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OBJECTIVE: To evaluate whether pathologic complete response (pCR) exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR following trimodality therapy for esophagogastric adenocarcinoma is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adenocarcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage treatment response (TR) in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4–210.6); median OS was 48.3 months (95% CI, 42.2–58.8). Absence of residual nodal disease was independently associated with improved survival (P

This study examined the joint associations of sleep patterns and physical activity (PA) with all-cause, cardiovascular disease (CVD), and cancer mortality.A total of 341,248 adults (mean age = 39.7 years; men: 48.3%) were included in the study, with a 15-year follow-up. Participants reported sleep duration and disturbances (difficulty falling asleep, easily awakened, or use of sleeping medication). PA was classified into 4 levels:7.5, 7.5-14.9, 15.0-29.9, and ≥30.0 metabolic equivalent hours per week (MET-h/week). To understand the joint associations of sleep patterns and PA with mortality, Cox proportional hazard models were conducted, with exposure variables combining sleep duration/disturbances and PA.Compared with the reference group (sleeping 6-8 h/day), individuals who slept8 h/day had higher risk for all-cause mortality (hazard ratio (HR) = 1.307, 95% confidence interval (95%CI): 1.248-1.369), CVD mortality (HR = 1.298, 95%CI: 1.165-1.445), and cancer mortality (HR = 1.128, 95%CI: 1.042-1.220). Short sleep duration was not associated with mortality risk. Increased risk of all-cause and CVD mortality was found in participants who had difficulty falling asleep (HR = 1.120, 95%CI: 1.068-1.175; HR = 1.163, 95%CI: 1.038-1.304, respectively), and used sleeping medication (HR = 1.261, 95%CI: 1.159-1.372; HR = 1.335, 95%CI: 1.102-1.618, respectively) compared with those who slept well. Long sleep duration and sleep disturbances were not associated with risk of all-cause and CVD mortality among individuals achieving a PA level of ≥15 MET-h/week, and in particular among those achieving ≥30 MET-h/week.Long sleep duration, difficulty falling asleep, and use of sleeping medication were related to a higher risk of death. Being physically active at a moderate intensity for 25-65 min/day eliminated these detrimental associations.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30-40% of lymphoma diagnoses. Though aggressive, cure is achievable in approximately 60% of cases with primary chemo-immunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R-CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, CNS prophylaxis and the optimal treatment for patients with high-risk disease. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice. This article is protected by copyright. All rights reserved.

The urge to be vaccinated has increased rapidly during the outbreak of the COVID-19 pandemic. Resorting vaccine products is seen as the only way to break the chain of COVID-19 spread and eventually stop the pandemic. To this dire need, many consumers face the dilemma to be vaccinated or to opt-out of the vaccination program when the safety issues of vaccine products are widely circulated. The Muslim consumers, particularly, experiences double worry on the issue of safety and halal status of the vaccine product. Due to the emergency call to have the vaccine in the market as soon as possible, the innovation and production were carried out in an expedited manner, and the necessity to have the vaccine be certified as halal was bypass. When the news on the vaccine product uses non-halal ingredients reaches the Muslim community in Malaysia, they were taken aback and demanded immediate answers from the authorities. Thus, in addressing this issue, this study intends to critically analyse the role of NPRA and JAKIM in ensuring the safety and halal status of a product with the aim of suggesting a review of the existing role. This article adopts a qualitative research methodology where interviews will be the supporting method to a library-based and doctrinal study.

Purpose This paper aims to examine whether conditional conservatism is affected by chief financial officer (CFO) attributes as this issue is understudied in Malaysia. Given that CFOs have a direct responsibility for financial reporting, therefore, their individual attributes are important in influencing conservatism in financial reporting. Design/methodology/approach This study uses non-financial listed firms in the Main Market of Bursa Malaysia from the years 2016 until 2019. Findings The results show that CFOs’ attributes, namely, gender, age, education level and ethnicity, affect earnings conservatism. To test for robustness, the authors use difference-in-difference, propensity score-matching and unconditional conservatism, namely, market-to-book ratio and the authors find the results hold with an exception for age and education level. Further, the effect of these attributes is more profound in non-Big4 audited firms, suggesting that CFO attributes act as a substitute mechanism for lower audit quality. Originality/value This study complements existing studies by documenting the first evidence on the significant effects of CFOs’ attributes in influencing accounting conservatism in an emerging country, namely, Malaysia. This is the first paper, to the humble knowledge, that examines CFOs’ attributes on accounting conservatism in Malaysia.

Study Design: An experimental study with extracellular vesicles (EVs) from mesenchymal stem cell (MSC) of the epidural fat (EF) of the spine.Purpose: This study aims to isolate the exosomes from epidural fat-derived mesenchymal stem cells (EF-MSCs) and fully characterize the EF-MSC-EVs.Overview of Literature: EF-MSCs were reported in 2019, and a few studies have shown the positive outcomes of using EF-MSCs to treat specific spine pathologies. However, MSCs have significant limitations for conducting basic studies or developing therapeutic agents. Although EVs are an emerging research topic, no studies have focused on EVs, especially exosomes, from EF and EF-MSCs.Methods: In this study, we isolated the exosomes using the tangential flow filtration (TFF) system with exosome-depleted fetal bovine serum and performed the characterization tests via western blotting, reverse transcription–polymerase chain reaction, nanoparticle tracking analysis (NTA), and transmission electron microscopy.Results: In transmission electron microscopy, the exosome had a diameter of approximately 100–200 nm and had a spherical shape, whereas in the NTA, the exosome had an average diameter of 142.8 nm with a concentration of 1.27×1010 particles/mL. The flow cytometry analysis showed the expression of CD63 and CD81. The western blotting analysis showed the positive markers.Conclusions: These findings showed that isolating the exosomes via TFF resulted in high-quality EF-MSC exosome yield. Further studies with exosomes from EF-MSC are needed to evaluate the function and role of the EF tissue.

