clinically investigated agents, and explores the mechanisms of cell death induced by radiopharmaceuticals. It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Assessing whether single-lead ECG can be effectively and relatively inexpensively used in large-scale OSA screening, and identifying factors influencing moderate-to-severe OSA among elderly hypertensive patients without atypical symptoms in primary care., Methods: The study gathered data from 15 medical institutions in Ningxia between January and December 2022 using cloud platforms. The dataset included basic information and 72-h ECG monitoring for 2573 hypertensive patients over 65. OSA screening was conducted using the single-lead wearable ECG devices based on the ACAT algorithm. A multivariable logistic regression identified the main factors affecting OSA severity in these patients, and the AUC was used to assess the model's predictive accuracy., Results: The study found an OSA detection rate of 87.10%, with 55.42% being moderate to severe cases. Key risk factors associated with developing moderate-to-severe OSA included cardiac irregularities like supraventricular extrasystole and atrioventricular block, male gender, lifestyle factors like alcohol consumption and smoking, and health indicators such as SDNN ≤ 100 ms, abnormal LF/HF ratio, BMI, and age. The model's accuracy for predicting OSA, indicated by a ROAUC of 0.625, was moderate. Factors like gender, tea consumption, stroke history, and ventricular tachycardia were also independently linked to OSA severity., Conclusion: This study combines single-lead wearable ECG devices with the ACAT algorithm for OSA screening in Ningxia, China. Initial screening identified 87.10% of participants as having OSA, with 55.42% being moderate to severe cases. This suggests a convenient, low-cost, and repeatable ECG-based method for OSA screening, potentially improving early detection and management of OSA by identifying potential risk factors., Competing Interests: Declarations Ethics approval and consent to participate All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional. This study was approved by the Ethics Committee of the First People's Hospital of Yinchuan City on October 6, 2021 (project number 2021-SF-009) and obtained informed consent from the participants. Competing interest All authors declare that they have no conficts of interest. Disclosures None., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Up to 80% of biliary tract cancer (BTC) patients relapse within 3 years after surgery and the efficacy of second-line treatment remains dismal for patients who progressed on gemcitabine and cisplatin chemotherapy. Median overall survival of patients with palliative chemotherapy is less than 1 year. The feasibility and safety of targeted therapies plus immunotherapies remain scanty currently, and patients with recurrent or advanced BTCs often experience a rapid decline in Eastern Cooperative Oncology Group (ECOG) performance status. This case report is the first report suggesting a 17-month progression-free survival (PFS), partial response, and another 11-month PFS after progressive disease of anlotinib plus toripalimab in advanced BTC with high ECOG performance status. We report a 67-year-old Chinese male with BTC. He was observed with progressive disease after surgical resection, adjuvant chemotherapy, palliative chemotherapy, and diagnosed with American Joint Committee on Cancer clinical stage IV (cT3N0M1) extrahepatic BTC. The patient experienced a rapid decline in performance status, and he received oral anlotinib and toripalimab with informed consent. MRI scans showed partial response on 22 June 2022. PET-CT showed that tumor activity has been inhibited on 8 March 2023. He achieved 17 months of PFS. Although the patient developed solitary lung metastasis, he had a continuous survival benefit from treatment of anlotinib plus toripalimab after lung radiotherapy. Until the writing of the case draft, he had achieved another 11 months of PFS. The present case suggests that anlotinib plus toripalimab might be a potential effective treatment for advanced BTCs patients with high ECOG performance status., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Multi-mode emissive materials with stimuli-responsive producing invisible signals are very attractive for advanced security applications, but development of such materials remains highly challenging. In this work, oxygen-doped carbon nitrides (O-CNs) are prepared via microwave-assisted heating of urea, which exhibit ultraviolet (UV) solid-state fluorescence (SSFL), visible room temperature phosphorescence (RTP) and thermal-stimuli production of invisible UV delayed fluorescence (DF) properties. Further studies confirmed that the SSFL and RTP could be attributed to the introduction of oxygen functional group (e. g., C=O) in the skeleton of O-CNs, thus minimizing the aggregation caused quenching effect, facilitating intersystem crossing, and stabilizing the excited triplet states. The specific thermal-stimuli production of UV DF is deemed to be the relatively large energy gap between ground and excited singlet states as well as an effective triplet-triplet annihilation. Notably, the emission maximum of UV DF locates at ~310 nm with an ultra-narrow full width at half maximum (FWHM) down to 19 nm, so it is completely invisible to the naked eyes, but detectable by a UV camera. To employ the unique characteristics of O-CNs, security protection strategies with superior concealment by virtue of the thermal-stimuli quenching visible RTP and meanwhile producing invisible UV DF are demonstrated., (© 2024 Wiley-VCH GmbH.)

