Fractional model for Middle East respiratory syndrome coronavirus on a complex heterogeneous network.

In this paper, we present a new fractional epidemiological model on a heterogeneous network to investigate Middle East respiratory syndrome (MERS-CoV), which is caused by a virus in the coronavirus family. We also consider the development of equations for the camel population, given that it is the primary animal source of the virus, as well as direct human interaction with this population. The model is configured in an SIS form for both the human population and the camel population. We study the equilibrium positions of the system and the conditions for the existence of each of them, as well as the local stability of each equilibrium position. Then, we provide some numerical examples that compare real data and numerical results.

A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.

BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

A fractional complex network model for novel corona virus in China.

As is well known the novel coronavirus (COVID-19) is a zoonotic virus and our model is concerned with the effect of the zoonotic source of the coronavirus during the outbreak in China. We present a SEIS complex network epidemic model for the novel coronavirus. Our model is presented in fractional form and with varying population. The steady states and the basic reproductive number are calculated. We also present some numerical examples and the sensitivity analysis of the basic reproductive number for the parameters.

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.

BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. CLINICAL TRIALS NUMBER: NCT02143466.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).

Volume measurement of crowns in mandibular primary central incisors by micro-computed tomography.

OBJECTIVE: To determine sex differences in the tissue proportions of crowns of mandibular primary central incisors in Chinese children and to quantify the volume of crown components in three dimensions using micro-computed tomography (micro-CT). MATERIALS AND METHODS: The specimens used in this study were 41 mandibular first deciduous incisor teeth with intact crowns (21 males and 20 females) obtained from patients between 5-6 years of age. Each specimen was scanned using micro-CT at a resolution of 0.05 mm and 3D-rendered images were created. The volume of each component of the crown was measured and examined for differences in different sex and ages. RESULTS: The pulp chamber volume decreased with age and the volume ratio of the pulp chamber to the whole crown was significantly smaller in 6-year-olds than in 5-year-olds (p < 0.05). CONCLUSIONS: Males had significantly larger tooth crown volumes and dentin volumes than females did (p < 0.001), while the volume of enamel showed no sexual dimorphism.

Anthropometric studies on the Turkish population--a historical review.

A historical review of anthropometric studies conducted on Turkish children and adults is presented. In view of observed differences in growth status between children of different societies, the need for local reference standards and the methodology to be used for such studies have been stressed. The importance of local studies in reflecting the state of health and nutrition both in children and adults has also been mentioned. While a number of studies in children cited in this paper are designed to compare the growth of children from different socioeconomic levels, other studies aim to establish local reference data for Turkish children. While the historical studies in adults aim to define racial characteristics, the more recent studies aim to bring out nutritional characteristics with emphasis on increasing frequency of obesity.

Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study.

BACKGROUND: A phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1-14 or carboplatin-paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented. RESULTS: The updated analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793-1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm (HR 0.713; 95% CI 0.476-1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859-1.308) for those with non-SCC. CONCLUSIONS: These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology.

Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency.

Using targeted exome sequencing, we identified mutations in NNT, an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased reactive oxygen species (ROS) levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands.

On fractional order models for Hepatitis C.

In this paper we present a fractional order generalization of Perelson et al. basic hepatitis C virus (HCV) model including an immune response term. We argue that fractional order equations are more suitable than integer order ones in modeling complex systems which include biological systems. The model is presented and discussed. Also we argue that the added immune response term represents some basic properties of the immune system and that it should be included to study longer term behavior of the disease.

Age estimation based on three-dimensional measurement of mandibular central incisors in Japanese.

The purpose of this study was to investigate an age estimation method that considers gender as well as three-dimensional measurement of the components, specifically enamel and dentin. A total of 155 mandibular central incisors aged 12-79 years old which was chosen from the collection stored at the Department of Anatomy in Tokyo Dental College and had no opened apex, caries or restorative treatment, were examined. Samples were scanned using micro-CT HMX225 ACTIS4. Based on the sliced image data, three-dimensional structures were obtained and the volumes of enamel, dentin, and pulp cavity were measured. Regression equations for age estimation were then determined. The accuracy of age estimation equations for each region, volume ratio, and sex was assessed using the determination coefficient R(2) as well as the standard errors of estimated values. The root region alone had a comparable accuracy to that of the whole tooth and the crown region had a relatively lower accuracy. In the whole tooth and the crown region, slightly higher correlations were observed for pulp/tooth volume ratios in which enamel was excluded. Females tended to have higher accuracy compared to males. The estimated age was higher in males compared to females for the same volume ratio of the pulp cavity. The highest correlation in both genders with age was observed for the volume ratio of the pulp cavity to the whole tooth excluding the enamel (males, R(2)=0.67; females, R(2)=0.76). The 95% confidence intervals for the population regression showed different distributions for each sex. In the 95% prediction intervals for age estimation, females tended to have narrower intervals and higher accuracy compared to males. Therefore, the use of gender-specific equations is recommended for age estimation.

Novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions.

