Search

Background/Purpose The intergenic SNP rs10865331 at 2p15 was identified as a major risk factor for ankylosing spondylitis (AS) susceptibility in genome-wide association studies (GWAS). B3GNT2 gene regulates polylactosamine synthesis is potentially functionally relevant to AS disease development. We investigated whether SNP rs10865331 and two B3GNT2 SNPs (rs11900673 and rs1136151) are associated with AS susceptibility and disease severity in Taiwanese. Methods Distributions of genotypes, alleles, and haplotypes of three SNPs were compared between 1,472 AS patients and 2,117 healthy blood donors and among AS patients stratified by clinical characteristics. Results The intergenic SNP rs10865331 was significantly associated with AS (PFDR = 1.02E-05) in Taiwanese. In AS patients stratified by positivity of HLA-B27 and syndesmophyte formation, all three B3GNT2 locus SNPs (rs11900673, rs1136151, and rs10865331) were significantly associated with syndesmophyte formation among HLA-B27 positive AS patients. Haplotype analyses revealed that the “CTA” (rs11900673C/rs1136151T/rs10865331A) haplotype was significantly associated with AS susceptibility (Padj = 0.0177) and syndesmophyte formation (Padj = 0.016) in HLA-B27 positive patients. In contrast, “TCG” (rs11900673T/rs1136151C/rs10865331G) haplotype showed protection against AS development (Padj = 0.0005 for HLA-B27 positive and Padj = 0.004 for HLA-B27 negative, respectively) and syndesmophyte formation (Padj = 0.0017) in HLA-B27 positive patients. Furthermore, B3GNT2 mRNA expressions were negatively associated with erythrocyte sedimentation rate (ESR, P = 0.0103), C-reactive protein (CRP, P = 0.0353), Bath ankylosing spondylitis functional index (BASFI, P = 0.0171), and syndesmophyte formation (P = 0.0148). Conclusion Our data suggest that B3GNT2 gene may contribute to AS development and affect AS severity by interacting with HLA-B27 in Taiwanese.

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation.Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review.A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study.Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.

Background The aim of the study was to assess programmed death‐ligand‐1 (PD‐L1) expression in different histological types and gene mutation status of patients with non‐small cell lung cancer (NSCLC). Methods A total of 4062 pathology‐confirmed lung cancer patients were retrospectively screened at Kaohsiung Chang Gung Memorial Hospital from November 2010 to June 2017. There were 699 NSCLC patients with confirmed PD‐L1 expression level retrospectively enrolled for analysis. Results There was a trend of higher PD‐L1 expression in squamous cell carcinoma and adenosquamous cell carcinoma than in adenocarcinoma (p = 063). Significant higher PD‐L1 expression in EGFR wild‐type was noted (p, A trend or significant differences in PD‐L1 expression between different histologic types in NSCLC, different EGFR status, and different ALK status, and different tumor tissue storage time. A higher survival benefit (TTF or OS) was observed in no PD‐L1 expression than with PD‐L1 expression in adenocarcinoma, EGFR mutation, and ALK mutation patients. PD‐L1 assay should be performed as early as possible if tissue is available.

Microbial fuel cells (MFCs) are recognized as an efficient method to utilize biomass to generate power while simultaneously treats wastewater. Micro-electro-mechanical system (MEMS) technology enables miniaturization of the MFCs system. Miniaturized MFCs through MEMS strengthen the system’s reaction capacity that makes it suitable for environmental sense field applications such as sensors or biomedical actuators. In this work, MEMS technology is employed to deposit metal layers on the surface of the anode/cathode electrode to enhance the power density of the MFC. Hence, micromixers and micro-pillars in the anode tank along with the influence of the electron transport media on MFC performance were evaluated. The introduction of the micro-mixers promotes the full mixing of the anolyte. The inclusion of the micro-pillars increases the surface area of the electrode, thereby enhancing the electrical energy output of the MFC. Results revealed that the introduction of the microstructure and the electron transfer media to the anolyte in the MFC have yielded a maximum current of 66.55 μ A cm−2, a maximum power density of 3.28 μ W cm−2, and an internal resistance value of 2 . 57 k Ω . Moreover, the inclusion of several micro-mixers and micro-pillar structures to the anode tank has shown the performance enhancement of MFC. Relevant research results will provide a reference for future research on the combination of MFCs and sensors.

Purpose To investigate the survival benefit with first/second generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) and osimertinib in different treatment sequences. Methods We retrospectively screened 3807 patients diagnosed with cancer between 2013 and 2019 at Kaohsiung Chang Gung Memorial Hospital. In total, 76 patients with EGFR T790M mutation who received osimertinib after re‐biopsy or liquid biopsy were enrolled for the analysis. Results The median progression‐free survival (PFS), median overall survival (OS), and median OS2 of the 76 patients were 11.93, 66.53, and 29.57 months, respectively. A significant difference was observed in the disease control rate between those who received osimertinib treatment after chemotherapy (group A) and those who received osimertinib immediately following EGFR‐TKI therapy (group B) (34 [94.4%] vs. 31 [77.5%], p = 0.036). In addition, chronic obstructive pulmonary disease tended to be a poor prognostic factor for PFS and OS. Conclusion This real‐world analysis revealed that previous chemotherapy could affect the treatment outcomes of patients with non‐small cell lung cancer treated with osimertinib. Osimertinib treatment following first/second generation EGFR‐TKI treatment or chemotherapy resulted in improved survival benefit., Osimertinib treatment after one line of chemotherapy (group A) had a better response rate and a better PFS than osimertinib treatment immediately following treatment with first/second generation EGFR‐TKIs (group B). COPD tended to a poor prognostic factor for PFS and OS2 in patients with osimertinib use.