Background : Acute kidney injury (AKI), a prevalent postoperative complication, predominantly manifests as stage 1, characterized by a mild elevation in serum creatinine (SCr). There is yet to be a consensus regarding the association between stage 1 AKI and adverse outcomes in surgical patients. Methods: This retrospective study enrolled adult patients who underwent at least one surgery during hospitalization from the MIMIC IV database. AKI was diagnosed when the KDIGO creatinine criteria were satisfied within 7 days after surgery. Stage 1a AKI was defined as an absolute increase in SCr of 26.5 μmol/L, and stage 1b was defined as a 50% relative increase. Stage 1 AKI was also divided into transient and persistent substages based on whether the AKI recovered within 48 h after onset. The association between stage 1 AKI and its substages and in-hospital mortality was evaluated. Results: Among 49,928 patients enrolled, 9755 (19.5%) developed AKI within 7 days after surgery, of which 7659 (78.5%) presented with stage 1 AKI. The median follow-up was 369 (367, 372) days. Stage 1 AKI was significantly associated with in-hospital mortality after adjustment (aHR, 2.73; 95% CI, 2.29, 3.26). Subgroup analyses showed that the risk of stage 1 AKI on in-hospital mortality was attenuated by age ≥ 65 years ( p for interaction = 0.017) or a baseline eGFR < 60 mL/min per 1.73 m 2 ( p for interaction = 0.001). Compared with non-AKI, patients with stage 1b (aHR, 3.06; 95% CI, 2.56, 3.66) and persistent stage 1 (aHR, 2.03; 95% CI, 1.61, 2.57) AKI had an increased risk of in-hospital mortality; however, this risk was not significant in those with stage 1a (aHR, 1.01; 95% CI, 0.68, 1.51) and transient stage 1 (aHR, 1.11; 95% CI, 0.79, 1.57) AKI. Conclusions: Stage 1 AKI exhibits an independent correlation with a heightened mortality risk among surgical patients. Consequently, a tailored adaptation of the KDIGO AKI classification may be necessitated for the surgical population, particularly those presenting with decreased baseline kidney function.

This study assessed the potential of large language models (OpenAI's ChatGPT 3.5 and 4.0, Google Bard, Meta Llama2, and Anthropic Claude2) in addressing 30 common migraine-related queries, providing a foundation to advance artificial intelligence-assisted patient education and insights for a holistic approach to migraine management., (©Linger Li, Pengfei Li, Kun Wang, Liang Zhang, Hongwei Ji, Hongqin Zhao. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 23.07.2024.)

