Differences in the Prognostic Impact between Single-zone and Multi-zone N2 Node Metastasis in Patients with Station-based Multiple N2 Non-Small Cell Lung Cancer.

Purpose: The International Association for the Study of Lung Cancer suggest further subdivision of pathologic N (pN) stage in non-small-cell lung cancer (NSCLC) by incorporating the location and number of involved lymph node (LN) stations. We reclassified patients with the station-based N2b disease into single-zone and multi-zone N2b groups and compared survival outcomes between the groups. Materials and Methods: This retrospective study included patients with pN2 NSCLC who underwent lobectomy from 2006 to 2019. The N2 disease was subdivided into four categories: single-station N2 without N1 (N2a1), single-station N2 with N1 (N2a2), multiple-station N2 with single zone involvement (single-zone N2b), and multiple-station N2 with multiple zone involvement (multi-zone N2b). LN zones included in the subdivision of N2 disease were upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal. Results: Among 996 eligible patients, 211 (21.2%), 394 (39.6%) and 391 (39.4) were confirmed to have pN2a1, pN2a2, and pN2b disease, respectively. In multivariable analysis after adjustment for sex, age, pT stage, and adjuvant chemotherapy, overall survival was significantly better with single-zone N2b disease (n=125, 12.6%) than with multi-zone N2b disease (n=266, 26.7%) (hazard ratio 0.67, 95% confidence interval 0.49-0.90, p<0.009) and was comparable to that of N2a2 disease (1.12, 0.83-1.49, p=0.46). Conclusion: Prognosis of single-zone LN metastasis was better than that of multiple-zone LN metastasis in patients with N2b NSCLC. Along with the station-based N descriptors, zone-based descriptors might ensure optimal staging, enabling the most appropriate decision-making on adjuvant therapy for patients with pN2 NSCLC.

Individualized antibiotic dosage regimens for patients with augmented renal clearance.

Objectives: Augmented renal clearance (ARC) is a state of enhanced renal function commonly observed in 30%-65% of critically ill patients despite normal serum creatinine levels. Using unadjusted standard dosing regimens of renally eliminated drugs in ARC patients often leads to subtherapeutic concentrations, poor clinical outcomes, and the emergence of multidrug-resistant bacteria. We summarized pharmaceutical, pharmacokinetic, and pharmacodynamic research on the definition, underlying mechanisms, and risk factors of ARC to guide individualized dosing of antibiotics and various strategies for optimizing outcomes. Methods: We searched for articles between 2010 and 2022 in the MEDLINE database about ARC patients and antibiotics and further provided individualized antibiotic dosage regimens for patients with ARC. Results: 25 antibiotic dosage regimens for patients with ARC and various strategies for optimization of outcomes, such as extended infusion time, continuous infusion, increased dosage, and combination regimens, were summarized according to previous research. Conclusion: ARC patients, especially critically ill patients, need to make individualized adjustments to antibiotics, including dose, frequency, and method of administration. Further comprehensive research is required to determine ARC staging, expand the range of recommended antibiotics, and establish individualized dosing guidelines for ARC patients.

Early Outcomes of COVID-19 Lung Transplantation Recipients in Korea: A Single-Center Study.

Background: Coronavirus disease 2019 (COVID-19) has been found to cause life-threatening respiratory failure, which can progress to irreversible lung damage. Lung transplantation can be a life-saving treatment in patients with terminal lung disease (e.g., acute respiratory distress syndrome caused by infection). This study aimed to present the clinical course and results after initial lung transplantation in patients with severe COVID-19 who did not recover even with optimal medical care. Methods: From August 2019 to February 2022, this study enrolled 10 patients with COVID-19 (5 men; median age, 55.7 years) who underwent lung transplantation at a single center in Korea. All patients' characteristics, clinical pathway, overall survival, complications, and operative data were collected and analyzed. Results: Veno-venous extracorporeal membrane oxygenation or an oxygenator in a right ventricular assist device circuit was applied to 90% of the patients, and the median length of extracorporeal life support before operation was 48.5 days. There were no cases of mortality after a median follow-up of 372.8 days (interquartile range, 262.25-489 days). The major complications included the requirement for postoperative extracorporeal membrane oxygenation support in 2 cases (20%), re-transplantation in 1 case (10%), and re-exploration due to bleeding in 2 cases (20%). During the follow-up period, 3 out of 10 patients died. Conclusion: Excellent early outcomes were observed for patients who underwent lung transplantation. Thus, lung transplantation can be an effective and feasible treatment for patients with end-stage lung disease caused by COVID-19.