OBJECTIVES Osimertinib is the main treatment choice for pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) T790M mutations. However, the choice of subsequent therapy when progressive disease has developed after osimertinib treatment remains a major therapeutic challenge. This study evaluated the efficacy of osimertinib-based combination therapies in patients who developed progressive disease after treatment with osimertinib. MATERIAL AND METHODS We enrolled NSCLC patients harbouring T790M mutations pretreated with first- or second-generation EGFR tyrosine-kinase inhibitors and were receiving osimertinib at two tertiary referral centres between August 2015 and July 2019, and the subsequent treatment efficacy was assessed. RESULTS Osimertinib-based combination therapy yielded better overall survival (OS) than chemotherapy alone (not achieved vs. 7.8 months; hazard ratio, 0.39; 95 % confidence interval 0.17-0.89; P = 0.025) according to the Cox proportional hazards model adjusted for possible confounders. Synergism (combination index

Purpose Uterine fibroids are benign gynecologic tumors and commonly occur in women by the age of 50. Women with symptomatic uterine fibroids generally receive surgical intervention, while they do not favor the invasive therapies. To evaluate the feasibility and safety of a novel magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) modality, ArcBlate, in the treatment of uterine fibroids. Methods Nine patients with uterine fibroids and one patient with adenomyosis were treated with ArcBlate MRgHIFU. Tumor size and quality of life were evaluated postoperatively at 1 and 3 months by magnetic resonance imaging (MRI) and the 36-Item Short Form Survey (SF-36), respectively. Results All patients completed the ArcBlate MRgHIFU procedure and there were no treatment-related adverse effects either during the procedure or during the 3 months of follow-up. Despite limiting the ablation volume to under 50% of the treated fibroid volume as a safety precaution, tumor volumes were markedly reduced in four patients by 15.78–58.87% at 3-month post-treatment. Moreover, SF-36 scale scores had improved at 3 months from baseline by 2–8 points in six patients, indicating relief of symptoms and improved quality of life. Conclusion This study evidence demonstrates the safety and feasibility of ArcBlate MRgHIFU and suggests its potential for treating uterine fibroids.

Introduction The clinical features of patients with metastatic epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving first-line therapy based on erlotinib combined with bevacizumab are unclear. Here, we sought to analyze the clinical features of this patient group. Methods Data were analyzed for the period from January 2015 to August 2019 for 49 patients with metastatic EGFR-mutated lung adenocarcinoma receiving first-line erlotinib-and-bevacizumab combination therapy from the Linkou and Kaohsiung Chang Gung Memorial Hospitals. Results The combination of erlotinib and bevacizumab showed an 83.7% objective response rate and a 97.9% disease control rate. The median progression-free survival (PFS) and overall survival (OS) were 22.0 [95% CI (19.7–22.33)] and 47.6 [95% CI (38.87–56.37)] months, respectively, for all patients. The secondary EGFR-T790M mutation rate in the patients with acquired resistance to the combination was 72.4%. No predictive factor associated with the appearance of secondary EGFR-T790M mutations was found. The most frequent adverse event (AE) caused by the combination therapy was dermatitis (100%), and most of the AEs were manageable and grades 1 and 2. Conclusion Erlotinib combined with bevacizumab is an effective and safe therapy for untreated metastatic EGFR-mutated lung adenocarcinoma. The combination does not alter secondary EGFR-T790M mutations in patients with acquired resistance and is feasible in real-world clinical practice. Graphic Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40487-021-00152-6.

Background Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. Methods Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. Results Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31–1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0–1 vs. 2–3 HR 0.09 [95% CI, 0.02–0.33]; p p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01–0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08–1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. Conclusion Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Objective To determine whether ultrasound (US)-detected synovitis affects the therapeutic efficacy of hyaluronic acid (HA) injection for treating knee OA. Methods Patients with symptomatic knee OA were recruited. All the patients received HA injection two times at 2-week intervals. Clinical assessments were performed using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities OA Index (WOMAC) at baseline and 1 and 6 months after treatment. Imaging evaluation was based on complete knee US examination and the Kellgren–Lawrence grading. Suprapatellar synovial fluid (SF) depth, synovial hypertrophy (SH) and vascularity were measured through US. Results In total, 137 patients who fulfilled the inclusion criteria were included in the analysis. All patients demonstrated improvement in VAS and WOMAC scores at 1 and 6 months after treatment (P Conclusion Ultrasound detected suprapatellar effusion predicts reduced efficacy of HA injection in knee OA

Rationale: The endemic of peri-implantitis affects over 25% of dental implants. Current treatment depends on empirical patient and site-based stratifications and lacks a consistent risk grading system. Methods: We investigated a unique cohort of peri-implantitis patients undergoing regenerative therapy with comprehensive clinical, immune, and microbial profiling. We utilized a robust outlier-resistant machine learning algorithm for immune deconvolution. Results: Unsupervised clustering identified risk groups with distinct immune profiles, microbial colonization dynamics, and regenerative outcomes. Low-risk patients exhibited elevated M1/M2-like macrophage ratios and lower B-cell infiltration. The low-risk immune profile was characterized by enhanced complement signaling and higher levels of Th1 and Th17 cytokines. Fusobacterium nucleatum and Prevotella intermedia were significantly enriched in high-risk individuals. Although surgery reduced microbial burden at the peri-implant interface in all groups, only low-risk individuals exhibited suppression of keystone pathogen re-colonization. Conclusion: Peri-implant immune microenvironment shapes microbial composition and the course of regeneration. Immune signatures show untapped potential in improving the risk-grading for peri-implantitis.

The ferroelectric (FE) negative capacitance (NC) has emerged as a potential candidate for low-power electronics. In this study, we experimentally demonstrate the capacitance magnification of a paraelectric (PE) HfO2 capacitance (CHfO2) connected in series with a FE ZrO2 capacitance (CZrO2), which is higher than the value predicted by the series capacitance formula (CZrO2−1 + CHfO2−1)−1 and has a capacitance magnification ratio in the range 1.79–2.24. A model based on the switching of the net polarization in FE multi-domains is proposed to explain the capacitance magnification. In addition, the operation bandwidth of the NC effect was investigated by the frequency response of the capacitance magnification from 1 kHz to 10 GHz for the first time. The result reveals vanishing of the capacitance magnification at a frequency of about tens of megahertz, which suggests that the operation speed of NC is below ∼100 MHz.

The performance enhancements of Si junctionless transistors (JLTs) with a short gate length (LG) below 10 nm by a pronounced ferroelectric (FE) gate dielectric were demonstrated for the first time. A TiN gate with LG = ∼8 nm was defined by helium ion beam lithography (HIBL) using hydrogen silsesquioxane as a resist. As compared with the paraelectric HfO2 gate oxide, the FE Hf0.5Zr0.5O2 gate dielectric leads to a suppression of the off-state current (IOFF) by ∼2 orders of magnitude and a reduction of the minimum subthreshold swing (SS) to ∼33 mV dec−1, along with an enhancement of the on/off ratio in the reverse-sweep direction in JLTs with LG = ∼8 nm. JLTs with a long LG = 5 μm were also investigated for comparison, revealing a decrease of IOFF by ∼25× and the sub-60 mV dec−1 SS across ∼3 orders of drain current (ID) under a large drain voltage (VD = 0.5 V) operation during the reverse sweep in FE JLTs. A time domain analysis indicated that the transient negative capacitance (TNC) effect takes place in the FE gate dielectric. A physical model was proposed to account for the TNC effect and the sub-60 mV dec−1 SS based on the capacitance increase during the FE polarization switching. This study also demonstrates for the first time the fabrication of nanoelectronic devices with a sub-10 nm critical dimension by using the HIBL technique with a damage-free dose.

