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Purpose: For people with metabolic syndrome (MetS), altering the macronutrient composition of their diets might ameliorate metabolic abnormalities. The common method of clinical assessment only measures total lipid concentrations but ignores the individual species that contribute to these total concentrations. Thus, to predict the amelioration of MetS following caloric restriction (CR) and the intake of fish oil, we used lipidomics to investigate changes in plasma lipids and identify potential lipid metabolites. Methods: Lipidomics was performed using ultra-high-performance liquid chromatography–tandem mass spectrometry on plasma samples from a clinical trial conducted over 12 weeks. Subjects were randomized into two groups: CR (n = 12) and CR with fish oil (CRF, n = 9). Anthropometric and clinical parameters were measured and correlated with plasma lipidomics data. Results: Compared with baseline, significant differences were observed in body weight, waist circumference, blood pressure and interleukin-6 in both groups, but triglyceride (TG) levels significantly decreased in only the CRF group (all p < 0.05). A total of 138 lipid species were identified. Levels of species containing long-chain polyunsaturated fatty acids were significantly elevated—greater than twofold—following fish oil intake, these included TG (60:9) and phosphatidylcholine (p40:6) (all q < 0.05). TG (60:9) tended to correlate negatively with body weight, body mass index, blood pressure, and HbA1c following fish oil intake. Conclusion: CR and fish oil can ameliorate MetS features, including anthropometric parameters, blood pressure, and blood lipid concentrations. The levels of particular lipid species such as TG-containing docosapentaenoic acid were elevated post-intervention and negatively associated with MetS features. TG (60:9) may be proposed as a lipid metabolite to predict amelioration in MetS following the intake of CR and fish oil. [ABSTRACT FROM AUTHOR]

Purpose: Prenatal stress (PS) during pregnancy affects in utero- and postnatal child brain-development. Key systems affected are the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS). Maternal- and fetal ANS activity can be gauged non-invasively from transabdominal electrocardiogram (taECG). We propose a novel approach to assess couplings between maternal (mHR) and fetal heart rate (fHR) as a new biomarker for PS based on bivariate phase-rectified signal averaging (BPRSA). We hypothesized that PS exerts lasting impact on fHR.Methods: Prospective case-control study matched for maternal age, parity, and gestational age during the third trimester using the Cohen Perceived Stress Scale (PSS-10) questionnaire with PSS-10 over or equal 19 classified as stress group (SG). Women with PSS-10 < 19 served as control group (CG). Fetal electrocardiograms were recorded by a taECG. Coupling between mHR and fHR was analyzed by BPRSA resulting in fetal stress index (FSI). Maternal hair cortisol, a memory of chronic stress exposure for 2-3 months, was measured at birth.Results: 538/1500 pregnant women returned the questionnaire, 55/538 (10.2%) mother-child pairs formed SG and were matched with 55/449 (12.2%) consecutive patients as CG. Maternal hair cortisol was 86.6 (48.0-169.2) versus 53.0 (34.4-105.9) pg/mg (p = 0.029). At 36 + 5 weeks, FSI was significantly higher in fetuses of stressed mothers when compared to controls [0.43 (0.18-0.85) versus 0.00 (- 0.49-0.18), p < 0.001].Conclusion: Prenatal maternal stress affects the coupling between maternal and fetal heart rate detectable non-invasively a month prior to birth. Lasting effects on neurodevelopment of affected offspring should be studied.Trial Registration: Clinical trial registration: NCT03389178. [ABSTRACT FROM AUTHOR]

Incidence and mortality of cervical cancer in South Africa is still very high and 4-6% of women present with FIGO stage IVB disease. However, the management of oligometastatic cervical cancer is not well decribed in literature. Treatment of stage IVB cervical cancer is individualised, but it mainly involves palliative systemic chemotherapy with a median survival time of about ten months. There is a growing body of evidence showing that in women with low volume oligometastatic disease, curative doses of radiation therapy to the pelvis and metastatic sites with or without chemotherapy can prolong survival significantly. Since South Africa is one of the few countries in Africa with functional chemoradiation therapy facilities, there is a need to review this evidence and see if the standard of care has to be changed in women with oligometastatic cervical cancer. [ABSTRACT FROM AUTHOR]

The low-loss Li2Mg4TiO7 dielectric ceramics were prepared by the conventional solid-state method. The relationship among sintering behavior, phase composition, microstructure and dielectric properties of Li2Mg4TiO7 ceramics was investigated. All the sintered samples exhibited the single phase with rock-salt structure belonging to Fm-3m space group. The higher Q•f values of samples above 1500 °C were depending on crystal structure and phase composition. IR reflectivity spectrum indicated that the dielectric constant of Li2Mg4TiO7 was mainly affected by the polar optical phonons. Typically, the ceramics sintered at 1600 °C exhibited excellent microwave dielectric properties with εr = 13.43, Q•f = 233,600 GHz and Υf = -7.24 ppm/°C. [ABSTRACT FROM AUTHOR]

What is known and objectives Choosing an alternative statin is recommended when managing statin-associated muscle symptoms ( SAMS) and new hydrophilic statins are often suggested. We report on a case of statin-associated muscle damage that was successfully managed by simplifying the patient's combination therapy with simvastatin-ezetimibe to simvastatin alone. Case summary The patient experienced SAMS when he was successively treated with atorvastatin, rosuvastatin, Xuezhikang capsule and combined simvastatin/ezetimibe therapy. However, the patient tolerated simvastatin therapy well even at a dose of 40 mg/day. What is new and conclusion Our case suggests that patients with SAMS who are intolerant to a wide variety of statins may be successfully managed with simvastatin monotherapy. [ABSTRACT FROM AUTHOR]

A case is presented of a 67-year-old woman referred to the authors’ institution with endometrioid endometrial cancer with a leucoerythroblastic blood film and marked thrombocytopenia. On further evaluation, it was confirmed that she had grade 3 endometrial cancer with bone marrow involvement (FIGO stage IVB). This is a rare complication of endometrial cancer and her marked thrombocytopenia severely limited her treatment options. [ABSTRACT FROM AUTHOR]

Polymorphism of kappa casein gene (κ-Cn) at exon 5 in 259 Chinese Holstein cattle was investigated using polymerase chain reaction-single strand conformation (PCR-SSCP) technique, to verify its effect on milk composition (fat, protein, lactose, total solids (TS) and solids not fat (SNF) content and influence of other factors such as parity and season of calving; aiming at utilizing it as a genetic aid in selection to improve the quality of production of this herd. A 218 bp fragment containing exon 1V of kappa casein gene was amplified by PCR and SSCP was applied to identify the structural gene polymorphism of κ-Cn. General linear model (GLM) was used to analyze differences between genotypes. The results indicated that κ-Cn genotypes significantly (P<0.05) affected fat, protein and lactose content. But it had no effect (P>0.05) on TS and SNF. However, cows with genotype TT showed higher fat and protein contents (3.89 and 3.50%, respectively) than those of genotypes CC and TC (3.62 and 3.66% for fat; 3.35 and 3.36 % for protein, respectively). Except for lactose content; parity had no effect on milk components. Also, the results disclosed that season of calving did not affect (P>0.05) milk composition. This study indicated that the κ-Cn genetic variants may be used as a genetic aid through increasing the frequency of desired genotypes to improve the quality of production of this herd. [ABSTRACT FROM AUTHOR]

Summary Free radicals are normally generated in many metabolic pathways. They are closely associated with inflammatory diseases. The aim of this study was to investigate the effects of free radicals and their antioxidants on the formation of pyridinoline using human fibroblasts from normal skin and hypertrophic scars. The significance of the increase in pyridinoline cross-links is that large quantities have been found in hypertrophic scars formed post-burn than in normal skin, and that catalase was effective in reducing the pyridinoline cross-link formation in hypertrophic scars. The pyridinoline cross-link concentration expressed in nM/µg hydroxyl proline was found to be higher in the culture supernatants of the fibroblasts from hypertrophic scars (9.04 ± 2.74) than that of normal skin (7.55 ± 2.1). When the human fibroblasts from normal skin and hypertrophic scar were subject to hydroxyl radicals generated by the Fenton reaction, there was no significant increase in pyridinoline cross-link concentration (nm/µg hydroxyl proline) in the supernatants compared with the control. When the controls plus various treatments with free radicals were subject to different antioxidants, including superoxide dismutase, catalase, glutathione peroxidase, and desferrioxamine, it was found that catalase alone was most effective in scavenging hydroxyl radicals as determined by the decrease in pyridinoline cross-links. [ABSTRACT FROM AUTHOR]