In the present study, the authors evaluated the diagnostic utility of a novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions. A total of 118 patients were included in this prospective study. Bronchoscopic examination was performed using a 5.9-mm standard bronchoscope. If no visible endobronchial lesion was found, transbronchial biopsies were performed with 1.5-mm biopsy forceps under fluoroscopic guidance and the bronchus were washed with 10-20 mL of saline solution, using a prototype 3.5-mm thin bronchoscope with a 1.7-mm working channel. Endobronchial lesion was visualised with the standard bronchoscope in 16 patients, and the other 102 patients underwent biopsies with the thin bronchoscope. The mean bronchus levels reached with the standard bronchoscope and the thin bronchoscope were 2.3 and 4.3 generations, respectively. Endobronchial abnormality was revealed with the thin bronchoscope in a further 14 patients. Diagnostic material was obtained in 50 of 68 (74%) patients with malignant disease and 18 of 30 (60%) patients with benign disease. Four patients did not return to follow-up. The diagnostic yield was 57%, even in lesions <20 mm. There were no major complications. In conclusion, bronchoscopy using a 3.5-mm thin bronchoscope with a 1.7-mm working channel is useful and safe for the diagnosis of peripheral pulmonary lesions.

In situ transmission electron microscopy observation of the growth of bismuth oxide whiskers.

Growth of bismuth oxide (most probably Bi2O3) was observed in situ in a transmission electron microscope. Bi liquid particles were dispersed on the substrates of diamond or SiO2. Introduction of oxygen up to 5 x 10-4 Pa resulted in formation of bismuth oxide (most probably Bi2O3) whiskers. The growth mechanism of the whisker was discussed in terms of a vapor-liquid-solid (VLS) mechanism. It is suggested that the liquid droplet of Bi acts as a physical catalyst for growth of bismuth oxide (most probably Bi2O3) whiskers.

High frequency of Panton-Valentine leukocidin genes in invasive methicillin-susceptible Staphylococcus aureus strains and the relationship with methicillin-resistant Staphylococcus aureus in Córdoba, Argentina.

In the study presented here, the genetic characteristics of methicillin-susceptible Staphylococcus aureus (MSSA) strains isolated from patients attending hospitals in the city of Córdoba, Argentina, during 1999-2002 were evaluated to determine their genetic relationship with methicillin-resistant S. aureus (MRSA) clones as part of an effort to control the potential emergence of new epidemic MRSA strains. The results showed there is a high frequency of MSSA strains carrying Panton-Valentine leukocidin genes in invasive infections in Córdoba, Argentina, particularly in those occurring in hospital settings. Panton-Valentine leukocidin genes were found in the genomic background of one clone (ST30-N pulsotype) belonging to a successful internationally distributed MSSA lineage (clonal complex 30), which is closely related to the EMRSA-16 pandemic clone. These genes were also detected in the ancestral clone (ST5-M pulsotype) of the most prevalent MRSA epidemic clone causing healthcare-associated infections in this region, known as the Cordobes/Chilean clone. The molecular characterization of circulating MSSA strains, including the detection of Panton-Valentine leukocidin genes, is thus a useful marker for investigating the evolving epidemiology of hospital- and community-acquired MRSA clones.

A phase II study of single-agent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer.

The aim of this study was to evaluate the efficacy and tolerability of gefitinib ('IRESSA') in Japanese patients with previously untreated stage IV non-small-cell lung cancer (NSCLC). This was a multi-institutional phase II study. Thirty-four patients with previously untreated stage IV NSCLC were enrolled between May 2003 and September 2004. Gefitinib was administered orally 250 mg once a day and was continued until there was either disease progression or severe toxicity. Objective tumour response rate was 26.5% (95% confidence interval, 11.7-41.3%). Adverse events were generally mild (National Cancer Institute-Common Toxicity Criteria grade 1 or 2) and consisted mainly of skin rash, fatigue and liver dysfunction. No pulmonary toxicity was observed. The global health status revealed that there was no change in quality of life during the study. This study found that single-agent gefitinib is active and well tolerated in chemo-naive Japanese patients with advanced NSCLC.

Virulence factors of non-O1 non-O139 Vibrio cholerae isolated in Córdoba, Argentina / Factores de virulencia de Vibrio cholerae no-O1 no-O139 aislados en Córdoba, Argentina

V. cholerae non-O1 non-O139 serogroups isolated from clinical and environmental sources in Córdoba, Argentina, were analyzed for the presence and expression of virulence genes. Most of the strains studied contained the genes toxR and hlyA, but lacked ctxA, zot, ace, tcpA and stn. The culture supernatants were tested for hemolytic and cytotoxic activity. The enterotoxic potential of the strains was studied in a rabbit ileal loop assay and their genetic profiles were compared by PFGE. The environmental strains varied in their virulence phenotype and showed no-clonal relationships. The clinical strains were highly enterotoxic, hemolytic, proteolytic and showed indistinguishable PFGE profiles, although they differed in their cytotoxic activity. This is the first description, using cell culture and “in vivo” studies, of the virulence properties of non-O1 non-O139 V. cholerae from Argentina.