We examine worker effort as a potential margin of adjustment to a minimum wage hike using unique data on piece rate workers who perform a homogenous task and whose individual output is rigorously recorded. By employing a difference-in-differences strategy that exploits the increase in Florida’s minimum wage from $6.79 to $7.21 on January 1, 2009, and worker location on the pre-2009 productivity distribution, we provide evidence consistent with incumbent workers’ positive effort responses.

Objectives Loss of smell or taste are early symptoms of COVID-19. Given the high asymptomatic rate of COVID-19, as well as unreliable temperature checking and contact history taking, it is important to understand the role of olfactory and gustatory dysfunction (OGD) in the diagnosis of COVID-19. The aim of this study is to determine how initial symptoms of OGD can be used to screen patients for COVID-19 laboratory testing. Methods We followed recommendations from the Preferred Reporting Items for Systemic Reviews and Meta-analysis (PRISMA) statement to conduct this systematic review study. We used OGD-related key words to search for literature published between January 1, 2020 and September 30, 2020 on Pubmed, Ovid Medline databases. We estimated the prevalence of OGD and compared it with that of other OGD-related symptoms. The weighted summary proportion under the fixed and random effects model was assessed using MedCalc statistical software. Whenever there was heterogeneity, a random effects model was selected. Publication bias was assessed by funnel plot asymmetry and Egger's regression test. Results A total of 25 articles (evidence level III:5; IV:20) were identified and reviewed. Data synthesis of 19 articles revealed that the pooled prevalence of olfactory dysfunction in COVID-19 is 53.56% (range 5.6-100%, 95% CI 40.25-66.61%). The pooled prevalence of gustatory dysfunction in COVID-19 is 43.93% (range 1.5-85.18%, 95% CI 28.72-59.74%), just behind fever (62.22%, range 18.18-95.83%, 95% CI 54.82-69.33%), cough (64.74%, range 38.89-87.5%, 95% CI 57.97-71.22%), and fatigue (56.74%, range 6.25-93.62%, 95% CI 32.53-79.35%). The prevalence of gustatory dysfunction in subgroup with objective evaluation is lower than those without (9.91% vs. 49.21%, relive risk 2.82, p Conclusion Our updated systematic review attests that OGD is an important early symptom of COVID-19 infection. Screening for OGD should be further emphasized to prioritize patients for laboratory test.

In proton therapy, a highly conformal proton dose can be delivered to the tumor by means of the steep distal dose penumbra at the end of the beam range. The proton beam range, however, is highly sensitive to range uncertainty, which makes accurately locating the proton range in the patient difficult. In-vivo range verification is a method to manage range uncertainty, one of the promising techniques being prompt gamma imaging (PGI). In earlier studies, we proposed gamma electron vertex imaging (GEVI), and constructed a proof-of-principle system. The system successfully demonstrated the GEVI imaging principle for therapeutic proton pencil beams without scanning, but showed some limitations under clinical conditions, particularly for pencil beam scanning proton therapy. In the present study, we upgraded the GEVI system in several aspects and tested the performance improvements such as for range-shift verification in the context of line scanning proton treatment. Specifically, the system showed better performance in obtaining accurate prompt gamma (PG) distributions in the clinical environment. Furthermore, high shift-detection sensitivity and accuracy were shown under various range-shift conditions using line scanning proton beams.

With the increasing interest in smart card data and transport-vulnerable population segments, data-based analysis has become increasingly important. This study aimed to design transfer trips by using smart card usage data to analyze vulnerable transfer routes for each user group. After merging smart card and basic information data such as stops, stations, and facilities, we constructed a transfer dataset of individual users according to the specified transfer time ranges and conditions. The transfer analysis targets were limited to transfers between the bus and subway, and transfer patterns for each user group (general population, youth, children, elderly, and disabled) were analyzed by date and time. The analyzed populations were then divided into general and vulnerable groups, and vulnerable transfer routes were identified. The actual transfer time differences between the general and vulnerable groups were then analyzed. We directly measured the expected transfer time differences between these groups based on map data and different walking speeds. We then calculated the differences between the expected and actual transfer times and analyzed the correlation between the number and location of accessible facilities in subway stations. We hope that this analysis will be useful for guiding the installation of accessible facilities in subway stations.

Introduction Mutations in BRAF occur in 2-4% of lung adenocarcinoma (LUAD) patients. Combination dabrafenib/trametinib or single-agent vemurafenib is approved only for patients with cancers driven by the V600E BRAF mutation. Targeted therapy is not currently available for patients harboring non-V600 BRAF mutations. Methods An LUAD patient-derived xenograft (PDX) model (PHLC12) with wild-type and non-amplified epidermal growth factor receptor (EGFR) was tested for response to EGFR tyrosine kinase inhibitors (TKI). A cell line derived from this model (X12CL) was also used to evaluate drug sensitivity and to identify potential drivers by siRNA knockdown. Kinase assays were used to test direct targeting of the candidate driver by the EGFR TKIs. Structural modeling including, molecular dynamics (MD) simulations, and binding assays were conducted to explore the mechanism of off-target inhibition by EGFR TKIs on the model 12 driver. Results Both PDX PHLC12 and the X12CL cell line were sensitive to multiple EGFR TKIs. The BRAFG469V mutation was found to be the only known oncogenic mutation in this model. siRNA knockdown of BRAF, but not the EGFR, killed X12CL, confirming BRAFG469V as the oncogenic driver. Kinase activity of the BRAF protein isolated from X12CL was inhibited by treatment with the EGFR TKIs gefitinib and osimertinib, and expression of BRAFG469V in non-EGFR-expressing NR6 cells promoted growth in low serum, which was also sensitive to EGFR TKIs. . Structural modeling, MD simulations, and in vitro binding assays support BRAFG469V being a direct target of the TKIs. Conclusion Clinically approved EGFR TKIs can be repurposed to treat NSCLC patients harboring the BRAFG469V mutation.

