An Automated, Dynamic Radiation Oncology Prescription Checking System.

PURPOSE: Despite serving as a critical communication tool, radiation oncology prescriptions are entered manually and prone to error. An automated prescription checking system was developed and implemented to help address this problem. METHODS AND MATERIALS: Rules defining clinically appropriate prescriptions were generated, examining specific types of errors: (1) unapproved dose per fraction for a given disease site; (2) dose per fraction too large for nonstereotactic treatment technique; and (3) dose per fraction too low. With a goal of catching errors as upstream as possible to minimize their propagation, a report was created and ran every 30 minutes to check all newly written or approved prescriptions against the 3 rules. When a prescription violated these rules, an automated email was immediately sent to the prescriber alerting them of the potential error. System performance was continuously monitored and the criteria triggering an alert adjusted to balance error detection against false positives. Alerts leading to prescription amendment were considered true errors. RESULTS: From June 2021 to November 2022, the system checked 24,047 prescriptions. A total of 241 email alerts were triggered, for an average alert rate of 1%. Of the 241 alerts, 198 (82.2%) were unapproved doses per fraction for the disease site, 14 (5.8%) were doses per fraction that were too low, and 29 (12%) were doses too large for nonstereotactic treatment technique. Thirty-one percent of alerts led to a change of prescription, suggesting they were true errors. The baseline rate of erroneous prescription entry was 0.3%. A regression model showed that trainee prescription entry and dose per fraction <150 cGy were significantly associated with true errors. CONCLUSIONS: Given the significant consequences of erroneous prescription entry, which ranged from wasted resources and treatment delays to potentially serious misadministration, there is significant value in implementing automated prescription checking systems in radiation oncology clinics.

Videolaryngoscopy vs. flexible fibrescopy for tracheal intubation in patients with cervical spine immobilisation: a randomised controlled trial.

In patients with cervical spine immobilisation, tracheal intubation devices other than a direct laryngoscope are frequently used to facilitate tracheal intubation and avoid related complications. In this randomised controlled trial, we compared videolaryngoscopic and fibrescopic tracheal intubation in patients with a cervical collar. Tracheal intubation was performed using either a videolaryngoscope with a non-channelled Macintosh blade (n = 166) or a flexible fibrescope (n = 164) in patients having elective cervical spine surgery whose neck was immobilised with a cervical collar to simulate a difficult airway. The primary outcome was the first attempt success rate of tracheal intubation. Secondary outcomes were the overall success rate of tracheal intubation; time to tracheal intubation; use of additional airway manoeuvres; and incidence and severity of tracheal intubation-related airway complications. First attempt success rate was higher in the videolaryngoscope group than in the fibrescope group (164/166 (98.8%) vs. 149/164 (90.9%), p = 0.003). Tracheal intubation was successful within three attempts in all patients. Median (IQR [range]) time to tracheal intubation was shorter (50.0 (41.0-72.0 [25.0-170.0]) s vs. 81.0 (65.0-107.0 [24.0-178.0]) s, p < 0.001) and additional airway manoeuvres were less frequent (30/166 (18.1%) vs. 91/164 (55.5%), p < 0.001) in the videolaryngoscope group compared with the fibrescope group. The incidence and severity of intubation-related airway complications were not different between the two groups. When performing tracheal intubation in patients with a cervical collar, videolaryngoscopy with a non-channelled Macintosh blade was superior to flexible fibrescopy.

Geriatric nutritional risk index as the prognostic factor in older patients with fragility hip fractures.