Limited data exist in the clonal dynamics of serial ctDNA as a predictive biomarker in advanced solid tumor pts receiving immune checkpoint blockade. Pts with mixed solid tumors received single agent P (anti-PD-1) 200 mg IV Q3wks in the investigator-initiated phase II INSPIRE trial (NCT02644369). ctDNA was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera™). Samples were considered ctDNA positive if ≥ 2 of 16 pt-specific targets met the qualifying confidence score threshold. Table: 113P Table: 113P Endpoint ORR N = 72 * CBR N = 72 * Endpoint PFS N = 73 * OS N = 73 * Subgroup CR/PR N = 15 SD/PD N = 57 CR/PR/SD≥6 cycles N = 22 CR/PR/SD<6 cycles N = 50 Subgroup ↑ from baseline N = 33 ↓ from baseline N = 40 ↑ from baseline N = 33 ↓ from baseline N = 40 ΔctDNA (% change) Median = -91.5% Range = -100% to 60% Median = 40% Range = -98.4% to 2458% Median = -75% Range = -100% to 96% Median = 52% Range = -94.6% to 2458% Results based on ΔctDNA Median = 7.9m6m = 51.5% Median = 2.8m6m = 10.0% Median = not reached 6m = 91% 12m = 82% Median = 9.1m6m = 73% 12m = 45% P-value P < 0.001 P < 0.001 Adjusted HR (95% CI)^ 0.43 (0.25-0.75) P = 0.003 0.35 (0.18–0.67) P = 0.002 ^Adjustment on cohorts; * 2 pts were excluded from ORR/CBR analyses as baseline ctDNA = 0; 1 of these 2 pts (with PR) excluded from PFS/OS analyses as C3 ctDNA = 0 Of 94 pts are presented. Demographics: male 38%; median age=55 yrs (range 21–81); triple negative breast (19%), ovarian (19%) and head and neck (17%) cancers comprised the major malignancies. Median no. of P cycles=3 (range 1–35); follow up was 14m (range 0.6-35.4); RECIST responses: CR 3.2% (n = 3), PR 14% (n = 13), CBR (CR+PR+SD>6 cycles) 28% (n = 26), RECIST/clinical PD (n = 61/18; 65%/19%). Median PFS=2.5m and median OS = 14m. In all 94 pts, ctDNA B correlated with PFS (adjusted HR 0.53, 95% CI 0.34-0.84, p = 0.01) and OS (adjusted HR 0.47, 95% CI 0.28-0.8, p = 0.01). Among 74 pts with both ctDNA B and ctDNA C3 , the change (ΔctDNA) correlated with clinical efficacy parameters (Table). Strong correlations exist between both ctDNA B and ΔctDNA with clinical outcome, suggesting both prognostic and predictive values in pts with mixed solid tumors. NCT02644369, December 31, 2015. University Health Network, Toronto. Merck, Netera, Terry Fox Research Institute, Princess Margaret Cancer Foundation. S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A.R. Hansen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Karyopharm. P. Bedard: Honoraria (institution), Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Oncothyreon. S. Lheureux: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Tesaro. A. Spreafico: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Oncology/Johnson & Johnson; Research grant / Funding (institution): Array Biopharma. A.A. Razak: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): CASI Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Adaptimmune. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. P.S. Ohashi: Honoraria (self), Advisory / Consultancy: Symphogen Inc; Honoraria (self), Advisory / Consultancy: Providence Therapeutics. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netera. L.L. Siu: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfiser; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/Medimmune; Honoraria (self), Advisory / Consultancy: Morphosys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self), Advisory / Consultancy: GeneSeeq; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: Oncorus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boerhinger-Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Intensity Therapeutics; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Shattucks; Spouse / Financial dependant: Agios. S. Bratman: Research grant / Funding (self): Nektar Therapeutics; Licensing / Royalties, Co-inventor of a patent relating to circulating tumor DNA detection technology: Roche Molecular Diagnostics. T.J. Pugh: Honoraria (self): Merck; Honoraria (self): Prosigna; Honoraria (self): Chrysalis Medical Advisors; Advisory / Consultancy: DynaCare; Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Circulating tumor DNA (ctDNA) is a promising, non-invasive biomarker for preclinical detection and monitoring of various cancers. The utility of ctDNA assessment in renal cell carcinoma (RCC) in not well established. Here, we evaluate the potential of a bespoke, multiplex PCR, whole exome sequencing (WES)-based approach for ctDNA detection. The cohort consisted of 42 patients with stage Ib-IV RCC who underwent complete surgical resection. ctDNA was measured in plasma samples drawn pre-surgery (n = 34; baseline) and at post-operative time points (n = 41) using the bespoke assay targeting patient-specific tumor variants. A median of 11.7 ng (1.4-175 ng) of cfDNA was extracted from a median plasma volume of 3.2 mL (1.2-3.8 mL). ctDNA was detected with a mean mutant molecules/mL of 5.3 (0.22-62). Baseline ctDNA was detected in 41% (14/34) of patients. Presence of ctDNA was significantly associated with increased tumor size (mean 9.7 vs 7.1cm, p < 0.05), advanced tumor stage (stage III-IV vs I-II, p < 0.05) and poorly differentiated tumors (grade III-IV vs II, p < 0.0001). In the postoperative setting, 8/8 ctDNA-positive patients relapsed (positive predictive value (PPV=100%), while 16/33 ctDNA-negative patients relapsed (NPV=52%). Positive ctDNA status was associated with reduced relapse-free survival at post-surgical timepoints (HR: 2.8; 95% CI:1.2-6.6). None of the post-surgical samples from a control cohort of 17 non-relapsing patients were ctDNA-positive (specificity of 100%; median follow up of 64 months). Presence of presurgical ctDNA strongly correlates with advanced stage RCC. Despite low plasma volumes, the bespoke assay detected ctDNA in 41% of baseline samples. Postoperative ctDNA presence is correlated with clinical relapse. However, absence of ctDNA does not preclude recurrence as RCC is known to shed limited amounts of ctDNA. Higher sample volumes and multiregion tumor biopsies could enhance detection rates. This personalized approach has the potential to be used for ctDNA-based detection of relapse in patients with advanced stage RCC. Natera, Inc.; Fox Chase Cancer Center. Natera, Inc.; Fox Chase Cancer Center. M. Balcioglu: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. H. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. S. Dashner: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. S. Shchegrova: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. E. Kalashnikova: Full / Part-time employment: Natera, Inc. H. Pawar: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R.G. Uzzo: Advisory / Consultancy: Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Argos. A. Aleshin: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. H. Sethi: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. R. Salari: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. M. Louie: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. B. Zimmermann: Shareholder / Stockholder / Stock options, Full / Part-time employment, I am an employee of Natera and own stock/options to stock.: Natera, Inc. P. Abbosh: Advisory / Consultancy, Advisory: Janssen; Advisory / Consultancy, Advisory: AstraZeneca. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Mutations in the DNAJB6 gene have been identified as a rare cause of dominantly inherited limb-girdle muscular dystrophy or distal-onset myopathy. Materials and Methods Exome sequencing was performed to investigate a Taiwanese family with a dominantly inherited distal-onset myopathy. Functional effects of the causal mutation were investigated in vitro. Results Exome sequencing of the two affected individuals in this family identified a heterozygous mutation, c. 287C>T (p. Pro96Leu) in the DNAJB6 gene, which co-segregated with the myopathy within all 12 family members. Notably, this mutation is novel and localizes within the glycine and phenylalanine-rich (G/F) domain and alters an amino acid residue previously reported with a different mutation. Furthermore, immunofluorescence analyses and filter trap assay demonstrated that the c. 287C>T (p. Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein. Conclusion This study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the feasibility of a low-dose contrast medium protocol for 64-detector row computed tomography angiography (CTA) of the neck using a low-tube-voltage/high-tube-current setting. MATERIALS AND METHODS: A phantom study was performed using 64-detector row spiral CT at multiple tube voltage and current settings. Iodine contrast medium attenuation curves were acquired by processing and used to select the best contrast medium-to-noise ratio (CNR). A prospective clinical study was then performed on 84 patients requiring neck CTA. Patients were randomly divided into two groups of 42. Group A was examined using the conventional imaging protocol (120 kV, 400 mAs) and group B was examined at 80 kV and 600 mAs along with a 50% reduction in contrast medium dose. The CT dose index-volume (CTDIvol), background noise (BN), and CNR were measured and statistically analysed. Various image quality criteria were evaluated by two senior radiologists using a qualitative five-point scale. RESULTS: Comparing group B with A, CTDIvol decreased by 54% (B: 27.48 mGy, A: 59.11 mGy), however, the CNR increased by 50%. The mean attenuation, which was caused by venous streak artefacts, was significantly lower in group B than A. Qualitative image analysis found that all criteria were significantly better for group B than A. CONCLUSION: At 64-detector row spiral CT, the low-tube-voltage/high-tube-current with low-dose contrast medium protocol was superior to the conventional protocol regarding radiation dose, venous streak artefacts, and image quality, and is feasible for CTA of the neck. [ABSTRACT FROM AUTHOR]