SARS-CoV-2 infection has been associated with increased morbidity and mortality in organ transplant recipients, and data are limited on 2-dose or 3-dose vaccine immunogenicity against SARS-CoV-2 variants in this population. In this secondary analysis of a randomized trial of a third dose of mRNA-1273 vaccine versus placebo, the authors assessed neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses., Visual Abstract. SARS-CoV-2 Variant Neutralization After Vaccine in Transplant Recipients. SARS-CoV-2 infection has been associated with increased morbidity and mortality in organ transplant recipients, and data are limited on 2-dose or 3-dose vaccine immunogenicity against SARS-CoV-2 variants in this population. In this secondary analysis of a randomized trial of a third dose of mRNA-1273 vaccine versus placebo, the authors assessed neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses. Visual Abstract. SARS-CoV-2 Variant Neutralization After Vaccine in Transplant Recipients. SARS-CoV-2 infection has been associated with increased morbidity and mortality in organ transplant recipients, and data are limited on 2-dose or 3-dose vaccine immunogenicity against SARS-CoV-2 variants in this population. In this secondary analysis of a randomized trial of a third dose of mRNA-1273 vaccine versus placebo, the authors assessed neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses., Background: COVID-19 is more severe in transplant recipients. Variants of concern have supplanted wild-type virus. In transplant recipients, data are limited on 2-dose or 3-dose vaccine immunogenicity against variant viruses. Objective: To assess neutralizing antibody responses against SARS-CoV-2 variants in transplant recipients after 2 and 3 vaccine doses. Design: Secondary analysis of a randomized, double-blind, controlled trial of a third dose of mRNA-1273 vaccine versus placebo. (ClinicalTrials.gov: NCT04885907) Setting: Single-center transplant program. Patients: Organ transplant recipients. Intervention: Third dose of mRNA-1273 vaccine versus placebo. Measurements: Sera were analyzed for neutralization against wild-type virus and the Alpha, Beta, and Delta variants using a surrogate virus neutralization assay and a spike-pseudotyped lentivirus assay. Results: A total of 117 transplant recipients were analyzed (60 in the mRNA-1273 group and 57 in the placebo group). Sera were obtained before and 4 to 6 weeks after the third dose. After 2 doses, the proportion of patients with positive neutralization for all 3 variants was small compared with wild-type virus. After the third dose of mRNA-1273 vaccine, the proportion with a positive neutralization response versus placebo was improved for all 3 variants as measured by both assays. Based on the pseudovirus neutralization assay against the Delta variant, 33 of 60 (55%) patients were positive in the mRNA-1273 group versus 10 of 57 (18%) in the placebo group (difference, 37 [95% CI, 19 to 53] percentage points). The differences were 36 (CI, 17 to 51) percentage points for the Alpha variant and 31 (CI, 15 to 46) percentage points for the Beta variant. In the mRNA-1273 group, lower neutralization values were observed for variants compared with wild-type virus, especially the Beta variant. Limitations: There is no clear correlate of protection for neutralizing antibody. This was a secondary analysis. Conclusion: In organ transplant recipients, a third dose of mRNA vaccine increases neutralizing antibody response against SARS-CoV-2 variants compared with placebo. Primary Funding Source: Ajmera Transplant Centre.

Metabolic syndrome (MetS) has become a major clinical challenge worldwide due to rise of urbanisation, surplus energy intake, increasing obesity and sedentary lifestyle. C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-18 (IL-18) are associated with MetS. We performed a systematic review to investigate the effects of exercise on these markers in MetS patients and therefore to determine the best exercise regime for them. We searched Medline (Pubmed and Ovid), Scopus and CINAHL databases. The searches were standardized by using the same search strategy which included the terms such as ‘metabolic syndrome’, ‘CRP’, ‘IL-6’, ‘IL-18’ and ‘exercise’. Only clinical human studies published from Jan 2007 to May 2018 were included. A total of 11 clinical trials (466 participants) were selected. Majority of the studies were randomized controlled studies (90.9%). All studies showed a decrease in serum levels of the biomarkers. However, not all were statistically significant. The main type of exercise in most of the studies was aerobic. Aerobic-resistance exercise was more effective rather than aerobic alone, but aerobic exercise was the only effective as a sole intervention. Aerobic exercise showed promising role as the main lifestyle intervention in MetS. It is concluded that patients with MetS should have combined aerobic-resistance exercise.

Purpose Because of the heightened environmental awareness of the public, local governments (LGs) are being pressured to improve on the extent and quality of environmental disclosures (EDs) provided in an array of reporting media. The lack of an accounting tool to identify, measure and report EDs has propelled the infusion of environmental management accounting (EMA) to support the reporting practices. This paper aims to examine the institutional pressures influencing EMA adoption by Malaysian LGs. Design/methodology/approach Using the consensus approach, a self-administered questionnaire survey is conducted on accountants in LGs in Peninsular Malaysia. The items in the questionnaire are based on the findings of prior studies on EMA adoption. Findings The results suggest that coercive isomorphism from the state government is perceived to be the influential institutional factor placing intense pressures on LGs to adopt EMA. Research limitations/implications The results solidify the potential role of the state government in any public policy changes which could further stimulate and promote the adoption of EMA. Originality/value Insufficient empirical evidence on the adoption of EMA in LGs within a developing country’s perspective contributes to a limited understanding on the development of environmental-related practices in different economic stages and environment as well as within the public sector’s perspective.