This study investigated the long-term survival and incidence of secondary fractures after fragility hip fractures. The 5-year survival rate was 62%, and the mortality risk was seen in patients with GNRI < 92. The 5-year incidence of secondary fracture was 22%, which was significantly higher in patients with a BMI < 20. BACKGROUND: Malnutrition negatively influences the postoperative survival of patients with fragility hip fractures (FHFs); however, little is known about their association over the long term. OBJECTIVE: This study evaluated the ability of the geriatric nutritional risk index (GNRI) as a risk factor for long-term mortality after FHFs. METHODS: This study included 623 Japanese patients with FHFs over the age of 60 years. We prospectively collected data on admission and during hospitalization and assessed the patients' conditions after discharge through a questionnaire. We examined the long-term mortality and the incidence of secondary FHFs and assessed the prognostic factors. RESULTS: The mean observation period was 4.0 years (range 0-7 years). The average age at the time of admission was 82 years (range 60-101 years). The overall survival after FHFs (1 year, 91%; 5 years, 62%) and the incidence of secondary FHFs were high (1 year, 4%; 5 years, 22%). The multivariate Cox proportional hazard analysis revealed the risk factors for mortality as older age (hazard ratio [HR] 1.04), male sex (HR 1.96), lower GNRI score (HR 0.96), comorbidities (malignancy, HR 2.51; ischemic heart disease, HR 2.24; revised Hasegawa dementia scale ≤ 20, HR 1.64), no use of active vitamin D3 on admission (HR 0.46), and a lower Barthel index (BI) (on admission, HR 1.00; at discharge, HR 0.99). The GNRI scores were divided into four risk categories: major risk (GNRI, < 82), moderate risk (82-91), low risk (92-98), and no risk (> 98). Patients at major and moderate risks of GNRI had a significantly lower overall survival rate (p < 0.001). Lower body mass index (BMI) was also identified as a prognostic factor for secondary FHFs (HR 0.88 [p = 0.004]). CONCLUSIONS: We showed that older age, male sex, a lower GNRI score, comorbidities, and a lower BI are risk factors for mortality following FHFs. GNRI is a novel and simple predictor of long-term survival after FHFs.

Accelerated Synthetic MRI with Deep Learning-Based Reconstruction for Pediatric Neuroimaging.

BACKGROUND AND PURPOSE: Synthetic MR imaging is a time-efficient technique. However, its rather long scan time can be challenging for children. This study aimed to evaluate the clinical feasibility of accelerated synthetic MR imaging with deep learning-based reconstruction in pediatric neuroimaging and to investigate the impact of deep learning-based reconstruction on image quality and quantitative values in synthetic MR imaging. MATERIALS AND METHODS: This study included 47 children 2.3-14.7 years of age who underwent both standard and accelerated synthetic MR imaging at 3T. The accelerated synthetic MR imaging was reconstructed using a deep learning pipeline. The image quality, lesion detectability, tissue values, and brain volumetry were compared among accelerated deep learning and accelerated and standard synthetic data sets. RESULTS: The use of deep learning-based reconstruction in the accelerated synthetic scans significantly improved image quality for all contrast weightings (P < .001), resulting in image quality comparable with or superior to that of standard scans. There was no significant difference in lesion detectability between the accelerated deep learning and standard scans (P > .05). The tissue values and brain tissue volumes obtained with accelerated deep learning and the other 2 scans showed excellent agreement and a strong linear relationship (all, R 2 > 0.9). The difference in quantitative values of accelerated scans versus accelerated deep learning scans was very small (tissue values, <0.5%; volumetry, -1.46%-0.83%). CONCLUSIONS: The use of deep learning-based reconstruction in synthetic MR imaging can reduce scan time by 42% while maintaining image quality and lesion detectability and providing consistent quantitative values. The accelerated deep learning synthetic MR imaging can replace standard synthetic MR imaging in both contrast-weighted and quantitative imaging.

Onychopapilloma: its clinical, dermoscopic and pathologic features.

