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The multi-generation heredity trait of hypertension in human has been reported, but the molecular mechanisms underlying multi-generational inheritance of hypertension remain obscure. Recent evidence shows that prenatal inflammatory exposure (PIE) results in increased incidence of cardiovascular diseases, including hypertension. In this study we investigated whether and how PIE contributed to multi-generational inheritance of hypertension in rats. PIE was induced in pregnant rats by intraperitoneal injection of LPS or Poly (I:C) either once on gestational day 10.5 (transient stimulation, T) or three times on gestational day 8.5, 10.5, and 12.5 (persistent stimulation, P). Male offspring was chosen to study the paternal inheritance. We showed that PIE, irrespectively induced by LPS or Poly (I:C) stimulation during pregnancy, resulted in multi-generational inheritance of significantly increased blood pressure in rat descendants, and that prenatal LPS exposure led to vascular remodeling and vasoconstrictor dysfunction in both thoracic aorta and superior mesenteric artery of adult F2 offspring. Furthermore, we revealed that PIE resulted in global alteration of DNA methylome in thoracic aorta of F2 offspring. Specifically, PIE led to the DNA hypomethylation of G beta gamma (Gβγ) signaling genes in both the F1 sperm and the F2 thoracic aorta, and activation of PI3K/Akt signaling was implicated in the pathologic changes and dysregulated vascular tone of aortic tissue in F2 LPS-P offspring. Our data demonstrate that PIE reprogrammed DNA methylome of cells from the germline/mature gametes contributes to the development of hypertension in F2 PIE offspring. This study broadens the current knowledge regarding the multi-generation effect of the cumulative early life environmental factors on the development of hypertension.

Objectives Circulating tumor cells (CTCs) are associated with tumor spread, whereas cancer stem cells may be related to drug resistance. However, few studies have analyzed the levels of circulating cancer stem cells (CCSCs) and CTCs in patients with advanced non-small cell lung cancer (NSCLC). Materials and Methods Treatment-naive patients with EGFR-mutated NSCLC who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy were recruited prospectively. The cell surface vimentin antibody was used for CTC detection and CD133 antibody for CCSC detection. CCSC and CTC levels were measured as cell count per 4 mL of blood, before treatment, after 2 and 12 weeks of treatment, and at disease progression. Data on clinical characteristics and outcomes were also collected. Results At diagnosis (n = 29), the median CCSC and CTC levels were 0 (interquartile range, 0–2) and 3 (2–9), respectively. After 12 weeks, the CCSC and CTC levels were lower than those at diagnosis (CCSC: 0 (0−0), p = 0.14; CTC: 1 (0–4), p = 0.048). At disease progression, the median CCSC and CTC levels were 0 (0–1) and 1 (0–2), respectively. Patients with higher CCSC and CTC levels at diagnosis had a numerically shorter progression-free survival. Conclusion In patients with EGFR-mutated NSCLC, CCSC and CTC levels became lower after 12 weeks of EGFR-TKI therapy and remained low at disease progression. High pre-treatment CCSC and CTC levels may be associated with a trend towards poor treatment outcomes.

Background/Objectives Streptococcus is a common cause of post-traumatic endophthalmitis in children. This study aimed to analyse the clinical features, antibiotic susceptibilities and outcomes of traumatic endophthalmitis caused by streptococcus in preschool children. Subjects/Methods Patients aged ≤6 years with traumatic streptococcal endophthalmitis seen at Zhongshan Ophthalmic Center between January 2013 and December 2018 were included in this retrospective study. Results In total, 21 patients (21 eyes) were included. The mean age of the patients was 3.3 ± 1.7 years, where 57.1% were males. Scissors (28.6%, n = 6) were the most common cause of injury; 86.7% of patients were injured at home. Zone I (80.9%) was the most common wound site; 90.5% of patients presented with a traumatic cataract. In general, Streptococcus pneumoniae (47.6%) was the most common isolate. Viridans group streptococci accounted for 58.3% of cases in children aged 0–3 years, while S. pneumoniae accounted for 66.7% of cases in children aged 4–6 years. The susceptibility rates of streptococcus to cefuroxime, levofloxacin and ofloxacin were 100%, 95.0% and 90.5%, respectively. Although all the patients underwent vitrectomy combined with silicone oil tamponade, the final visual outcomes were no better than counting fingers. Conclusions Although S. pneumoniae was the most prevalent organism in general, the dominant species varied between different age groups. The commonly used antibiotics, cefuroxime and fluoroquinolone, showed higher antibiotic susceptibility. Despite prompt treatment, the visual outcomes of paediatric post-traumatic endophthalmitis in preschool children were poor.

Driven by the lifestyle habits of modern people, such as excessive smoking, drinking, and chewing betel nut and other cancer-causing foods, the incidence of oral cancer has increased sharply and has a trend of becoming younger. Given the current mainstream treatment means of surgical resection will cause serious damage to many oral organs, so that patients lose the ability to chew, speak, and so on, it is urgent to develop new oral cancer treatment methods. Based on the strong killing effect of photothermal therapy on exposed superficial tumors, we developed a pH-responsive charge reversal nanomedicine system for oral cancer which is a kind of classic superficial tumor. With excellent photothermal properties of polydopamine (PDA) modified black phosphorus nanosheets (BP NSs) as basal material, then used polyacrylamide hydrochloride-dimethylmaleic acid (PAH-DMMA) charge reversal system for further surface modification, which can be negatively charged at blood circulation, and become a positive surface charge in the tumor site weakly acidic conditions due to the breaking of dimethylmaleic amide. Therefore, the uptake of oral cancer cells was enhanced and the therapeutic effect was improved. It can be proved that this nanomedicine has excellent photothermal properties and tumor enrichment ability, as well as a good killing effect on oral cancer cells through in vitro cytotoxicity test and in vivo photothermal test, which may become a very promising new model of oral cancer treatment.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of systematic administration of bisphosphonates (BPs). Sensory innervation is crucial for bone healing. We established inferior alveolar nerve injury (IANI) and inferior alveolar nerve transection (IANT) models characterized by disorganized periosteum, increased osteoclasts, and unbalanced neuropeptide expression. Zoledronate injection disrupted neuropeptide expression in the IANI and IANT models by decreasing calcitonin gene-related peptide (CGRP) and increasing substance P (SP); associated with this, BRONJ prevalence was significantly higher in the IANT model, followed by the IANI model and the sham control. CGRP treatment significantly reduced BRONJ occurrence, whereas SP administration had the opposite effect. In vitro, RAW 264.7 cells were treated with BPs and then CGRP and/or SP to study changes in zoledronate toxicity; combined application of CGRP and SP decreased zoledronate toxicity, whereas CGRP or SP applied alone showed no effects. These results demonstrate that sensory denervation facilitates the occurrence of BRONJ and that CGRP used therapeutically may prevent BRONJ progression, provided that SP is also present. Further studies are necessary to determine the optimal ratio of CGRP to SP for promoting bone healing and to uncover the mechanism by which CGRP and SP cooperate.

Introduction In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide®) plus as-needed, short-acting β2 agonists (SABAs) in Taiwanese patients with inadequate asthma control. Methods Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4–5 and 12–16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3±1.3 μg/d, n=551; fluticasone/salmeterol, 1013.8±1.4 μg/d, n=172). Results At baseline, 72.5% and 27.5% of all patients had “partly” and “uncontrolled” asthma, respectively. Mean±SD ACQ-5 scores were 1.54±1.06 and 1.46±1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (−0.91±1.11) than the fluticasone/salmeterol group (−0.69±1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups. Conclusion Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA. Trial Registration ClinicalTrials.gov registration number: NCT00784953.

Purpose To analyze the etiology, microbiological isolates, and antibiotic susceptibilities of endophthalmitis in pediatric patients. Methods Patients aged Results A total of 127 patients (127 eyes) were included, and 108 (85%) had posttraumatic endophthalmitis. Streptococcus (21.4%), coagulase-negative Staphylococcus (14.5%), Aspergillus (6.9%), and Bacillus cereus (5.3%) were the common organisms. The proportion of Streptococcus decreased with age (40.0% in 0–3 years, 16.3% in 4–12 years, and 6.3% in 13–17 years), while coagulase-negative Staphylococcus increased from 5.7% to 18.8%. Overall, fluoroquinolones achieved the highest antibiotic susceptibility rate (> 95%), while the susceptibility of isolated bacteria to tobramycin and cefazolin was only 60.2% and 59.4%, respectively. The susceptibility rates of Gram-positive cocci to cephalosporins were nearly 90%. For Gram-negative bacilli, susceptibility to neomycin was 91.3%. Conclusion Trauma was the main etiology for pediatric endophthalmitis. Although Streptococcus was the most prevalent organism in general, the dominant pathogen varied with age, which merits clinical attention. Fluoroquinolones showed the highest antibiotic efficacy; however, commonly used antibiotics tobramycin and cefazolin showed relatively low antibiotic susceptibility. Thus, antibiotic resistance in pediatric populations merits clinical attention.