Infected Left Atrial Myxoma Presenting Without Bacterial Growth on Blood Cultures: A Case Report.

Although cardiac myxoma is one of the most common types of benign cardiac tumors, infected cardiac myxoma is very infrequent. The diagnosis of infected cardiac myxoma may be challenging because the presenting symptoms are non-specific and established management guidelines are lacking. This report describes a 39-year-old woman with a 5-month history of uncontrolled fever, chills, and myalgia who was diagnosed with myxoma and underwent mass excision. Although blood and urine cultures were negative for growing bacteria, a pathologic examination showed that the excised mass was a left atrial myxoma, with pan-bacterial polymerase chain reaction (PCR) of the surgical specimen revealing Haemophilus parainfluenzae at 99.87%, resulting in a diagnosis of infected cardiac myxoma. Laboratory tests, such as PCR, may supplement culture results in the diagnosis of infected cardiac myxoma.

Mini-access open arch repair.

BACKGROUND: The use of minimally invasive approaches is scarce in open aortic arch repair because of its perceived high operative risk and technical difficulty. METHODS: This study enrolled 59 consecutive patients (aged 58.2±13.2 years) undergoing elective arch replacement either through upper hemi-sternotomy (n=58) or mini-thoracotomy (n=1) between 2015 and 2020. Of these, 44 underwent hemiarch replacement and 15 underwent total arch replacement. Moderate hypothermic circulatory arrest was used for all patients while antegrade cerebral perfusion was selectively used for total arch repair. For more efficient distal aortic anastomosis in limited spaces, inverted graft anastomosis was utilized whenever possible. RESULTS: Hemi-sternotomy involved upper sternal separation down to the second, third, and fourth intercostal spaces in 1 (1.7%), 30 (50.8%), and 27 (45.8%) patients, respectively. Concomitant cardiac procedures included root replacement in 19 patients (32.2%) and aortic valve replacement in 21 patients (35.6%). Circulatory arrest, cardiac ischemic, cardiopulmonary bypass, and total procedural times were 8.9±3.4, 91.1±31.1, 114.6±46.2, and 250.3±79.5 min, respectively for total arch repair, and 25.0±12.1, 72.3±16.6, 106.0±16.9, and 249.1±41.7 min, respectively for hemiarch repair. Conversion to full-sternotomy was required in 1 patient (1.7%) due to bleeding. There was one case of mortality (1.7%) attributable to low-cardiac output syndrome following hemiarch repair concomitantly with Bentall procedure. Major complications included requirement for mechanical support in 1 (1.7%), temporary neurologic deficit in 1 (1.7%), newly initiated dialysis in 3 (5.1%), and re-exploration due to bleeding in 2 (3.4%). CONCLUSIONS: Mini-access open arch repair is technically feasible and achieved excellent early outcomes.

Learning from reproducing computational results: introducing three principles and the Reproduction Package.

We carry out efforts to reproduce computational results for seven published articles and identify barriers to computational reproducibility. We then derive three principles to guide the practice and dissemination of reproducible computational research: (i) Provide transparency regarding how computational results are produced; (ii) When writing and releasing research software, aim for ease of (re-)executability; (iii) Make any code upon which the results rely as deterministic as possible. We then exemplify these three principles with 12 specific guidelines for their implementation in practice. We illustrate the three principles of reproducible research with a series of vignettes from our experimental reproducibility work. We define a novel Reproduction Package, a formalism that specifies a structured way to share computational research artifacts that implements the guidelines generated from our reproduction efforts to allow others to build, reproduce and extend computational science. We make our reproduction efforts in this paper publicly available as exemplar Reproduction Packages. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.

Prediction of venous thromboembolism using clinical and serum biomarker data from a military cohort of trauma patients.