Background To evaluate the use of a human fibrin glue (Tisseel) for minor bleeding control and approximation of ovarian defect during transvaginal natural orifice ovarian cystectomy (TNOOC) of benign and non-endometriotic ovarian tumors. Methods A total of 125 women with benign and non-endometriotic ovarian tumors who underwent TNOOC between May 2011 and January 2020: 54 with the aid of Tisseel and 71 with traditional suture for hemostasis and approximation of ovarian defect. Surgical outcomes such as length of surgery, operative blood loss, postoperative pain score, and postoperative hospital stay were recorded. Before and immediately (10 days) and at 6 months after the procedure, serum anti-Müllerian hormone (AMH) levels were also determined. Results Complete hemostasis and approximation of ovarian defect were achieved in all cases. No significant difference was noted in the operating time, operative blood loss, postoperative pain scores after 12, 24 and 48 h, length of postoperative stay, and baseline AMH levels between the two groups. The operation did not have a negative effect on the immediate and 6-month postoperative AMH levels in the suture group. However, the decline in the AMH levels was significant immediately after surgery in the Tisseel group, nevertheless, no significant difference was noted in the AMH levels at 6 months (3.3 vs. 1.7 mg/mL; p = 0.042, adjusted p = 0.210). Conclusion The use of Tisseel in TNOOC of benign and non-endometriotic ovarian tumors without suturing the ovarian tissue is clinically safe and feasible.

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

The development of renewable and clean energy has been the priority of the global research field due to the urgent effects of climate change. Microbial fuel cell (MFC) is recognized as a sustainable approach to simultaneously generate power and treat wastewater through the employment of microorganisms as catalyst. The use of buffer solution in the wastewater treatment makes the commercial application of MFCs challenging due to their environmental impact and high costs. This work uses rotational motion to generate the flow stress in the anode chamber of the MFCs to enhance biofilm growth and mass transfer that leads to an overall performance improvement of the system. The effects on pH, chemical oxygen demand (COD), and power density were evaluated under rotational speeds of the magnetic stirrer from 0 to 640 rpm. The influence of the stirrer was then assessed utilizing the same parameters specified for scenarios with and without buffer. The results reveal that at 480 rpm of stirring speed, the pH value was neutral with a maximum COD removal of 82 % for bufferless and 93 % for buffered scenarios. In addition, for bufferless operation at 480 rpm yielded a power density of 402 mWm−2. The results of the flow stress analysis for bufferless and buffered MFCs are beneficial for the commercialization and future development of the system for wastewater treatment applications.

Scaling up of microbial fuel cells is a challenge for practical applications in wastewater treatment. In addition, the flow control is an important aspect for the electrochemical reactions occurring at the electrodes are influenced by fluid motions. By using dimensionless parameter analysis fluid regimes can be investigated in different scales of reactors. In this study, four important dimensionless flow parameters such as Reynolds number, Peclet number, Schmidt number, and Sherwood number were used for systematic analysis of hydrodynamic effects and power performance of recirculation mode microbial fuel cells together with computational fluid dynamics method. Results showed that the higher value of Reynolds number enhanced the convective flow of anolyte due to the dominant inertial forces in the flow field. Therefore, Reynolds number of 1.6 × 101 were obtained high mass transfer coefficient of 4.76 × 10−7 m s-1 and thin diffusion layer thickness of 2.52 × 10-3 m. Maximum power density and limited current density of 2422.8 mW m-2 and 4736.4 mA m-2 were obtained respectively which were higher than Reynolds number of 0 by 1.61 and 1.69 times. These findings shall be useful for effective recirculation flow mode MFCs power production and have a great possibility for large scale applications.

Summary Background We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. Methods In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov , NCT01982955 , and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. Findings From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9–6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2–6·8; hazard ratio [HR] 0·67, 90% CI 0·35–1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1–37·3) versus 18·7 months in the chemotherapy group (15·9–20·7; HR 0·69, 0·34–1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1–16·6] vs 4·4 months [4·1–6·8]; HR 0·35, 0·17–0·74; median OS 37·3 months [90% CI 24·2–37·3] vs 17·9 months [12·0–20·7]; HR 0·33, 0·14–0·76) or MET amplification (n=19; median PFS 16·6 months [8·3–not estimable] vs 4·2 months [1·4–7·0]; HR 0·13, 0·04–0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25–not estimable]; HR 0·08, 0·01–0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. Interpretation Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. Funding Merck KGaA.

In recent times, many scientists have given great attention to nutraceuticals (complementary medicine) as it widely used for promoting health status. In particular for the prevention and treatment of various neurological diseases or disorders without or less adverse effects. The current mini-review was intended to compile all popular (major) nutraceuticals against various neurodegenerative diseases (NDDs) including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) with special reference to clinical trials. Preliminary reviews indicated that nutraceuticals like curcumin, resveratrol, Epigallocatechin-3-gallate (EGCG), Coenzyme Q10, ω-3 FA (DHA/EPA/ALA), showed better neuroprotective activity against various NDDs in human setting (clinical trial). Hence this contribution will focus only on those popular nutraceuticals with proposed brief mechanisms (antioxidant, anti-inflammatory, mitochondrial homeostasis, autophagy regulation, promote neurogenesis) and its recommendation. This mini-review would aid common people to choose better nutraceuticals to combat various NDDs along with standard neuroprotective agents and modified lifestyle pattern., Graphical abstract Image 1