Background: Clinical information of Elizabethkingia meningoseptica (EM) bacteremia in intensive care unit (ICU) patients is limited and the impact on outcomes uncertain. The aim of this study was to investigate the clinical features and impact of EM bacteremia compared to other glucose non-fermenting Gram-negative bacilli (GNF-GNB) bacteremia in ICU patients. Methods: This retrospective cohort study enrolled 70 patients who developed GNF-GNB bacteremia after ICU admission, including 19 cases of EM bacteremia (19/70, 27.1%). The main outcome measure was in-hospital mortality. Results: The patients with EM bacteremia had a lower rate of appropriate antibiotic therapy (15.8% vs. 62.7%, p

Background The purpose of this study was to retrospectively analyze clinical characteristics and prognostic risk factors of urosepsis patients admitted to two intensive care units in Shanghai, China. Methods Clinical data from patients diagnosed with urosepsis were retrospectively retrieved and analyzed from ICU in two regional medical centers from January 2015 to December 2019. Results Two hundred two patients were included in the subsequent analysis eventually, with an average age of 72.02 ± 9.66 years, 79.21% of the patients were female and the mortality rate of 15.84%.The proportion of patients with chronic underlying diseases such as diabetes and hypertension was relatively high (56.44, 49.50%, respectively), and the incidence of shock was also high (41.58%) correspondingly. The most common pathogen isolated was Escherichia coli (79.20%), of which the extended-spectrumβ-lactamases (ESBLs)(+) accounted for 42.57%. In multivariate analysis, the strongest predictors for death were mechanical ventilation (OR 7.260, 95% CI 2.200–23.963; P = 0.001),chronic kidney disease (CKD) (OR 5.140, 95% CI 1.596–16.550; P = 0.006), APACHE II score (OR 1.321, 95% CI 1.184–1.473; P P = 0.020). Both APACHE II score and lactate had the ideal predictive value, with the area under the ROC curve (AUC) of 0.858 and 0.805 respectively. Conclusion The patients with urosepsis were characterized by a higher proportion of female, older age, more percentage of comorbidities in this region, and patients with ESBLs (+) Escherichia coli infection were more prone to shock. Mechanical ventilation, comorbidity with CKD, APACHE II score and lactate were independent risk factors for death in urosepsis patient, but lactate level and APACHE II score had better predictive value for prognosis.

Lixia Lin,* Feng Mei,* Jingyu Liao, Yao Yang, Fang Duan, Xiaofeng Lin Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaofeng Lin; Fang DuanState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, People’s Republic of ChinaTel +86 18922103830; +86 13710790313Email linxiaof@mail.sysu.edu.cn; duanfangg@126.comPurpose: To analyze the pathogen spectrum of isolated pathogens and antibiotic susceptibility trends of infectious endophthalmitis over 9 years from a large referral eye center in southern China.Methods: Data from all inpatients who were clinically diagnosed with infectious endophthalmitis and underwent microbiological evaluation at the Zhongshan Ophthalmic Center from January 2010 to December 2018 were collected retrospectively and analyzed according to different clinical etiologies.Results: A total of 816 cases were collected in the study. Open-globe injuries had caused 473 (57.97%) cases, 70 (8.58%) cases presented endophthalmitis after infectious keratitis, 156 (19.12%) cases were postoperative, and endogenous causes accounted for 117 (14.34%) cases. Among the 309 culture-positive cases, the predominant pathogen for both postoperative and posttraumatic endophthalmitis was gram-positive cocci (59.52% and 49.72%, respectively). Regarding keratitis-related endophthalmitis, the main pathogens were filamentous fungi (57.58%) and gram-negative bacilli (30.30%). The pathogens of endogenous endophthalmitis were almost evenly distributed among gram-positive cocci, gram-negative bacilli, and fungi. Eighty-five (10.42%) cases underwent evisceration/enucleation, including 42 cases secondary to keratitis-related endophthalmitis. The incidence of evisceration/enucleation was much higher in keratitis-related endophthalmitis than the total endophthalmitis population (χ 2 =123.61, P< 0.001). Overall bacteria showed high susceptibility to fluoroquinolones (75.36– 100.00%). Gram-positive cocci showed much higher sensitivity to cephalosporins compared to gram-negative bacilli (85.11– 92.59% vs 25.42– 35.72%). For the five first-line antibiotics analyzed for time trend of susceptibility, four exhibited a significant decrease of susceptibility from 2010– 2014 to 2015– 2018.Conclusion: Between 2010 and 2018, posttraumatic endophthalmitis was the most common form of the treated endophthalmitis in Zhongshan Ophthalmic Center. The causative pathogens varied according to different clinical settings. Even though the overall antibiotic susceptibilities were fairly high, we observed a substantial decrease of susceptibility for most first-line antibiotics.Keywords: infectious endophthalmitis, pathogen spectrum, antibiotic resistance, time trend, evisceration/enucleation

The rapid evolution of treatment for advanced lung cancer is a story of how scientists have struggled to move from nonselective cytotoxic chemotherapy to personalized precision medicine. In this century, extraordinary advances have been made in the management of advanced and metastatic non–small cell lung cancer, especially in the development of small molecules targeting specific tyrosine kinase receptors and immune checkpoint inhibitors. These developments have led to a significant improvement in survival for lung cancer patients with metastatic disease. Now, the core guidelines to treat non–small cell lung cancer are based on the identification of targetable driver mutations and immune checkpoints. Continued investigations of newly identified druggable genetic alterations, explorations of biomarkers of immune checkpoint inhibitors, development of next-generation immunotherapy, and optimization of combination therapy are necessary to provide better treatment outcomes for lung cancer patients in the future.

Background/Purpose: Currently, data on the real-world use of dronedarone, an antiarrhythmic drug for atrial fibrillation (AF), are contradictory and often based on patient populations comprised of Caucasians. We prospectively investigated the efficacy and safety of dronedarone and risk factors related to treatment outcomes in a real-world use setting. Methods: The prospective, observational, single-arm, multi-center study included a total of 824 Taiwanese patients with a diagnosis of paroxysmal or persistent AF and receiving dronedarone treatment. Risk factors analysis, efficacy, and safety of dronedarone were assessed with a follow-up of six months. Results: Of the 824 patients enrolled (mean age, 75.3 ± 7.2 years), 95.2% had at least one cardiovascular risk factor. An increase in the proportion of patients with sinus rhythm following treatment was seen (52.1% at baseline vs. 67.4% at 6 months). A decrease in the mean duration of AF episodes (388.4 min vs. 62.3 min) and an increase in total AFEQT (65.4 ± 16.2 vs. 74.0 ± 11.8) were also observed after 6 months of treatment. Females, those under the age of 75, and those with symptomatic AF had higher odds of treatment success. At 6 months, 10.5% of patients reported treatment-related AEs. However, only 0.2% of the AEs were both severe in nature and causally related to dronedarone. Conclusion: This six-month study showed dronedarone to be relatively safe and efficacious and to improve quality-of-life in Taiwanese patients with atrial fibrillation. Odds of treatment success were related to the patient's gender, age, and AF type. Keywords: Atrial fibrillation, Dronedarone, Observational, Safety, Quality of life

Background: The objective is to study the molecular mechanism(s) underlying cardiac troponin I autoantibody (cTnIAAb) binding to cardiomyocyte and resultant myocardial damage/dysfunction. Methods: cTnIAAb was purified from serum of 10 acute myocardial infarction (AMI) patients with left ventricular remodeling. Recombinant human cTnI was used to generate three mouse-derived monoclonal anti-cTnI antibodies (cTnImAb1, cTnImAb2, and cTnImAb3). The target protein in cardiac myocyte membrane bound to cTnImAb and effect of cTnIAAb and cTnImAb on apoptosis and myocardial function were determined. Findings: We revealed that cTnIAAb/cTnImAb1 directly bound to the cardiomyocyte membraneI±-Enolase (ENO1) and triggered cell apoptosis via increased expression of ENO1 and Bax, decreased expression of Bcl2, subsequently activating Caspase8, Caspase 3, phosphatase and tensin homolog (PTEN) while inhibiting Akt activity. This cTnIAAb-ENO1-PTEN-Akt signaling axis contributed to increased myocardial apoptosis, myocardial collagen deposition, and impaired systolic dysfunction. Interpretation: cTnIAAb is not only the independent risk factor of ventricular remodeling after myocardial injury in patients with AMI, but also involved in the process of ventricular remodeling. Funding Statement: This research was supported by the National Natural Science Foundation of China (Grant#: 81260026) and the Doctoral Innovation Fund from Second military Medical University of China. Declaration of Interests: The authors state: "None." Ethics Approval Statement: This study was approved by the Medical Ethics Committee at Changhai Hospital and Changcheng Hospital Affiliated to Nanchang University and patients enrolled provided signed informed consent. The animal protocol was planned in compliance with the animal protection, animal welfare, and ethical principles and was approved by the IACUC of the Second Military Medical University.