INTRODUCTION: Venous thromboembolism (VTE) is a frequent complication of trauma associated with high mortality and morbidity. Clinicians lack appropriate tools for stratifying trauma patients for VTE, thus have yet to be able to predict when to intervene. We aimed to compare random forest (RF) and logistic regression (LR) predictive modelling for VTE using (1) clinical measures alone, (2) serum biomarkers alone and (3) clinical measures plus serum biomarkers. METHODS: Data were collected from 73 military casualties with at least one extremity wound and prospectively enrolled in an observational study between 2007 and 2012. Clinical and serum cytokine data were collected. Modelling was performed with RF and LR based on the presence or absence of deep vein thrombosis (DVT) and/or pulmonary embolism (PE). For comparison, LR was also performed on the final variables from the RF model. Sensitivity/specificity and area under the curve (AUC) were reported. RESULTS: Of the 73 patients (median Injury Severity Score=16), nine (12.3%) developed VTE, four (5.5%) with DVT, four (5.5%) with PE, and one (1.4%) with both DVT and PE. In all sets of predictive models, RF outperformed LR. The best RF model generated with clinical and serum biomarkers included five variables (interleukin-15, monokine induced by gamma, vascular endothelial growth factor, total blood products at resuscitation and presence of soft tissue injury) and had an AUC of 0.946, sensitivity of 0.992 and specificity of 0.838. CONCLUSIONS: VTE may be predicted by clinical and molecular biomarkers in trauma patients. This will allow the development of clinical decision support tools which can help inform the management of high-risk patients for VTE.

Hesperidin alleviates cholestasis via activation of the farnesoid X receptor in vitro and in vivo.

Cholestasis causes the intrahepatic accumulation of bile acids leading to hepatobiliary injury. Recently obeticholic acid, a farnesoid X receptor (FXR) agonist, was FDA-approved to treat cholestatic liver diseases, providing a new therapeutic strategy for cholestasis. The purpose of the current study was to characterize a novel FXR agonist and verify the anti-cholestatic effect of hesperidin (HP) in vivo and in vitro. Based on a molecular docking study that predicted that HP would bind to FXR, the hepatoprotective effect of HP against cholestasis and hepatotoxicity was evaluated in mice and in normal and FXR-suppressed HepaRG cells. HP prevented bile acid toxicity in HepaRG cells, and this effect was blocked by FXR silencing. HP appears to activate FXR to prevent cholestatic liver injury. Dynamic change analysis of bile acids revealed that HP promoted bile acid excretion into feces and reduced hepatic accumulation via the regulation of the FXR-target genes bile salt export pump, multi-drug resistance-associated protein 2, and Na+-taurocholate cotransporting polypeptide. Furthermore, HP down-regulated enzymes involved in bile acid synthesis including cholesterol 7α-hydroxylase and sterol 27-hydroxylase. HP produced a protective effect against cholestasis via FXR activation, and may be an effective approach for the prevention and treatment of cholestatic liver diseases.

[Efficacy of esophageal cancer screening program on population at high risk: a survey carried out in people aged 40-69 years in Yangzhong, Jiangsu province].

Objective: To understand the incidence of esophageal cancer in population at high risk in Yangzhong of Jiangsu province. Methods: Cluster random sampling method was conducted to select several natural villages from the high risk area of esophageal cancer in Yangzhong during 2011-2017. Local residents aged 40-69 years were selected as the target population and a total of 14 687 persons were diagnosed esophageal cancer by endoscopy and pathology. Results: Precancerous lesions were detected in 341 persons, with the detection rate as 2.32% (341/14 687). Among them, there were 234 (1.59%) cases with mild and 107 (0.73%) cases with moderate esophageal hyperplasia. There were 77 positive cases with esophageal hyperplasia and the detection rate was 0.52%. Among these positive cases, 41 showed severe esophageal hyperplasia/carcinoma in situ (0.28%), with another 19 as early esophageal cancer (0.13%) and 17 with invasive carcinoma (0.12%). The overall early detection rate of positivity through active screening was 77.92% (60/77), with trends of upwarding and then downwarding. The detection rate of esophageal lesions in men was higher than that in women (P<0.05), but without significant gender specific differences seen in the detection rates of early esophageal cancer or invasive carcinoma (P>0.05). The detection rates of all lesions other than invasive carcinoma, gradually increased with age (P<0.05). The detection rate of invasive carcinoma reached the highest (0.39%, 10/2 547) in the age group of 60-years and slightly decreased in the age group of 65-years old. Conclusions: Considerable numbers of patients with cancer and precancerous lesions in groups at high-risk can be found through the screening program for esophageal cancer, suggesting that the screening program is of great significance in improving the survival rate and quality of life. Attention should be paid to men, with elderly groups in particular, at high-risk in order to increase the detection rate of early cases.