A study was conducted in the marine finfish cage culture area in Sungai Udang, Penang, at the northern part of the Malacca Straits to examine the phytoplankton composition and abundance especially for potentially harmful phytoplankton. Monthly sampling were taken from March 2016 to January 2017 at nine sampling stations. Physio-chemical parameters of surface seawater such as pH, dissolved oxygen, temperature, salinity, total suspended solids, and nutrients (nitrate, nitrite, ammonium, phosphate and silicate) were also measured. A total of 54 phytoplankton taxa were recorded, with 37 genera belonged to diatoms, 15 of dinoflagellates, and 2 of cyanobacteria. The composition of phytoplankton was dominated by diatoms (>85%) at all sampling stations throughout the sampling period. The phytoplankton abundance ranged between 2.6×103 cells L-1 and 5.8×106 cells L-1. The potentially harmful toxic phytoplankton observed throughout the sampling period are dinoflagellates Alexandrium spp., Prorocentrum micans and Dinophysis caudata and diatoms, Pseudo-nitzchia spp but in low cell density. A total of six bloom-forming phytoplankton that can potentially trigger mass mortality of cultured fish such as Akashiwo sanguinea, Chaetoceros spp., Ceratium furca, Ceratium fusus, Margalefidinium spp. and Karlodinium spp. recorded at this area were relatively low in cell densities. Furthermore, no fish kill incident was reported in the area from blooms of phytoplankton during the period of study. Even though potentially harmful phytoplankton present were in low densities, they may pose significant risks to aquaculture activity if there is a sudden bloom. Hence, a monitoring program should be implemented to provide early warning of harmful algae blooms and safeguard the aquaculture industry in Sungai Udang, Penang.

Background/aims : Percutaneous transhepatic cholangioscopy (PTCS) is used for the diagnosis and treatment of biliary diseases in patients with failed endoscopic retrograde cholangiopancreatography, particularly those with surgically altered anatomy. However, few studies are available on the clinical use of Spyglass DS direct visualization system (SpyDS)-assisted PTCS. This study aimed to assess the efficacy and safety of SpyDS-assisted PTCS in patients with surgically altered anatomy, particularly those with a Roux-en-Y reconstruction. Methods Thirteen patients (six women, median age 71.4 years [range, 53 to 83 years]) with surgically altered anatomy (four Roux-en-Y choledochojejunostomies, seven Roux-en-Y hepaticojejunostomies, and two Roux-en-Y esophagojejunostomies) who underwent SpyDS-assisted PTCS between January 2019 and August 2020 were included and the data was acquired by retrospectively reviewing electronic medical record. Results A total of 19 SpyDS-assisted PTCS procedures were performed in the 13 patients: eight had bile-duct stones, and five had biliary strictures. All SpyDS-assisted PTCS procedures were successfully performed. The total procedure time was 42.42±18.0 minutes (mean±standard deviation). Bile duct clearance was achieved in all bile duct stone cases after a median of 2 (range, 1 to 3) procedures. In the five biliary stricture cases, the results of SpyBite forceps-guided targeted biopsy were consistent with adenocarcinoma (100% accuracy). The median hospitalization duration was 20 days (range, 14 to 30 days). No procedure-related morbidity or mortality occurred. Conclusions SpyDS-assisted PTCS may be a safe, feasible, and effective procedure for the diagnosis and treatment of biliary diseases in patients with surgically altered anatomy, particularly in those with the Roux-en-Y reconstruction requiring a percutaneous approach. However, our findings need to be validated in further studies.

Purpose This study aimed to develop a model for predicting pathologic extracapsular extension (ECE) and seminal vesicle invasion (SVI) while integrating magnetic resonance imaging-based T-staging (cTMRI, cT1c-cT3b).Materials and Methods A total of 1,915 who underwent radical prostatectomy between 2006-2016 met the inclusion/exclusion criteria. We performed a multivariate logistic regression analysis as well as Bayesian network (BN) modeling based on possible confounding factors. The BN model was internally validated using 5-fold validation.Results According to the multivariate logistic regression analysis, initial prostate-specific antigen (iPSA) (β=0.050, p < 0.001), percentage of positive biopsy cores (PPC) (β=0.033, p < 0.001), both lobe involvement on biopsy (β=0.359, p=0.009), Gleason score (β=0.358, p < 0.001), and cTMRI (β=0.259, p < 0.001) were significant factors for ECE. For SVI, iPSA (β=0.037, p < 0.001), PPC (β=0.024, p < 0.001), Gleason score (β=0.753, p < 0.001), and cTMRI (β=0.507, p < 0.001) showed statistical significance. BN models to predict ECE and SVI were also successfully established. The overall area under the receiver operating characteristic curve (AUC)/accuracy of the BN models were 0.76/73.0% and 0.88/89.6% for ECE and SVI, respectively. According to internal comparison between the BN model and Roach formula, BN model had improved AUC values for predicting ECE (0.76 vs. 0.74, p=0.060) and SVI (0.88 vs. 0.84, p < 0.001).Conclusion Two models to predict pathologic ECE and SVI integrating cTMRI were established and installed on a separate website for public access to guide radiation oncologists.

Purpose Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.Materials and Methods We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.Results In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.Conclusion Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

Current chemopreventive strategies require 3–5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. Prevention Relevance: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.

Key Points Consistent with previous results, pola + BR has a tolerable safety profile.The survival benefit of pola + BR vs BR persists with longer follow-up; efficacy in the pola + BR extension and randomized arms was similar., Visual Abstract, Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. After the randomized phase, 106 additional patients received pola + BR in a single-arm extension cohort. We report updated results from the randomized arms and results of the extension cohort. In this phase 1b/2 study, patients with R/R DLBCL who were transplant ineligible received up to six 21-day cycles of pola + BR or BR. The primary end point of the randomized arms was the complete response (CR) rate at end of treatment. Primary objectives of the extension cohort were safety, pharmacokinetic profile, and efficacy of pola + BR. As of 7 July 2020, a total of 192 patients with R/R DLBCL were enrolled in the pola + BR cohort (n = 152 [safety run-in, n = 6; randomized, n = 40; extension cohort, n = 106]) or the BR cohort (n = 40). Significant survival benefit with pola + BR vs BR persisted in the randomized arms (median progression-free survival, 9.2 vs 3.7 months [hazard ratio, 0.39; 95% confidence interval, 0.23-0.66]; median overall survival, 12.4 vs 4.7 months [hazard ratio, 0.42; 95% confidence interval, 0.24-0.72]). In the extension cohort, the independent review committee–assessed objective response rate was 41.5%, and the CR rate was 38.7%; median independent review committee–assessed progression-free survival and overall survival were 6.6 months and 12.5 months, respectively. No new safety signals with pola + BR were identified. Pola + BR is an effective treatment option for patients with R/R DLBCL, with a well-characterized and manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02257567.

e16038Background: Esophageal cancer primarily affects older adults, who are at highest risk for poor nutritional status due to medical comorbidities, physiological changes of aging and geriatric is...