En este trabajo se analizó la presencia y expresión de genes de virulencia en V. cholerae no-O1 no-O139 de origen clínico y ambiental, aislados en Córdoba, Argentina. La mayoría de las cepas estudiadas contiene los genes toxR y hlyA, pero no ctxA, zot, ace, tcpA y stn. Se analizó la actividad hemolítica y citotóxica de estas cepas en los sobrenadantes de cultivo, así como su potencial enterotóxico en ensayos de asa ileal ligada de conejo. Además, los aislamientos fueron comparados por sus perfiles genéticos en PFGE. Las cepas del medio ambiente mostraron variación en su fenotipo de virulencia y no mostraron relación clonal. Las cepas clínicas fueron muy enterotóxicas, hemolíticas, proteolíticas y mostraron perfiles indistinguibles de PFGE, aunque mostraron diferencias en su actividad citotóxica. En este trabajo se describen por primera vez, utilizando ensayos de cultivo celular e “in vivo”, propiedades de virulencia de V. cholerae no-O1 no-O139 aislados en Argentina.

Three-dimensional observation of pulp cavities in the maxillary first premolar tooth using micro-CT.

AIM: To observe three-dimensional morphological changes with age in the pulp cavities of maxillary first premolar teeth. METHODOLOGY: The specimens used in this study were 10 maxillary first premolar teeth (five males and five females) obtained from patients in three age groups, namely in their twenties (20s), forties (40s) and sixties (60s). Each specimen was imaged by a micro-CT to reconstruct the three-dimensional structure. Then, using the reconstructed images, the morphological characteristics of the pulp cavity, the volume ratio at the horn region, the floor region and the overall region of the pulp chamber and the diameters of the buccal and lingual orifices of the root canals were compared between the three age groups. RESULTS: The mesio-distal widths and the heights of the pulp cavity decreased with age. The volume ratio and the diameter of the root canal orifices also decreased. The decrease in volume was not constant but showed a large decrease between the 20s and the 40s, compared to those of 40s to 60s. CONCLUSIONS: Morphological features of the pulp cavity of maxillary first premolar teeth in different age groups were observed three dimensionally using micro-CT. Decreases in pulp cavity size and shape with age were clarified using a three-dimensional technique.

Virulence factors of non-O1 non-O139 Vibrio cholerae isolated in Córdoba, Argentina.

V. cholerae non-O1 non-O139 serogroups isolated from clinical and environmental sources in Córdoba, Argentina, were analyzed for the presence and expression of virulence genes. Most of the strains studied contained the genes toxR and hlyA, but lacked ctxA, zot, ace, tcpA and stn. The culture supernatants were tested for hemolytic and cytotoxic activity. The enterotoxic potential of the strains was studied in a rabbit ileal loop assay and their genetic profiles were compared by PFGE. The environmental strains varied in their virulence phenotype and showed no clonal relationships. The clinical strains were highly enterotoxic, hemolytic, proteolytic and showed indistinguishable PFGE profiles, although they differed in their cytotoxic activity. This is the first description, using cell culture and "in vivo" studies, of the virulence properties of non-O1 non-O139 V. cholerae from Argentina.

Virulence factors of non-O1 non-O139 Vibrio cholerae isolated in Córdoba, Argentina.

V. cholerae non-O1 non-O139 serogroups isolated from clinical and environmental sources in Córdoba, Argentina, were analyzed for the presence and expression of virulence genes. Most of the strains studied contained the genes toxR and hlyA, but lacked ctxA, zot, ace, tcpA and stn. The culture supernatants were tested for hemolytic and cytotoxic activity. The enterotoxic potential of the strains was studied in a rabbit ileal loop assay and their genetic profiles were compared by PFGE. The environmental strains varied in their virulence phenotype and showed no clonal relationships. The clinical strains were highly enterotoxic, hemolytic, proteolytic and showed indistinguishable PFGE profiles, although they differed in their cytotoxic activity. This is the first description, using cell culture and [quot ]in vivo[quot ] studies, of the virulence properties of non-O1 non-O139 V. cholerae from Argentina.

[Extended-spectrum beta-lactamases in Klebsiella pneumoniae isolated at the Cordoba Children's Hospital, Argentina]. / Beta-lactamasas de espectro extendido en Klebsiella pneumoniae aisladas en el Hospital de Niños de Córdoba, Argentina.

The aim of the present study was to investigate the presence of extended-spectrum beta-lactamases (ESBL) in Klebsiella pneumoniae isolated at the "Hospital de Niños de Córdoba". The strains were collected from inpatients between January 1996 and July 2000. A total of 150 ESBL producer isolates were detected. During 1996 the prevalence of ESBL producer K. pneumoniae was 20%, but since 1998 the values have increased to approximately 60%. Phenotypic analysis such as isoelectric point (pl) and antibiotyping performed in 32 randomly selected isolates showed two different enzyme profiles: 81% had ESBL with pl = 7.9 and preferential activity against cefotaxime, while 19% showed ESBL with pl = 5.4 and preferential activity against ceftazidime. No isolates resistant to imipenem or ciprofloxacin were detected. Susceptibility to other antimicrobial agents varied, but resistance to gentamicin was strongly associated with ESBL producer isolates. Resistance determinants could be transferred to Escherichia coli by conjugation assays.