The appropriate treatment for patients with coexistent chronic obstructive pulmonary disease (COPD) and heart failure (HF) remains unclear. Data from the Taiwan National Health Insurance Research Database was used for this retrospective cohort study. Patients diagnosed with both diseases between 1997 and 2012 were enrolled as the COPD-heart failure overlap cohort. Patients were categorized as non-users and users of specific COPD and HF medications. Medication prescriptions in each 3-month and 1-year period served as time-dependent covariates. The primary endpoint was cumulative survival. The validation study confirmed the accuracy of definitions of COPD (94.0% sensitivity) and HF (96.3% sensitivity).The study included 275,436 patients with COPD-heart failure overlap, with a mean follow-up period of 9.32 years. The COPD-heart failure overlap cohort had more medical service use and higher mortality than did the COPD alone cohort. Use of inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations, long-acting muscarinic antagonist (LAMA), angiotensin receptor blockers (ARBs), β blockers, aldosterone antagonists, and statins reduced mortality risk compared with non-use. Sensitivity and subgroup analyses confirmed the consistency and robustness of results.ICS/LABA combinations, LAMA, ARBs, β blockers, aldosterone antagonists, and statins use was associated with a lower mortality risk in patients with COPD-heart failure overlap.

This study aims to explore the predictive noninvasive biomarker for obstructive coronary artery disease (CAD). By using the data set GSE90074, weighted gene co‐expression network analysis (WGCNA), and protein–protein interactive network, construction of differentially expressed genes in peripheral blood mononuclear cells was conducted to identify the most significant gene clusters associated with obstructive CAD. Univariate and multivariate stepwise logistic regression analyses and receiver operating characteristic analysis were used to predicate the diagnostic accuracy of biomarker candidates in the detection of obstructive CAD. Furthermore, functional prediction of candidate gene biomarkers was further confirmed in ST‐segment elevation myocardial infarction (STEMI) patients or stable CAD patients by using the datasets of GSE62646 and GSE59867. We found that the blue module discriminated by WGCNA contained 13 hub‐genes that could be independent risk factors for obstructive CAD (P .05). This four‐gene signature could also act as a prognostic biomarker to discriminate STEMI patients from stable CAD patients. These findings suggest a four‐gene signature (NCF2, MYO1F, S1PR4, and FCN1) alone or combined with two risk factors (male sex and hyperlipidemia) as a promising prognostic biomarker in the diagnosis of STEMI. Well‐designed cohort studies should be implemented to warrant the diagnostic value of these genes in clinical purpose.

The purpose of this study was to evaluate the pathological changes of the pulmonary arterioles in patients ≥ 2 years of age who first underwent a pulmonary artery banding (PAB) procedure, followed by bidirectional Glenn or Fontan according to their specific conditions. This was a prospective study of 15 children diagnosed and treated with PAB at the Department of Cardiothoracic Surgery of Anzhen Hospital between January 2009 and December 2012. The percentage of media area (%MS) of pulmonary arteriole, the percentage of media thickness (%MT), and pulmonary arterial density (APSC) were calculated from lung tissue sections. Pulmonary artery pressure decreased significantly after PAB surgery (P

Background: Evaluating the options for antibiotic treatment for carbapenem-resistant Gram-negative bacteria (CR-GNB)-associated pneumonia remains crucial. We compared the therapeutic efficacy and nephrotoxicity of two combination therapies, namely, colistin + carbapenem (CC) versus colistin + tigecycline (CT), for treating CR-GNB-related nosocomial pneumonia in critically ill patients. Methods: In this multicenter, retrospective, and cohort study, we recruited patients admitted to intensive care units and diagnosed with CR-GNB-associated nosocomial pneumonia. We divided the enrolled patients into CC (n = 62) and CT (n = 59) groups. After propensity score matching (n = 39), we compared the therapeutic efficacy by mortality, favorable outcome, and microbiological eradication and compared nephrotoxicity by acute kidney injury between groups. Results: There was no significant difference between the CC and CT groups regarding demographic characteristics and disease severities as assessed using the Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, and other organ dysfunction variables. Therapeutic efficacy was non-significantly different between groups in all-cause mortality, favorable outcomes, and microbiological eradication at days 7, 14, and 28, as was the Kaplan-Meier analysis of 28-day survival. For nephrotoxicity, both groups had similar risks of developing acute kidney injury, evaluated using the Kidney Disease Improving Global Outcomes criteria (p = 1.000). Conclusions: Combination therapy with CC or CT had similar therapeutic efficacy and risk of developing acute kidney injury for treating CR-GNB-associated nosocomial pneumonia in critically ill patients.

Little is known about whether venous thromboembolism (VTE) causes worse critical limb events in populations with atrial fibrillation (AF). A retrospective cohort study using claims data from Taiwan’s National Health Insurance program between 2001 and 2013 compared AF patients with or without VTE. Outcomes were percutaneous transluminal angioplasty (PTA), amputation, systemic thromboembolism, all-cause mortality, cardiovascular death, ischemic stroke, and acute myocardial infarction. Patients ( n = 316,817) with newly diagnosed AF were analyzed; of those, 2514 (0.79%) had VTE history. After inverse probability of treatment weighting, a history of VTE was significantly associated with higher risks of PTA (3.3 vs 2.2%; subdistribution hazard ratio [SHR] 1.47; 95% confidence interval [CI] 1.17–1.84); above knee amputation (0.7 vs 0.3%; HR 2.15; 95% CI 1.10–4.21); systemic thromboembolism (5.8 vs 3.9%; SHR 1.48; 95% CI 1.21–1.80); all-cause mortality (53 vs 46.4%; HR 1.20, 95% CI 1.12–1.29); and cardiovascular death (34.8 vs 29.4%; HR 1.25, 95% CI 1.14–1.36). In conclusion, VTE might increase the risk of critical lower limb events (PTA and above-knee amputation), systemic thromboembolism, and mortality in the AF population. However, current data cannot confirm a causal relationship between VTE and clinical outcomes in this population.

Background: Patients with hyperthyroidism have higher risk of atrial fibrillation (AF). However, the risk of thromboembolic event in patients with hyperthyroidism-related AF is controversial. Objectives: The aim of the study was to examine the risk of thromboembolic events in AF patients with/without hyperthyroidism. Methods: The national retrospective cohort study enrolled AF population was derived from the Taiwan National Health Insurance Research Database. The comparison between the AF patients with clinical hyperthyroidism (HT-AF group) and AF patients without hyperthyroidism (non-thyroid AF group) was made in a propensity score matched cohort and in a real-world setting, of which, the CHA2DS2-VASc level was treated as a stratum variable. The outcomes were ischemic stroke and systemic thromboembolism. Results: There were 3,880 patients in HT AF group and 178,711 in non-thyroid AF group. After propensity score analysis, the incidence of thromboembolism event and ischemic stroke were lower in HT AF patients than non-thyroid AF patients (1.6 versus 2.2 events per 100 person-years; HR, 0.73; 95% CI, 0.64–0.82 and 1.4 versus 1.8 events per 100 person-years; HR, 0.74; 95% CI, 0.64–0.84, respectively) in the 4.3 ± 3.2 year follow up period. The differences persistently existed in those receiving anticoagulants or not. In AF patients without anticoagulants, the incidence densities of ischemic stroke/systemic thromboembolism were significantly lower in HT AF group than those in non-thyroid AF group at CHA2DS2-VASc scores ≤ 4 (HR, 0.41; 95% CI, 0.35–0.48, p < 0.001), while the differences disappeared in case of score ≥ 5 (HR, 0.80; 95% CI, 0.63–1.02, p = 0.071). Conclusion: Patients with HT AF had lower incidence of thromboembolic events as compared to non-thyroid AF patients. The threshold of CHA2DS2-VASc score for anticoagulation in AF patients with clinical hyperthyroidism should be further evaluated. Highlights The incidence of thromboembolic event was different between hyperthyroidism-related atrial fibrillation (HT-AF) and non-thyroid AF patients. Hyperthyroidism did not confer additional risk of thromboembolic event at CHA2DS2-VASc of ≤ 4. The benefit of anticoagulation strategy in patients with hyperthyroidism-related AF should be further evaluated, especially at low CHA2DS2-VASc score.