BACKGROUND: Onychopapilloma is a benign tumour of the nail bed and distal matrix and commonly presents as longitudinal erythronychia, longitudinal leukonychia or longitudinal melanonychia. Because onychopapilloma is rare, its clinical characteristics and dermoscopic findings have not been well investigated in Asia. OBJECTIVES: This study aimed to investigate the clinical characteristics and dermoscopic and pathologic findings of onychopapilloma in Korea. METHODS: We retrospectively reviewed the medical records and clinical/dermoscopic photographs of 39 patients diagnosed with onychopapilloma in the Pusan National University Hospitals (Busan and Yangsan) for 11 years (2010-2021). RESULTS: Among 39 patients, 23 (59.0%) were men, and 16 (41.0%) were women. The mean age was 46.1 (16-77) years. All lesions were single, and most of them were located on the fingers (92.3%), especially the thumb (66.7%). The most common clinical feature was longitudinal erythronychia (56.4%), and the most common dermoscopic finding was distal subungual hyperkeratosis (100%). We found two new dermoscopic features: macrolunula and trailing lunula along the longitudinal band. Among 18 patients who underwent surgical excision, only 6 (33.3%) showed typical acanthosis and papillomatosis on the nail bed. CONCLUSIONS: We found that Asian onychopapilloma has similar clinicodermoscopic findings to the Caucasian one, that is to say, longitudinal erythronychia and distal subungual hyperkeratosis were the most common nail change and dermoscopic finding, respectively. We propose two new dermoscopic features of onychopapilloma: macrolunula and trailing lunula along the longitudinal band.

Effect of dipeptidyl peptidase IV inhibitors, thiazolidinedione, and sulfonylurea on osteoporosis in patients with type 2 diabetes: population-based cohort study.

The population-based cohort study used the Korean National Health Insurance claims database to evaluate the effect of anti-diabetic drugs on osteoporosis. The use of DPP-IV inhibitors does not increase the risk of osteoporosis compared with the use of sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis. PURPOSE: The current study aimed to evaluate the effect of dipeptidyl peptidase IV inhibitors (DPP-IVi), thiazolidinedione (TZD), and sulfonylurea (SU) on osteoporosis in patients with type 2 diabetes. METHODS: A population-based cohort study was conducted in the Republic of Korea using the Korean National Health Insurance claims database. Data from 2012 to 2017 for patients of 50-99 years of age who were prescribed DPP-IVi, TZD, or SU during 2013-2015 were extracted from the database. Based on pre-defined criteria, a total of 381,404 patients were analyzed after inverse probability of treatment weighting. The association between the study drugs and osteoporosis was estimated using Cox proportional hazards models. Data of 220,166 patients who were prescribed DPP-IVi, 18,630 who were prescribed TZD, and 142,608 patients who were prescribed SU were set. RESULTS: In the multivariate-adjusted analysis, the hazard ratio (HR) of osteoporosis in the DPP-IVi group was not significantly different from that of the SU group (HR: 0.97; 95% confidence interval (CI) 0.94-1.00), whereas the HR of osteoporosis in the TZD group was higher (HR: 1.13; 95% CI 1.06-1.20). In the subgroup analysis, the HRs of osteoporosis were higher with pioglitazone (HR: 1.14; 95% CI 1.06-1.23) in the TZD group and with glibenclamides (HR: 1.39; 95% CI 1.09-1.77) in the SU group, whereas drugs with lower HR in the DPP-IVi group were saxagliptin (HR: 0.93; 95% CI 0.87-0.99) and sitagliptin (HR: 0.93; 95% CI 0.89-0.97). CONCLUSION: DPP-IV inhibitors do not increase the risk of osteoporosis compared with sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis.

Impact of perceived contraceptive policy changes on long acting reversible contraception dispensing trends.