In this letter, we propose a learning-based compressive sensing (CS) algorithm for denoising side scan sonar (SSS) images. The proposed method is a deep learning-based CS method with enhanced nonlinearity based on an iterative shrinkage and thresholding algorithm (ISTA). Since noise intensity varies depending on the position within SSS images, the proposed method also incorporates CoordConv, which provides coordinate information to the network to help remove nonhomogeneous noise. Through end-to-end training, both the deep learning module and the CS characteristics can be jointly optimized. Representative experimental results show that the proposed method is better than state-of-art methods in terms of both noise removal and memory requirements.

This study aims to examine the effects of the risk management committee’s characteristics on the market performance of non-financial listed firms in Malaysia between 2015 and 2017. The regression result shows that risk management committee (RMC) size, independence, expertise and female RMC members have a substantial negative influence on firm performance. By employing a different measurement of expertise, further analysis shows that RMC members with risk management expertise have a significantly positive relationship with firm performance. The results suggest that RMC members with specific risk management expertise can promote efficient risk monitoring, thus, enhancing the value of firms compared to RMC members with only general financial and accounting backgrounds. Nevertheless, the results are the same for the female members of the RMC even though different measurements are used. The robust negative result is supported by the tokenism interpretation for female members in the risk management committee.

This study examines the skill development factors influencing Information Technology (IT) competency in respect of external auditors. It applies the human capital theory (HCT) as the underpinning theory to develop the research framework. A questionnaire is administered to 328 external auditors in public and private audit companies in Yemen. Data are analysed via the partial least square-structural equation modeling (PLS-SEM) approach to examine the posited research hypotheses. The PLS-SEM approach reveals that self-direct learning is the strongest factor that influences the IT competency of auditors. This is followed by accounting education that records a significant positive effect on IT competency. The originality of this study is the application of the quantitative method to investigate the factors that influence IT competency among external auditors in developing countries, such as Yemen, who are facing the issue of low level IT competency in doing their tasks. The results underpin new and extensive inputs into skills and enlarge the emergent literature related to skills and competency development in IT.

Multi-objective swarm intelligence (MOSI) metaheuristics were proposed to solve multi-objective optimization problems (MOPs) that consists of two or more conflict objectives, in which improving an objective leads to the degradation of the other. The MOSI algorithms are based on the integration of single objective algorithms and multi-objective optimization (MOO) approach. The MOO approaches include scalarization, Pareto dominance, decomposition and indicator-based. In this paper, the status of MOO research and state-of-the-art MOSI algorithms namely, multi-objective particle swarm, artificial bee colony, firefly algorithm, bat algorithm, gravitational search algorithm, grey wolf optimizer, bacterial foraging and moth-flame optimization algorithms have been reviewed. These reviewed algorithms were mainly developed to solve continuous MOPs. The review is based on how the algorithms deal with objective functions using MOO approaches, the benchmark MOPs used in the evaluation and performance metrics. Furthermore, it describes the advantages and disadvantages of each MOO approach and provides some possible future research directions in this area. The results show that several MOO approaches have not been used in most of the proposed MOSI algorithms. Integrating other different MOO approaches may help in developing more effective optimization algorithms, especially in solving complex MOPs. Furthermore, most of the MOSI algorithms have been evaluated using MOPs with two objectives, which clarifies open issues in this research area.

Purpose: Advances in the diagnosis and treatment of prostate cancer have increased the patients’ stress level and decreased the quality of life. A variety of instruments are currently available to evaluate patients with prostate cancer. However, only a few tools are available to assess Korean patients, and therefore we demonstrated a linguistic validation of Korean Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP).Methods: EPIC-CP was translated into Korean and the linguistic validation was evaluated. The evaluation process includes permission for translation, forward translation, reconciliation, backward translation, cognitive debriefing, and proofreading. Two bilingual translators independently translated the original questionnaire, discussed the feasibility and naturalness of initial translation, followed by revision to the reconciled version. Another translator then performed a backward translation into English. Ten patients with prostate cancer completed the translated questionnaire and performed cognitive debriefing.Results: The original EPIC-CP was translated into 2 Korean versions. The different wording in both versions and the ordinary words in the initial translations were changed considering the nuances and meanings of medical terms. During the backward translation, the panels made slight changes to clarify the meaning and nuances of the translated questionnaire. During cognitive debriefing, 10 patients answered the questionnaire and offered their opinions regarding comprehensibility and naturalness. Most patients agreed that the translation was comprehensible in general.Conclusions: Our study provides a successful linguistic validation of the EPIC-CP questionnaire. The translation is a helpful diagnostic tool to ensure the quality of life of patients with prostate cancer attending crowded clinics.

BACKGROUND Caregivers of children with disabilities often experience poor health. One way for caregivers to promote their own health may be to participate in physical activity (PA). AIMS The purpose of this study was to examine the association between PA and psychological and physical health problems in caregivers of children with disabilities. METHODS 2018 National Health Interview Survey (NHIS) data was used, and 890 household representatives were identified as caregivers of children with disabilities. Based on the national PA guidelines, caregivers were classified into three groups: inactive (IA), aerobically active (AA), and aerobically and muscularly active (AMA). RESULTS Multivariable logistic regression indicated that the AMA group had a lower likelihood of reporting depression compared to the IA group (OR: 0.73 [95% confidence interval: 0.54, 0.98]). The AMA group also had a lower likelihood of reporting back pain and obesity compared to the IA group (OR:0.69 [95% confidence interval: 0.56, 0.84] and OR:0.63 [95% confidence interval: 0.52, 0.76], respectively). CONCLUSIONS The results of the current study suggest that caregivers of children with disabilities may benefit from PA, especially from the combination of aerobic and muscle-strengthening PA.