Background: Glycated hemoglobin (HbA1c) is commonly used in the diagnosis and evaluation of glycemic control in diabetes, and it may be influenced by several non-glycemic and glycemic factors, including albumin. This retrospective study investigated the influence of albumin on HbA1c and HbA1c-defined glycemic status.Methods: The demographic, hematological, and biochemical data were collected for 11,922 patients undergoing routine physical examination. Univariate and multivariate linear regression analyses, stratified analyses and interaction analyses, and multiple logistic regression were conducted to identify the association between albumin and HbA1c in people with different glycemic status.Results: HbA1c levels were inversely associated with serum albumin level (P < 0.0001) in all participants. Risk factors leading to the association included age > 45 years, high fasting plasma glucose (≥7.0 mmol/L), and anemia. The negative association between HbA1c and albumin was curved (P < 0.0001) and had a threshold effect in the HbA1c-defined diabetic population; the association was significantly stronger when the albumin level fell below 41.4 g/L (β: −0.31, 95% CI: −0.45 to −0.17, P < 0.0001). A 2 g/L increase in albumin reduced the odds of HbA1c-defined dysglycemia, diabetes, and poor glycemia control by 12% to 36%, after adjustment for all possible confounders.Conclusions: HbA1c was inversely associated with albumin level in all participants, and the association was significantly stronger in people with diabetes (defined by HbA1c criteria). For diabetic patients with lower albumin level, there was an increased risk of an erroneous HbA1c-based identification and management of glycemic status.

Background: Venous interventions of the legs are less predictable owing to a lock of objective tools. Methods: One hundred and twenty patients with lower extremity venous disease were evaluated anatomically using TRANCE MRI. Then, a QFlow analysis was performed in 53 patients with only one leg affected for hemodynamic evaluation. Those patients with complete QFlow were classified into obstructive and nonobstructive. Results: The QFlow—namely, stroke volume, forward flow volume, mean flux, stroke distance (SD), and mean velocity (MV) in the external iliac vein (EIV), femoral vein (FV), popliteal vein (PV), and great saphenous vein (GSV). The obstructed group had a shorter SD and lower MV in the EIV, EIV/FV, and GSV/PV (SD: p-values of 0.025, 0.05, and 0.043, respectively; MV: p-values of 0.02, 0.05, and 0.048, respectively). A good performance in discriminating obstructive venous disease was reported for SD in the EIV (area under the curve (AUC) = 67.9%, 95% confidence interval (CI) = 53.2–82.7%), EIV/FV (AUC = 72.4%, 95% CI = 58.2–86.5%), and GSV/PV (AUC = 67.9%, 95% CI = 51.7–84.1%). The SD in the EIV, EIV/FV, and GSV/PV had the ability to discriminate between obstructive and nonobstructive diseases (p-values of 0.025, 0.005, and 0.043). The MV in the EIV, EIV/FV, and GSV/PV had ability to discriminate between obstructive and nonobstructive venous diseases (p-values of 0.02, 0.005, and 0.048). Conclusions: The SD and MV were lower for obstructive than nonobstructive disease in the EIV.

Acute kidney injury (AKI) requiring renal replacement therapy (RRT) increases the mortality of acute respiratory distress syndrome (ARDS) patients. The aim of this study was to investigate the outcomes and predictors of RRT in patients with influenza pneumonia-related ARDS. This retrospective cohort study includes patients from eight tertiary referral centers in Taiwan between January and March 2016, and all 282 patients with influenza pneumonia-related ARDS were enrolled. Thirty-four patients suffered from AKI requiring RRT, while 16 patients had underlying end stage renal disease (ESRD). The 30- and 60-day mortality rates were significantly higher in patients with AKI requiring RRT compared with those not requiring RRT (50.0% vs. 19.8%, p value &lt, 0.001, 58.8% vs. 27.2%, p value = 0.001, respectively), but the patients with ESRD had no significant difference in mortality (12.5% vs. 19.8%, p value = 0.744, 31.3% vs. 27.2%, p value = 0.773, respectively). The predictors for AKI requiring RRT included underlying chronic liver disease and C-reactive protein. The mortality predictors for patients with AKI requiring RRT included the pneumonia severity index, tidal volume, and continuous renal replacement therapy. In this study, patients with influenza pneumonia-related ARDS with AKI requiring RRT had significantly higher mortality compared with other patients.

Background Colistin is widely used in the treatment of nosocomial infections caused by carbapenem-resistant gram-negative bacilli (CR-GNB). Colistin-induced nephrotoxicity is one of the major adverse reactions during colistin treatment. Comparisons of colistin-induced nephrotoxicity between different formulations of colistin are rarely reported. Methods In this retrospective cohort study, we enrolled intensive care unit–admitted patients if they had culture isolates of CR-GNB and underwent intravenous treatment with colistin. The occurrence of acute kidney injury (AKI) during intravenous treatment with colistin was recorded. The occurrence of colistin-induced nephrotoxicity was compared between two formulations of colistin, Locolin®, and Colimycin®. Treatment outcomes associated with the occurrence of colistin-induced nephrotoxicity were also investigated. Results Among 195 patients, 95 who were treated with Locolin® and 100 who were treated with Colimycin® were included for analysis. Patients treated with Locolin® had a higher rate of occurrence of stage 2 (46.3% vs. 32%, p = 0.040) and stage 3 (29.5% vs. 13%, p = 0.005) AKI than did those treated with Colimycin®. In multivariate analysis, the presence of septic shock (adjusted odds ratio [aOR] 2.17, 95% confidence interval [CI] 1.10–4.26) and inappropriate colistin dosage (aOR 2.52, 95% CI 1.00–6.33) were clinical factors associated with colistin-induced nephrotoxicity. Treatment with Colimycin® was an independent factor associated with a lower risk of colistin-induced nephrotoxicity (aOR 0.37, 95% CI 0.18–0.77). The mortality rate was comparable between patients with and without colistin-induced nephrotoxicity. Conclusions The risk of colistin-induced nephrotoxicity significantly varied in different formulations of colistin in critically ill patients. Colistin-induced nephrotoxicity was not associated with increased mortality rate.

Although great progresses have been made in the diagnosis and treatment of hepatocellular carcinoma (HCC), its prognostic marker remains controversial. In this current study, weighted correlation network analysis and Cox regression analysis showed significant prognostic value of five autophagy-related long non-coding RNAs (AR-lncRNAs) (including TMCC1-AS1, PLBD1-AS1, MKLN1-AS, LINC01063, and CYTOR) for HCC patients from data in The Cancer Genome Atlas. By using them, we constructed a five-AR-lncRNA prognostic signature, which accurately distinguished the high- and low-risk groups of HCC patients. All of the five AR lncRNAs were highly expressed in the high-risk group of HCC patients. This five-AR-lncRNA prognostic signature showed good area under the curve (AUC) value (AUC = 0.751) for the overall survival (OS) prediction in either all HCC patients or HCC patients stratified according to several clinical traits. A prognostic nomogram with this five-AR-lncRNA signature predicted the 3- and 5-year OS outcomes of HCC patients intuitively and accurately (concordance index = 0.745). By parallel comparison, this five-AR-lncRNA signature has better prognosis accuracy than the other three recently published signatures. Furthermore, we discovered the prediction ability of the signature on therapeutic outcomes of HCC patients, including chemotherapy and immunotherapeutic responses. Gene set enrichment analysis and gene mutation analysis revealed that dysregulated cell cycle pathway, purine metabolism, and TP53 mutation may play an important role in determining the OS outcomes of HCC patients in the high-risk group. Collectively, our study suggests a new five-AR-lncRNA prognostic signature for HCC patients.