OBJECTIVE: We observed the long-term trend of Long Acting Reversible Contraception (LARC) usage before and after the 2016 presidential election. METHODS: We observed the rate of LARC dispensed at a university student health centre in the 18 months preceding and 27 months following the 2016 U.S. presidential election which posed threat to contraception access. We applied a segmented regression model using two linear regression line segments to evaluate whether there is a time point where the trend of LARC dispensing changed. We fit the regression models with a breakpoint at month 0 (election month) and 3 months with a Locally Estimated Scatterplot Smoothing (LOESS) estimate with parameters obtained by estimating simple linear regression models separately below and above the breakpoint '0'. RESULTS: There were a total of 2067 LARC methods dispensed from May 2015 to February 2019. The average number of LARC methods dispensed before November 2016 was 38/month and increased to 51/month post-presidential election. The LARC dispense rate significantly increased each month (0.38, 1.74; 95% confidence level, p < 0.05) until a breakpoint at 6 months (standard error 4.11) post-election followed by slower decrease (-0.59/month, 95% confidence level: -1.37, 0.20; p=not significant). CONCLUSION: Our study is the first to report long-term trends (27 months post-election) in LARC uptake amidst the public discourse that suggested the end of a policy that provided LARC insurance coverage. Although this observational study cannot suggest causality, the findings could reflect actions taken to prevent unintended pregnancy in response to the event of uncertain national policy.

Molecular insights into the development of hepatic metastases in colorectal cancer: a metastasis prediction study.

OBJECTIVE: Colorectal cancer is presently the third most commonly diagnosed cancer in the United States. In this study, we identified molecular differences between hepatic and non-hepatic metastases in colorectal cancer and evaluated their prognostic significance. MATERIALS AND METHODS: We downloaded primary data from the NCBI Gene Expression Omnibus (GSE6988, GSE62321, GSE50760, and GSE28722). To identify the molecular differences, we used the Significance Analysis of Microarray method. We selected nine prognostic genes (SYTL2, PTPLAD1, CDS1, RNF138, PIGR, WDR78, MYO7B, TSPAN3, and ATP5F1) with hepatic metastasis prediction score in colorectal cancer (hereafter referred to as LASSO Score). We confirmed the prognostic significance of the LASSO Score by using Kaplan-Meier survival analysis, multivariate analysis, the time-dependent area under the curve (AUC) of Uno's C-index, and the AUC of the receiver operating characteristic curve at 1-5 years. RESULTS: Survival analysis revealed that a high LASSO Score is associated with a poor prognosis in colorectal cancer patients with hepatic metastases (p = 0). Analysis of C-indices and AUC values from the receiver operating characteristic curve further supported this prediction by the LASSO Score. Multivariate analysis confirmed the prognostic significance of the LASSO Score (p = 1.13e-06). CONCLUSIONS: This study reveals the biological mechanisms underlying hepatic metastases in colorectal cancer and will help in developing targeted therapies for colorectal cancer.

Comparison of dermoscopic features between congenital and acquired acral melanocytic nevi in Korean patients.

BACKGROUND: The dermoscopic patterns of acral melanocytic nevi (AMNs) are crucial in differentiating them from acral melanoma. Several studies have reported the dermoscopic patterns of acquired acral melanocytic nevi (AAMNs). However, few have investigated the dermoscopic patterns of congenital acral melanocytic nevi (CAMNs). OBJECTIVE: To compare the clinical and dermoscopic features of CAMNs and AAMNs. METHODS: The present study included 43 patients with CAMNs and 40 with AAMNs. We reviewed their medical records as well as their clinical and dermoscopic findings. RESULTS: Congenital acral melanocytic nevis were more asymmetrical than AAMNs (P = 0.002) and presented more frequently as comma-shaped (P = 0.005). Regarding dermoscopic findings, globular pattern (55.8%) was the most common feature of CAMNs, while parallel furrow pattern (37.5%) was the most common feature of AAMNs. The presence of fibrillar, globular, and parallel ridge patterns, and diffuse multi-component pigmentation differed significantly between the groups (P < 0.05). Furthermore, CAMNs showed melanoma-specific dermoscopic patterns, such as parallel ridge (18.6%) and diffuse multi-component pigmentation (25.6%). CONCLUSION: The dermoscopic patterns of CAMNs and AAMNs differed markedly. In terms of dermoscopic patterns, CAMNs resembled acral melanoma more often than AAMNs did.

Search for a Dark Matter-Induced Annual Modulation Signal in NaI(Tl) with the COSINE-100 Experiment.

