BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

OBJECTIVE: Since 2018, the surviving sepsis campaign recommended one-hour bundle therapy in septic shock patients. On the other hand, evidence for the effectiveness of bundle therapy has not been established. The object of this study was to determine the prognostic value of one-hour bundle completion in septic shock patients. METHODS: This prospectively collected registry-based, retrospective observational study, between January 2016 and December 2018. A one-hour bundle in septic shock was defined by the serum lactate measurements, blood cultures, administration of antibiotics, and adequate fluid administration within one hour from emergency department admission. Eligible septic shock patients were included in the analysis, and the prognostic abilities of the completion of the one-hour bundle and each item were analyzed. The primary outcome was the 28-day mortality. RESULTS: The study included 381 patients, and the overall 28-day mortality was 24.7%. The overall one-hour bundle completion rate was 11.3%, and each completion rate of serum lactate measurement, blood cultures, administration of antibiotics, and adequate fluid administration were 85.8%, 74.3%, 19.4%, and 48.6%, respectively. On the other hand, overall bundle completion as well as each bundle were not associated with the 28-day mortality except for adequate fluid administration (odds ratio [OR], 0.67 [95% confidence interval (CI), 0.30–1.50]; OR, 1.33 [95% CI, 0.66–2.70]; OR, 1.50 [95% CI 0.85–2.64]; OR, 1.17 [95% CI 0.66–2.07]; and OR, 0.54 [95% CI, 0.34–0.87], respectively). Multivariate logistic regression analysis showed that adequate fluid administration was independently associated with the 28-day mortality (OR, 0.22 [95% CI, 0.09–0.55]; P=0.001). CONCLUSION In this study, most of the one-hour bundle completions were not associated with 28-day mortality. Although adequate fluid administration was associated with the 28-day mortality, multicenter interventional study will be needed to generalize this result.

Bullous pemphigoid (BP) is a chronic and recurrent bullous disorder that may be associated with the administration of certain drugs. Recently, bullous cutaneous adverse events after immunotherapy (IT) or targeted therapy have been increasingly reported. Here, we report a case of BP in a patient diagnosed with metastatic melanoma after treatment with pembrolizumab, dabrafenib, and trametinib. Histopathological examination showed a subepidermal blister with perivascular lymphocytic and eosinophilic infiltration; the accompanying findings of linear immunoglobulin G and C3 deposition by immunofluorescence microscopy were consistent with BP. Since IT agents may initiate immune dysregulation and pathologic autoantibody production, which are required for the pathogenesis of BP, the lesions were thought to be cutaneous adverse events caused by IT.

Objective: This study compared the prognostic performance of the following five injury severity scores: the Geriatric Trauma Outcome Score (GTOS), the Injury Severity Score (ISS), the New Injury Severity Score (NISS), the Revised Trauma Score (RTS), and the Trauma and Injury Severity Score (TRISS) for in-hospital mortality in severe geriatric trauma patients. Methods: A retrospective, cross-sectional, observational study was conducted using a database of severe geriatric trauma patients (age ≥65 years and ISS ≥16) who presented to a single regional trauma center between November 2016 and October 2018. We compared the baseline characteristics between the survivor and mortality groups and the predictive ability of the five scoring systems. Results: A total of 402 patients were included in the analysis; the in-hospital mortality rate was 25.6% (n=103). The TRISS had the highest area under the curve of 0.953 (95% confidence interval [CI], 0.927-0.971); followed by RTS, 0.777 (95% CI, 0.733-0.817); NISS, 0.733 (95% CI, 0.687-0.776); ISS, 0.660 (95% CI, 0.612-0.707); and GTOS, 0.660 (95% CI, 0.611-0.706) in severe geriatric trauma. The TRISS also had the highest area under the curve of 0.961 (0.919-0.985) among the injury severity scoring systems in polytrauma. The predictive ability of TRISS was significantly higher than the other four scores with respect to overall trauma and polytrauma (P<0.001). Conclusion The TRISS showed the highest prognostic performance for predicting in-hospital mortality among all the injury severity scoring systems in severe geriatric trauma.

Objective: This study compared the prognostic performance of the following five injury severity scores: the Geriatric Trauma Outcome Score (GTOS), the Injury Severity Score (ISS), the New Injury Severity Score (NISS), the Revised Trauma Score (RTS), and the Trauma and Injury Severity Score (TRISS) for in-hospital mortality in severe geriatric trauma patients. Methods: A retrospective, cross-sectional, observational study was conducted using a database of severe geriatric trauma patients (age ≥65 years and ISS ≥16) who presented to a single regional trauma center between November 2016 and October 2018. We compared the baseline characteristics between the survivor and mortality groups and the predictive ability of the five scoring systems. Results: A total of 402 patients were included in the analysis; the in-hospital mortality rate was 25.6% (n=103). The TRISS had the highest area under the curve of 0.953 (95% confidence interval [CI], 0.927-0.971); followed by RTS, 0.777 (95% CI, 0.733-0.817); NISS, 0.733 (95% CI, 0.687-0.776); ISS, 0.660 (95% CI, 0.612-0.707); and GTOS, 0.660 (95% CI, 0.611-0.706) in severe geriatric trauma. The TRISS also had the highest area under the curve of 0.961 (0.919-0.985) among the injury severity scoring systems in polytrauma. The predictive ability of TRISS was significantly higher than the other four scores with respect to overall trauma and polytrauma (P<0.001). Conclusion The TRISS showed the highest prognostic performance for predicting in-hospital mortality among all the injury severity scoring systems in severe geriatric trauma.