Background: Ivabradine is indicated for heart failure (HF) patients with reduced left ventricular ejection fraction who are in sinus rhythm. However, limited data are available with regards to the use of ivabradine in symptomatic HF patients with reduced EF (HFrEF) and a history of paroxysmal atrial fibrillation (AF). Methods: We conducted a multi-center observational matched cohort study enrolled patient who was diagnosed with symptomatic HFrEF from 2015/01/01 to 2018/12/31 with had a history of paroxysmal AF in Chang Gung Memorial Hospital medical database in Taiwan. After inverse probability of treatment weighting (IPTW), the outcomes of interest during a 12-month observation period were analyzed. The primary outcome was HF hospitalization and cardiovascular death. Results: A total of 2,042 patients were eligible for the study, of whom 887 were prescribed with ivabradine and 1,115 were not. After IPTW, the ivabradine group had a significant lower mean heart rate after 12 months than the non-ivabradine group (P < 0.05). The primary outcome was also significantly higher in the ivabradine group than the non-ivabradine group after 12 months (hazard ratio [HR] = 1.58; 95% confidence interval [CI], 1.26-2.00, P < 0.001). Moreover, the ivabradine group had a significantly higher event rate of HF hospitalization (HR = 1.56; 95% CI, 1.40-1.75, P < 0.001) and HF death (HR = 1.67; 95% CI, 1.14-2.44, P = 0.009) than the non-ivabradine group. Conclusions: Ivabradine treatment was associated with an increased risk of HF hospitalization in symptomatic HFrEF patients with a history of paroxysmal AF, and further prospective studies are warranted. Funding Information: This work was supported by a grant from Chang Gung Memorial Hospital, Taiwan (grant CGRPG6J0041, CMRPG6H0481 and CMRPG6H0482). Declaration of Interests: The authors declare that there is no conflict of interest. Ethics Approval Statement: The Institutional Review Board of Chang Gung Memorial Hospital: (201900915B1).

Introduction Recent advances in the detection of genomic DNA from plasma samples allow us to follow tumor DNA shedding in plasma during systemic treatment. Osimertinib is the standard of care for patients with NSCLC with acquired EGFR T790M mutations. We assessed changes in serial plasma cell-free circulating tumor DNA (ctDNA) genomic alterations to predict osimertinib efficacy. Methods We prospectively collected plasma from patients having EGFR-mutated advanced NSCLC previously treated with EGFR tyrosine kinase inhibitor therapy and with acquired EGFR T790M mutation detected by standard methods. Plasma samples were collected before starting osimertinib treatment, 4 weeks after osimertinib treatment, and on progression. ctDNA was analyzed using the Guardant360 assay. Results A total of 15 eligible patients received osimertinib. Before starting treatment, EGFR-activating mutations were detected in the ctDNA of all patients, and EGFR T790M was detected in 93% of the cases. Osimertinib treatment was associated with an objective response rate of 53% and a median progression-free survival of 7.3 months. A total of 12 of the 15 patients had undetectable plasma T790M and decreased activating mutation allelic frequency (AF) at week 4. None of the 12 patients had disease progression within 16 weeks. For the remaining three patients, with detectable plasma T790M (n = 2) or increased activating mutation AF (n = 1) at week 4, two had progressive disease within 16 weeks (p = 0.03). Conclusions In patients with EGFR-mutated advanced NSCLC, persistent EGFR T790M or increasing activating mutation AF as detected in ctDNA 4 weeks after the start of osimertinib treatment may predict disease progression within 16 weeks.

ObjectivesLarge-scale, population-based real-world studies on the treatment outcomes of first-line tyrosine kinase inhibitors (TKIs) and subsequent systemic chemotherapy agents for lung adenocarcinoma (with activating epidermal growth factor receptor [EGFR] mutations) remain limited.Materials and MethodsFrom March 2014 to December 2016, patients with advanced lung adenocarcinoma, identified from the Taiwan Cancer Registry were included in this study if they received any of the three TKIs as first-line treatment. The primary outcome was overall survival (OS). The secondary outcome was time-to-treatment discontinuation (TTD).ResultsA total of 4,889 patients (median age: 67 years and two-thirds with distant metastasis) were recruited (1,778 gefitinib, 1,599 erlotinib, and 1,512 afatinib users). A 1:1 propensity score (PS)-matched cohorts of 1,228 afatinib/erlotinib and 1054 afatinib/gefitinib was created. After PS matching, it was found that afatinib was not associated with better OS (afatinib vs. erlotinib, HR: 0.96, 95% CI: 0.86–1.07; afatinib vs. gefitinib, HR: 0.91, 95% CI: 0.81–1.02). In the subgroup analysis, afatinib demonstrated a survival benefit in patients with active smoking (afatinib vs. erlotinib, HR: 0.69, 95% CI: 0.51–0.93; afatinib vs. gefitinib, HR: 0.67, 95% CI: 0.48–0.94) and ECOG > 1 (afatinib vs. erlotinib, HR: 0.79, 95% CI: 0.63–0.99; afatinib vs. gefitinib, HR: 0.78, 95% CI: 0.62–0.98). A total of 41.1% (n = 1992) of first-line TKI users received subsequent chemotherapy. Among the three TKI groups, pemetrexed usage was associated with better OS compared with other chemotherapy agents, with the exception of gemcitabine in the afatinib and gefitinib groups. Pemetrexed and gemcitabine had the longest TTD of 3–4 months.ConclusionsAmong patients with EGFR mutant lung adenocarcinoma, afatinib use may not provide longer OS compared with first-generation TKIs. Afatinib may be preferably considered among patients with active smoking and should not be withheld among those with worse performance status. With 40% of patients receiving subsequent chemotherapy, pemetrexed may be the preferred agent, while gemcitabine can be a reasonable alternative.

Background. Baveno VI criteria, based on liver stiffness (LS) measured by transient elastography and platelet counts (PLT), have been proposed to avoid unnecessary endoscopy screening for high-risk varices (HRVs). However, the cut-off value of LS measured by 2D-SWE and PLT to predict HRVs in compensated hepatitis B-related cirrhotic patients remains unknown. Aims. To prospectively analyze the cut-off of the combination of LS measured by 2D-SWE and PLT in predicting HRVs and the influence of antiviral therapies in its efficacy. Methods. Serum parameters, LS, and endoscopy results were obtained from 160 compensated hepatitis B-related cirrhotic patients. The accuracy of the combined algorithm was assessed in the whole cohort and subgroups with or without consecutive antiviral therapies in the past 6 months. Results. In the whole cohort, the optimal cut-off value of LS for HRVs was 14.5 kPa. Patients with a LS value < 14.5 kPa with a PLT value > 110 × 10 9 / L can be excluded from HRVs ( NPV = 0.99 , endoscopy saved rates = 0.68 ). Conversely, a LS value of ≥14.5 kPa and a PLT value of ≤ 110 × 10 9 / L indicated HRVs, with accurate rates of 82.35%, and 10.63% of patients can avoid additional endoscopy screening. Moreover, antiviral therapy had no significant effect on the accuracy and rates saved from further endoscopy screening, when comparing patients with or without antiviral therapies (all p values > 0.05). Conclusions. The combination of LS (14.5 kPa) measured by 2D-SWE and PLT ( 110 × 10 9 / L ) can predict HRVs accurately in compensated hepatitis B-related cirrhotic patients without significant interference of antiviral therapy histories.

Summary Background The existence of vascular disease in patients with atrial fibrillation (AF) is associated with an increased risk of thromboembolic events. It is unclear whether coronary artery disease (CAD) and/or peripheral artery disease (PAD) have similar presentations and complication rates. Aim To investigate thromboembolic events among patients with AF who have CAD, PAD or polyvascular disease. Methods Patients with a new diagnosis of AF without anticoagulation (n = 306,386) were identified from the National Health Insurance Research Database in Taiwan (2001–2013). Ischaemic stroke (IS), systemic thromboembolism (STE) and their combination (IS/STE) were compared in four groups (No-CAD/PAD, CAD-only, PAD-only, CAD + PAD), and secondarily in patients with only CAD versus only PAD. Last, we compared propensity score-matched patients with only CAD or PAD with those with CAD and PAD. Results There were 185,169 patients without CAD or PAD, 8113 patients with only PAD, 105,715 patients with only CAD, and 7389 patients with CAD and PAD eligible for analysis (mean ± SD follow-up 3.2 ± 3.2 years). The incidences of STE and IS/STE differed in the four groups, with the highest in the CAD + PAD group and the lowest in the No-CAD/PAD group. The proportions of IS and STE also varied, with higher proportions of STE in patients with PAD, but higher proportions of IS in patients with CAD. After propensity score matching, the PAD-only group had significantly higher incidences of STE and IS/STE than the CAD-only group, across all levels of CHA2DS2-VASc score. Patients with CAD and PAD had a significantly higher incidence of STE and IS/STE than propensity score-matched patients with CAD or PAD. Conclusions PAD or CAD in patients with AF did not contribute equally to the risk prediction and presentation of IS and STE. Patients with polyvascular disease should be considered at higher risk than those with either condition.