Background: In early breast cancer (EBC) patients, we aimed to determine whether circulating tumor DNA (ctDNA) analysis following primary surgery, before systemic therapy, identified molecular residual disease and was associated with risk of relapse and relapse-free survival (RFS)., Methods: Plasma was collected, retrospectively, before surgery, 1-14 weeks post-operatively, and before adjuvant therapy, and in a subset of patients after adjuvant therapy. A personalized, tumor-informed, multiplex PCR next generation sequencing assay (Signatera™) was used for ctDNA detection and quantification. The primary objective was to compare RFS and distant recurrence-free survival (DRFS) in patients with detected versus non-detected ctDNA., Results: A total of 48 patients with EBC (median age 50.5 years) [34 hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), 5 HER2+, 9 triple-negative breast cancer) were included. ctDNA was detected in 64.5% (20/31) of patients before surgery, and 35.4% (17/48) after surgery. ctDNA detection before surgery was associated with tumor grade (P = 0.019), ctDNA detection after surgery was associated with receptor subtype (P = 0.01). Patients with ctDNA detected after surgery had worse DRFS [hazard ratio = 5.5, 95% confidence interval (CI) 1.1-28.5, P = 0.04]. RFS in patients with ctDNA detected after surgery was worse than in those with lack of ctDNA detection, although not statistically significant (hazard ratio = 3.7, 95% CI 0.9-15.7, P = 0.073). Patients with ctDNA detected preoperatively or post-operatively had a trend towards worse RFS (hazard ratio = 7.8, 95% CI 0.9-63.7, P = 0.05) and DRFS (hazard ratio = 6.8, 95% CI 0.8-57, P = 0.07) compared with those with ctDNA undetected at both timepoints. ctDNA detection anticipated clinical relapse with a median lead time of 16 months., Conclusions: In patients with treatment-naive EBC, ctDNA is detectable after surgery. The absence of ctDNA at a single post-surgical timepoint is associated with improved DRFS, supporting the development of future trials studying de-escalation of systemic therapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Molybdenum cofactor deficiency type A has successfully been treated in a small number of children with daily intravenous administration of cyclic pyranopterin monophosphate. Pharmacodynamic data for this novel treatment have not been published and alternative dosing intervals have not been explored. We monitored pharmacodynamic biomarkers of sulfite oxidase and xanthine oxidoreductase activity in three patients with MoCD-A for a period of 2 to 9 months after discontinuation of cPMP substitution. We found that the clinical and metabolic effects were sustained for longer than expected, over 7 days at least. Our data implicate a biological half-life of the molybdenum cofactor dependent enzyme activities of approximately 3 days and suggest the possibility that less frequent than once daily dosing intervals could be a safe alternative to current practice., Competing Interests: Declaration of competing interest BCS was principal investigator for clinical trials sponsored by Alexion Pharma International, and Origin Biosciences Inc. He reports a personal fee for attendance at an Advisory Board meeting and an unconditional educational grant from Origin Biosciences Inc. KB, HTW, AH, EE and VK have no conflict of interests to report. cPMP for the treatment of patients was provided free of charge on compassionate grounds from Colbourne Pharmaceuticals GmbH and Origin BioSciences Inc., respectively., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects and clinical significance of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activated by interleukin (IL)-17A in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: Patients underwent nasal endoscopic surgery in the Third Affiliated Hospital of Sun Yat-sen University from January 2020 to December 2021 were collected, including 28 CRSwNP (including 19 males and 9 females, aged 19 to 67 years), 22 chronic rhinosinusitis without nasal polyps (CRSsNP) and 22 controls. qRT-PCR was used to detect the expressions of IL-17A, NLRP3, IL-1β and IL-18 in the three groups, and their correlations were analyzed. The positions of IL-17A, NLRP3 and IL-18 in nasal polys were analyzed by immunofluorescence. Western Blotting and ELISA were employed to detect the expression of NLRP3, IL-1β and IL-18 in the human nasal epithelial cells after using IL-17A stimulation or IL-17A receptor inhibitor. Immunofluorescence was used to observe the NLRP3, IL-1β, and IL-18 protein expression after IL-17A stimulating human nasal epithelial cells, and after the use of IL-17A receptor inhibitor and NLRP3 inhibitor MCC950. The correlations between NLRP3, IL-1β, IL-18 and CT scores, nasal endoscopic scores, visual analogue scale (VAS) scores, and sino-nasal outcome test (SNOT) 22 scores of CRSwNP patients were analyzed. SPSS 20.0 software was used for statistical analysis. Results: The expressions of IL-17A, NLRP3, IL-1β and IL-18 in the tissues of CRSwNP patients were significantly higher than those in CRSsNP group( P =0.018, P <0.001, P =0.005, P =0.016) and the control group(all P <0.001). IL-17A was positively correlated with the expression of NLRP3, IL-1β, and IL-18( r ralue was 0.643,0.650,0.629,respectively, all P <0.05). IL-17A, NLRP3, and IL-18 were co-localized in the epithelial propria of polyp tissue. IL-17A stimulated the expressions of NLRP3, IL-1β, and IL-18 in human nasal epithelial cells. After the use of IL-17A receptor inhibitor, the expressions of NLRP3, IL-1β, and IL-18 were significantly down-regulated. After the use of NLRP3 inhibitor MCC950, IL-17A was significantly down-regulated to promote the expression of NLRP3, IL-1β, and IL-18. The expressions of NLRP3, IL-1β and IL-18 were positively correlated with CT, nasal endoscopy, VAS, and SNOT22 scores in patients with CRSwNP. Conclusions: IL-17A promotes the release of IL-1β and IL-18 by activating the NLRP3 inflammasome and aggravates the severity of the disease in CRSwNP.