Human papillomavirus (HPV) is the well‐established etiologic factor for cervical neoplasia. Cervical conization constitutes an effective treatment for high‐grade cervical intraepithelial neoplasia (HG‐CIN). We conducted an observational study for long‐term outcomes and HPV genotype changes after conization for HG‐CIN. Between 2008 and 2014, patients with newly diagnosed HG‐CIN before conization (surveillance new [SN] group) and those who had undergone conization without hysterectomy (surveillance previous [SP] group) were enrolled. HPV testing and Pap smear were performed periodically for the SN and SP (collectively S) groups. All other patients receiving conization for HG‐CIN during the study period were identified from our hospital database. Those eligible but not enrolled into our study were assigned to the non‐surveillance (non‐S) group. For the S group (n = 493), the median follow‐up period was 74.3 months. Eighty‐four cases had recurrent CIN Grade 2 or worse (CIN2+) (5‐year cumulative rate: 14.8%), of which six had invasive cancer. Among the 84 patients, 65 (77.4%) exhibited type‐specific persistence in the paired HPV results, whereas only 7 (8.3%) harbored new HPV types that belonged to the 9‐valent vaccine types. Among the 7397 non‐S patients, 789 demonstrated recurrent CIN2+, of which 57 had invasive cancer. The stages distribution of those progressed to invasive cancer in the non‐S group were more advanced than the S group (P = .033). Active surveillance might reduce the severity of those progressed to cancer. Because a majority of the patients with recurrent CIN2+ had persistent type‐specific HPV infections, effective therapeutic vaccines are an unmet medical need., What's new? High‐grade cervical intraepithelial neoplasia (HG‐CIN), a cervical carcinoma precursor, frequently is caused by high‐risk human papillomavirus (hr‐HPV) infection. HG‐CIN can be treated by cervical conization, though the procedure does not eradicate hr‐HPV, potentially enabling CIN recurrence. Here, in Taiwanese patients, investigation of HPV genotype changes in relation to HG‐CIN status after conization shows that 77.4 percent of patients with recurrent CIN 2 grade or worse (CIN2+) after conization had persistent type‐specific HPV infections. Vaccination against the remaining high‐risk HPVs prevented recurrent CIN2+ in only 8.3 percent of patients, revealing an unmet need for effective therapeutic vaccines.

Background: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused severe pneumonia at December 2019. Since then, it has been wildly spread from Wuhan, China, to Asia, European, and United States to become the pandemic worldwide. Now coronavirus disease 2019 were globally diagnosed over 3 084 740 cases with mortality of 212 561 toll. Current reports variants are found in SARS-CoV-2, majoring in functional ribonucleic acid (RNA) to transcribe into structural proteins as transmembrane spike (S) glycoprotein and the nucleocapsid (N) protein holds the virus RNA genome; the envelope (E) and membrane (M) alone with spike protein form viral envelope. The nonstructural RNA genome includes ORF1ab, ORF3, ORF6, 7a, 8, and ORF10 with highly conserved information for genome synthesis and replication in ORF1ab. Methods: We apply genomic alignment analysis to observe SARS-CoV-2 sequences from GenBank (http://www.ncbi.nim.nih.gov/genebank/): MN 908947 (China, C1); MN985325 (United States: WA, UW); MN996527 (China, C2); MT007544 (Australia: Victoria, A1); MT027064 (United States: CA, UC); MT039890 (South Korea, K1); MT066175 (Taiwan, T1); MT066176 (Taiwan, T2); LC528232 (Japan, J1); and LC528233 (Japan, J2) and Global Initiative on Sharing All Influenza Data database (https://www.gisaid.org). We adopt Multiple Sequence Alignments web from Clustalw (https://www.genome.jp/tools-bin/clustalw) and Geneious web (https://www.geneious.com. Results: We analyze database by genome alignment search for nonstructural ORFs and structural E, M, N, and S proteins. Mutations in ORF1ab, ORF3, and ORF6 are observed; specific variants in spike region are detected. Conclusion: We perform genomic analysis and comparative multiple sequence of SARS-CoV-2. Large scaling sequence alignments trace to localize and catch different mutant strains in United possibly to transmit severe deadly threat to humans. Studies about the biological symptom of SARS-CoV-2 in clinic animal and humans will be applied and manipulated to find mechanisms and shield the light for understanding the origin of pandemic crisis.

Propolis is a bee wax rich in various phytocomponents and traditionally used to treat various ailments. Propolis is reported to possess an array of biological properties including anti-inflammatory, antioxidant, anti-cancer, and anti-diabetic as well as cardioprotective, hepatoprotective, renoprotective, and derma protective activities. A plethora of studies confirmed that propolis is effective against various types of cancer including head and neck, lung, liver, brain (glioma), pancreas, kidney, prostate, skin (melanoma), breast, oral, esophagus, gastric, colorectal, and bladder cancers. However, many researchers have demonstrated that propolis displays potent chemoprotective/chemopreventive or anti-cancer activity against only a few types of cancers like oral, gastrointestinal, dermal (melanoma), breast, and prostate cancers. Therefore, this mini-review only summarizes the chemopreventive/chemotherapeutic activities of propolis and its updated underlying mechanisms. Taken together, propolis displays potent chemoprotective or anti-cancer effect due to the presence of various phytocomponents which contribute to pro-apoptotic, cytotoxic, anti-proliferative (cell cycle arrest), anti-metastatic, anti-invasive, anti-angiogenic and anti-genotoxic or anti-mutagenic properties along with antioxidant, immunomodulatory, and anti-inflammatory functions. Hence, propolis could be used as an adjuvant for treating various cancers along with standard chemotherapeutic drugs. However, many large-scale clinical studies are needed to justify such applications.

BACKGROUND: China announced an outbreak of new coronavirus in the city of Wuhan on December 31, 2019; lash to now, the virus transmission has become pandemic worldwide. Severe cases from the Huanan Seafood Wholesale market in Wuhan were confirmed pneumonia with a novel coronavirus (2019-nCoV). Understanding the molecular mechanisms of genome selection and packaging is critical for developing antiviral strategies. Thus, we defined the correlation in 10 severe acute respiratory syndrome coronavirus (SARS-CoV2) sequences from different countries to analyze the genomic patterns of disease origin and evolution aiming for developing new control pandemic processes. METHODS: We apply genomic analysis to observe SARS-CoV2 sequences from GenBank (http://www.ncbi.nim.nih.gov/genebank/): MN 908947 (China, C1), MN985325 (USA: WA, UW), MN996527 (China, C2), MT007544 (Australia: Victoria, A1), MT027064 (USA: CA, UC), MT039890 (South Korea, K1), MT066175 (Taiwan, T1), MT066176 (Taiwan, T2), LC528232 (Japan, J1), and LC528233 (Japan, J2) for genomic sequence alignment analysis. Multiple Sequence Alignment by Clustalw (https://www.genome.jp/tools-bin/clustalw) web service is applied as our alignment tool. RESULTS: We analyzed 10 sequences from the National Center for Biotechnology Information (NCBI) database by genome alignment and found no difference in amino acid sequences within M and N proteins. There are two amino acid variances in the spike (S) protein region. One mutation found from the South Korea sequence is verified. Two possible "L" and "S" SNPs found in ORF1ab and ORF8 regions are detected. CONCLUSION: We performed genomic analysis and comparative multiple sequences of SARS-CoV2. Studies about the biological symptoms of SARS-CoV2 in clinic animals and humans will manipulate an understanding on the origin of pandemic crisis.