Diagnostic potential of urinary monocyte chemoattractant protein-1 for Alzheimer's disease and amnestic mild cognitive impairment.

BACKGROUND AND PURPOSE: The chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of Alzheimer's disease (AD). This study aimed to investigate whether urinary MCP-1 can distinguish patients with AD, patients with amnestic mild cognitive impairment (aMCI) and cognitively normal (CN) subjects. METHODS: A total of 754 participants, including 97 patients with AD, 50 patients with aMCI and 84 age- and sex-matched CN controls as well as a cohort of 523 CN subjects of different ages, were enrolled from five hospitals located in different areas of China. Urinary MCP-1 levels were determined using enzyme-linked immunosorbent assays. The correlations between urinary MCP-1 levels and cognition test scores or age were analysed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis. RESULTS: In the cohort of CN subjects of different ages, urinary MCP-1 levels increased with ageing and were correlated with age. The urinary MCP-1 levels were higher in females than in males. In the cohort composed of patients with AD, aMCI and age- and sex-matched CN controls, urinary MCP-1 levels were significantly higher in patients with AD and aMCI than in CN controls. There were no differences in urine MCP-1 levels between the AD group and the aMCI group. The urinary MCP-1 levels were correlated with the Mini-Mental State Examination scores and age, and were able to differentiate patients with AD and aMCI from CN subjects. CONCLUSIONS: Urinary MCP-1 is a potential biomarker for the diagnosis of AD and aMCI.

[Needs of pre-exposure prophylaxis for HIV infection and related barriers among men who have sex with men].

Objective: To understand the actual needs for the pre-exposure prophylaxis (PrEP) for HIV infection and the factors hindering PrEP utilization in men who have sex with men (MSM). Methods: Participants were recruited by using MSM social application software Blued 6.5.0 and through MSM peer referral, sample size was 600. An electronic questionnaire survey was conducted anonymously with guidance of investigators via "Questionnaire Star" platform. The contents of the survey included demographic characteristics of the participants, the awareness of PrEP related knowledge, willingness and concerns about using PrEP, actual need for PrEP and self-efficacy of using PrEP. Results: A total of 622 MSM completed the survey, of whom 56.4% (351/622) and 4.3% (27/622) ever heard of and received PrEP, respectively. The need assessment of PrEP showed that 67.2% (418/622) of the participants had actual needs for PrEP and 21.2% (132/622) used PrEP with good self-efficacy. Structural equation modeling analysis showed that the awareness of PrEP related knowledge and concerning about PrEP utilization in MSM played a direct positive role in their self-efficiency of using PrEP, and the effect coefficients were 0.08 and 0.13, respectively. MSM self-discrimination indirectly affected the self-efficiency of using PrEP through concerns about PrEP use, the effect coefficient was 0.035. The result of generalized linear mixed model analysis demonstrated that the utilization of PrEP can improve the self-efficacy of using PrEP (OR=5.55), which increased by 0.14 times and 0.07 times with the increase of 1 score of the awareness of PrEP related knowledge and concern about using PrEP respectively. In addition, this survey found that in the participants, the main concerns about using PrEP were side effects, HIV prevention effect and its expense, accounting for 61.1% (380/622), 60.1% (374/622) and 53.2% (331/622), respectively. Most participants hoped to obtain PrEP services from CDC, MSM social organization and internet, accounting for 75.6% (470/622), 65.4% (407/622), and 63.8% (397/622), respectively. Conclusions: MSM showed difference of high need but low utilization of PrEP services. Low awareness of PrEP related knowledge, concerns about the prevention effect, side effects and expense of PrEP as well as self-discrimination were the factors hindering the use of PrEP in MSM. It is necessary to establish a suitable PrEP service model to meet the needs for PrEP in MSM.

[Cost-effectiveness and cost-benefit analysis of upper gastrointestinal cancer screening in Yangzhong City, Jiangsu Province, from 2009 to 2015].