Objective: To establish a model of long-term free drinking mouse by feeding mice with alcohol to simulate the state of human voluntary long-term drinking, and on this basis, to further discuss the evaluation criteria of long-term free drinking mice model in sports, anxiety and cognitive behavior., Methods: Forty six-week-old SPF C57BL/6 male mouse were randomly divided into two groups: Long-term free drinking group ( n =20) and normal control group ( n =20). The two groups were given solid feed normally. The long-term free drinking group was free to take 10% alcohol and water every day, while the normal drinking group only took water every day. The mice were fed for 7 months, and were evaluated by a series of behavioral methods, including Rota-rod test, balance beam test, open filed test, the elevated plus maze, two-box social behavior, new object recognition, Y maze and water maze., Results: With the increase of drinking days, the mice showed significant alcohol addiction in the alcohol preference test. With the increase of alcohol intake, the mice in the long-term free choice drinking group had slightly shiny fur and reduced diet. Compared with the control group, the weight gain began to slow down from the third month, and the weight decreased significantly by the sixth and seventh months ( P =0.006, P < 0.001). The mice showed reduced balance locomotion ability ( P =0.003, P =0.001) in the rotary bar and balance beam test. In the open field and elevated cross test, the mice had obvious anxiety-like behavior ( P < 0.001). The mice showed decreased social ability in the two boxes of social behavior ( P < 0.016). In the experiment of new object recognition and Y maze, the exploration of new object decreased ( P =0.018, P =0.040). In the water maze, cognitive functions, such as learning and spatial memory were reduced ( P < 0.001)., Conclusion: The successful establishment of the long-term free drinking mouse model is more convenient for us to carry out further research on the neural mechanism of alcohol addiction, and lays an experimental foundation for exploring the neural mechanism of alcohol addiction and related new targets.

Objective: To preliminarily analyze the expression of angiotensin-converting enzyme 2 (ACE2) and to investigate its potential regulatory mechanism in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: Patients underwent nasal endoscopic surgery in the Third Affiliated Hospital of Sun Yat-sen University from February 2020 to May 2021 were selected, including 17 males and 6 females, aging from 23 to 66 years old. Expression of ACE2 was evaluated via immunohistochemical staining in controls with non-chronic rhinosinusitis, non-eosinophilic CRSwNP (non-ECRSwNP), and eosinophilic CRSwNP (ECRSwNP) tissue, respectively. Correlations between ACE2 and the indicated Th1/Th2-related cytokines (IFN-γ, IL-4, IL-5, IL-13, IL-25, IL-33, TSLP and periostin) were analyzed based on GSE72713 dataset. Protein-protein interaction (PPI) network was constructed via string database, immune infiltration of GSE72713 dataset was evaluated using cibersort algorithm. ACE2 was comprehensively analyzed by microRNA regulatory network, gene set enrichment analysis (GSEA) and pharmacological analysis. Statistical analysis was performed using GraphPad 7.0 and SPSS 20.0 software. Results: ACE2 was up-regulated in non-ECRSwNP compared with ECRSwNP. Microarray analysis showed that ACE2 was positively correlated with IFN-γ while inversely correlated with IL-5, IL-13 and periostin significantly. Analysis of immune infiltration suggested that ACE2 expression correlated positively with the number of M1 macrophage while negatively with M2 macrophage. GSEA demonstrated that interferon-related signaling pathways were up-regulated in non-ECRSwNP, and miRNA-200B/miRNA-200C/miRNA-429 pathways targeting ACE2 were enriched in ECRSwNP. Results of pharmacological analysis indicated that ampicillin was able to promote the expression of ACE2 whereas acetaminophen could down regulated the expression of ACE2. Conclusion: Expression pattern of ACE2 is varied in non-ECRSwNP and ECRSwNP, which may be related to the different infiltration of indicated cytokines and different regulatory pathways of miRNA.

Background: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence., Patients and Methods: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years., Results: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5)., Conclusions: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival., Competing Interests: Disclosure The following authors are employees of Natera, Inc. (HS, H-TW, RS, AT, SS, HP, PB, AA, ML, BZ). LJVV is co-founder, stockholder, and part-time employee of Agendia NV. The remaining authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: COVID-19 outbreak is still under global pandemic. China is facing the risks of importation and local rebound of COVID-19. Under the circumstances, preparations for medical resources are in urgently needed. Methods: Based on current understanding of the disease, we set up five scenarios and use the infectious disease transmission dynamic and pandemic theoretical static models to evaluate the demand for medical resources. Results: Different epidemic strength and strategies of disease control and prevention resulted in different levels of medical resource request, and active control strategy and effective measures could significantly decrease the requirement. During the epidemic rising phase, the cost of prevention and control measures and the requirement of professional response capacities would increase with potential high risk of medical resource demand sharply increasing. Conclusion: Regions with different economic level, population scale, and different prevention and control capabilities should all initiate scientific assessment of medical resource requirement under emergency response and prepare for possible future rebound and epidemic.

Objective: To explore the feasibility of clinical factors to predict the pathological complete response after neoadjuvant chemoradiotherapy in rectal cancer. Methods: A retrospective analysis was performed on clinical factors of 162 patients with rectal cancer, who underwent neoadjuvant chemoradiotherapy in the General Hospital of People's Liberation Army from January 2011 to December 2018.According to the postoperative pathological results, the patients were divided into pathological complete response (pCR) group and non-pathological complete response group (non-pCR group) to check the predictive clinical factors for pCR. Results: Twenty-eight cases achieved pCR after neoadjuvant chemoradiation (17.3%, 28/162). Univariate analysis showed that patients with higher differentiation ( P= 0.024), tumor occupation of the bowel lume n ≤1/2 ( P= 0.006), earlier clinical T stage ( P= 0.013), earlier clinical N stage ( P= 0.009), the time interval between neoadjuvant chemoradiotherapy and surgery>49 days ( P= 0.006), and maximum tumor diamete r ≤5 cm ( P= 0.019) were more likely to obtain pCR, and the differences werestatistically significant. Multivariate analysis showed that tumor occupation of the bowel lume n ≤1/2 ( P= 0.01), maximum tumor diamete r ≤5 cm ( P= 0.035), and the interval>49 days ( P= 0.009) were independent factors in predicting pCR after neoadjuvant therapy. Conclusion: Tumor occupation of the bowel lumen, maximum tumor diameter, and the time interval between neoadjuvant chemoradiotherapy and surgery can predict the pCR in rectal cancer.

Objective: To explore changing trend in prognosis of primary hypopharyngeal carcinoma and to analyze the reasons at the Eye, Ear, Nose and Throat Hospital of Fudan University. Methods: We retrospectively analyzed the clinical data of 461 patients with primary hypopharyngeal carcinoma treated at the Eye, Ear, Nose and Throat Hospital of Fudan University from 2003 to 2007 (Group 1) and 2010 to 2014 (Group 2) according to the inclusion criteria. 142 from Group 1, including 133 males and 9 females, rangedfrom 38 to 82 years old and 319 from Group 2, including 313 males and 6 females, ranged from 39 to 81 years old, were included in this work. The laryngeal function preservation rate, survival outcome, application and effect of pre-and post-operative adjuvant therapy were compared. SPSS 24.0 was used for statistical analyses. Results: There were 62 patients with early disease (T1-2N0) including 18 in Group 1 and 44 in Group 2, in whom 3 (16.7%) underwent surgical procedures with laryngeal function preservation in Group 1, while, 30 (68.2%) underwent laryngeal function preservation surgery in Group 2. The laryngeal function preservation rate showed an obviously upward trend in recent years (χ(2)=13.617, P< 0.001), whereas, the recurrence-free survival rate (RFS) and overall survival rate (OS) showed no significant differences between two groups ( P= 0.469 and 0.808, respectively). Among the 399 patients with advanced disease, 124 were in Group 1 and 275 in Group 2. After propensity score matching (PSM) was used, the OS rate was significantly higher for Group 2 than Group 1 ( P= 0.017), while the application of laryngeal function preservation surgery was significantly higher in Group 2 (χ(2)=4.686, P= 0.030). The application rates of preoperative adjuvant therapy and postoperative adjuvant chemotherapy were significantly higher in group 2 than in group 1 (χ(2)=5.687, P= 0.017; χ(2)=19.407, P< 0.001). Conclusion: The application of laryngeal function preserving surgery significantly increases the retention rate of laryngeal functions in patients with early-stage hypopharyngeal carcinoma, with similar long-term survival outcomes. The application of comprehensive treatment including preoperative adjuvant therapy and postoperative adjuvant treatments, especially postoperative chemoradiotherapy, shows an obvious increase in the function preservation rate and long-term survival in patients with advanced hypopharyngeal carcinoma.