Biliary tract cancers are solid tumors with poor prognosis and over 70% of patients present in advanced stages. The efficacy of second-line treatment for patients who progressed on GC chemotherapy is limited. Median OS of these patients is less than 1 year with palliative treatment. Despite the success of anti-HER2 therapy in HER2-positive breast cancer, the targeted therapy of HER2 mutations in BTCs is still being explored. This case report is the first report suggesting a 15-month PFS and partial response of pyrotinib in HER2-positive BTC. We report a 64-year-old female with HER2-positive biliary tract cancer. She was diagnosed with AJCC clinical stage IV (cT3N1M1) intrahepatic biliary tract cancer and got PD after 3 cycles of systemic chemotherapy of gemcitabine plus cisplatin. Due to the HER2-positive signature, pyrotinib (400 mg daily in 21-day cycles), an oral irreversible pan-ErbB TKI was prescribed in September 2021, with her informed consent. The tumor shrank significantly after this treatment and imaging assessments conducted on 24 September 2022 showed PR. Until the writing of the case draft, the patient had achieved 15 months of PFS. The present case suggests that Pyrotinib might be a potential effective treatment for HER2-positive advanced BTC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Proximal crescentic metatarsal osteotomy and distal soft tissue reconstruction have been introduced to correct severe HV. The intrinsically unstable proximal first crescentic osteotomy depends on enough force fixation for stability. It is necessary to judge the number of fixation screws for osteotomy., Method: Fifty-two feet of 50 adult patients with severe HV were included in this study. The treatment was proximal crescentic metatarsal osteotomy with a single screw and distal soft tissue reconstruction in Group 1 and the fixation with two screws with distal soft tissue reconstruction in Group 2. Clinical and radiological follow-ups were assessed after 4 and 12 months of operation. In Group 1, HVA decreased from 46.4 ±3.28 to 19.9 ±4.70 after 12 months of operation and from 45.1 ±3.45 to 19.1 ±4.70 in Group 2. Regarding the intermetatarsal angle (IMA) in Group 1, it was changed from 18.5 ±1.98 to 9.25 ±1.11 after 12 months of operation. For group 2, it decreased from 18.3 ±1.81 to 9.53 ±1.70. Meanwhile, the AOFAS score improved from 63.1 to 83.9 after 12 months of operation in Group 1 and improved from 64.3 to 82.8 in Group 2., Results: Furthermore, the VAS score reduced from 4.5±1.01 to 1.7± 0.43 in Group 1 and from 4.7±0.92 to 1.7±0.55 in Group 2 after 12 months of operation. There were no significant differences identified between Group 1 and Group 2 in terms of VAS and AOFAS scores and HVA and IMA measurements., Conclusion: There is less complication in two-screw fixation for crescentic osteotomy compared to a single-screw fixation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Facial nerve palsy is one of the complications of temporal bone fracture. Several approaches can be used for facial nerve decompression which include the middle cranial fossa approach, transmastoid approach and translabyrinthine approach. When the site of injury is identified at the tympanic segment and perigeniculate area, total transcanal endoscopic approach (TTEA) is an excellent surgical option. This approach is safe and less invasive avoiding external incision and mastoid drilling. Our patient showed recovery to House-Brackmann grade II facial function and reduction of the air-bone gap 6 months after the surgery., Competing Interests: Conflict of interestThe authors shared no conflicts of interest in regards of the research and publication of this article., (© Association of Otolaryngologists of India 2021.)

MiR-499a-5p was significantly downregulated in degenerative tissues and correlated with apoptosis. Nonetheless, the biological function of miR-499a-5p in acute ischemic stroke has been still unclear. In this study, we found that the plasma levels of miR-499a-5p were significantly downregulated in 64 ischemic stroke patients and negatively correlated with the National Institutes of Health Stroke Scale score. Then, we constructed cerebral ischemia/reperfusion (I/R) injury in rats after middle cerebral artery occlusion and subsequent reperfusion and oxygen-glucose deprivation and reoxygenation (OGD/R)-treated SH-SY5Y cell model. Transfection with miR-499a-5p mimic was accomplished by intracerebroventricular injection in the in vivo I/R injury model. We further found that miR-499a-5p overexpression decreased infarct volumes and cell apoptosis in the in vivo I/R stroke model using TTC and TUNEL staining. PDCD4 was a direct target of miR-499a-5p by luciferase report assay and Western blotting. Knockdown of PDCD4 reduced the infarct damage and cortical neuron apoptosis caused by I/R injury. MiR-499a-5p exerted neuroprotective roles mainly through inhibiting PDCD4-mediated apoptosis by CCK-8 assay, LDH release assay, and flow cytometry analysis. These findings suggest that miR-499a-5p might represent a novel target that regulates brain injury by inhibiting PDCD4-mediating apoptosis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intraparotid facial nerve schwannoma is a rare condition, which is difficult to preoperatively diagnose without a definite biopsy, yet the diagnosis is important for surgical planning and avoiding accidental injury to the facial nerve. Considering the benign indolent nature of the schwannomas, the management should be prioritized on the long-term tumor control with special attention to the facial nerve function and facial cosmesis. Microscope-assisted intracapsular enucleation is an excellent treatment option for such lesions. Our patient showed House-Brackmann grade II facial function after the surgery. This technique is safe and offers a favorable outcome of facial nerve function., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest., (© Copyright Istanbul Medeniyet University Faculty of Medicine.)