BACKGROUND: More than half of patients treated with esophagectomy for esophageal cancer experience recurrence. Oligometastasis, a proposed intermediate state of isolated local or solid-organ recurrence that occurs before widespread systemic disease, is a potential target for aggressive local intervention. We investigated presentation and prognosis between solid-organ recurrence sites. METHODS: Patients with isolated solid-organ recurrence at the liver, lung, or brain who underwent R0 esophagectomy from 1995 to 2016 were identified. Clinicopathologic characteristics and outcomes were compared between sites of recurrence. Overall survival was quantified using the Kaplan-Meier approach and Cox proportional hazards models. RESULTS: In total, 104 patients were included (site: brain, 37; lung, 27; liver, 40). Eighty percent of liver, 51% of brain, and 44% of lung oligometastases occurred in the first 12 months after esophagectomy. Despite the limited use of aggressive therapy, patients with lung oligometastasis had significantly longer median overall survival (2.41 years; 95% confidence interval [CI], 1.58–3.31) than patients with brain (0.95 years; 95% CI, 0.62–1.49) or liver (0.95 years; 95% CI, 0.82–1.41) oligometastasis (p

Purpose of Review This review describes recent data supporting locoregional ablative radiation in the treatment of oligometastatic colorectal cancer liver metastases. Recent Findings Stereotactic body radiotherapy (SBRT) demonstrates high rates of local control in colorectal cancer liver metastases when a biologically equivalent dose of > 100 Gy is delivered. Future innovations to improve the efficacy of SBRT include MRI-guided radiotherapy (MRgRT) to enhance target accuracy, systemic immune activation to treat extrahepatic disease, and genomic customization. Selective internal radiotherapy (SIRT) with y-90 is an intra-arterial therapy that delivers high doses to liver metastases internally which has shown to increase liver disease control in phase 3 trials. Advancements in transarterial radioembolization (TARE) dosimetry could improve local control and decrease toxicity. Summary SBRT and SIRT are both promising options in treating unresectable metastatic colorectal cancer liver metastases. Identification of oligometastatic patients who receive long-term disease control from either therapy is essential. Future advancements focusing on improving radiation design and customization could further improve efficacy and toxicity.

This letter presents a deep convolutional neural network (CNN) with attention module that improves the performance of the classification of various earthquake events. Addressing all possible earthquake events, including not only microearthquakes and artificial-earthquakes but also large-earthquakes, requires both suitable feature expression and a classifier that can effectively discriminate seismic waveforms under adverse conditions. To robustly classify earthquake events, a deep CNN with an attention module was proposed in raw seismic waveforms. Representative experimental results show that the proposed method provides an effective structure for earthquake events classification and, with the Korean peninsula earthquake database from 2016 to 2018, outperforms previous state-of-the-art methods.

PURPOSE: Patients with cancer frequently encounter financial hardship, yet systematic strategies to identify at-risk patients are not established in care delivery. We assessed sensitivity of distress-based screening to identify patients with cancer-related financial hardship and associated care delivery outcomes. METHODS: A survey of 225 patients at a large cancer center assessed cancer-related financial hardship (0-10 Likert scale; highest quintile scores ≥ 5 defined severe hardship). Responses were linked to electronic medical records identifying patients’ distress screening scores 6 months presurvey (0-10 scale) and outcomes of missed cancer care visits and bad debt charges (unrecovered patient charges) within 6 months postsurvey. A positive screen for distress was defined as score ≥ 4. We analyzed screening test characteristics for identifying severe financial hardship within 6 months and associations between financial hardship and outcomes using logistic models. RESULTS: Although patients with positive distress screens were more likely to report financial hardship (odds ratio [OR], 1.21; 1.08-1.37; P < .001), a positive distress screen was only 48% sensitive and 70% specific for identifying severe financial hardship. Patients with worse financial hardship scores were more likely to miss oncology care visits within 6 months (for every additional point in financial hardship score from 0 to 10, OR, 1.28; 1.12-1.47; P < .001). Of patients with severe hardship, 72% missed oncology visits versus 35% without severe hardship ( P = .006). Patients with worse hardship were more likely to incur any bad debt charges within 6 months (OR, 1.32; 1.13-1.54; P < .001). CONCLUSION: Systematic financial hardship screening is needed to help mitigate adverse care delivery outcomes. Existing distress-based screening lacks sensitivity.

In this Case Report, a patient with Buerger’s disease who had a leg amputation below his lower right knee and a vascular bypass of right leg, developed a wound caused by his prosthetic leg and subjective discomfort. The patient received skin flap surgery but the wound did not heal properly. He was admitted to the Korean Medicine Hospital where his wound, right leg coldness, and phantom pain were treated with combined Korean medicine. The patient was hospitalized again where he underwent micro-drilling surgery. The patient was re-admitted to the Korean Medicine Hospital where he received combined Korean medicine treatment (CKMT) and carbon arc light treatment (CALT) for his wound, leg coldness, stiffness, and hypoplasia. The temperature of his right leg increased, the numeric rating scale score for assessing pain fell from 5 to 1.5, and subjective discomfort was reduced (< 20%) suggesting this may be an effective treatment.

Objectives To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship. Methods Key topics regarding head and neck cancer survivorship were identified by the multidisciplinary membership of the American Head and Neck Society Survivorship, Supportive Care & Rehabilitation Service. Guidelines were generated by combining expert opinion and a review of the literature and categorized by level of evidence. Results Several areas regarding survivorship including dysphonia, dysphagia, fatigue, chronic pain, intimacy, the ability to return to work, financial toxicity, lymphedema, psycho‐oncology, physical activity, and substance abuse were identified and discussed. Additionally, the group identified and described the role of key clinicians in survivorship including surgical, medical and radiation oncologists; dentists; primary care physicians; psychotherapists; as well as physical, occupational, speech, and respiratory therapists. Conclusion Head and neck cancer survivorship is complex and requires a multidisciplinary approach centered around patients and their caregivers. As survival related to head and neck cancer treatment improves, addressing post‐treatment concerns appropriately is critically important to our patient's quality of life. There continues to be a need to define effective and efficient programs that can coordinate this multidisciplinary effort toward survivorship.