Objective: To determine the relationship between nodal disease distribution patterns and oncological outcome and optimum management of cN0/cN1 patients with hypopharyngeal squamous cell carcinoma (HPSCC). Methods: The collected clinical data and the follow-up disease-free survival (DFS) information from 154 patients with HPSCC treated between 2001 and 2014 in Eye Ear Nose and Throat Hospital of Fudan University were retrospectively analyzed. Kaplan-Meier method was used to calculate DFS rate. Log-rank test and Cox regression model were performed to evaluate the survival prognostic factors for univariate and multivariate analyses. Results: Among 154 patients (63 cN0 patients, 91 cN1 patients) with HPSCC,in whom 148 were male, 6 were female, with an arerage age of (58.6±9.9), 63 cN0 patients received lateral neck dissection, of whom 9 were histologically positive nodes. Particularly, occult metastasis rate was 15.6%(7/45) for HPSCC in pyriform sinus and 18.2%(2/11) for HPSCC in posterior pharyngeal wall. Among 91 cN1 HPSCC, 34 underwent radical neck dissection and 54 underwent selective neck dissection. DFS for patients(T3-4N1) with radical neck dissection was lower than that for patient with selective neck dissection(15.2% vs.39.5%, χ(2)=5.153, P <0.05). The DFS of cN0 HPSCC was overestimated by the false-negative patients (cN0→pN+) for cN0 HPSCC and the DFS of cN1 HPSCC was underestimated by the false-positive(cN1→pN0) for cN1 HPSCC. Conclusions: For cN1 HPSCC, compared with radical neck dissection, selective neck dissection may be considered as a more adequate method for removal of metastatic lymph nodes. Postoperative combined therapy and follow-up strategy should be established according to pathological N staging.

Objective: To investigate the effectiveness of endoscopic keel placement for the prevention and treatment of bilateral vocal cord adhesion. Method: There are 47 cases with bilateral vocal cord lesions and 38 cases with laryngeal adhesion in this study. Bilateral vocal cord lesions were removed and laryngeal adhesion was cut and divided. Afterwards, a silicone keel was placed in each case using a Lichtenberger endo-extralaryngeal needle carrier. The keel was removed 4 weeks post-surgery and the vocal cords were observed using a laryngoscopy monthly. Result: During the 1-year follow-up, 39 (83.0%) cases with bilateral vocal cord lesions and 28(73.7%) cases with laryngeal adhesion did not develop laryngeal webs. A pseudomembrane covering the vocal cords was observed at the time of keel removal in 16 cases of all. Unfortunately, 15 cases (93.75%) developed laryngeal webs among them. However, in the cases without a pseudomembrane, only 3 (4.35%) cases formed glottic webs post-surgery( P <0.01). Conclusion: Endoscopic keel placement is an effective method for the prevention and treatment of bilateral vocal cord adhesion. The pseudomembrane detected at the time of keel removal is probably a risk factor for the development of glottic webs., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Objective: To investigate the risks of pre-pregnancy overweight, excessive gestational weight gain on macrosomia. Methods: We conducted one hospital-based cohort study, focusing on pregnant women from January 2015. All pregnant women attending to this hospital for maternal check-ups, were included in our cohort and followed to the time of delivery. Data related to general demographic characteristics, pregnancy and health status of those pregnant women, was collected and maternal pre-pregnant BMI and maternal weight gain were calculated. Logistic regression was used to explore the risk difference of pre-pregnancy BMI, excessive gestational weight gain on macrosomia. Results: The overall incidence of macrosomia in our cohort appeared as 6.6% (149/2 243). After adjusting the confounding factors including age and histories on pregnancy, pre-pregnancy overweight/obesity was associated with higher risks of macrosomia ( OR =3.12, 95 %CI : 1.35-7.22, P =0.008; OR =2.99, 95 %CI : 1.17-7.63, P =0.022) when comparing to those with normal pre-pregnancy weight. Cesarean delivery and sex of the offspring were associated with higher risk of macrosomia, while excessive gestational weight gain showed no significant difference ( OR =1.41, 95 %CI : 0.96-2.09, P =0.084). Our data showed that Macrosomia was statistically associated with gestational weight gain ( P =0.002). After controlling parameters as age, history of pregnancy and related complications of the pregnant women, results from the logistic regression showed that women with gestational inadequate weight gain having reduced risks to deliver macrosomia, when compared to those pregnant women with adequate weight gain ( OR =0.52, 95 %CI : 0.30-0.90, P =0.019). Conclusion: Pre-pregnancy overweight and obesity were on higher risks to macrosomia.

Objective: To explore the association between the morphological classification and prognosis of conservative treatment for vocal fold leukoplakia. Method: Patients with different types of vocal fold leukoplakia received conservative treatment first. Those who had failed response to conservative treatment or recurred received carbon dioxide laser resection. Then the efficacy and recurrence rate were compared among the three types of vocal fold leukoplakia. Result: Two hundred and thirty-six patients consisted of 78 flat and smooth cases, 146 bulge and smooth cases, and 12 rough cases. The complete response rate of conservative treatment for the three types was 80.8%, 65.1%, and 0%, respectively ( P <0.01). Out of 158 patients who had complete response to conservative treatment, 10.1% cases recurred in 1 year (flat and smooth vs. bulge and smooth, 6.3% vs. 12.6%, P =0.283). Totally, 78 patients had no complete response to conservative treatment and 16 patients experienced recurrence, whose complete response rate of carbon dioxide resection was 89.5%, 85.7%, and 75.0%, respectively ( P =0.53). The pathological results were significantly different among three types. The complete response rate of conservative treatment combined with surgery for three types was 97.4%, 93.8%, and 75.0%, respectively, and the complete response rate of flat and smooth type was significantly higher than that of rough type ( P =0.002). Conclusion: The Conservative treatment could be based on the morphological classification of vocal fold leukoplakia. The treatment modality that conservative treatment combined with surgery had no impact on the prognosis of vocal fold leukoplakia., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Objective: To investigate work-related musculoskeletal disorders (WMSDs) of workover workers in an oilfield and explore the influencing factors. Methods: In June 2016, 685 workover workers were selected as working group, and 191 other workers exposed to toxic and harmful operations were selected as control group. Cross sectional investigation was conducted by self-made questionnaire, and the influencing factors of musculoskeletal disorders were analyzed by unconditional multivariate Logistic regression. Results: The total annual prevalence of WMSDs for workover workers was 90.5%, with the highest prevalence of low back pain of 71.5%. The prevalence of WMSDs increased with the increase of service age, and the difference between the drinkers was higher than that of the non drinkers ( P <0.05) . Multivariate Logistic regression analysis showed that working age, drinking and the posture of lifting heavy objects were risk factors for WMSDs in workover workers. Conclusion: The WMSDs appears to be a serious problem in oilfield workover workers. Corresponding measures should be taken to prevent the risk factors and control the occurrence of diseases effectively.

Objective: To explore the fundamental clinical characteristics and survival prognostic factors of laryngeal squamous cell carcinoma (LSCC) patients treated with open laryngeal function-preserving operations. Method: The collected clinical data and the follow-up survival information from 760 patients with LSCC undergoing open laryngeal function-preserving operations between January 2005 and December 2010 in Eye & ENT Hospital of Fudan University were retrospectively analyzed. Kaplan-Meier was applied to calculate survival rates. Log-rank test and Cox regression model were performed to evaluate the survival prognostic factors for univariate and multivariate analysis. Result: Among the enrolled 760 cases, 697 patients were glottic cancer, followed by 59 cases in supraglottis and 4 cases in subglottis. The number of laryngeal cancer patients staged in T1 to T4 was 222, 420, 112 and 6, respectively. 27 patients had positive cervical lymph nodes. There were 220, 408, 111 and 21 patients with clinical stage Ⅰ to Ⅳ, respectively. The 5-year overall survival (OS), disease free survival (DFS) and disease specific survival (DSS) rates were 89.3%, 83.9% and 89.8%, respectively. Multivariate Cox analysis indicated that clinical stage and second primary tumor were independent influencing factors for the OS rate, while, age, primary site, pathological differentiation, T stage, clinical stage and surgical margin were independent risk factors for tumor recurrence and progression ( P <0.05). Conclusion: Open laryngeal function-preserving operation is a crucial therapeutic strategy applicable to LSCC patients in early and selected advanced stage in China. Early diagnosis and therapy, and sufficient safety surgical margin are keys for improving the survival rate and reducing the risk of relapse for laryngeal cancer patients.