Small flexible force-sensing resistor (FSR) sensors can detect laryngeal excursion during swallowing, but the detected laryngeal excursion has not been correlated with videofluoroscopic swallowing study (VFSS) results. Here, we tested the correlation of temporal parameters between the laryngeal excursion recording by FSR sensor and the hyoid motion recording by VFSS under simultaneously swallowing test recordings. Swallowing measurements were recorded in a radiological suite by simultaneously using VFSS and FSR sensors to detect hyoid motion and laryngeal excursion, respectively. Volunteers sat with their head vertical to the Frankfort plane. Two FSR sensors, each for detecting thyroid cartilage excursion and thumb pressing, were placed. VFSS images and FSR sensor signals during single 5-mL barium liquid (30% wt/volume %) bolus swallowing were collected and analyzed for four swallows per participant. In total, 15 men (28.0 ± 4.1 years old); 14 women (28.4 ± 4.2 years old) were recruited. Temporal parameters between VFSS and noninvasive system demonstrated a strong correlation by Pearson’s correlation analysis: in men (R = 0.953–0.999) and in women (R = 0.813–0.982), except for VT1–V1 compared with FT1–F1, which demonstrated a moderate correlation in women (R = 0.648; all p p = 0.001). Therefore, this is the first study to simultaneous record VFSS and noninvasive signals by FSR sensor. The correlation of temporal parameters between these two tests was strong. This finding is valuable for future applications of this noninvasive swallowing study tool.

To discover the nonlinear optical (NLO) materials with strong second harmonic generation (SHG), the design of NLO-active molecular units with large polarization is considered as a common strategy. Herein, we propose that the local structural distortion induced with vacancies, apart from the NLO-active units, can be employed to improve the NLO effect in solids as well. Accordingly, a new tungsten bronze (TB) oxide, Pb

The impact of atomic layer bombardment (ALB) was investigated on the aluminum nitride (AlN) passivation layer between the HfO2 gate dielectric and the n-type epitaxial germanium (Ge). The ALB techn...

BACKGROUND To investigate the frequency of systemic drugs taken by elderly patients with or without periodontitis and the possible association between medication consumption and the severity of periodontitis. METHODS A total of 1221 patients, including 608 with generalized moderate to severe periodontitis (periodontitis group) and 613 age- and gender-matched individuals with healthy periodontium (healthy group) were selected. Systemic conditions, medications and periodontal status were recorded. Medication intake frequency (%) was compared using unconditional logistic regression. RESULTS The top three most common medications were angiotensin-converting enzyme (ACE) inhibitors (17.9%), antidepressants (17.8%), and lipid-lowering medications (16.5%). Both ACE inhibitors and antidepressants showed statistically higher intake frequency in the periodontitis group relative to healthy controls (21.5% versus 14.4%; odds ratio [OR] = 1.64), (21.1% versus 14.5%, OR = 1.57) (P

This randomized, double-blind, clinical trial was designed to compare the endurance capacity (ergogenic property) in healthy athletes after consumption of apple cider vinegar (ACV) and a commercial sports drink (CSD) before and during endurance exercise. Fourteen healthy participants were enrolled in this trial and were divided into two groups as ACV and CSD with seven participants in each. Participants were requested to consume 500 mL of either commercial ACV or CSD 1 h before endurance exercise (bicycle ergometer). Blood samples were collected at baseline, 0, 20, 40, 60 min until exhaustion to assess glucose, lactate, ammonia and non-esterified fatty acids (NEFA). Respiratory exchange rate (RER) score was measured every 15 min and the heart rate (HR) was measured every 5 min. The outcome of the present trial clearly showed that no significant differences were observed between ACV and CSD except in the blood level of ammonia (only at exhaustion time). Thus, these results show that ACV and the CSD both possessing the ergogenic property, enhanced blood glucose, NEFA, and suppress the production of lactate as well as maintains normal RER score, and HR throughout the endurance exercise. Overall this trial showcases that ACV did not significantly improve the ergogenic activity over the CSD. Keywords: Apple vinegar, Lactate, Ammonia, RER score, Endurance, Physical performance

More than 50% of the world’s population is infected with Helicobacter pylori. H. pylori is the major causative agent of gastric ulcers and gastric cancer. H. pylori eradication using antibiotics either alone or together with a proton pump inhibitor is the primary strategy to decrease the incidence of gastric cancer. Although eradication therapy is effective, there are significant adverse effects and more importantly, resistance to antibiotics occurs, which represents a major therapeutic challenge. Multiple natural products have been shown to suppress H. pylori both in vitro and in animal model systems. However, only a handful of natural products have been evaluated in human clinical trials. The focus of this review is to summarize the results of published human clinical trials to assess the ability of natural products to reduce or eliminate H. pylori infections. Current evidence suggests that these products appear to have great potential to be developed as pharmaceutical candidates for eradication of H. pylori, hopefully both antibiotic-sensitive and antibiotic-resistant strains. Frequent consumption of locally produced foodstuff for controlling H. pylori infection in different countries around the world may well be a feasible long-term solution to fight against this worldwide prevalent pathogen.

Study Objective This study was designed to evaluate the learning curve of transvaginal natural orifice surgery (NOS) for adnexal tumors based on the type of procedure (adnexectomy or cystectomy). Design Retrospective cohort study. Setting Tertiary-care university hospital. Patients One hundred thirty-six women with adnexal tumors. Interventions A series of 136 consecutive transvaginal NOS for adnexal tumor were performed between April 2011 and June 2016. Eighty-five patients (62.5%) had undergone cystectomy, and 51 patients (37.5%) had undergone adnexectomy. Measurements and Main Results The transvaginal NOS procedures included vaginal, endoscopic, single-port access techniques and were divided into 2 categories: adnexectomy and cystectomy. Operating time was electronically recorded and was defined as the time from the creation of a posterior colpotomy incision until the complete closure of the posterior colpotomy opening. The average operating time for the cystectomy and adnexectomy groups was 42.7 and 37.7 minutes, respectively (p = .015). The learning curve was analyzed using the cumulative summation method and showed that 36 cases were needed to achieve proficiency in transvaginal NOS for ovarian cystectomy. However, there was no significant cut-off point to determine the number of patients who had undergone adnexectomy. Conclusion A well-trained gynecologic endoscopist can achieve surgical proficiency in transvaginal NOS cystectomy after 36 cases. It is suggested that the surgical transvaginal NOS procedure should begin with adnexectomy rather than with cystectomy to avoid initial technical challenges.