We present new constraints on the dark matter-induced annual modulation signal using 1.7 years of COSINE-100 data with a total exposure of 97.7 kg yr. The COSINE-100 experiment, consisting of 106 kg of NaI(Tl) target material, is designed to carry out a model-independent test of DAMA/LIBRA's claim of WIMP discovery by searching for the same annual modulation signal using the same NaI(Tl) target. The crystal data show a 2.7 cpd/kg/keV background rate on average in the 2-6 keV energy region of interest. Using a χ-squared minimization method we observe best fit values for modulation amplitude and phase of 0.0092±0.0067 cpd/kg/keV and 127.2±45.9 d, respectively.

Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2.

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis (Pg)-induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides (Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, ß-proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

First Direct Search for Inelastic Boosted Dark Matter with COSINE-100.

A search for inelastic boosted dark matter (IBDM) using the COSINE-100 detector with 59.5 days of data is presented. This relativistic dark matter is theorized to interact with the target material through inelastic scattering with electrons, creating a heavier state that subsequently produces standard model particles, such as an electron-positron pair. In this study, we search for this electron-positron pair in coincidence with the initially scattered electron as a signature for an IBDM interaction. No excess over the predicted background event rate is observed. Therefore, we present limits on IBDM interactions under various hypotheses, one of which allows us to explore an area of the dark photon parameter space that has not yet been covered by other experiments. This is the first experimental search for IBDM using a terrestrial detector.

Antiviral activity of hypothiocyanite produced by lactoperoxidase against influenza A and B viruses and mode of its antiviral action.

Hypothiocyanite (OSCN-) is a natural component of human saliva and is produced by the lactoperoxidase (LPO)/thiocyanate/hydrogen peroxide (H2O2) system. OSCN- has been previously shown to exhibit antiviral activity against influenza viruses (IFV) A/H1N1/2009 and A/H1N2/2009 in vitro as well as antimicrobial and antifungal activities. We elucidated the antiviral activity of OSCN- against both IFV types A and B and the mode of its antiviral action. OSCN- was produced constantly at 900 ± 200 µmol/l in Na3PO4 buffer solution containing NaSCN and LPO in the presence of H2O2 as an original OSCN- solution. In a plaque reduction assay, IFV A/PR/8/34 (H1N1), A/Fukushima/13/43 (H3N2), B/Singapore/222/97, and B/Fukushima/15/93 were exposed to various concentrations of OSCN- for 0 to 30 min before adsorption to MDCK cells, and plaque formation was examined. OSCN- exhibited significant similar antiviral activities against all four viruses without cytotoxicity, and the EC50 values for them were from 57 ± 16 to 148 ± 27 µmol/l regardless of the exposure times. The exposure of MDCK cells to OSCN- before viral adsorption did not affect its anti-IFV activity (EC50: more than 450 µmol/l), but the exposure after viral adsorption affected it moderately (EC50: 380 ± 40 µmol/l). Moreover, the exposure of virus particles to OSCN- at 450 µmol/l did not affect the hemagglutinin activity of IFV in hemagglutination inhibition assay. These results suggest that the attachment of OSCN- to the viral envelope critically contributes to the mode of antiviral action of OSCN- without interfering with viral adsorption. Keywords: hypothiocyanite; influenza virus type A; influenza virus type B; lactoperoxidase; antiviral activity.

Alitretinoin can be a good treatment option for idiopathic recalcitrant trachyonychia in adults: an open-label study.