Objective: The utility of fetal heart rate (FHR) monitoring can only be achieved with an acquisition sampling rate that preserves the underlying physiological information on the millisecond time scale (1000 Hz rather than 4 Hz). For such acquisition, fetal ECG (fECG) is required, rather than the ultrasound to derive FHR. We tested one recently developed algorithm, SAVER, and two widely applied algorithms to extract fECG from a single-channel maternal ECG signal recorded over the xyphoid process rather than the routine abdominal signal., Approach: At 126dG, ECG was attached to near-term ewe and fetal shoulders, manubrium and xyphoid processes (n  =  12). fECG served as the ground-truth to which the fetal ECG signal extracted from the simultaneously-acquired maternal ECG was compared. All fetuses were in good health during surgery (pH 7.29  ±  0.03, pO 2 33.2  ±  8.4, pCO 2 56.0  ±  7.8, O 2 Sat 78.3  ±  7.6, lactate 2.8  ±  0.6, BE  -0.3  ±  2.4)., Main Result: In all animals, single lead fECG extraction algorithm could not extract fECG from the maternal ECG signal over the xyphoid process with the F1 less than 50%., Significance: The applied fECG extraction algorithms might be unsuitable for the maternal ECG signal over the xyphoid process, or the latter does not contain strong enough fECG signal, although the lead is near the mother's abdomen. Fetal sheep model is widely used to mimic various fetal conditions, yet ECG recordings in a public data set form are not available to test the predictive ability of fECG and FHR. We are making this data set openly available to other researchers to foster non-invasive fECG acquisition in this animal model.

Objective: To evaluate the oncologic and functional outcomes of supracricoid partial laryngectomy (SCPL) in the treatment of laryngeal carcinoma. Methods: A total of 298 laryngeal carcinoma patients who underwent SCPL treatment from January 2005 to December 2013 were reviewed retrospectively. Clinical data of demographic and clinical characteristics, postoperative complications, rehabilitation information, recurrence and metastasis were analysed. Survival and local control were used to evaluate the clinical outcome.Data were analyzed by SPSS 23.0 software. Results: Thirty-one patients with supraglottic carcinoma underwent cricohyoidoepiglottopexy (CHEP)and 267 with glottic carcinoma underwent cricohyoidopexy (CHP) were enrolled in this study. The mean duration of followed up was 74 months, ranging from 12 to 146 months. Fifty-four cases died at last follow-up. With respect to 31 patients with supraglottic carcinoma, 5- and 10-year overall survival rates and disease specific survival rates all were 78.1%; 5- and 10-year disease free survival rates were 72.1% and 63.7% respectively; and 5- and 10-year local control rates were both 84.2%. In 267 patients with glottic carcinoma, 5- and 10-year overall survival rates were 85.8% and 77.1% respectively; 5- and 10-year disease specific survival rates were 86.6% and 78.4% respectively; 5- and 10-year disease free survival rates were 80.6% and 74.2% respectively; and 5- and 10-year local control rates were 90.0% and 89.4% respectively. The survival rate of patients with glottic carcinoma at stage T1 was higher than that at stage T2 or T3, and the disease free survival rate of patients with early stage was superior than that of patients with advance stage. Cox regression analysis showed that tumor stage T2, and T3, tumor recurrence, and tumor metastasis were independent risk factors for survival. Furthermore, nasogastric feeding tube removal rate was 100% and the decannulation rates of SCPL were 96% in the patients with SCPL. Conclusions: SCPL is a safe procedure with tumor resection for laryngeal carcinoma, with preserving of swallowing, respiration, and phonation functions, and has excellent survival and local control rates. This procedure could be considered as a standard function-sparing treatment for selected patients with laryngeal carcinoma of stages T1b-T3.

Objective: To summarize the clinical features of patients with ovarian tumor and anti-N-methyl-D-aspartate receptor(NMDAR) encephalitis, and to explore the influence of operation patterns on the prognosis. Methods: The clinical information of patients with ovarian tumor and anti-NMDAR encephalitis in The 3rd Affiliated Hospital of Sun Yat-Sen University and The Zhujiang Hospital of Southern Medical University were collected and analyzed. Results: There were 15 patients were enrolled in this study, with the average age of 24.5±5.0 years old. The most frequent first symptom was psychosis. The main clinical features were psychosis, seizures, conscious disturbance, autonomic dysfunction, dyskinesia, central hypoventilation and impaired memory. Most patients' symptoms were relieved after immunotherapy and surgery. The number of favorable prognosis of patients (mRS score 0-2) with ovariectomy was higher than that of the patients with ovarian cystectomy (5 vs 3). But the difference had no statistical significance ( P =0.529). Conclusions: For young female patients with psychosis, we should be alert to the possibility of anti-NMDAR encephalitis and screen for tumor. Treated with immunotherapy and operation, most patients can get a favorable prognosis.

Neurotrophins particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are crucial modulators in the neurodevelopment and maintenance of central and peripheral nervous systems. Neurotrophin hypothesis of schizophrenia (SCZ) postulated that the changes in the brains of SCZ patients are the result of disturbances of developing processes involving neurotrophic factors. This hypothesis was mainly supported by the abnormal regulation of BDNF in SCZ, especially the decreased peripheral blood BDNF levels in SCZ patients validated by several meta-analyses. However, the regulation of NGF in SCZ remains unclear because of the inconsistent findings from the clinical studies. Therefore, we undertook, to the best of our knowledge, the first systematic review with a meta-analysis to quantitatively summarize the peripheral blood NGF data in SCZ patients compared with healthy control (HC) subjects. A systematic search of Pubmed, PsycINFO and Web of Science identified 13 articles encompassing a sample of 1693 individuals for the meta-analysis. Random-effects meta-analysis showed that patients with SCZ had significantly decreased peripheral blood levels of NGF when compared with the HC subjects (Hedges's g=-0.633, 95% confidence interval (CI)=-0.948 to -0.318, P<0.001). Subgroup analyses revealed reduced NGF levels both in serum (Hedges's g=-0.671, 95% CI=-1.259 to -0.084, P=0.025) and plasma (Hedges's g=-0.621, 95% CI=-0.980 to -0.261, P<0.001) of the patients, and in drug-free (Hedges's g=-0.670, 95% CI=-1.118 to -0.222, P=0.003) and medicated (Hedges's g=-0.357, 95% CI=-0.592 to -0.123, P=0.003) patients with SCZ. Furthermore, meta-regression analyses showed that age, gender and sample size had no moderating effects on the outcome of the meta-analysis, whereas disease severity might be a confounding factor for the meta-analysis. These results demonstrated that patients with SCZ are accompanied by the decreased peripheral blood NGF levels, strengthening the clinical evidence of an abnormal neurotrophin profile in the patients with SCZ.