Objective: To evaluate the effectiveness and benefit of the upper gastrointestinal cancer screening in Yangzhong city, Jiangsu province, from 2009 to 2015. Methods: From 2009 to 2015, 31 natural villages with high-incidence of upper gastrointestinal cancer were selected from Baqiao town, Youfang town and Xinglong sub-district in Yangzhong city. 13 776 residents aged 40 to 69 years old were recruited and screened for upper gastrointestinal cancer by using endoscopic examination and pathological diagnosis. Two economic evaluation methods, cost-effectiveness analysis and cost-benefit analysis, were performed to evaluate the current screening schemes. Results: The mean age of all respondents were (53.60±8.14) years old and the males accounted for 43.64% (6 012). A total of 502 cases of upper gastrointestinal tract lesions were detected, including 100 cases of cancer (62 cases of esophagus, gastric/cardiac early stage cancer, 38 cases of advanced stage cancer), 38 cases of severe esophageal hyperplasia/carcinoma in situ, and 15 cases of high-grade intraepithelial neoplasia in stomach/cardia, the detection rate was 0.73%, 0.28% and 0.11%, respectively; the early diagnosis rate was 75.16% (115/153). The cost of a precancerous lesion, a case diagnosed at the early stage and a positive case identified through the upper gastrointestinal cancer screening in Yangzhong City was 10 037.17, 30 460.64 and 22 895.25 RMB, respectively. The early detection cost index from 2009 to 2015 was 0.52, 0.56, 0.48, 0.48, 0.21, 0.30, and 0.26, respectively. The effectiveness-cost ratio from 2009 to 2015 was 3.41, 2.77, 2.66, 2.58, 4.99, 3.12, and 3.48, respectively. Conclusions: The project of early diagnosis and treatment of upper gastrointestinal tract cancer in Yangzhong city has achieved good results and benefits.

CD56bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long-term entecavir-treated patients switching to peginterferon alfa-2a.

HBV surface antigen (HBsAg) reduction is well observed in chronic hepatitis B (CHB) patients treated with pegylated interferon alpha-2a (PegIFNα). However, the mechanism of HBsAg suppression has not been fully elucidated. Twenty-seven of 55 entecavir-treated CHB e antigen positive patients were switched to PegIFNα treatment (Group A) whereas 28 patients continued entecavir treatment (Group B). The percentage or absolute number of CD56bright /CD56dim NK cells, expression of receptors and cytokines were evaluated by flow cytometry for 48 weeks and correlated with treatment efficacy. In vitro, purified NK cells were co-cultured with HepAD38 cells for measurement of HBsAg, apoptosis and covalently closed circular DNA (cccDNA). In association with a reduction of HBsAg, the percentage and absolute number of CD56bright NK cells was significantly elevated in patients in group A, especially in Virologic Responders (VRs, HBsAg decreased). Furthermore, the percentage of NKp30+ , NKp46+ , TRAIL+ , TNF-α+ and IFNγ+ CD56bright NK cells were significantly expanded in Group A, which were positively correlated with the decline of HBsAg at week 48. In vitro, peripheral NK cells from Group A induced a decline of HBsAg in comparison with NK cells from Group B which was significantly inhibited by anti-TRAIL, anti-TNF-α and anti-IFNγ antibodies. Furthermore, apoptosis of HepAD38 cells and levels of cccDNA, were significantly reduced by TRAIL+ and TNF-α+ /IFNγ+ NK cells from Group A, respectively. A functional restoration of CD56bright NK cells in entecavir-treated patients who were switched to PegIFNα contributes to HBsAg and cccDNA clearance through TRAIL-induced cytolysis and TNF-α/IFNγ-mediated noncytolytic pathways.

Effect of local scrotal heating on the expression of tight junction-associated molecule Occludin in boar testes.

The aim of this study was to determine whether local scrotal heating (42°C, for 1 hr) had an effect on the expression of tight junction (TJ)-associated molecule Occludin in boar testes. Adult boars (Landrace, n = 6) were used and randomly divided into two groups (n = 3 each). Three boars were given local scrotal exposure to 42°C for approximately 1 h with a home-made electric blanket of controlled temperature as local scrotal heating group, the other three boars received no heat treatment and were left at standard room temperature as control group. After 6 hr, all boars were castrated and the testes were harvested. qRT-PCR, Western blotting and immunohistochemistry were used to explore the expression and localization of Occludin. qRT-PCR and Western blotting showed that the protein and mRNA levels of Occludin significantly decreased in local scrotal heating group as compared to the control. Furthermore, immunoreactivity staining of Occludin was localized at the sites of the blood-testis barrier (BTB) and formed an almost consecutive and strong immunoreactivity strand in the control, while Occludin was limited to Sertoli cells (SCs) and no obvious immunoreactivity strand was present in local scrotal heating group. These data indicated that local scrotal heating decreased the expression of TJ-associated molecule Occludin, which may be involved in heat-induced spermatogenesis damage.