BACKGROUND: Trachyonychia can be refractory to conventional treatments including topical, intralesional or systemic corticosteroids, as well as cyclosporine and retinoids. Therefore, new treatment options are needed for recalcitrant trachyonychia. OBJECTIVE: To evaluate the efficacy and safety of oral alitretinoin for idiopathic recalcitrant trachyonychia. METHODS: A total of 21 adult patients with 210 nails affected by idiopathic recalcitrant trachyonychia were evaluated in this open-label prospective study. All patients took 30 mg of alitretinoin daily for at least 3 months. Clinical outcomes were assessed using the Physician Global Assessment (PGA) scale proposed by Park et al. (degree of roughness: 0, clear; 1, mild; 2, moderate; 3, marked; 4, severe) at baseline and 1, 3 and 6 months after treatment. RESULTS: After 1, 3 and 6 months of treatment, 74.3% (123/210), 98.1% (206/210) and 99.2% (119/120) of nails showed clinical improvement, respectively; 0% (0/210), 22.9% (48/210) and 69.2% (83/120) were completely free from nail abnormalities. The mean PGA score at baseline was 3.4, decreasing significantly to 2.7, 1.3 and 0.7 at 1, 3 and 6 months following treatment, respectively. LIMITATIONS: A small number of participants and lack of a control group were limitations. CONCLUSIONS: For the first time, this study evaluated the efficacy and safety of oral alitretinoin for idiopathic recalcitrant trachyonychia in adults. The results suggest that oral alitretinoin can be a good treatment option for adult patients with recalcitrant trachyonychia.

Autonomic function test in progressive lacunar infarction.

OBJECTIVE: Neurological progression is a major problem in managing the patients with acute lacunar infarction. The purpose of this was to investigate whether autonomic dysfunction is associated with neurological progression in patients with acute lacunar infarction. MATERIALS AND METHODS: The study comprised 60 patients with acute lacunar infarction. All enrolled subjects underwent autonomic function tests including the 30° head-up tilt test, Valsalva test, heart rate response to deep breathing, and sympathetic skin response. The primary endpoint is the neurological progression, and the secondary endpoint is the 3-month outcome. RESULTS: Increased initial National Institute of Health stroke scale (NIHSS), decreased time to admission from onset, decreased rise of heart rate in the 30° head-up tilt test, abnormal blood pressure response in the Valsalva test, and decreased rise of systolic blood pressure in stage IV of the Valsalva test are associated with neurological progression of acute lacunar infarction; an abnormal blood pressure response in the Valsalva test is significant in logistic regression analysis of neurological progression. Advanced age, increased initial NIHSS and modified Rankin scale, decreased expiration/inspiration ratio of heart rate to deep breathing, decreased rise of systolic blood pressure in stage IV of the Valsalva test, and neurological progression were associated with an unfavorable 3-month outcome; neurological progression was significant in logistic regression analysis of 3-month outcome. CONCLUSIONS: An abnormal blood pressure change in the Valsalva test is associated with neurological progression in patients with acute lacunar infarction, and neurological progression can induce an unfavorable 3-month outcome.

Human Papillomavirus 16 E6 Induces FoxM1B in Oral Keratinocytes through GRHL2.

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

Estimation of dispersion curves of water-loaded structures by using approximated acoustic mass.

For coupled structures surrounded by heavy fluids, it is difficult to obtain dispersion curves from an eigenvalue analysis, because the external fluid term in the coupled equation includes transcendental functions for frequency and wavenumber. Thus, in this study, the acoustic mass of the external fluid was approximated as a function of frequency or wavenumber only. The coupled equation can then be used to calculate eigenvalues, and can estimate dispersion curves from an eigenvalue analysis. Because of this assumption, those dispersion curves will contain errors. Accordingly, those errors were evaluated in this study through a comparison with a dispersion curve derived from forced responses. The acoustic mass was also evaluated for a water-loaded plate; this can be formulated theoretically. As a result, the acoustic mass is less sensitive to frequency changes than wavenumber changes, and using the fluid term defined at a low frequency has advantages when estimating the dispersion curve. Finally, the generality of the proposed method was identified through the application for a submerged cylindrical shell.

Progressive topological disorganization of brain network in focal epilepsy.