Background: Ethyl ferulate (EF) is a derivative of ferulic acid (FA), which is a monomeric component purified from the traditional medicinal herb Ferula, but its effects have not been clear yet. The purpose of this study was to evaluate whether EF can reduce inflammation levels in macrophages by regulating the Nrf2-HO-1 and NF-кB pathway., Methods: The LPS-induced raw 264.7 macrophage cells model was used to determine the anti-inflammatory and anti-oxidative stress effects of EF. The levels of IL-1β, IL-6, TNF-α and PGE2 were analyzed by ELISA. The mRNA and protein of COX-2, iNOS, TNF-α, IL-6, HO-1 and Nrf2 were identified by RT-PCR analysis and western blotting. Intracellular ROS levels were assessed with DCFH oxidation staining. The expressions of NF-кB p-p65 and Nrf2 were analyzed by immunofluorescence assay. The inhibitory effect of Nrf2 inhibitor ML385 (2μM) on mediatation of antioxidant activity by raw 264.7 macrophage cells was evaluated. The effect of EF was confirmed in acute lung injury mice model., Results: In our research, EF reduced the expression of iNOS, COX2 and the production of PGE2. EF could inhibit the production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in lipopolysaccharide (LPS) stimulated macrophages and decreased expression of IL-6 and TNF-α in LPS stimulated macrophages. Furthermore, EF inhibited NF-кB p65 from transporting to the nucleus, decreased the expression of p-IкBα, significantly decreased the level of intracellular reactive oxygen species (ROS) and activated Nrf2/HO-1 pathways. EF could attenuate the degree of leukocyte infiltration, reduced MPO activity, mRNA levels and secretion of TNF-α and IL-6 in vivo. EF exhibited potent protective effects against LPS-induced acute lung injury in mice., Conclusions: Collectively, our data showed that EF relieved LPS-induced inflammatory responses by inhibiting NF-κB pathway and activating Nrf2/HO-1 pathway, known to be involved in the regulation of inflammatory responses by Nrf2., Competing Interests: The authors have declared that no competing interests exist.

In the practical selective laser melting (SLM) manufacturing process, the scan strategy often varies between layers to avoid overlapping of the melted area, which affects the residual stress and deflection of the final build. Yet not much modelling work has been done to accommodate the angle between layers. The paper proposed an analytical thermal model to address the scan strategy difference, such as laser scan direction difference between layers, which brings the model closer to the practical scan situation. The analytical transient moving point heat solution is adopted in this model. The laser movement is first considered in a laser coordinates, which originates at the laser radiation spot, and then transferred into a stationary coordinate, which originates at the starting point of the build. The model takes account of multi-track and multi-layer effect by considering thermal property changes caused by remaining heat, which is further adopted for temperature distribution calculation. The scan direction difference leads to different laser path at each layer, and alters heating and cooling time for a specific point on the build. The proposed model is validated by comparing the predicted melt pool geometries to documented experimental data. The effect of scan direction difference between layers is further discussed in the later part. It is found that the uni- and bi- directional scan leads to diverse temperature profile but its effect on melt depth is not significant. Although the laser rotation angle between layers leads to changes in the melt depth, it is not in a large scale. The proposed model shows that scan strategy does not change melt pool geometry in a significant scale but affects the thermal profile as well as thermal history. It can be used as a step for further modelling work for porosity and deflection.