Interleukin-10 (IL-10) is a pathophysiological factor in acute ischaemic stroke (AIS) and is relevant to mood disorders after stroke. We evaluated the predictive value of IL-10 in patients with post-stroke depression (PSD).A total of 350 stroke patients were recruited at baseline, and 151 AIS patients were screened and completed a 1-month follow-up. Serum IL-10 levels were measured within 24 h of admission. We used the 17-item Hamilton Depression Scale (HAMD-17) to evaluate depression symptoms; PSD was defined as an HAMD score ≥ 7.Fifty-one (33.8%) patients showed a more serious stroke degree, larger infarction volume, and poorer daily life activities and prognosis (P0.05) and were diagnosed with PSD at the 1-month follow-up. Their IL-10 level decreased significantly compared to the non-PSD group (P0.001). After adjusting for confounders, IL-10 could be used as an independent predictor for PSD with an adjusted odds ratio (OR) of 0.615 (95% CI 0.410-0.923, P = 0.019). In addition, the optimal cut-off value of IL-10 was 0.615 pg/mL based on an area under the receiver operating characteristic curve of 0.692 (95% CI 0.604-0.781, P0.001), demonstrating that IL-10 could predict the occurrence of PSD. Moreover, IL-10 was an indicator of stroke severity, living ability, and functional outcomes (P0.05).IL-10 was only measured upon admission; dynamic changes need to be further monitored. This was also a single-centre study with a relatively small sample.Lower IL-10 levels may be used to predict PSD.

To determine the value of gadobenate dimeglumine (Gd-BOPTA)–enhanced biliary imaging from the hepatobiliary phase in predicting hepatic decompensation and insufficiency for patients with cirrhosis. This single-center retrospective study included 270 patients who underwent Gd-BOPTA-enhanced magnetic resonance imaging. The relative enhancement ratios of the biliary system (REB) and liver parenchyma (REL) in patients with normal liver function without underlying chronic liver disease and three groups of patients with Child-Pugh A, Child-Pugh B, and Child-Pugh C disease were measured. After a mean follow-up of 38.5 ± 22.5 months, prognostic factors were evaluated using the Cox proportional hazards regression model. Receiver operating characteristic (ROC) curve analyses were performed to assess the capacity of the REB and REL to predict the development of hepatic decompensation and insufficiency. During the follow-up period, nine of 79 patients with Child-Pugh A disease developed hepatic decompensation. The REB was a significant predictive factor (hazard ratio (HR) = 0.40 (0.19–0.84); p = 0.016), but the REL showed no association with hepatic decompensation. Moreover, the areas under the ROC curves (AUCs) were 0.83 and 0.52 for the REB and REL, respectively. Thirty-eight of 207 patients with cirrhosis developed hepatic insufficiency. The REB was a significant predictive factor (HR = 0.24 (0.13–0.46); p < 0.0001), but the REL did not show statistically significant association with hepatic insufficiency. The AUCs were 0.82 and 0.57 for the REB and REL, respectively. Gd-BOPTA-enhanced biliary imaging from the hepatobiliary phase was valuable in predicting hepatic decompensation and insufficiency for cirrhotic patients. • Gd-BOPTA-enhanced biliary imaging was a significant predictive factor for hepatic decompensation in patients with cirrhosis. • Gd-BOPTA-enhanced biliary imaging was a significant predictive factor for hepatic insufficiency in patients with cirrhosis. • Gd-BOPTA-enhanced biliary imaging showed superior predictive values for adverse clinical outcomes compared to liver parenchymal imaging at the hepatobiliary phase.

Background Hypertension, a major risk factor of cardiovascular mortality, is a critical issue for public health. Although Baduanjin (Eight Brocades, EB), a traditional Chinese exercise, might influence blood pressure, glucose, and lipid status, the magnitude of true effects and subgroup differences remains unclear. Therefore, we performed a systematic review of relevant randomized controlled trials (RCTs) to evaluate the effect of EB on patient-important outcomes. Methods We systematically searched PubMed, the Cochrane Library, Web of Science, and Chinese databases since inception until March 30, 2020. Meta-analysis was carried out using “meta” package in R 3.4.3 software. A prespecified subgroup analysis was done according to the type of comparisons between groups, and the credibility of significant subgroup effects (P Results Our meta-analysis, including 14 eligible trials with 1058 patients, showed that compared with routine treatment or health education as control groups, the mean difference (MD) in systolic blood pressure (SBP) of the EB groups was − 8.52 mmHg (95%CI:[− 10.65, − 6.40], P P = 0.15; DBP P = 0.37), so it could be easily attributed to chance. Conclusion Regularly EB exercising may be helpful to control blood pressure, but the evidence is only low certainty for blood pressure and very low certainty for cardiovascular morbidity and mortality. Rigorously designed RCTs that carry out longer follow-up and address patient-important outcomes remain warranted. Trial registration PROSPERO Registration number: CRD42018095854.

Objectives To investigate the association between adjunctive nebulized colistin and treatment outcomes in critically ill patients with nosocomial carbapenem-resistant Gram-negative bacterial (CR-GNB) pneumonia. Methods This retrospective, multi-centre, cohort study included individuals admitted to the intensive care unit with nosocomial pneumonia caused by colistin-susceptible CR-GNB. Enrolled patients were divided into groups with/without nebulized colistin as adjunct to at least one effective intravenous antibiotic. Propensity score matching was performed in the original cohort (model 1) and a time-window bias-adjusted cohort (model 2). The association between adjunctive nebulized colistin and treatment outcomes was analysed. Results In total, 181 and 326 patients treated with and without nebulized colistin, respectively, were enrolled for analysis. The day 14 clinical failure rate and mortality rate were 41.4% (75/181) versus 46% (150/326), and 14.9% (27/181) versus 21.8% (71/326), respectively. In the propensity score-matching analysis, patients with nebulized colistin had lower day 14 clinical failure rates (model 1: 41% (68/166) versus 54.2% (90/166), p 0.016; model 2: 35.3% (41/116) versus 56.9% (66/116), p 0.001). On multivariate analysis, nebulized colistin was an independent factor associated with fewer day 14 clinical failures (model 1: adjusted odds ratio (aOR) 0.59, 95% CI 0.37–0.92; model 2: aOR 0.37, 95% CI 0.21–0.65). Nebulized colistin was not associated independently with a lower 14-day mortality rate in the time-dependent analysis in both models 1 and 2. Conclusions Adjunctive nebulized colistin was associated with lower day 14 clinical failure rate, but not lower 14-day mortality rate, in critically ill patients with nosocomial pneumonia caused by colistin-susceptible CR-GNB.

Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians' choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression-free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15-9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20-8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10-9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18-20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02-0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients' clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.

Backgrounds: Severe influenza infection causes substantial morbidity and mortality worldwide and remains an important threat to global health. This study addressed factors related to treatment outcomes in subjects of complicated influenza infection with acute respiratory distress syndrome (ARDS) during the Taiwan epidemic in the Spring of 2016. Methods: This is a retrospective study conducted by Taiwan Severe Influenza Research Consortium (TSIRC), including eight tertiary referral medical centers. Patients with virology-proven influenza infection admitted to intensive care unit (ICU) between January and March 2016 were included for analysis. Results: We identified 263 patients with complicated influenza infection who fulfilled ARDS criteria; the mean age was 59.8 ± 14.6 (years), and 66.1% (166/263) were male. Type A influenza (77.9%, 205/263) virus was the main pathogen during this epidemic. The 30-day mortality rate was 23.2% (61/263). The mean tidal volume (VT) in the first three days after intubation was greater than 8 mL/kg of predicted body weight (PBW). Patients whose first measured VT was >8 mL/kg PBW had an increased 30-day mortality (p = 0.04, log-rank test). In a multivariate Cox proportional hazard regression model, an increase of 1 mL/kg PBW of first VT was associated with 26.1% increase in 30-day mortality (adjusted hazard ratio 1.261, 95% confidence interval [CI] 1.072–1.484, p

This study aimed to evaluate the efficacy of Chinese herbal medicine (CHM) in patients with severe/critical coronavirus disease 2019 (COVID-19). In this retrospective study, data were collected from 662 patients with severe/critical COVID-19 who were admitted to a designated hospital to treat patients with severe COVID-19 in Wuhan before March 20, 2020. All patients were divided into an exposed group (CHM users) and a control group (non-users). After propensity score matching in a 1:1 ratio, 156 CHM users were matched by propensity score to 156 non-users. No significant differences in seven baseline clinical variables were found between the two groups of patients. All-cause mortality was reported in 13 CHM users who died and 36 non-users who died. After multivariate adjustment, the mortality risk of CHM users was reduced by 82.2% (odds ratio 0.178, 95% CI 0.076–0.418; P < 0.001) compared with the non-users. Secondly, age (odds ratio 1.053, 95% CI 1.023–1.084; P < 0.001) and the proportion of severe/critical patients (odds ratio 0.063, 95% CI 0.028–0.143; P < 0.001) were the risk factors of mortality. These results show that the use of CHM may reduce the mortality of patients with severe/critical COVID-19.