Objective: To explore the reconstruction methods of oropharyngeal defects after resection of tonsillar cancer by mandibular swing approach. Method: Twenty four cases of patients with tonsillar carcinoma hospitalized in our institution from January, 2010 to December, 2015 were analyzed. Based on the degree and extent of tissue defects, they were divided into three categories.①Small defects, including loss of tonsillar fossa and pharyngeal arches; ②Moderate defects, including small defects of soft palate or tongue root besides lateropharyngeal defects; ③Large defects, including large defects of soft palate and tongue root besides lateropharyngeal defects. The tissue defects of 8 patients belonged to small defects, of whom 4 cases were repaired with mid-thick skin and the others were restored by radial forearm flaps. There were 5 cases of patients with moderate oropharyngeal defects after surgery of tonsillar carcinoma. These defects were reconstructed by radial forearm flaps(2 cases) and anterolateral femoral skin flaps (3 cases) respectively, while the remaining large defects of 11 patients were renovated using pectoralis major myocutaneous flaps(9 cases) and anterolateral femoral skin flaps(2 cases). Result: All the patients healed by first intention after surgery.Four transplanted skin grafts on the regions of small defects survived completely.5 cases of radial forearm flaps and anterolateral femoral skin flaps also survived well, whereas only one radial forearm flap suffered from vascular crisis leading to failure at 5 days postoperatively. The necrotic flaps were then removed by submaxillary space and oral cavity and the wounds were self-healed. The tissue defects were successfully repaired by pectoralis major myocutaneous flaps. Although the surgical wounds swelled, they were obviously relieved half a year later. In the tonsillar cancer patients encroached on soft palates, one occurred nasopharyngeal reflux and 3 spoke vaguely but understandably. The other patients' function of chewing, deglutition, respiration and speech were restored well. Conclusion: Small defects after resection by mandibular swing approach could be repaired by mid-thick skin or radial forearm flaps. Moderate defects of T3 tonsillar cancer could be restored using radial forearm flaps or anterolateral femoral skin flaps, while anterolateral femoral skin flaps or pectoralis major myocutaneous flaps could reconstructed the large defects of T3 or T4 tonsillar cancer., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Objective: To investigate the clinical value of acoustic radiation force impulse (ARFI)technique in predicting esophageal and gastric varices in patients with biliary atresia after Kasai portoenterostomy. Methods: A total of 42 patients with biliary atresia after Kasai portoenterostomy were collected from September 2015 to May 2016 in Tianjin First Central Hospital.ARFI technique was used to measure the stiffness of liver and spleen, and 28 healthy children as control.According to the result of CT examination , patients with biliary atresia were divided into two groups , twenty-three patients with esophageal and gastric varices(A group) and nineteen patients without esophageal and gastric varices (B group), Comparing the difference of liver and spleen stiffness between the two groups.The ROC curve analysis was carried out to test the diagnostic power of effective parameter. Results: The ARFI value of liver (2.98±0.80) m/s and spleen (3.00±0.33) m/s of patients with biliary atresia was significantly higher than that of control group((1.10±0.16) m/s, (2.12±0.32) m/s), the differences had statistical significance (both P <0.01). Between group A and group B, the spleen ARFI value of group A(3.16±0.26) m/s was higher than group B(2.83±0.32) m/s, the difference had statistical significance ( P <0.01), whereas there was no statistical difference of liver ARFI value between two group((2.93±0.65), (3.02±0.96) m/s)( P >0.05). The cut-off ARFI value of spleen to diagnose esophageal and gastric varices in biliary atresia was 3.02 m/s, and the biggest area under the ROC curve, sensitivity, and specificity were 0.81, 78.6% and 84.5%, respectively. Conclusion: ARFI can be used as a noninvasive method to predict the presence of esophageal and gastric varices in patients with biliary atresia after Kasai portoenterostomy.

Head and neck squamous cell carcinoma(HNSCC) is the sixth most common malignancies of human beings. The prognosis of advanced HNSCC is poor despite improvements in traditional treatment strategies including surgery, chemotherapy, and radiotherapy. Cancer immunotherapy is the use of the immune system to treat cancer, which provides a sustained antitumor reaction but an absense of chemoresistance. Cancer immunotherapy is becoming the forth treatment strategy towards cancer. Therefore, we reviewed the current state of immunotherapy for HNSCC.

Objective: The aim of this study is to investigate the clinical and pathological features of vocal cord polyp. Method: Retrospective analyzed the clinical and pathological data of 1116 cases in vocal cord polyp patients treated with suspension microlaryngoscopic surgery. Result: The bradycardia was observed in 170 cases(15.2%) during the suspension of laryngoscope under general anesthesia. In this case，the suspension was stopped or the laryngoscope was taken out of mouth and atropine was administrated by intravenous injection. After that, heartbeat gradually accelerated and approached to normal,then the suspension was begun again to complete microlaryngoscopic surgery. Among the 1116 cases,1094(98%) were cured,22(2%) were improved，and no case was invalid. No pharyngeal injury was in 865 cases(77.5%). Mild,moderate and severe palatoglossal arch injury was observed in 139 (12.5%)cases，86(7.7%)cases,and 26 (2.3%) cases，respectively. The incidences of epithelial hyperplasia and dysplasia in vocal cord polyp were 35.3% and 5.0%, respectively. The prevalence rates of epithelial hyperplasia and dysplasia in male and female patients of vocal cord polyp were 76.2%,23.8% ( P <0.01) and 78.6%,21.4% ( P <0.01),respectively. And the prevalence rates of keratinization and parakeratosis in male and female patients were 93.1%,6.9% ( P <0.01) and 93.1%,6.9% ( P <0.01),respectively.The incidence of keratinization in patients of no epithelial hyperplasia, epithelial hyperplasia and epithelial dysplasia were 2.1%,18.2% and 30.3%,respectively，with significant difference in pairwise comparison. Conclusion: High incidence of vocal cord polyp is at the age from 31 to 60 years old.Although laryngomicrosurgery is an effective treatment for vocal cord polyp, pharyngeal injury and laryngopharyngeal vagal reflex should be noticed during the operation.In addition,vocal cord polyps in male patients are susceptible to epithelial dysplasia and keratinization., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: This work was to evaluate the efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) with lobaplatin and docetaxel to treat peritoneal carcinomatosis (PC) from gastric cancer (GC)., Methods: A total of 50 consecutive GC PC patients treated by 52 CRS+HIPEC procedures with lobaplatin 50 mg/m(2) and docetaxel 60 mg/m(2) in 6000 mL of normal saline at (43 ± 0.5) °C for 60 min. The primary endpoint was overall survival (OS), and the secondary endpoints were perioperative safety profiles., Results: At the median follow-up of 22.5 (range, 5.1-50.7) months, the median OS was 14.3 (95% CI 7.6-21.0) months, and the 1-, 2-, and 3-year survival rates were 58%, 40%, and 32%, respectively. Mortality and serious adverse event (grade 3-5) morbidity rates in postoperative 30 days were 0.0% and 23.1%, respectively. Univariate analysis identified 4 parameters with significant effects on OS: completeness of cytoreduction (CC) 0-1, normal (N) the preoperative tumor markers level (TM), adjuvant chemotherapy ≥6 cycles, and peritoneal cancer index ≤20. However, multivariate analysis identified CC0-1, perioperative TM (N), adjuvant chemotherapy ≥6 cycles as the independent predictor for better survival., Conclusions: CRS+HIPEC with lobaplatin and docetaxel to treat selected GC PC could improve OS, with acceptable perioperative safety., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the clinical characteristics, surgical treatment outcomes and prognostic factors of hypopharyngeal carcinoma., Methods: A retrospective review of the Eye & ENT Hospital of Fudan University patients' database between January 2003 and June 2013 was conducted and a total of 386 patients were enrolled in the study. Patients' clinical and oncological information was collected and survival rates were analyzed using Kaplan-Meier curves. Prognostic factors were evaluated with multivariate Cox model survival analysis., Results: Among the 386 patients 95.9% were males and 4.1% were females, with an average age of (58.4±9.4) years. The primary tumor sites were pyriform sinus (76.7%), posterior hypopharyngeal wall (17.3%) and postcricoid region (6.0%). There were 31(8.0%), 83(21.5%), 175(45.3%) and 97(25.1%) patients with stage T1 to T4, respectively, 99(25.6%), 74(19.2%), 181(46.9%) and 32(8.3%) patients with stage N0 to N3, respectively , and 3 patients with distant metastasis to lung on initial diagnosis. Second primary cancers were found in 28 cases (7.3%). The 5-year overall survival (OS), disease specific survival (DSS) and disease free survival (DFS) were 45.8%, 48.1% and 46.0% respectively according to Kaplan-Meier survival curves. Multivariate Cox regression model showed significant association between 5-year overall survival rate and T stage (P<0.001), N stage (P=0.003) and second primary tumors (P=0.017). Advanced T stage and lymphovascular invasion were associated with a higher rate of recurrence (P<0.001)., Conclusions: Hypopharyngeal squamous cell carcinoma has a dismal prognosis, with high rates of submucosal infiltration, cervical lymph node metastasis and distant metastasis. Treatment choices should be made according to TNM stage and overall health conditions in order to achieve ideal oncologic and functional results. Surgery with postoperative chemoradiation therapy is the main treatment for advanced-stage hypopharyngeal cancer.