Objective: Postoperative delirium (POD) is a form of delirium that affects patients who have undergone surgical procedures and anesthesia, usually peaking between 1 and 3 days after their operation. The aim of this meta-analysis was to determine whether monitoring of depth of anesthesia may influence the incidence of POD., Methods: A systematic literature search was conducted on studies that reported POD in elderly patients (>60 years old) who underwent surgery. This meta-analysis was carried out using random-effects model., Results: Compared with control group, intraoperative bispectral index (BIS) monitoring reduced POD (odds ratio 1.32, 95% confidence interval 1.11-1.57, P = 0.001, I 2  = 51%). In the mixed-surgery group, compared with the control group, BIS monitoring decreased the incidence of POD (odds ratio 1.24, 95% confidence interval 1.07-1.44, P = 0.004, I 2  = 61%). There was also no significant difference in the incidence of POD among patients who underwent cardiac, colon, and orthopedic surgeries., Conclusions: BIS monitoring during surgery can reduce the incidence of POD in elderly patients. Whether BIS monitoring may reduce the incidence of POD in a single type of surgery needs further study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The purpose of this study was to provide an initial assessment of treatment for talar posterior process fractures using open reduction and internal fixation (ORIF) through posteromedial approach and percutaneous screw fixation. From January 2014 to December 2018, 12 cases with displaced fracture of talar posterior process were treated in our department. The clinical and radiological results were assessed after 4 and 12 months of operation with Visual Analog Scale (VAS) pain and American Orthopedic Foot and Ankle Society (AOFAS) scores. ORIF was performed in four of the cases and percutaneous screw fixation was performed in eight of the cases. The average follow-up period was 13 months. Complications such as wound infection, nerve injury, screw loosening, malunion or nonunion of fracture were absent. For clinical assessment, considerable mprovements were observed for the AOFAS and VAS scores at 4 and 12 months postoperatively for both techniques. There was no significant difference for AOFAS scores and VAS scores between the two techniques (p > 0.05). Both techniques showed good functional outcome and were performed for posterior talar process fracture following the fracture displacement guidelines. Percutaneous screw fixation treatment with computer-assisted three-dimensional evaluation shortened the operation time and reduced incidences of surgical complications.

Background: Percutaneous screw fixation can provide stable fixation with a minimally invasive surgical technique for posterior talar process fracture., Objectives: The purpose of this study was to investigate the optimal posterior screw placement and the geometry of safe zone for screw insertion in the posterior talar process by analyzing with 3-dimensional (3D) technology., Methods: 100 adult feet computed tomography (CT) scans were evaluated. CT data were imported into Materiaise's interactive medical image control system (MIMICS) 18.01 software for 3-dimensional reconstruction. Two 3.0mm-diameter screws were simulated from the posterior to anterior position for posterior talar process. The morphology parameters of posterior talar process were also quantitatively measured. The safe zone and the length and entry point of screw were defined., Results: The optimal entry point of screw for posterior talar process fracture was lateral tubercle from the posterior to anterior position. The safe zone of medial tubercle entry point was smaller in lateral tubercle. These gender-specific measurements were all significant (P <.001)., Conclusions: The predefined zone with computer-assisted 3D techniques for the most frequently positioned percutaneous screws may aid in preoperative planning, shorten the operation time and reduce the incidence of surgical complications.

Background and Objectives: Colorectal cancer is one of the most common cancers and the leading cause of cancer-related death worldwide. The impact of the primary tumor location on the prognosis of patients with colorectal cancer has long been a concern, but studies have led to conflicting conclusions. Methods: In total, 465 colorectal cancer patients who received radical surgery were reviewed in this study. Enrolled patients were divided into two groups according to the tumor location. Disease-free survival (DFS) and overall survival (OS) were analyzed via the Kaplan-Meier method. A Cox regression model was employed to evaluate the independent prognostic factors for DFS and OS. Results: The right colorectal cancer (RCC) and left colorectal cancer (LCC) groups comprised 202 and 140 patients, respectively. Univariate and multivariate analyses revealed that the tumor location and TNM stage were independent predictors of DFS and OS. Subgroup analyses by stage demonstrated that there were significant differences in DFS and OS between patients with stage II and III RCC and LCC, but not for those with stage I colorectal cancer. Conclusions: Patients with stage II and III LCC had better survival than those with RCC. However, this improvement in DFS and OS was not observed in patients with stage I colorectal cancer., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest

Purpose: The aim of this study was to evaluate the occurrence of anatomical variations of the musculotendinous junction of the flexor hallucis longus (FHL) muscle, the relationship between FHL tendon or muscle and the tibial neurovascular bundle at the level of the posterior ankle joint in human cadavers., Methods: Seventy embalmed feet from 20 male and 15 female cadavers, the cadavers' mean age was 65.4 (range from 14 to 82) years, were dissected and anatomically classified to observe FHL muscle morphology define the relationship between FHL tendon or muscle and the tibial neurovascular bundle. The distance between the musculotendinous junction and the relationship between FHL tendon or muscle and the tibial neurovascular bundle was determined., Results: Three morphology types of FHL muscle were identified: a long lateral and shorter medial muscle belly, which was observed in 63 specimens (90%); equal length medial and lateral muscle bellies, this variant was only observed in five specimens (7.1%); one lateral and no medial muscle belly, which was observed in two specimens (2.9%). No statistically significant difference was observed according to gender or side (p > 0.05). Two patterns were identified and described between FHL tendon or muscle and the tibial neurovascular bundle. Pattern 1, the distance between the neurovascular bundle and FHL tendon was 3.46 mm (range 2.34-8.84, SD = 2.12) which was observed in 66 specimens (94.3%); Pattern 2, there was no distance which was observed in four specimens (5.7%)., Conclusion: Knowing FHL muscle morphology, variations provide new important insights into secure planning and execution of a FHL transfer for Achilles tendon defect as well as for the interpretation of ultrasound and magnetic resonance images. With posterior arthroscopic for the treatment of various ankle pathologies, posteromedial portal may be introduced into the posterior aspect of the ankle without gross injury to the tibial neurovascular structures because of the gap between the neurovascular bundle and FHL tendon.

Background: In the era of intensity-modulated radiotherapy (IMRT), the role of additional concurrent chemotherapy (CC) to radiotherapy (RT) after induction chemotherapy (IC) compared to IC followed by RT alone remains unclear for stage II-IVB nasopharyngeal carcinoma (NPC) patients. The aim of this study was to evaluate the efficacy and toxicities of IC/RT and IC/CCRT in the treatment of NPC with volumetric modulated arc therapy (VMAT)., Methods: From January 2012 to March 2016, a total of 217 NPC patients were retrospectively assessed. Of the 217 patients, 139 patients received IC followed by VMAT alone and 78 patients received IC plus CCRT. Overall survival (OS), progression-free survival (PFS) and toxicities were assessed., Results: The 5-year OS, PFS rates were 57.5%, 41.8% and 47.8%, 38.4% for the IC/RT and IC/CCRT arms, respectively, without significant difference in survival between the two groups (both p > 0.05). Multivariate analysis indicated that treatment modality (IC/RT vs. IC/CCRT) was not an independent prognostic factor for OS or PFS. Grade 3-4 leukopenia/neutropenia (3.60% vs. 20.51%, p < 0.001), gastrointestinal disorder (nausea/vomiting/diarrhea, 2.16% vs. 41.03%, p < 0.001), mucositis (29.50% vs. 47.44%, p = 0.01) and xerostomia (34.53% vs. 48.72%, p = 0.04) were more frequent in the IC/ CCRT arm than in the IC/RT arm during VMAT., Conclusions: No significant difference in OS and PFS was observed between IC plus VMAT alone and IC/CCRT in the treatment of stage II-IVB NPC patients, however, more side effects were observed in the IC/CCRT arm.

Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell lung cancer (NSCLC). Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals. Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively. Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.

The EP300 protein is a histone acetyltransferase that regulates transcription via chromatin remodelling and is important in the processes of cell proliferation and differentiation. EP300 acetylation of TP53 in response to DNA damage regulates its DNA-binding and transcription functions. A role for EP300 in cancer has been implied by the fact that it is targeted by viral oncoproteins, it is fused to MLL in Leukaemia and two missense sequence alterations in EP300 were identified in epithelial malignancies. Nevertheless, direct demonstration of the role of EP300 in tumorigenesis by inactivating mutations in human cancers has been lacking. Here we describe EP300 mutations, which predict a truncated protein, in 6(3%) of 193 epithelial cancers analysed. Of these six mutations, two were in primary tumours (a colorectal cancer and a breast cancer) and four were in cancer cell lines (colorectal, breast and pancreatic). In addition, we identified a somatic in-frame insertion in a primary breast cancer and missense alterations in a primary colorectal cancer and two cell lines (breast and pancreatic). Inactivation of the second allele was demonstrated in five of six cases with truncating mutations and in two other cases. Our data show that EP300 is mutated in epithelial cancers and provide the first evidence that it behaves as a classical tumour-suppressor gene.