OBJECTIVE: Increasing evidence has suggested that epilepsy is a network disease. Graph theory is a mathematical tool that allows for the analysis and quantification of the brain network. We aimed to evaluate the influences of duration of epilepsy on the topological organization of brain network in focal epilepsy patients with normal MRI using the graph theoretical analysis based on diffusion tenor imaging. METHODS: We prospectively enrolled 66 patients with focal epilepsy (18/66 patients were newly diagnosed) and 84 healthy subjects. All of the patients with epilepsy had normal MRI on visual inspection. All of the subjects underwent diffusion tensor imaging that was analyzed using graph theory to obtain network measures. RESULTS: The measures of characteristic path length and small-worldness in the patients with focal epilepsy were significantly decreased, even after multiple corrections (P < .01). Moreover, the measures including mean clustering coefficient and global efficiency in the patients with epilepsy had strong tendency to decrease compared to those in healthy subjects (P = .0153 and P = .0138, respectively). When comparing the measures among the patients with newly diagnosed/chronic epilepsy and healthy subjects using ANOVA, the characteristic path length (P = .006), small-worldness (P = .032), and global efficiency (P = .004) were significantly different. In addition, the duration of epilepsy was negatively correlated with global efficiency (r = -.249, P = .0454). CONCLUSIONS: We newly found a progressive topological disorganization of the brain network in focal epilepsy. In addition, we demonstrated disrupted topological organization in focal epilepsy, shifting toward a more random state.

Interleukin-17A negatively regulates lymphangiogenesis in T helper 17 cell-mediated inflammation.

During inflammation lymphatic vessels (LVs) are enlarged and their density is increased to facilitate the migration of activated immune cells and antigens. However, after antigen clearance, the expanded LVs shrink to maintain homeostasis. Here we show that interleukin (IL)-17A, secreted from T helper type 17 (TH17) cells, is a negative regulator of lymphangiogenesis during the resolution phase of TH17-mediated immune responses. Moreover, IL-17A suppresses the expression of major lymphatic markers in lymphatic endothelial cells and decreases in vitro LV formation. To investigate the role of IL-17A in vivo, we utilized a cholera toxin-mediated inflammation model and identified inflammation and resolution phases based on the numbers of recruited immune cells. IL-17A, markedly produced by TH17 cells even after the peak of inflammation, was found to participate in the negative regulation of LV formation. Moreover, blockade of IL-17A resulted in not only increased density of LVs in tissues but also their enhanced function. Taken together, these findings improve the current understanding of the relationship between LVs and inflammatory cytokines in pathologic conditions.

Environmental and health effects of the herbicide glyphosate.

The herbicide glyphosate, N-(phosphonomethyl) glycine, has been used extensively in the past 40years, under the assumption that side effects were minimal. However, in recent years, concerns have increased worldwide about the potential wide ranging direct and indirect health effects of the large scale use of glyphosate. In 2015, the World Health Organization reclassified glyphosate as probably carcinogenic to humans. A detailed overview is given of the scientific literature on the movement and residues of glyphosate and its breakdown product aminomethyl phosphonic acid (AMPA) in soil and water, their toxicity to macro- and microorganisms, their effects on microbial compositions and potential indirect effects on plant, animal and human health. Although the acute toxic effects of glyphosate and AMPA on mammals are low, there are animal data raising the possibility of health effects associated with chronic, ultra-low doses related to accumulation of these compounds in the environment. Intensive glyphosate use has led to the selection of glyphosate-resistant weeds and microorganisms. Shifts in microbial compositions due to selective pressure by glyphosate may have contributed to the proliferation of plant and animal pathogens. Research on a link between glyphosate and antibiotic resistance is still scarce but we hypothesize that the selection pressure for glyphosate-resistance in bacteria could lead to shifts in microbiome composition and increases in antibiotic resistance to clinically important antimicrobial agents. We recommend interdisciplinary research on the associations between low level chronic glyphosate exposure, distortions in microbial communities, expansion of antibiotic resistance and the emergence of animal, human and plant diseases. Independent research is needed to revisit the tolerance thresholds for glyphosate residues in water, food and animal feed taking all possible health risks into account.