Purpose Associations between Asian lung cancer (LC) and breast cancer (BC) are unknown. This study evaluates associations between LC and BC in the Taiwan population. Methods This study was based on the Taiwan National Health Insurance data and Taiwan Cancer Registry. The cohorts included women with newly diagnosed LC or BC between 2000 and 2011 and an age- and sex-stratified random sample as a noncancer comparison cohort during the same period. Cox proportional hazards regression analysis was used to determine the risks. The National Taiwan University Hospital (NTUH) cohort, which comprised patients with confirmed pathology diagnoses of double BC/LC, was reviewed. Results In 32,824 women with LC, there were increased risks for synchronous BC in patients younger than age 50 years (hazard ratio, 5.80; 95% CI, 1.83 to 18.73), age 50 to 59 years (HR, 2.37; 95% CI, 1.02 to 5.54), and age 60 to 69 years (HR, 4.42; 95% CI, 1.91 to 10.2). In the 88,446 women with BC, there were increased risks for synchronous LC in patients age 40 to 59 years (HR, 5.86; 95% CI, 3.05 to 11.3) and older than 60 years (HR, 1.98; 95% CI, 1.04 to 3.77). In the 128-patient NTUH double LC/BC cohort, 77 (60%) had both cancers diagnosed within 5 years of each other. Conclusion LC is associated with an increased risk for synchronous BC in Taiwan and vice versa. Radiotherapy might not be a major risk factor for LC in BC survivors. Etiology for double LC/BC deserves additional exploration and cross-racial genomic studies.

Background and aims Statins improve clinical outcomes in patients with ischemic stroke but there is no evidence of the effect of continuing long-term statin therapy in patients with intracerebral hemorrhage (ICH). The aim of this study was to evaluate the impact of continuing statin after ICH. Methods Data on patients with ICH was retrieved from the National Health Insurance Research Database of Taiwan. The final population was separated into two groups according to those who continued and those who discontinued statin treatment. All-cause mortality and cardiovascular outcomes were analyzed after a 3 year follow-up after propensity score matching (PSM). Results Of the 114,101 patients with ICH, who were initially enrolled, 2468 patients with dyslipidemia and ICH were included. After PSM, the benefit of statin therapy on mortality appeared from 1 year to the end of the 3-year follow-up period after discharge (statin group versus non-statin group: 4.9% vs.12.3% at 1 year (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.26–0.57) and 12.9% vs. 25.3% at the end of the 3 year follow-up period (HR, 0.45; 95% CI, 0.35–0.58). Compared with the patients using lipophilic statins, those using hydrophilic statins had a significantly lower incidence of all-cause mortality (HR = 0.65, 95% CI = 0.43–0.99). There were no differences between those prescribed moderate-intensity statins and those prescribed high-intensity statins in terms of stroke and all-cause mortality (HR = 0.76; 95% CI = 0.40–1.46). Conclusions There was a lower risk of all-cause mortality following ICH in patients who continued statin treatment compared with those without statin treatment, especially in those treated with hydrophilic statins.

Qixing Mao,1–4,* Louqian Zhang,1–3,* Yi Zhang,1,* Gaochao Dong,1,3 Yao Yang,4 Wenjie Xia,1–4 Bing Chen,1–3 Weidong Ma,1–3 Jianzhong Hu,4 Feng Jiang,1,3 Lin Xu1,3 1Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China; 2The Fourth Clinical College of Nanjing Medical University, Nanjing, China; 3Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China; 4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA *These authors contributed equally to this work Background: A substantial increase in the number of non-smoking lung adenocarcinoma (LAC) patients has been drawing extensive attention in the past decade. However, effective biomarkers, which could guide the precise treatment, are still limited for identifying high-risk patients. Here, we provide a network-based signature to predict the survival of non-smoking LAC.Materials and methods: Gene expression profiles were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus. Significant gene co-expression networks and hub genes were identified by Weighted Gene Co-expression Network Analysis. Potential mechanisms and pathways of co-expression networks were analyzed by Gene Ontology. The predictive signature was constructed by penalized Cox regression analysis and tested in two independent datasets.Results: Two distinct co-expression modules were significantly correlated with the non-smoking status across 4 Gene Expression Omnibus datasets. Gene Ontology revealed that nuclear division and cell cycle pathways were main mechanisms of the blue module and that genes in the turquoise module were involved in lymphocyte activation and cell adhesion pathways. Seventeen genes were selected from hub genes at an optimal lambda value and built the prognostic signature. The prognostic signature distinguished the survival of non-smoking LAC (training: hazard ratio [HR]=3.696, 95% CI: 2.025–6.748, P

Tributyltin (TBT), an endocrine disrupting chemical, can be found in food (particular in fish and seafood) and drinking water by contamination. Here, we elucidated the effects and possible mechanisms of low-dose TBT on the growth and function of pancreatic β-cells and glucose metabolism in mice. Submicromolar-concentration of TBT significantly induced β-cell cytotoxicity and apoptosis, which were accompanied by poly (ADP-ribose) polymerase cleavage and mitogen-activated protein kinases-JNK and ERK1/2 phosphorylation. TBT could also suppress the glucose-stimulated insulin secretion in β-cells and isolated mouse islets. TBT increased reactive oxygen species production. TBT-induced β-cell cytotoxicity and apoptosis were significantly prevented by antioxidant N-acetylcysteine (NAC) and JNK inhibitor SP600125, but not ERK1/2 inhibitor PD98059 and p38 inhibitor SB203580. Both NAC and SP600125 inhibited JNK phosphorylation and reduced cell viability in TBT-treated β-cells. Four-week exposure of TBT (0.25 mg/kg) to mice revealed the decreased plasma insulin, increased blood glucose and plasma malondialdehyde, suppressed islet insulin secretion, and increased islet caspase-3 activity, which could be reversed by NAC treatment. After removing the TBT exposure for 2 weeks, the TBT-induced glucose metabolism alteration was significantly reversed. These results suggest that low-dose TBT can induce β-cell apoptosis and interfere with glucose homeostasis via an oxidative stress-related pathway.

Background Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor alpha, inhibits the signals of interleukin-4 and interleukin-13, and has also shown significant efficacy in patients with moderate-to-severe atopic dermatitis (AD), while the effect of it on adverse events remains controversial. Objective To assess the influence of dupilumab on adverse events in adults with moderate-to-severe AD. Method Randomised controlled trials (RCTs) that compared dupilumab with a placebo for patients with moderate-to-severe AD were searched in the MEDLINE, EMBASE, Web of Science and Cochrane databases. The outcome of the study was the incidence of adverse events during the observation period. Results Eight RCTs were analysed in this study. Meta-analysis showed that patients treated with dupilumab had a lower risk of skin infection (risk ratio [RR] 0.54; 95% confidence interval [CI] 0.42–0.69) and exacerbation of AD (RR 0.44, 95% CI 0.34–0.59), but had a higher risk of injection-site reaction (RR 2.24, 95% CI 1.68–2.99), headache (RR 1.47, 95% CI 1.05–2.06), and conjunctivitis (RR 2.64, 95% CI 1.79–3.89) than did patients treated with a placebo. Nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpes virus infection were found balanced in dupilumab groups and placebo groups. Conclusion Dupilumab moderately reduced the risk of skin infection and the exacerbation of AD, slightly increased the risk of headache, and moderately increased the risk of injection-site reaction and conjunctivitis, but had little effect on other infections in adults with moderate-to-severe AD.

Background: Immunotherapy that targets programmed death protein-1 (PD-1) provides improved treatment efficacy and survival in patients with metastatic non-small cell lung cancer (NSCLC), especially those with high tumor expression of PD-L1. However, data on this treatment are mostly from clinical trials enrolling highly selected patients. The real-world experience of anti-PD-1 treatment and the usefulness of tumor PD-L1 expression in prediction of treatment response are largely unknown. Methods: We retrospectively reviewed patients with stage IIIB/ IV NSCLC who received monotherapy with nivolumab or pembrolizumab, and evaluated response using RECIST 1.1 criteria. Factors associated with treatment response, progression free survival (PFS), and overall survival (OS) were determined. Results: Seventy-four NSCLC patients out of 116 examined patients were included, most of whom had adenocarcinoma (48/74, 64.9%) and received immunotherapy as a third-line or subsequent treatment (51/74, 68.9%). The median PFS and OS were 1.8 and 7.9 months, respectively. The objective response rate was 32%, but only 47 of 74 patients were evaluable. Through multivariate analysis, epidermal growth factor receptor (EGFR) mutation was independently associated with a poor treatment response. Good performance status (ECOG≤1) and smoking were independently associated with better PFS and OS. Data on tumor PD-L1 expression were available in 43 patients (58%); higher PD-L1 expression correlated with better treatment response and longer PFS. Severe treatment-related adverse events were uncommon. Conclusion: The efficacy and safety of anti-PD-1 medications for advanced NSCLC were comparable in real-world and clinical settings, except in those with poor ECOG scores. Prediction of treatment response from tumor PD-L1 expression seemed practical.