Tumor-associated autoantibodies are useful biomarkers in immunodiagnosis of α-fetoprotein-negative hepatocellular carcinoma.

AIM: To determine the prevalence and diagnostic value of autoantibodies in α-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC). METHODS: Fifty-six serum samples from AFP-negative HCC cases, 86 from AFP-positive HCC cases, 168 from chronic liver disease cases, and 59 from normal human controls were included in this study. Autoantibodies to nucleophosmin (NPM)1, 14-3-3zeta and mouse double minute 2 homolog (MDM2) proteins in AFP-negative HCC serum were evaluated by enzyme-linked immunosorbent assay. Partially positive sera were further evaluated by western blotting. Immunohistochemistry was used to detect the expression of three tumor-associated antigens (TAAs) in AFP-negative HCC and normal control tissues. RESULTS: The frequency of autoantibodies to the three TAAs in AFP-negative HCC sera was 21.4%, 19.6% and 19.6%, which was significantly higher than in the chronic liver disease cases and normal human controls (P < 0.01) as well as AFP-positive HCC cases. The sensitivity of the three autoantibodies for diagnosis of AFP-negative HCC ranged from 19.6% to 21.4%, and the specificity was approximately 95%. When the three autoantibodies were combined, the sensitivity reached 30.4% and the specificity reached 91.6%. CONCLUSION: Autoantibodies to NPM1, 14-3-3zeta and MDM2 may be useful biomarkers for immunodiagnosis of AFP-negative HCC.

Irinotecan-induced bile acid malabsorption is associated with down-regulation of ileal Asbt (Slc10a2) in mice.

Irinotecan, (CPT-11), an antitumor agent primarily used for the treatment of solid tumors, has often compromised clinical application due to the inducement of severe delay-onset diarrhea. Bile acid malabsorption (BAM) is widely accepted as the common cause of diarrhea. However, whether CPT-11-induced diarrhea has correlation with BAM is unknown. The aim of this study was to investigate the effect of CPT-11 on the bile acid homeostasis in mice. The mice were administrated with CPT-11 intravenously for four consecutive days. The total bile acids (TBAs) levels in the small intestine, colon, feces, liver, serum and gallbladder were evaluated by automatic biochemical analyzer, and the individual bile acids were also measured by LC-MS/MS. Real-time qPCR and Western blot techniques were used to evaluate the mRNA and protein expressions of Cyp7a1, Cyp27a1, Asbt, Ostα/ß. In situ loop method was carried out to evaluate the function of apical Na+-dependent bile salt transporter (Asbt). Results showed that the bile acid pool size was significantly reduced by 17%, 25%, and 40% respectively at 2, 3, and 4days post CPT-11 treatment. The fecal excretions of TBAs were significantly increased by 2.1-fold at 3 and 4days post CPT-11 treatment. The ileal expression of Asbt was significantly decreased at mRNA and protein levels, and the transport ability of Asbt was also attenuated after CPT-11 treatment. Moreover, the incidence of CPT-11-induced delay-onset diarrhea was also decreased after cholestyramine administration in CPT-11-treated mice. These results indicated that BAM may be partially responsible for CPT-11-induced delay-onset diarrhea, and the underlying mechanism may have correlation with down-regulation of the Asbt in the ileum of mice.

Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial.

Background: The optimal chemotherapy regimen administered currently with radiation in patients with stage III non-small cell lung cancer (NSCLC) remains unclear. A multicenter phase III trial was conducted to compare the efficacy of concurrent thoracic radiation therapy with either etoposide/cisplatin (EP) or carboplatin/paclitaxel (PC) in patients with stage III NSCLC. Patients and methods: Patients were randomly received 60-66 Gy of thoracic radiation therapy concurrent with either etoposide 50 mg/m2 on days 1-5 and cisplatin 50 mg/m2 on days 1 and 8 every 4 weeks for two cycles (EP arm), or paclitaxel 45 mg/m2 and carboplatin (AUC 2) on day 1 weekly (PC arm). The primary end point was overall survival (OS). The study was designed with 80% power to detect a 17% superiority in 3-year OS with a type I error rate of 0.05. Results: A total of 200 patients were randomized and 191 patients were treated (95 in the EP arm and 96 in the PC arm). With a median follow-up time of 73 months, the 3-year OS was significantly higher in the EP arm than that of the PC arm. The estimated difference was 15.0% (95% CI 2.0%-28.0%) and P value of 0.024. Median survival times were 23.3 months in the EP arm and 20.7 months in the PC arm (log-rank test P = 0.095, HR 0.76, 95%CI 0.55-1.05). The incidence of Grade ≥2 radiation pneumonitis was higher in the PC arm (33.3% versus 18.9%, P = 0.036), while the incidence of Grade ≥3 esophagitis was higher in the EP arm (20.0% versus 6.3%, P = 0.009). Conclusion: EP might be superior to weekly PC in terms of OS in the setting of concurrent chemoradiation for unresectable stage III NSCLC. Trial registration ID: NCT01494558.