Background: Dysphagia is a common and critical condition that occurs in Parkinson's disease (PD), and it may appear in early stages. However, few reliable swallowing-related questionnaires are currently available. Therefore, finding efficient questionnaires for surveying dysphagia during the early stages of PD is necessary. Purpose: This prospective study aimed to identify the correlations between the M.D. Anderson Dysphagia Inventory (MDADI) with dysphagia limit (DL) and the Unified Parkinson Disease Rating Scale (UPDRS) in early-stage PD. Methods: Forty-two patients with early-stage PD were recruited from a medical center. Data were collected for analysis of swallowing-related quality of life using the MDADI, symptom severity using the UPDRS, and DL using a noninvasive swallowing–respiration assessment system. Results: Our results showed that the MDADI, including its composite and subscales, was not correlated with DL. The composite scores of the MDADI were moderately correlated with the total score of the UPDRS (r = −0.504; p

In this paper, we propose user grouping, subcarrier allocation, and bit allocation schemes in multicarrier nonorthogonal multiple access (NOMA) systems on downlink beamforming to reduce the total transmit power while considering the data-rate and the error-rate constraints of practical modulation types. Power control is also considered. In this system, each subcarrier can be assigned to multiple users for data transmission. Each subcarrier is allocated to a cluster that contains groups of two users for data transmission. A subset of subcarriers is assigned to the same cluster for sharing. The system is based on orthogonal frequency division multiple access (OFDMA), in which a primary user (PU) is more important than a secondary user, and we ensure that all assigned subcarriers transmit data to the PU in the system. In the proposed schemes, the user-grouping operation is performed first and the subcarrier allocation along with the bit loading and power assignment are performed subsequently based on the user-grouping results. The simulation results obtained using the proposed schemes in conjunction with the nonorthogonal multiple access to allocate bits, subcarriers, and transmit power show that the proposed schemes outperform the conventional OFDMA system in terms of transmit power.

A novel “atomic layer substrate biasing (ALSB)” technique is proposed to improve the dielectric properties including film density, dielectric constant (K), and leakage current density (Jg) and the reliability of nanoscale thin films. In the ALSB process, in situ Ar plasma generated by substrate biasing is layer-by-layer introduced into each cycle of atomic layer deposition. Energy delivery from the plasma toward the as-deposited layer boosts the migration of adatoms, leading to ∼10% increase of the film density, ∼3-order-of-magnitude reduction of Jg, and an increment of K being as large as 40.7 of a ZrO2 layer of ∼5 nm. The reliability enhancement upon the ALSB treatment is demonstrated by constant-voltage-stress (CVS) and the time-dependent-dielectric-breakdown (TDDB) tests, which confirm the suppression of stress-induced traps and a high electric field of 4.7 MV cm−1 projected for a 10 year lifetime. Significant improvements in the film density, Jg, K, and the reliability indicate that ALSB is a highly effective technique to modify the quality of ALD-deposited thin films, which can be widely used in a variety of fields including energy saving, green energy, nanoelectronics, and biomedical applications.

Despite the crucial role of examiner reliability on quality research and practice, there is still limited literature analyzing factors affecting examiner variability of peri-implant clinical measurements. The present study investigated clinical peri-implant parameters to quantify their repeatability and investigate factors that may affect their accuracy. Thirty-three implants were examined by 4 operators. Peri-implant probing depth (PD), recession (REC), and gingival index (GI) were measured for agreement and included in the analysis. Agreement was quantified using intraclass correlation coefficients (ICCs; 95% confidence interval); mixed linear and logistic regressions were used to assess additional variables. The overall interexaminer agreement was comparable between PD (0.80) and REC (0.78) but significantly worse for GI (0.45; P < .001). Similarly, the intraexaminer agreement was similar for PD (0.81) and REC (0.80) but significantly worse for GI (0.57; P < .05). The magnitude of PD did not influence the agreement. In contrast, increasing disagreement was noted for positive REC (odds ratio [OR]: 3.0), negative REC (OR: 4.8), and lower GI (OR: 4.4). The incidence of bleeding on probing and severity of GI increased for deeper PD (0.113-unit increase per millimeter). Negative and positive values of recession and lower GI were associated with increasing disagreement. Radiographic bone loss, restoration contour, and implant diameter did not affect PD accuracy in this study. In conclusion, within the limitations of the study, GI measurements presented higher variability than PD and REC did. The PD and GI were associated with one another and increased after multiple measurements.

Hypoxia is known as an important trigger for the development of metastases in human cancers. Heat shock proteins (Hsps) are up-regulated by cellular stressors including hypoxia. To date, the functional role of Hsps within the hypoxic tumor microenvironment for esophageal squamous cell cancer (ESCC) remains poorly defined. Methods CoCl₂ was used to induce hypoxia in cultured ESCC cells which was confirmed by 2′,7′ –dichlorofluorescin diacetate (DCFDA) assay. 7-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a selective Hsp90 inhibitor, was used to treat 2 ESCC cell lines, KYSE-170 and -510 cells pretreated with or without CoCl₂₂₂₂₂ in different concentrations, followed by cytotoxicity (MTT) and migration assays. In parallel, expression of Hsp90, vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), and markers related to epithelial-mesenchymal transition (EMT) such as snail/E-cadherin, by immunoblot or ELISA while analyzing cell proliferation and migration of treated ESCC cells. Results CoCl₂ induced hypoxia was supported by induction of reactive oxygen species (ROS). CoCl₂ (200 μM) significantly suppressed cell viability and proliferation with a concomitant up-regulation of VEGF and HIF-1α in a dose-dependent fashion. In contrast, cell migration was significantly increased in response to CoCl₂ while down-regulating E-cadherin with a concomitant increase in Snail expression. 17-DMAG decreased expression of VEGF and HIF-1α while inhibiting cell migration and invasion. Conclusion Our data demonstrate that CoCl2 induced hypoxia promotes EMT and angiogensis, which are inhibited by 17-DMAG. These results suggest that hypoxia induced EMT and angiogensis is Hsp90 dependent in ESCC.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib-treated cohort in which 516 EGFR-mutated NSCLC patients receiving afatinib as front-line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF /dT790MLAF ), non-T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type-I and the rest as type-II uncommon mutation. Four hundred and sixty-one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression-free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10-8 ). Type-I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60-7.64]; P