In vivo, serum concentrations of beta-lactamase inhibitors measured during the last part of the dosing interval are below the levels associated with in vitro activity. Nevertheless, beta-lactam plus beta-lactamase inhibitor combinations remain active in vivo throughout the dosing interval. One of the many reasons for this contradiction may be the PLIE. The PLIE can be evaluated only in the light of the postantibiotic effect (PAE). Also, accurate determination of the PLIE requires a careful investigation of all bacterial regrowth delays (BRDs) inherent to the technical procedures used. The purpose of the study reported herein was to determine the true in vitro PLIE of clavulanic acid (CA) against two beta-lactamase-producing strains, a Klebsiella pneumoniae strain (amoxicillin [AMX] MIC > 256 mg/L; CA MIC = 64 mg/L; and AMX + CA MIX = 4 mg/L) and a Haemophilus influenzae strain (AMX MIC = 32 mg/L; CA > 32 mg/L; AMX-CA = 1 mg/L). For each strain, a stationary phase inoculum of 10(7) was preexposed for 2 h to either CA alone or CA + AMX in various concentrations. Dilution to 10(-2) or 10(-3) was performed to eliminate the CA and/or AMX after the preexposition phase. Hourly bacterial counts were done between 0 and 8 h and after 24 h. Control cultures exposed to AMX after dilution showed a growth delay possibly ascribable to the time needed for bacteria to produce a large enough amount of beta-lactamases. Control experiments were done to unequivocally differentiate PLIE from PAE and BRD. The true PLIE values thus obtained ranged from 0 to 4.5 h for K. pneumoniae and from 0 to 15 h for H. influenzae. For both strains, a PLIE was demonstrated after exposure to CA alone.

OBJECTIVE: To investigate the pharmacodynamic disposition of two recently developed beta-lactam antibiotics, meropenem and cefpirome, in the Yucatan micropig model, and to compare the bactericidal activity of these drugs against bacteria in this in vitro/ex vivo micropig model after administration by both intermittent injection and continuous infusion. METHODS: Cefpirome (1 g) was given to the micropig over a 12-h period by direct intravenous injection and 6-h continuous infusion (500 mg). Meropenem (250 mg) was administered either by 30-min intravenous and 8-h continuous infusion. The two drugs were assayed by HPLC. The pharmacodynamics of these drugs were evaluated by means of (1) serum killing curve against Klebsiella pneumoniae producing extended-spectrum beta-lactamase, stably derepressed Enterobacter cloacae and methicillin-susceptible penicillinase-producing Staphylococcus aureus, and (2) calculations of index of surviving bacteria (ISB). RESULTS: The bactericidal activity of meropenem against K. pneumoniae and E. cloacae in this in vitro/ex vivo model was excellent, with a 4 log decrease at peak concentrations. Meropenem produced a mixed concentration- and time-dependent, killing effect against E. cloacae and K. pneumoniae. The ISB value ranged from 25% to 30% for E. cloacae. With concentrations above MIC for S. aureus (1 mg/L), cefpirome has a time-dependent bactericidal activity, as shown by the ISB ranging from 20% to 80% after 4 h and between 20% and 40% after an 8-h drug exposure. For both antibiotics, the higher concentrations obtained just after intermittent injection had a rapid and strong killing effect against the strains tested, but the trough levels had no bactericidal activity. The continuous infusions produce consistent concentrations of antibiotic that can be maintained above the MIC, and the bactericidal activity of which ranges from 2 to 4 log10 decrease of inoculum. CONCLUSIONS: In the present study the micropig has been shown to be an adequate model for the pharmacodynamic investigation of cefpirome and meropenem. In general, continuous infusion appears to optimize the pharmacodynamic profile of the two tested beta-lactam antibiotics. However, against Gram-negative bacilli, the administration of a loading dose prior to continuous infusion of beta-lactams would eliminate the only potential pharmacokinetic disadvantage of continuous infusion and ensure the rapid onset of antimicrobial activity.