Background: Respiratory failure requiring mechanical ventilation is the major reason for lung cancer patients being admitted to the intensive care unit (ICU). Though molecular targeted therapies, especially epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), have largely improved the survival of oncogene-driven lung cancer patients, few studies have focused on the performance of TKI in such settings. Materials and Methods: This was a retrospective cohort study enrolling non-small cell lung cancer (NSCLC) patients who harbored sensitizing EGFR mutation and had received EGFR-TKIs as first-line cancer therapy in the ICU with mechanical ventilator use. The primary outcome was the 28-day ICU survival rate, and secondary outcomes were the rate of successful weaning from the ventilator and overall survival. Results: A total of 35 patients were included. The 28-day ICU survival rate was 77%, and the median overall survival was 67 days. Multivariate logistic regression revealed that shock status was associated with a lower 28-day ICU survival rate independently (odds ratio (OR) 0.017, 95% confidence interval (CI), 0.000–0.629, p = 0.027), and that L858R mutation (L858R compared with exon 19 deletion, OR, 0.014, 95% CI 0.000–0.450, p = 0.016) and comorbidities of diabetes mellitus (DM) (OR, 0.032, 95% CI, 0.000–0.416, p = 0.014)) were independently predictive of weaning failure. The successful weaning rate was 43%, and the median of ventilator-dependent duration was 22 days (IQR, 12–29). Conclusions: For EGFR mutant lung cancer patients suffering from respiratory failure and undergoing mechanical ventilation, TKI may still be useful, especially in those with EGFR del19 mutation or without shock and DM comorbidity.

Objectives: Therapy outcomes for newly diagnosed, critically ill lung cancer patients have seldom been evaluated. This study evaluated therapy outcomes for treatment-naive lung cancer patients in the intensive care unit (ICU). Materials and Methods: Patients were excluded if they had previously received lung cancer treatment, such as systemic chemotherapy, targeted therapy, radiotherapy, or surgical lung resection before ICU admission. The therapeutic strategies for the treatment-naive patients were determined while they were in the ICU. The patients' demographic data, clinical outcomes, and treatment-related toxicities were analyzed. Results: Newly diagnosed lung cancer patients (n = 72) who did not receive any anticancer treatment before ICU admission were included. Most patients had locally advanced disease, and 61 (84.7%) required intensive care due to cancer-related events. In the ICU, 24 (33.3%) patients received chemotherapy, 24 (33.3%) received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and 24 (33.3%) received best supportive care (BSC). Patients receiving chemotherapy or EGFR-TKIs in the ICU demonstrated better ICU (p = 0.011) and in-hospital (p = 0.034) survival than those receiving BSC only. Among patients requiring mechanical ventilation, those receiving chemotherapy had higher weaning rates than those receiving EGFR-TKIs or BSC (p = 0.002). In multivariate analysis, receipt of chemotherapy (hazard ratio [HR], 0.443; p = 0.083) and mechanical ventilation (HR, 0.270; p = 0.022) were significantly associated with longer ICU survival after adjusting for clinical factors. Conclusions: Anticancer therapy in the ICU might provide better short-term ICU survival for treatment-naive, critically ill lung cancer patients.

// Chun-Nan Yeh 1 , Ming-Huang Chen 2, 3 , Yen-Yang Chen 4 , Ching-Yao Yang 5 , Chueh-Chuan Yen 3 , Chin-Yuan Tzen 6 , Li-Tzong Chen 7 and Jen-Shi Chen 8 1 Department of Surgery, GIST Team, Chang Gung Memorial Hospital and University, Taoyuan 333, Taiwan 2 School of Medicine, National Yang-Ming University, Taipei 112, Taiwan 3 Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan 4 Department of Internal Medicine, Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung 833, Taiwan 5 Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan 6 Department of Pathology and Laboratory Medicine, Cathay General Hospital, Taipei 100, Taiwan 7 National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan 8 Division of Hematology-Oncology, GIST Team, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, Taiwan Correspondence to: Chun-Nan Yeh, email: yehchunnan@gmail.com Keywords: regorafenib, GIST, exon 17 Received: January 17, 2017 Accepted: March 31, 2017 Published: April 21, 2017 ABSTRACT Background: Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%–90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2–3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. Patients and Methods: Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1–21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. Results: Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). Conclusion: Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. Trial registration: This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097. Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.

Objective The one and a half ventricle repair (1.5VR) is a common clinical choice for patients with right heart dysfunction. Considering the influence of blood circulation failure and reoperation in urgent need, this essay aims to explore the hemodynamic effects of different pulmonary vascular resistance (PVR) values on reoperation after 1.5VR failure. Methods The lumped parameter model (LPM) was used to simulate the reoperation, including the return biventricular repair (2VR), ligation of azygos vein (1.5VR') and return single ventricular repair (1.0VR). Firstly, the debugging parameters were used to simulate the hemodynamics of 2VR. Secondly, the value of PVR was changed from one to four times while the other parameters remained unchanged. Finally, 15 cardiac cycles were simulated and the 15th result was obtained. In this work, the left and right ventricular stroke work and their sum (Plv, Prv, Ptotal), the left and right ventricular ejection fraction (LVEF, RVEF), the mean Cardiac Output (mCO) and the mean pressure and flow-rate ratio of superior and inferior vena cava (mPsvc\mPivc and mQsvc\mQivc), respectively, were used to describe the hemodynamics of reoperation. Results With the change of PVR from one to four times, the values of Plv, Prv, Ptotal, LVEF, and RVEF gradually decreased. The change rate of Plv, Ptotal and LVEF of 1.0VR were the largest in the three kinds of reoperation. The change rate of Prv of 1.5VR' was larger than that of 2VR, but it was the opposite for their EF change rate. The mCO of 2VR, 1.5VR', and 1.0VR decreased by 18.53%, 37.58%, and 48.07%, respectively. The mPsvc\mPivc of 1.5VR' increased from 3.76 to 6.77 and the mQsvc\mQivc decreased from 0.55 to 0.36, while the mPsvc\mPivc and mQsvc\mQivc of 2VR and 1.0VR remained 1 and 0.67, respectively. The peak value of the tricuspid flow-rate (Qti) waveform of 2VR and 1.5VR' changed from "E peak" to "A peak." Conclusion The numerical results demonstrate the highly reoperation-dependent hemodynamic consequences and their responses to variations in PVR. Comprehensive analysis of EF, mCO and ventricular stroke work indicates that PVR has a greater impact on 1.5VR' and 1.0VR. Therefore, we suggest that the selection strategy of reoperation should focus on PVR.

Background Corticosteroid treatment has been widely used in the treatment of septic shock, influenza, and ARDS, although some previous studies discourage its use in severe influenza patients. This multicenter retrospective cohort study conducted in the intensive care units (ICUs) of eight medical centers across Taiwan aims to determine the real-world status of corticosteroid treatment in patients with influenza-associated acute respiratory distress syndrome (ARDS) and its impact on clinical outcomes. Between October 2015 and March 2016, consecutive ICU patients with virology-proven influenza infections who fulfilled ARDS and received invasive mechanical ventilation were enrolled. The impact of early corticosteroid treatment (≥ 200 mg hydrocortisone equivalent dose within 3 days after ICU admission, determined by a sensitivity analysis) on hospital mortality (the primary outcome) was assessed by multivariable logistic regression analysis, and further confirmed in a propensity score-matched cohort. Results Among the 241 patients with influenza-associated ARDS, 85 (35.3%) patients receiving early corticosteroid treatment had similar baseline characteristics, but a significantly higher hospital mortality rate than those without early corticosteroid treatment [43.5% (37/85) vs. 19.2% (30/156), p p Conclusions Early corticosteroid treatment was associated with a significantly increased hospital mortality in adult patients with influenza-associated ARDS. Earlier treatment and higher dosing were associated with higher hospital mortality. Clinicians should be cautious while using corticosteroid treatment in this patient group.