Background: Androgen deprivation therapy (ADT) suppresses the production of androgen, and ADT is broadly used for intermediate or higher risk disease including advanced and metastatic cancer. ADT is associated with numerous adverse effects derived from the pharmacological properties. Previous meta-analysis on fracture risk among ADT users possessed limited data without further subgroup analysis. Risk estimation of updated real-world evidence on ADT-related fracture remains unknown.Objectives: To assess the risk of fracture and fracture requiring hospitalization associated with ADT among prostate cancer population on different disease conditions, treatment regimen, dosage level, fracture sites.Methods: The Cochrane Library, PubMed, and Embase databases were systematically screened for eligible cohort studies published from inception to March 2020. Two authors independently reviewed all the included studies. The risks of any fracture and of fracture requiring hospitalization were assessed using a random-effects model, following by leave-one-out, stratified, and sensitivity analyses. The Grading of Recommendations Assessments, Development and Evaluations (GRADE) system was used to grade the certainty of evidence.Results: Sixteen eligible studies were included, and total population was 519,168 men. ADT use is associated with increasing fracture risk (OR, 1.39; 95% CI, 1.26–1.52) and fracture requiring hospitalization (OR, 1.55; 95% CI, 1.29–1.88). Stratified analysis revealed that high-dose ADT results in an elevated risk of fracture with little statistical heterogeneity, whereas sensitivity analysis restricted to adjust for additional factors indicated increased fracture risks for patients with unknown stage prostate cancer or with no restriction on age with minimal heterogeneity. The GRADE level of evidence was moderate for any fracture and low for fracture requiring hospitalization.Conclusion: Cumulative evidence supports the association of elevated fracture risk with ADT among patients with prostate cancer, including those with different disease conditions, treatment regimens, dose levels, and fracture sites. Further prospective trials with intact information on potential risk factors on fracture under ADT use are warranted to identify the risky population.

Background: There is limited data on the relative survival rate of first-line therapy of gefitinib, erlotinib (first-generation epidermal growth factor receptor-tyrosine kinase inhibitor [EGFR-TKI]), and afatinib (second-generation EGFR-TKI) in patients with EGFR-mutated advanced lung adenocarcinoma in real-world data, especially in the Asian population. This study aimed to compare the relative survival rate of gefitinib, erlotinib, and afatinib in patients with EGFR-mutated advanced lung adenocarcinoma by real-world data in Taiwan.Methods: This retrospective cohort population-based study included untreated adult patients diagnosed with advanced lung adenocarcinoma who were identified in the Taiwan National Health Insurance Research Database between 2014 and 2017. The date of EGFR-mutated advanced lung adenocarcinoma diagnosis was referred as index date. This outcome evaluated overall survival (OS) and time to treatment failure (TTF) between gefitinib, erlotinib, and afatinib. Switching EGFR-TKIs or chemotherapy and new development of brain metastases were proxies of TTF. Estimated relative treatment effects on OS and TTF among EGFR-TKIs were adjusted by inverse probability of treatment weighting (IPTW) in Cox proportional hazards model. Propensity score (PS) matched pair analyses were performed as sensitivity analyses.Results: The study cohort included 3,695 patients initiated with gefitinib, 3,310 with erlotinib, and 3,041 with afatinib. The mean age among the three treatment groups was 70.4 (±11.6), 66.8 (±11.6), and 64.3 (±11.4) years, and the female percentage was 70.4, 58.6, and 57.7%, respectively. Afatinib showed longer median OS than gefitinib (23.9 vs. 21.3 months; adjusted hazard ratio (aHR), 0.87; p < 0.001) and erlotinib (23.9 vs. 21.8 months; aHR, 0.87; p = 0.001). Consistent results were observed with TTF outcomes. For patients with brain metastases at diagnosis, afatinib showed similar OS with erlotinib (p = 0.917) but superior to gefitinib (p = 0.028). PS matching had similar results with IPTW adjustment in the study population.Conclusion: Afatinib as first-line therapy had better survival outcomes for EGFR-mutated advanced lung adenocarcinoma than gefitinib and erlotinib in the Taiwan population. Both erlotinib and afatinib demonstrated superior treatment effect in patients with initial brain metastases than gefitinib.

The global coronavirus disease 2019 (COVID-19) outbreak had a great impact on the tourism industry. Numerous hotels have ceased operations. Because of the increasing influence of blogs, various industries have adopted blogs as a publicity and marketing strategy. Companies utilize consumers’ trust and loyalty toward bloggers to effectively contact them. Hence, bloggers play a crucial role in the hotel industry. No past study has researched blogger selection by hotel managers. In this study, an innovative mixed multiple-criteria decision-making (MCDM) model including importance-performance analysis (IPA), analytic hierarchy process (AHP), and technique for order preference by similarity to ideal solution (TOPSIS) is established to assist hotel managers in selecting bloggers. We firstly collect the selection criteria via interviews with hotel managers and a review of literature on blogger selection. Messages with stick are understood, remembered, and have an enduring influence on opinions and behavior. Hence, we also introduce the concept of stick to the selection criteria. Based on IPA and the literature review, a hierarchical structure for blogger selection is constructed. Then, AHP and TOPSIS are integrated to assist the case company managers to select suitable bloggers.

Background: There are limited comparisons of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in large, real-world cohorts of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor ( EGFR) mutations. Methods: Patients with advanced NSCLC ( N = 612) with common EGFR mutations receiving first-line gefitinib/erlotinib and afatinib were grouped and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutations were analyzed. Results: The gefitinib/erlotinib and afatinib groups each contained 206 patients after matching. Compared with gefitinib/erlotinib, patients receiving afatinib achieved longer median PFS (16.3 versus 14.2 months; log-rank test p = 0.020) and had a lower risk of progression [hazard ratio (HR) 0.73 (95% confidence interval (CI), 0.57–0.94); p = 0.017]. Median OS (37.3 versus 34.2 months; log-rank test p = 0.500) and reduction in risk of death [HR 0.89 (95% CI, 0.65–1.23); p = 0.476] did not differ significantly between groups. T790M positivity was significantly higher in the gefitinib/erlotinib than afatinib group (70.9% versus 44.6%, p Conclusion: Compared with gefitinib/erlotinib, afatinib had a higher treatment efficacy and a lower secondary T790M positivity in a large, real-world cohort of Asian patients with EGFR-mutated NSCLC.

Objective To demonstrate an innovative idea for a four-petal method for performing laparoscopic adenomyomectomy on a patient with focal-type adenomyosis. Design A step-by-step explanation of the technique with narrated video footage. Setting University hospital. Patient(s) A 38-year-old female with a 7 × 4 cm adenomyoma at the anterior uterine wall. Intervention(s) Laparoscopic adenomyomectomy began with a cruciate incision to turn the adenomyoma into the shape of a blooming four-petal flower to fully expose the tumor and maximize the removal of adenomyotic tissue. During excision of the lesion, around a 1 cm thickness of the myometrium was preserved at the subendometrial region and around a 0.5 cm thickness of the serosa flap was also left in each “petal.” Suture repair in the method introduced is different from closing the wound by approximation of myometrium to myometrium as in traditional myomectomy; instead, herein we repaired the adenomyomectomy wound by anchoring the serosal flap to the subendometrial tissue, with care taken to avoid dead space. Main Outcome Measure(s) Subjective clinical symptoms as well as serial ultrasonographic measurement of the uterine size, shape, and wall thickness. Result(s) The specimen removed was 92 g in weight. The symptoms have dramatically decreased since the procedure and dysmenorrhea improved from visual analog scale 8 to 1 postoperatively. Besides achieving satisfactory symptomatic relief, the ultrasonographic measurement of the myometrium was of adequate thickness (2.3 cm) after the operation and did not increase in a serial follow-up of 33 months. Conclusion(s) The four-petal method of adenomyomectomy with cruciate incision offers full exposure to the localized adenomyosis. It greatly facilitates a balance between the maximized resection of the lesions and tailored reserves of myometrium. Subsequent repair by anchoring the serosal flap to the subendometrial tissue ensures adequate thickness of the uterine wall after the operation.