Extended-spectrum beta-lactamases (ESBLs) are found in numerous Enterobacteriaceae, mainly in Klebsiella pneumoniae. We investigated the pharmacodynamics of two new extended-spectrum cephalosporins, cefepime and cefpirome, alone and combined with either amikacin or gentamicin or ciprofloxacin by means of time-kill curves against ESBL-producing, aminoglycoside-resistant K. pneumoniae. When used alone, cefepime (8 and 16 mg/l) resulted in a 2 and 3 log decrease at 6 h, respectively, but at 24 h regrowth occurred. The combination of cefepime (8 mg/l) with amikacin (4 mg/l) resulted in a 4 log decrease at 6 h, but there were no surviving bacteria at 6 h when combined with amikacin (8 mg/l). The combination of cefepime (16 mg/l) with gentamicin (4 mg/l) resulted in a 4 log decrease in 24 h. The antimicrobial combination of cefepime (32 mg/l) with ciprofloxacin (2 mg/l) resulted in a 4 log decrease in 24 h. Cefpirome (8 mg/l) induced a 2 log decrease at 4 h; 32 mg/l cefpirome resulted in a 3 log decrease followed by regrowth at 24 h. The regrowth observed in the late phase with cefpirome alone disappeared when combined with aminoglycoside. When cefpirome (32 mg/l) was used in combination with ciprofloxacin (1 mg/l), it resulted in a 4 log decrease in 24 h.

Three female Yucatan micropigs were included and received a single dose of amikacin (15 mg/kg) by short infusion (30 min) combined either with a single dose of cefepime or cefpirome (30 mg/kg/12 h) or meropenem (7 mg/kg/8 h). The beta-lactams were administered either by intravenous intermittent injection or by continuous infusion. The mean elimination half-life and clearance value of amikacin were 1.88 h and 2.15 ml/min.kg-1 respectively. These pharmacokinetic parameters were similar to those obtained in man (t1/2 = 2,42 h et Cl = 1,61 ml/min kg-1). Furthermore, they were not affected by coadministration of cefepime, cefpirome and to meropenem. While resistant to cefepime, cefpirome and amikacin, Klebsiella pneumoniae producing ESBL was susceptible to combination of these cephalosporins with amikacin in an in vitro/ex vivo micropig model. For the six dosage regimens used in this study, the killing activities were similar and resulted in at least 4 log decrease at 6 h after drug exposure. For antimicrobial combination consisting of bolus dosing of amikacin plus continuous infusion of cefepime or cefpirome, the 12 h serum bactericidal titers (SBTs) were 1:8 for cefepime and 1:2 for cefpirome dosage regimen. When each drug administered intermittently, the 12 h SBTs were 1:4 for cefepime and 1:2 for cefpirome. The 8 h SBTs for dosing schedule containing meropenem combined with amikacin were 1:4 and 1:16 after 30 min short infusion and continuous infusion respectively. In conclusion, our study showed that the micropig model is a reliable model for pharmacokinetic investigation of amikacin. It was concluded that beta-lactam antibiotics tested with amikacin may be coadministered by using the standard recommended dosing regimen of amikacin. Continuous infusion of beta-lactams combined with once dosing of amikacin seems to be as or more effective than intermittent injection of each drug.

Nosocomial infections encountered in intensive care units are frequently due to Gram negative bacilli among which Stenotrophomonas maltophilia, Acinetobacter sp., and Enterobacter sp. The aim of the present study was to evaluate the in vitro bactericidal activity of the new broad spectrum cephalosporins cefepime (FEP) and cefpirome (CPO) alone or in combination with amikacin (AKN), gentamicin (GTN) or ciprofloxacin (CIP) against Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacter cloacae producing a derepressed cephalosporinase. This study was performed by using the time-kill curve method on 24 h with a starting inoculum of 10(6) - 10(7) cfu/ml. The combination of FEP (4 mg/l) with AKN (4 mg/l) against A. baumanii only results in about 1 log decrease at 24 h, but when FEP is combined at 8 mg/l, the decrease reaches 4 log in 24 h. The combination of FEP (16 and 32 mg/l) clavulanic acid (4 mg/l) resulted in 3 log decrease at 24 h. When combined with CIP 2 mg/l, FEP (16 and 32 mg) resulted in 5 and 6 log decrease in 24 h respectively. There were no survival bacteria at 6 h when FEP (32 mg/l) was combined with clavulanic acid (4 mg/l) and GTN (8 mg/l) at 6 h. Used alone FEP (1 mg/l) or CPO (1 mg/l) against E. cloacae, a 3 log decrease occurs at 6 h followed by a regrowth at 24 h. Combined with AKN (2 mg/l), FEP (1 mg/l) results in a 6 log decrease at 24 h, when CPO at 2 mg/l is needed for an equivalent result. These data show synergistic bactericidal activity of both new extended cephalosporins combined with AKN, GTN or CIP at concentrations achievable in biological fluid with adaptative dosage regimen.