Purpose How to make accurate action decisions based on visual information is one of the important research directions of industrial robots. The purpose of this paper is to design a highly optimized hand-eye coordination model of the robot to improve the robots’ on-site decision-making ability. Design/methodology/approach The combination of inverse reinforcement learning (IRL) algorithm and generative adversarial network can effectively reduce the dependence on expert samples and robots can obtain the decision-making performance that the degree of optimization is not lower than or even higher than that of expert samples. Findings The performance of the proposed model is verified in the simulation environment and real scene. By monitoring the reward distribution of the reward function and the trajectory of the robot, the proposed model is compared with other existing methods. The experimental results show that the proposed model has better decision-making performance in the case of less expert data. Originality/value A robot hand-eye cooperation model based on improved IRL is proposed and verified. Empirical investigations on real experiments reveal that overall, the proposed approach tends to improve the real efficiency by more than 10% when compared to alternative hand-eye cooperation methods.

Objective To demonstrate that oro‐pharyngo‐esophageal radionuclide scintigraphy (OPERS) not only detects tracheobronchial aspiration after swallowing, but also quantifies the amount of aspiration and subsequent clearance. Methods Data collected between 2014 and 2019 were reviewed for aspiration pneumonia at 12 and 24‐months after OPERS. The predictive value for aspiration pneumonia on flexible endoscopic evaluation of swallowing (FEES), videofluoroscopic swallowing study (VFSS), and OPERS, and the overall survival of patients with or without aspiration were determined. Results Thirty‐seven patients treated with radiotherapy for nasopharyngeal carcinoma (NPC) were reviewed. The incidence of aspiration detected on FEES, VFSS, and OPERS was 78.4%, 66.7%, and 44.4%, respectively. Using VFSS as a gold standard, the sensitivity and specificity of OPERS for aspiration was 73.7% and 100%. The positive and negative predictive values for aspiration were 100% and 66.7%, respectively, with an overall accuracy of 82.8%. A history of aspiration pneumonia was one factor associated with a higher chance of subsequent aspiration pneumonia within 12 months (odds ratio: 15.5, 95% CI 1.67–145.8, p

Echinobase (www.echinobase.org) is a third generation web resource supporting genomic research on echinoderms. The new version was built by cloning the mature Xenopus model organism knowledgebase, Xenbase, refactoring data ingestion pipelines and modifying the user interface to adapt to multispecies echinoderm content. This approach leveraged over 15 years of previous database and web application development to generate a new fully featured informatics resource in a single year. In addition to the software stack, Echinobase uses the private cloud and physical hosts that support Xenbase. Echinobase currently supports six echinoderm species, focused on those used for genomics, developmental biology and gene regulatory network analyses. Over 38 000 gene pages, 18 000 publications, new improved genome assemblies, JBrowse genome browser and BLAST + services are available and supported by the development of a new echinoderm anatomical ontology, uniformly applied formal gene nomenclature, and consistent orthology predictions. A novel feature of Echinobase is integrating support for multiple, disparate species. New genomes from the diverse echinoderm phylum will be added and supported as data becomes available. The common code development design of the integrated knowledgebases ensures parallel improvements as each resource evolves. This approach is widely applicable for developing new model organism informatics resources.

Racial/ethnic minorities experience higher rates of wait-list mortality and longer waiting times on the liver transplant wait list. We hypothesized that racial/ethnic minorities may encounter greater logistical barriers to maintaining "readiness" on the wait list, as reflected in offer nonacceptance. We identified all candidates who received an organ offer between 2009 and 2018 and investigated candidates who did not accept an organ offer using a free-text refusal reason associated with refusal code 801. We isolated patients who did not accept an organ offer due to "candidate-related logistical reasons" and evaluated their characteristics. We isolated 94,006 "no 801" patients and 677 "with 801 logistical" patients. Common reasons for offer decline among the 677 were 60% "unable to travel/distance," 22% "cannot be contacted," 13% "not ready/unspecified," and 5% "financial/insurance." Compared to "no 801," "with 801 logistical" patients were more likely to be Hispanic (19% vs. 15%, P&nbsp

Severe fever with thrombocytopenia syndrome (SFTS) is caused by infection with Dabie bandavirus [formerly SFTS virus (SFTSV)] and is an emerging zoonotic disease. Dogs can be infected with SFTSV, but its pathogenicity and transmissibility have not been fully elucidated. In experiment 1, immunocompetent dogs were intramuscularly inoculated with SFTSV. In experiment 2, immunosuppressed dogs (immunosuppressed group; oral azathioprine 5 mg/kg/day for 30 days) were intramuscularly inoculated with SFTSV. Both immunosuppressed and immunocompetent contact dogs were co-housed with the SFTSV-inoculated dogs that had been immunosuppressed. Immunocompetent SFTSV-infected dogs did not show any clinical symptom. However, immunosuppressed SFTSV-infected dogs showed high fever and weight loss without lethality. In all SFTSV-infected dogs, viral RNA could be measured in the serum only after 3 days post infection (DPI) and neutralizing antibodies were detected in the serum beginning 9 DPI. SFTSV shedding in the urine and faeces of some infected dogs occurred between 4 and 6 DPI. The immunocompromised SFTSV-infected dogs showed thrombocytopenia beginning 3 DPI to the end of the experiment (24 DPI). We confirmed SFTSV transmission to one of three immunocompetent co-housed dogs. This dog showed a high fever, weight loss, and shed viral RNA by urine. Viral RNA and neutralizing antibodies were also detected in the serum. These results demonstrated that intramuscular inoculation with SFTSV induced minor clinical symptoms in dogs, and intraspecies SFTSV transmission in dogs can occur by contact.