Objective: To evaluate the efficacy and economics of sublingual immunotherapy (SLIT) with Dermatophagoides farinae drops in patients with allergic rhinitis and allergic asthma. Method: Two hundred and three patients (aged 4-60 yr) with allergic rhinitis and allergic asthma induced by house dust mites were retrospectively analyzed. Eighty-six patients were treated by SLIT with standardized Dermatophagoides farina drops and pharmacotherapy (SLIT group), while 117 patients were treated by standardized pharmacotherapy (drug group). Patients were followed up for 2 years with one visit in every 3 months. Total nasal syptom score (TNSS), total rhinitis medicine score (TRMS), daytime asthma syptom score (DASS), nighttime asthma syptom score (NASS), total asthma medicine score (TAMS) and treatment charge were recorded at each visit. Result: There was no significant difference between two groups in TNSS, TRMS, DASS, NASS, TAMS before treatment (all P >0.05). After 1-year or 2-year duration, there were significant differences between the SLIT group and drug group in TNSS, TMSS, DASS, NASS, TAMS (all P <0.01). After 1-year or 2-year duration, the symptom scores and medication scores of SLIT group significantly decreased compared with those before treatment (all P <0.01). In terms of treatment charge, although direct cost of SLIT group was a little higher than that of drug group, the indirect cost of SLIT group was remarkably lower than that of drug group, showing significant difference ( P <0.01). Conclusion: SLIT with Dermatophagoides farinae drops is effective in patients with allergic rhinitis and allergic asthma, which may also reduce indirect cost., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: Heart rate variability (HRV) may reflect various physiological dynamics. In particular, variation of R-R peak interval (RRI) of electrocardiography appears regularly oscillatory in deeper levels of anaesthesia and less regular in lighter levels of anaesthesia. We proposed a new index, non-rhythmic-to-rhythmic ratio (NRR), to quantify this feature and investigated its potential to estimate depth of anaesthesia., Methods: Thirty-one female patients were enrolled in this prospective study. The oscillatory pattern transition of RRI was visualised by the time-varying power spectrum and quantified by NRR. The prediction of anaesthetic events, including skin incision, first reaction of motor movement during emergence period, loss of consciousness (LOC) and return of consciousness (ROC) by NRR were evaluated by serial prediction probability (PK ) analysis; the ability to predict the decrease of effect-site sevoflurane concentration was also evaluated. The results were compared with Bispectral Index (BIS)., Results: NRR well-predicted first reaction (PK  > 0.90) 30 s ahead, earlier than BIS and significantly better than HRV indices. NRR well-correlated with sevoflurane concentration, although its correlation was inferior to BIS, while HRV indices had no such correlation. BIS indicated LOC and ROC best., Conclusions: Our findings suggest that NRR provides complementary information to BIS regarding the differential effects of anaesthetics on the brain, especially the subcortical motor activity., (© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Metformin is widely used in clinic for handling the diabetic disorders. However, action mechanisms of metformin remain obscure. It has recently been indicated that guanidinium derivatives are ligands to activate type-2 imidazoline receptors (I-2 receptors) that can improve diabetes through increment in skeletal muscle glucose uptake. Also, activation of I-2 receptors can increase the release of ß-endorphin in diabetic animals. Because metformin is a guanidinium derivative, we were interested in the effect of metformin on I-2 receptors. In the present study, the marked blood glucose-lowering action of metformin in streptozotocin-induced type-1 like diabetes rats was blocked by specific I-2 receptor antagonist, BU224, in a dose-dependent manner. Also, the increase of ß-endorphin release by metformin was blocked by BU224 in same manner. A specific competition between metformin and BU224 was observed in isolated adrenal medulla. Otherwise, amiloride at the dose sufficient to block I-2A receptor abolished the metformin-induced ß-endorphin release, but only the blood glucose-lowering action of metformin was markedly reduced. In addition, the blood glucose-lowering action of metformin in bilateral adrenalectomized rats was diminished by amiloride at higher doses. These results suggest that metformin might activate imidazoline I-2 receptors while I-2A receptors link the increase of ß-endorphin release and I-2B receptors couple to the other actions for lowering of blood glucose in type-1 like diabetic rats., (© Georg Thieme Verlag KG Stuttgart · New York.)

The aim of this study was to generate a transgenic mouse that ubiquitously expressed enhanced green fluorescent protein (EGFP) under the control of the murine phosphoglycerate kinase 1 promoter by allotransplantation of transgenic mouse ovaries. The EGFP transgenic mice expressed green fluorescence in many organs, and the fluorescence was detected as early as the embryonic stage. Ovaries from the EGFP transgenic mice were allotransplanted into recipients and these mice were mated with normal male mice. Histological sections of EGFP-allotransplanted ovaries from the recipient mice showed the well development and formation at follicles and corpora lutea. The green fluorescence was clearly detectable at the allotransplanted section of the ovaries, which had fused with the normal ovary. The average size of the first litter from these mice was 6.8 ± 1.2 pups per recipient, and 17.8% of the pups expressed EGFP. These results demonstrated that allotransplantation of transgenic ovaries can restore a normal reproductive lifespan and can be used to generate a ubiquitously expressing EGFP animal model., (© 2009 Blackwell Verlag GmbH.)

Racecadotril is known as an inhibitor of enkephalinase. Increase of plasma insulin by racecadotril has been observed in rats while the mechanism of the action remains obscure. In the present study, intravenous injection of male Wistar rats with racecadotril significantly decreased blood glucose levels. However, this effect of racecadotril was not modified by naloxone at the dose sufficient to block opioid receptors. Thus, the blood glucose-lowering action of racecadotril might be through an endogenous opioid independent mechanism. Otherwise, we found that C-peptide content was also raised by racecadotril in parallel with the increase of insulin in Wistar rats. Thus, the blood glucose-lowering action of racecadotril was related to insulin secretion, but not through the inhibition of plasma insulin degradation. In addition, racecadotril showed no direct effect on insulin secretion in isolated islets or cultured HIT-T15 beta cells. The increase of plasma insulin and blood glucose-lowering action induced by racecadotril were reduced by pretreatment with atropine and enhanced by physotigmine. Direct inhibition of cholinesterase was not observed in brain homogenates treated with racecadotril. Moreover, actions of racecadotril were significantly reduced in rats receiving hemicholinium-3 at a sufficient dose to decrease endogenous acetylcholine. Activation of cholinergic tone is possibly involved in the blood glucose-lowering effect of racecadotril. Our results suggested that racecadotril increased insulin secretion to lower blood glucose mainly via regulation of parasympathetic tone in Wistar rats., (Georg Thieme Verlag KG Stuttgart New York.)

Aim: Transketolase-like enzyme 1 (TKTL1) is a glycolytic enzyme that has been found to be upregulated in several tumours, and it is associated with tumour progression. Nephroblastoma is the commonest paediatric renal malignancy and has a good prognosis except for those with anaplasia. To the best of the authors' knowledge, the expression of TKTL1 in nephroblastomas has not been studied before and the aim of this study was to compare the immunoexpression of TKTL1 in anaplastic and non-anaplastic nephroblastomas., Methods: Twenty-eight patients who had nephrectomies for nephroblastomas were studied. Archival formalin-fixed paraffin-wax-embedded tissue sections were stained with monoclonal TKTL1 antibody., Results: Six of the 15 anaplastic nephroblastomas showed staining in 80-100% of the tumour (p = 0.36). None of the 13 non-anaplastic nephroblastomas showed TKTL1 staining in >80% of the tumour., Conclusion: TKTL1 expression is associated with the presence of anaplasia and may be a mechanism via which anaplastic tumour cells thrive under different conditions. Glycolytic inhibitors may play a role in anaplastic nephroblastomas.