VOC exposures in California early childhood education environments.

Little information exists about exposures to volatile organic compounds (VOCs) in early childhood education (ECE) environments. We measured 38 VOCs in single-day air samples collected in 2010-2011 from 34 ECE facilities serving California children and evaluated potential health risks. We also examined unknown peaks in the GC/MS chromatographs for indoor samples and identified 119 of these compounds using mass spectral libraries. VOCs found in cleaning and personal care products had the highest indoor concentrations (d-limonene and decamethylcyclopentasiloxane [D5] medians: 33.1 and 51.4 µg/m³, respectively). If reflective of long-term averages, child exposures to benzene, chloroform, ethylbenzene, and naphthalene exceeded age-adjusted "safe harbor levels" based on California's Proposition 65 guidelines (10-5 lifetime cancer risk) in 71%, 38%, 56%, and 97% of facilities, respectively. For VOCs without health benchmarks, we used information from toxicological databases and quantitative structure-activity relationship models to assess potential health concerns and identified 12 VOCs that warrant additional evaluation, including a number of terpenes and fragrance compounds. While VOC levels in ECE facilities resemble those in school and home environments, mitigation strategies are warranted to reduce exposures. More research is needed to identify sources and health risks of many VOCs and to support outreach to improve air quality in ECE facilities.

Giant superconducting fluctuations in the compensated semimetal FeSe at the BCS-BEC crossover.

The physics of the crossover between weak-coupling Bardeen-Cooper-Schrieffer (BCS) and strong-coupling Bose-Einstein condensate (BEC) limits gives a unified framework of quantum-bound (superfluid) states of interacting fermions. This crossover has been studied in the ultracold atomic systems, but is extremely difficult to be realized for electrons in solids. Recently, the superconducting semimetal FeSe with a transition temperature Tc=8.5 K has been found to be deep inside the BCS-BEC crossover regime. Here we report experimental signatures of preformed Cooper pairing in FeSe, whose energy scale is comparable to the Fermi energies. In stark contrast to usual superconductors, large non-linear diamagnetism by far exceeding the standard Gaussian superconducting fluctuations is observed below T*∼20 K, providing thermodynamic evidence for prevailing phase fluctuations of superconductivity. Nuclear magnetic resonance and transport data give evidence of pseudogap formation at ∼T*. The multiband superconductivity along with electron-hole compensation in FeSe may highlight a novel aspect of the BCS-BEC crossover physics.

Metoprolol decreases the plasma exposure of metformin via the induction of liver, kidney and muscle uptake in rats.

Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1. The results showed that, after single or 7-day repeated administration, the plasma concentrations of metformin in the co-administration group were significantly decreased compared with that in the metformin group. However, the parameter V/F of metformin in the co-administration group was markedly increased compared with that in the metformin group. The hepatic, renal and muscular Kp of metformin were markedly elevated after co-administration with metoprolol. Consistently, metformin uptake in rat kidney slices was significantly induced by metoprolol. In addition, multiple administrations of metoprolol significantly reduced the expression of rMATE1 in rat kidney as well as the urinary excretion of metformin. Importantly, after long-term administration, lactic acid and uric acid levels in the co-administration group were increased by 25% and 26%, respectively, compared with that in the metformin group. These results indicate that metoprolol can decrease the plasma concentration of metformin via the induction of hepatic, renal and muscular uptake, and long-term co-administration of metformin and metoprolol can cause elevated lactic acid and uric acid levels. Copyright © 2016 John Wiley & Sons, Ltd.