The recent outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been causing respiratory diseases globally, damaging wide ranges of social-economic activities. This virus is transmitted through personal contact and possibly also through ambient air. Effective biosensor platforms for the detection of this virus and the related host response are in urgent demand. These platforms can facilitate routine diagnostic assays in certified clinical laboratories. They can also be integrated into point-of-care products. Furthermore, environmental biosensors can be designed to detect SARS-CoV-2 in the ambient air or in the intensive care ventilators. Here, we evaluate technical components of biosensors, including the biological targets of recognition, the recognition methods, and the signal amplification and transduction systems. Effective SARS-CoV-2 detectors can be designed by an adequate combination of these technologies.

The concept of the fixed wing Micro Air Vehicles (MAVs) has received increasing interest over the past few decades, with the principal aim of carrying out the surveillance missions. The design of the flapping wing MAVs still is in infancy stage. On the other hand, there has been increasing interest over the flow control using plasma actuators in worldwide. The aim of this research is to study the flow control of a flapping airfoil with and without plasma actuation in OpenFOAM. The OpenFOAM CFD platform has been used to develop our own plasma solver. For the plasma induced turbulence in the flow regime, k-ε turbulence model was adopted to address the interaction between plasma and fluid flows. For the plasma-fluid interaction, we use reduced-order modelling to solve the plasma induced electric force. A two dimensional NACA0012 flapping airfoil without plasma actuation study has been benchmarked with previous published literature. We have not only focused on the active flow control but also analyzed the important parameter reduced frequency at different values, those are 0.1, 0.05 and 0.025. Reduced frequency (κ) is very important parameter of an airfoil in the unsteady motion. Our major contribution is testing the several reduced frequencies with the plasma actuation. The positive and beneficial effects of the plasma actuator for all cases have been observed. From the observed results, the flapping with plasma actuation at reduced frequency of 0.1 showed the 14.285 percent lift improvement and the 16.19 percent drag reduction than the flapping without plasma actuation at the respective dynamic stall angles. The maximum lift coefficient is increased with the increase in reduced frequency. In overall, plasma actuators are effective in the flow control of a flapping airfoil. In future, the combination of the flapping with plasma actuators will be a promising application to boast the maneuverability of MAVs.

Background Approximately 3%-5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum-based chemotherapy as front-line treatment for patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the direct comparison between them in the front-line setting remains lacking. Methods A total of 48 patients with ALK-positive, previously untreated advanced NSCLC, who received crizotinib and ceritinib as front-line treatment were retrospectively investigated. The efficacy and pattern of disease progression were analyzed. Results Patients receiving ceritinib treatment were significantly younger than those receiving crizotinib treatment (52.0 vs. 63.0, P = 0.016). The median progression-free survival (PFS) was significantly longer with ceritinib than with crizotinib treatment (32.3 vs. 12.9 months; log-rank P = 0.020); the hazard ratio for disease progression or death, 0.27 (95% CI, 0.08-0.90; P = 0.033). An objective response was noted in all patients in the ceritinib group and in 23 patients in the crizotinib group (74.2%; 95% CI, 59.0 to 88.5). The rate of systemic progression was significantly lower over time with ceritinib treatment compared to crizotinib treatment (cause-specific hazard ratio, 0.21; 95% CI 0.06-0.73; P = 0.014). Serious adverse events were noted in one (2.9%) patient showing elevated liver function in the crizotinib group and three (23.1%) patients showing diarrhea in the ceritinib group. Dose reduction was needed in five out of 13 (38.5%) patients receiving ceritinib treatment. Conclusion Ceritinib showed higher efficacy associated with a better control of systemic progression compared to crizotinib for the front-line treatment of ALK-positive advanced NSCLCs.

The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo

Background: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum–etoposide) in treatment-naive patients with ES-SCLC. Methods: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum–etoposide; durvalumab plus tremelimumab plus platinum–etoposide; or platinum–etoposide alone. All drugs were administered intravenously. Platinum–etoposide consisted of etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum–etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum–etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum–etoposide group versus the platinum–etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. Findings: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–etoposide group and 269 to the platinum–etoposide group. Durvalumab plus platinum–etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–etoposide group versus 10·3 months (9·3–11·2) in the platinum–etoposide group, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum–etoposide group and 166 (62%) of 266 in the platinum–etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. Interpretation: First-line durvalumab plus platinum–etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. Funding: AstraZeneca.

BACKGROUND Clinical data on the outcomes of guided tissue regeneration (GTR) is scarce. The aim of this retrospective cohort study was to evaluate the outcomes after GTR, their stability and the survival of the treated teeth with periodontal infrabony defects. METHODS Infrabony defects treated with GTR using a bioabsorbable membrane and a bone graft substitute with at least 1-year follow-up were included. Survival and regression analyses were conducted to evaluate the outcomes, their stability, and the retention of the teeth. The effect of recorded variables on clinical attachment gain (CAL) and tooth survival were assessed via Cox proportional-hazards models and multivariate generalized linear models. RESULTS One hundred seventy-five treated defects were selected from a total of 641 charts. The average follow-up was 5.75 ± 4.6 years. At baseline, the mean CAL was 9.56 ± 1.93 mm with a mean pocket depth (PD) of 8.41 ± 1.42 mm. At the 1-year post-surgical recall, 3.55 ± 1.85 mm of CAL gain and 3.87 ± 1.87 mm PD reduction were observed (P < 0.05). The 5- and 10-year survival rates of the treated teeth were 85.0% and 72.7%, respectively. Baseline PD, smoking, and membrane exposure were significantly related to CAL gain, whereas baseline CAL, age, frequency in maintenance visits significantly affected tooth survival. CONCLUSION Within the limitations of this study, data suggests GTR is a good option for the treatment of infrabony defects because it can improve both tooth retention rate and overall clinical outcomes.