Background: There is currently a lack of evidence-based postresuscitation or postmortem guidelines for patients with out-of-hospital cardiac arrest (OHCA) in the setting of an emerging infectious disease. This study aimed to develop and validate a multimodal screening tool that aids in predicting the disease confirmation in emergency situations and patients with OHCA during a coronavirus disease 2019 (COVID-19) outbreak. Materials and Methods: We conducted a retrospective, multicenter observational study of adult patients with OHCA in Daegu, Korea. To identify the potential predictors that could be used in screening tools in the emergency department, we applied logistic regression to data collected from March 1 to March 14. The prediction performance of the screening variables was then assessed and validated on the data of patients with OHCA who were treated between February 19 and March 31, 2020. General patient characteristics and hematological findings of the COVID-19-negative and COVID-19-positive groups were compared. We also evaluated confirmation test criteria as predictors for COVID-19 positivity in patients with OHCA. Results: Advanced age, body temperature, and abnormal chest X-ray (CXR) revealed significant predictive ability in the derivation cohort. Of the 184 adult patients with OHCA identified in the validation cohort, 80 patients were included in the analysis. Notably, 9 patients were positive and 71 were negative on the COVID-19 reverse transcription polymerase chain reaction test. Five patients (55.6%) in the COVID-19-positive group had a fever before OHCA, and 12 (16.9%) of the COVID-19-negative group had a fever before OHCA (P = 0.018).Eight patients (88.9%) in the COVID-19-positive group had a CXR indicating pneumonic infiltration. Of the criteria for predicting COVID-19, fever or an abnormal CXR had a sensitivity of 100% (95% confidence interval [CI]: 65.4 – 100) and a specificity of 22.5% (95% CI: 13.5 – 34.0). Conclusion The screening tools that combined fever or abnormal CXR had a good discriminatory ability for COVID-19 infection in adult patients with OHCA. Therefore, during the COVID-19 outbreak period, it is recommended to suspect COVID-19 infection and perform COVID-19 test if patients present with a history of fever or show abnormal findings in postmortem CXR

Background: There is currently a lack of evidence-based postresuscitation or postmortem guidelines for patients with out-of-hospital cardiac arrest (OHCA) in the setting of an emerging infectious disease. This study aimed to develop and validate a multimodal screening tool that aids in predicting the disease confirmation in emergency situations and patients with OHCA during a coronavirus disease 2019 (COVID-19) outbreak. Materials and Methods: We conducted a retrospective, multicenter observational study of adult patients with OHCA in Daegu, Korea. To identify the potential predictors that could be used in screening tools in the emergency department, we applied logistic regression to data collected from March 1 to March 14. The prediction performance of the screening variables was then assessed and validated on the data of patients with OHCA who were treated between February 19 and March 31, 2020. General patient characteristics and hematological findings of the COVID-19-negative and COVID-19-positive groups were compared. We also evaluated confirmation test criteria as predictors for COVID-19 positivity in patients with OHCA. Results: Advanced age, body temperature, and abnormal chest X-ray (CXR) revealed significant predictive ability in the derivation cohort. Of the 184 adult patients with OHCA identified in the validation cohort, 80 patients were included in the analysis. Notably, 9 patients were positive and 71 were negative on the COVID-19 reverse transcription polymerase chain reaction test. Five patients (55.6%) in the COVID-19-positive group had a fever before OHCA, and 12 (16.9%) of the COVID-19-negative group had a fever before OHCA (P = 0.018).Eight patients (88.9%) in the COVID-19-positive group had a CXR indicating pneumonic infiltration. Of the criteria for predicting COVID-19, fever or an abnormal CXR had a sensitivity of 100% (95% confidence interval [CI]: 65.4 – 100) and a specificity of 22.5% (95% CI: 13.5 – 34.0). Conclusion The screening tools that combined fever or abnormal CXR had a good discriminatory ability for COVID-19 infection in adult patients with OHCA. Therefore, during the COVID-19 outbreak period, it is recommended to suspect COVID-19 infection and perform COVID-19 test if patients present with a history of fever or show abnormal findings in postmortem CXR