Supplemental Digital Content is available in the text., Background: The composite face lift is becoming increasingly popular following recent advances in understanding of facial anatomy that enable safe sub-superficial musculoaponeurotic system (SMAS) dissection. This article presents the authors’ technique for composite face lift in Asian patients and reviews their experience and outcome with this procedure. Methods: Composite face lifts were performed on 128 Asian patients between January of 2010 and June of 2020. Ninety-four were primary face lifts, and 34 were secondary or tertiary face lifts. The authors’ surgical technique and adaptations for the specific requirements of Asian patients are described in detail. The mean follow-up was 26 months (range, 6 to 108 months). Fat grafting was an integral part of our procedure, with 95 percent having concomitant facial fat grafting with their face lift. Results: Patients were followed up in accordance with a standardized schedule. The majority of patients reported high satisfaction with the aesthetic outcome of the technique, with natural, long-lasting results. The face lift plane of dissection is through the facial soft-tissue spaces, which provide atraumatic sub-SMAS access with precise release of the intervening retaining ligaments for effective flap mobilization. By emphasizing tension on the composite flap with no tension on the skin closure, the scars were discrete in the great majority of patients. Complications were few, with no hematomas or skin flap necrosis. The temporary nerve injury rate was 1.5 percent, with no patient having a permanent nerve injury. Conclusion: The composite face lift is an ideal technique for Asian patients, as it delivers natural, long-lasting results; a quick recovery; and high patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

México es centro de origen y de diversificación de especies hortícolas. A través de la diversidad genética que se posee, se han desarrollado diversos materiales mejorados, en los que, el Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias ha sido un pilar muy importante, por ser esta, una de sus principales actividades. En el programa de mejoramiento genético de hortalizas se aplican diferentes estrategias genotécnicas relevantes para el incremento del rendimiento de bulbo, fruto y tubérculo, como la selección de clones en ajo, selección individual o hibridación en cebolla, pedigrí o de formación de líneas puras por autofecundación en chile; selección recurrente o hibridación en jitomate, selección clonal en papa, selección familial de medios hermanos maternos en tomate de cáscara, con las que se han generado líneas experimentales, clones, híbridos y variedades. Producto de esas investigaciones se han liberado 19 variedades de ajo, 10 de cebolla, 21 de chile, 29 de papa y 2 de tomate de cáscara en los 35 años del INIFAP. Variedades que han sido adoptadas por productores en las diferentes regiones agroecológicas de México. Sin embargo, a pesar de los esfuerzos que los fitomejoradores hacen por continuar con la generación de materiales mejorados, no se ha podido impactar en un mercado dominado por empresas trasnacionales, por lo que, es necesario que el INIFAP implemente estrategias de posicionamiento e invierta en la conservación y mejora genética del germoplasma que posee, lo que a futuro resultará en la obtención mejores materiales genéticos que contribuyan al beneficio de la salud humana.

Real-world evidence can generate credible evidence to inform treatment decisions. Real-world evidence is in developmental stage and is fast evolving yet there are many unexplained attributes of real-world evidence. Real-world evidence informs benefit-risk decisions and is increasingly being used to support regulatory decision making. Potential benefits of real-world data include determination of extended outcomes including long-term outcomes, opportunities to partner with patients in innovative ways, and reduction in time and cost to generate dependable evidence. Limitations of real-world evidence include uncertainty in the quality of datasets and lack methodologic rigor in real-world studies. Use of real-world evidence for healthcare practices and policies is limited. Ensuring completeness, homogeneity, and linkage of datasets can enhance utility for epidemiological investigations and improvement in health outcomes. Research should be strengthened for real-world studies and technical standards should be reinforced. Collaborations of stakeholders is key to formulation and adoption of guidance for real-world evidence. Real-world data cannot be a substitute to randomized clinical studies but can possibly augment the generated evidence.

Radiotherapy plays an essential role in the treatment of more than half of all patients with cancer. In recent decades, advances in devices that deliver radiation and the development of treatment planning software have helped radiotherapy attain precise tumour targeting with minimal toxicity to surrounding tissues. Simultaneously, as more targeted drug therapies are being brought into the market, there has been significant interest in improving cure rates for cancer by adding drugs to radiotherapy to widen the therapeutic window, the difference between normal tissue toxicity and treatment efficacy. The development of new combination therapies will require judicious adaptation of preclinical models that are routinely used for traditional drug discovery. Here we highlight the strengths and weaknesses of each of these preclinical models and discuss how they can be used optimally to identify new and clinically beneficial drug–radiotherapy combinations.

Background/aims The work environment in which endoscopic retrograde cholangiopancreatography (ERCP) is conducted has influence on its efficacy and safety. We aimed to assess the current status of ERCP work environments and to investigate the trends associated with the basic techniques of ERCP in Korea. Methods The work environment and information on the basic techniques of ERCP were acquired by the Korean Pancreatobiliary Association (KPBA) through a national survey in 2019. The survey was performed at the KPBA conference in 2019. The contents of survey comprised of the current environment of ERCP, preparation before ERCP, and the preferred basic techniques used in ERCP. Results Completed questionnaires were returned from 84 KPBA members. The mean ERCP volume per year was approximately 500. About 60% (50/84) reported that they worked with a dedicated ERCP team with experienced nurses. Two-thirds (57/84, 68%) answered that they had a fluoroscopy room used solely for ERCP procedures. All respondents intravenously hydrated the patient to prevent post-ERCP pancreatitis (84/84, 100%). The preferred procedural sedations were balanced propofol sedation (50%) and midazolam-only sedation (47%). Wire-guided cannulation was most commonly used for selective cannulation (81%). Endoscopic retrograde biliary drainage was preferred over endoscopic nasobiliary drainage (60% vs 22%). The initial method of ampullary intervention was endoscopic sphincterotomy in 60%. Conclusions Data from the survey involving a large number of Korean ERCP doctors revealed considerable variabilities with regard to the work environment and basic techniques of ERCP in Korea. The study provides information regarding the current trends of ERCP that can be used to establish ERCP standards in Korea.

Background Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking. Methods We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods. Results Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4–8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2–11.2) for men and 8.1 months (95% CrI: 6.2–10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6–7.9) for men and 3.5 months (95% CrI: 1.3–6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3–3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0–12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%). Conclusion Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions