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In critically ill adults, unachieved nutrition targets owing to feeding intolerance are associated with poor outcomes. Erythromycin, a macrolide of antibiotics, exerts its gastrointestinal prokinetic as a motilin receptor agonist and subsequently promotes bowel movement. The application of erythromycin has been mentioned in the European Society for Clinical Nutrition and Metabolism (ESPEN) guideline with a grade B recommendation and strong consensus based on significant results from a meta-analysis of only three randomized controlled trials in a Mantel-Haenszel random-effects model.We reinspected the evidence by a random-effects model of meta-analyses through the frequentist approach with the Hartung-Knapp-Sidik-Jonkman (HKSJ) method, trial sequential analysis (TSA), and Bayesian inference.The results analyzed by the HKSJ method showed a risk ratio (RR) of 0.50 (95% confidence interval, 0.19-1.33; IThe effect of intravenous erythromycin in feeding intolerance for critically ill adults remained inconclusive, with very low certainty of evidence. Further large-scale randomized controlled trials with increased rigor are warranted to provide a solid conclusion.

BackgroundVagal maneuvers (VagMs) are recommended as the first-line treatment of supraventricular tachycardia (SVT). However, the optimal type of VagMs remains unproven.AimThis study aims to compare the effectiveness and adverse events amongst VagMs on SVT via network meta-analyses (NMAs).MethodsWe systematically searched randomized controlled trials (RCTs) that involved adults with SVT and compared VagMs without language restrictions. We determined the initial and final responses of conversion rate to sinus rhythm and adverse events. Risk of bias (RoB) was appraised by Cochrane revised tool, and contribution matrix was calculated. NMAs were synthesized using frequentist random-effects model and presented as relative risk (RR) with 95% CI. The order of probability was presented as surface under the cumulative ranking curve analysis (SUCRA). Sensitivity analysis was performed using both Bayesian and frequentist approach with fixed- or random-effects models. Certainty of evidence (CoE) was rated by using the Grading of Recommendations, Assessment, Development, and Evaluations methodology.ResultsFourteen RCTs with 2,180 patients were enrolled. Small portion of mixed estimates was contributed from high overall RoB studies. Compared with carotid sinus massage (CSM), the modified Valsalva maneuver (MVM) was the most effective VagM after initial performance [SUCRA: 0.9992, RR: 5.47 (1.77–16.93)] and at the end of study [SUCRA: 1.0000, RR: 3.62 (2.04–6.39), CoE: high]. The standard VM did not elicit better conversion rate to the sinus rhythm than CSM at the initial response [SUCRA: 0.4395, RR: 1.97 (0.63–6.15)] and at the end of the study [SUCRA: 0.4795, RR: 1.64 (0.94–2.87), CoE: moderate]. The SUCRA value of CSM at the initial and final responses was the least one amongst three VagMs (0.0613 and 0.0205, respectively). Adverse events amongst three VagMs were similar (CoE: low). Sensitivity analyses yielded consistent results.ConclusionWe recommended MVM as the first choice of VagM for rhythm conversion before the pharmacological management of SVT.

In pre-hospital settings, efficient cardiopulmonary resuscitation (CPR) is challenging; therefore, the application of mechanical CPR devices continues to increase. However, the evidence of the benefits of using mechanical CPR devices in pre-hospital settings for adult out-of-hospital cardiac arrest (OHCA) is controversial. This meta-analysis compared the effects of mechanical and manual CPR applied in the pre-hospital stage on clinical outcomes after OHCA. Cochrane Library, PubMed, Embase, and ClinicalTrials.gov were searched from inception until October 2021. Studies comparing mechanical and manual CPR applied in the pre-hospital stage for survival outcomes of adult OHCA were eligible. Data abstraction, quality assessment, meta-analysis, trial sequential analysis (TSA), and grading of recommendations, assessment, development, and evaluation were conducted. Seven randomized controlled and 15 observational studies were included. Compared to manual CPR, pre-hospital use of mechanical CPR showed a positive effect in achieving return of spontaneous circulation (ROSC) and survival to admission. No difference was found in survival to discharge and discharge with favorable neurological status, with inconclusive results in TSA. In conclusion, pre-hospital use of mechanical CPR devices may benefit adult OHCA in achieving ROSC and survival to admission. With low certainty of evidence, more well-designed large-scale randomized controlled trials are needed to validate these findings.

BackgroundIntravenous infusion of lidocaine (IVF-Lido) during the perioperative period is an option to accelerate bowel function recovery after major colorectal surgery. However, previous meta-analyses have shown inconsistent conclusions. Recent randomized controlled trials (RCTs) have been reported after the publication of a previous meta-analysis.AimWe conducted an updated and comprehensive meta-analysis to determine the effects of IVF-Lido on time to first flatus and defecation after major colorectal surgery.MethodsWe performed a systematic review according to the Preferred Reporting Items for the Systematic Reviews and Meta-Analysis Protocols 2020 guideline. Only RCTs were included. The revised Cochrane risk-of-bias tool was chosen for appraisal. Meta-analysis with meta-regression and trial sequential analysis was carried out. The Doi plot was presented to evaluate publication bias. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology was executed to evaluate the certainty of evidence (CoE).ResultsThirteen RCTs with 696 participants were enrolled. IVF-Lido significantly decreased the time to first flatus [mean difference (MD) = −6.03 h; 95% confidence interval (CI): (−8.80, −3.26)] and first defecation [MD = −10.49 h; 95% CI: (−15.58, −5.41)]. Trial sequential analysis yielded identical results and ampleness of required information sizes. No obviousness in publication bias was detected, and the CoE in GRADE was low in both outcomes. Meta-regression showed that a significantly shorter time to the first defecation was associated with studies with more improvement in pain control in comparison of two groups and better-improved analgesia in the control group.ConclusionsWe discretionarily suggest the use of IVF-Lido on postoperative bowel function recovery following major colorectal surgery. Beyond the analgesic effects, IVF-Lido might have additional benefits when postoperative pain relief has already been achieved. Considering the high heterogeneity in this updated meta-analysis, more RCTs are needed.Systematic Review Registrationhttps://inplasy.com/inplasy-2020-7-0023/, INPLASY [202070023].

BACKGROUND Multidisciplinary rounds (MDRs) are scheduled, patient-focused communication mechanisms among multidisciplinary providers in the intensive care unit (ICU). OBJECTIVE i-Dashboard is a custom-developed visualization dashboard that supports (1) key information retrieval and reorganization, (2) time-series data, and (3) display on large touch screens during MDRs. This study aimed to evaluate the performance, including the efficiency of prerounding data gathering, communication accuracy, and information exchange, and clinical satisfaction of integrating i-Dashboard as a platform to facilitate MDRs. METHODS A cluster-randomized controlled trial was performed in 2 surgical ICUs at a university hospital. Study participants included all multidisciplinary care team members. The performance and clinical satisfaction of i-Dashboard during MDRs were compared with those of the established electronic medical record (EMR) through direct observation and questionnaire surveys. RESULTS Between April 26 and July 18, 2021, a total of 78 and 91 MDRs were performed with the established EMR and i-Dashboard, respectively. For prerounding data gathering, the median time was 10.4 (IQR 9.1-11.8) and 4.6 (IQR 3.5-5.8) minutes using the established EMR and i-Dashboard (Pi-Dashboard (median 0, IQR 0-0) than with the established EMR (4, IQR 3-5; Pi-Dashboard than with the established EMR (Pi-Dashboard in association with the enhancement of care plan development and team participation during MDRs. CONCLUSIONS i-Dashboard increases efficiency in data gathering. Displaying i-Dashboard on large touch screens in MDRs may enhance communication accuracy, information exchange, and clinical satisfaction. The design concepts of i-Dashboard may help develop visualization dashboards that are more applicable for ICU MDRs. CLINICALTRIAL ClinicalTrials.gov NCT04845698; https://clinicaltrials.gov/ct2/show/NCT04845698

In this paper we discuss the classical 3D XY model whose nearest-neighbor interaction is a mixture of $\cos(\theta_i-\theta_j)$ (ferromagnetic) and $\cos2(\theta_i-\theta_j)$ (nematic). This model is dual to a theory with integer and half-integer vortices. While both types of vortices interact with a non-compact $U(1)$ gauge field (the "EM" interaction), the half-vortices interact with an extra interaction mediated by a $\mathbb{Z}_2$ gauge field. We shall discuss the confinement-deconfinement transition of the half-integer vortices, the Wilson and the 't Hooft loops and their mutual statistics in path integral language. In addition, we shall present a quantum version of the classical model which exhibits these physics., Comment: 4+4 pages, 3+0 figures

In this paper, we apply the K-theory to classify topological trivial fermionic phases which, nonetheless, host symmetry-protected non-trivial defects. An important implication of our work is that the existence of Majorana zero mode in the vortex core is neither a necessary nor a sufficient condition for the superconductor in question being topologically non-trivial.

Background: Remimazolam is a new ultrashort-acting benzodiazepine. Remimazolam has been approved for procedural sedation by the US Food and Drug Administration in 2020. However, prior trials and the participants they enrolled were limited.Aim: In this meta-analysis, we investigated the effectiveness and adverse events (AEs) of remimazolam during procedural sedation.Materials and Methods: The study protocol was registered (doi: 10.37766/inplasy2020.8.0043), and six databases were searched. We performed meta-analysis, trial sequential analysis (TSA), and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for judging the certainty of evidence (CoE).Results: A total of five randomized controlled trials with 1,248 participants were included. Compared with the use of midazolam, the utilization of remimazolam resulted in an increase in procedure success rate [odds ratio (OR) = 9.01, 95% confidence interval (CI): 2.35–34.57], a reduction in the application of rescue medication (OR = 13.58, 95% CI: 3.46–53.28), a decrease in time to recovery [minutes, weighted mean difference (WMD) = −5.70, 95% CI: −8.68 to −2.72], and a better cognitive recovery of Hopkins Verbal Learning Test-Revised (WMD = 5.22, 95% CI: 2.88–7.55). No difference was found in completion of procedure (OR = 1.68, 95% CI: 0.72–3.90) with inconclusive in TSA. Despite no difference of total AEs (OR = 0.60, 95% CI: 0.24–1.50), more detailed analysis of AEs remained inconclusive in TSA. The GRADE assessment demonstrated low to very low CoE.Conclusion: Our analysis suggested that remimazolam may be a better choice for procedural sedation than midazolam. Nevertheless, further studies are warranted to conclusively establish its safety.

To conduct a systematic review and meta-analysis to evaluate the effects of cold application on pain and anxiety reduction after chest tube removal (CTR).The act of removing the chest tube often causes pain among cardiothoracic surgery patients. Most guidelines regarding CTR do not mention pain management. The effects of cold application on reducing pain and anxiety after CTR are inconsistent.Systematic review and meta-analysis.We searched six databases, including Embase, Ovid Medline, Cochrane Library, Scopus, the Index to Taiwan Periodical Literature System and Airiti Library, to identify relevant articles up to the end of February 2021. We limited the language to English and Chinese and the design to randomised controlled trials (RCTs). All studies were reviewed by two independent investigators. The Cochrane Collaboration's tool was used to assess the risk of bias, Review Manager 5.4 was used to conduct the meta-analysis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was used for assessing certainty of evidence (CoE).Ten RCTs with 683 participants were included in the meta-analysis. The use of cold application could effectively reduce pain and anxiety after CTR. The subgroup showed that a skin temperature drops to 13°C of cold application was significantly more effective for the immediate reduction in pain intensity after CTR compared with control group. The GRADE methodology demonstrated that CoE was very low level.Cold application is a safe and easy-to-administer nonpharmacological method with immediate and persistent effects on pain and anxiety relief after CTR. Skin temperature drops to 13°C or lasts 20 min of cold application were more effective for immediate reduction of pain intensity following CTR.In addition to pharmacological strategy, cold application could be used as evidence for reducing pain intensity and anxiety level after CTR.

(1) Background: High-flow nasal cannula (HFNC) therapy or conventional oxygen therapy (COT) are typically applied during gastrointestinal (GI) endoscopic sedation. (2) Methods: We conducted a rigorous systematic review enrolling randomized controlled trials (RCTs) from five databases. Risk of bias was assessed using Cochrane’s RoB 2.0 tool; certainty of evidence (CoE) was assessed using GRADE framework. Meta-analysis was conducted using inverse-variance heterogeneity model and presented as relative risk (RR) with 95% confidence interval (CI). Trial sequential analysis was performed, and sensitivity analysis was conducted with Bayesian approach. (3) Results: Eight RCTs were included. Compared to COT, HFNC did not reduce the overall incidence of hypoxemia (RR 0.51; 95% CI 0.24–1.09; CoE: very low) but might reduce the incidence of hypoxemia in patients at moderate to high risk for hypoxemia (RR 0.54; 95% CI 0.31–0.96; and CoE: very low). HFNC might reduce the incidence of severe hypoxemia (RR 0.38; 95% CI 0.20–0.74; and CoE: low). HFNC might not affect the need of minor airway interventions (RR 0.31; 95% CI 0.08–1.22; and CoE: very low) and had no effect on procedure duration (CoE: very low); (4) Conclusions: During GI endoscopic sedation, HFNC might reduce the incidence of hypoxemia in patients at moderate to high risk for hypoxemia and prevent severe hypoxemia.

Background It has been a matter of much debate whether the co-administration of furosemide and albumin can achieve better diuresis and natriuresis than furosemide treatment alone. There is inconsistency in published trials regarding the effect of this combination therapy. We, therefore, conducted this meta-analysis to explore the efficacy of furosemide and albumin co-administration and the factors potentially influencing the diuretic effect of such co-administration. Methods In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched the PubMed, Embase, Medline, and Cochrane databases. Prospective studies with adult populations which comparing the effect of furosemide and albumin co-administration with furosemide alone were included. The outcomes including diuretic effect and natriuresis effect measured by hourly urine output and hourly urine sodium excretion from both groups were extracted. Random effect model was applied for conducting meta-analysis. Subgroup analysis and sensitivity analysis were performed to explore potential sources of heterogeneity of treatment effects. Results By including 13 studies with 422 participants, the meta-analysis revealed that furosemide with albumin co-administration increased urine output by 31.45 ml/hour and increased urine excretion by 1.76 mEq/hour in comparison to furosemide treatment alone. The diuretic effect of albumin and furosemide co-administration was better in participants with low baseline serum albumin levels (< 2.5 g/dL) and high prescribed albumin infusion doses (> 30 g), and the effect was more significant within 12 hours after administration. Diuretic effect of co-administration was better in those with baseline Cr > 1.2 mg/dL and natriuresis effect of co-administration was better in those with baseline eGFR < 60 ml/min/1.73m2. Conclusion Co-administration of furosemide with albumin might enhance diuresis and natriuresis effects than furosemide treatment alone but with high heterogeneity in treatment response. According to the present meta-analysis, combination therapy might provide advantages compared to the furosemide therapy alone in patients with baseline albumin levels lower than 2.5 g/dL or in patients receiving higher albumin infusion doses or in patients with impaired renal function. Owing to high heterogeneity and limited enrolled participants, further parallel randomized controlled trials are warranted to examine our outcome. Registration PROSEPRO ID: CRD42020211002; https://clinicaltrials.gov/.

Risk and prognostic factors for acute kidney injury (AKI) have been published in various studies across various populations. We aimed to explore recent advancements in and provide updated recommendations on AKI risk stratification and information about local AKI risk factors. The Taiwan Acute Kidney Injury Task Force reviewed relevant recently published literature and reached a consensus after group meetings. Systemic review and group discussion were performed. We conducted a meta-analysis according to the PRISMA statement for evaluating the diagnostic performance of the furosemide stress test. Several risk and susceptibility factors were identified through literature review. Contrast-associated AKI prediction models after coronary angiography were one of the most discussed prediction models we found. The basic approach and evaluation of patients with AKI was also discussed. Our meta-analysis found that the furosemide stress test can be used as a prognostic tool for AKI progression and to identify patients with AKI who are at low risk of renal replacement therapy. Factors associated with de novo chronic kidney injury or renal non-recovery after AKI were identified and summarized. Our review provided practical information about early identification of patients at high risk of AKI or disease progression for Taiwan local clinics.

The non-regularizability of free fermion field theories, which is the root of various quantum anomalies, plays a central role in particle physics and modern condensed matter physics. In this paper, we generalize the Nielsen-Ninomiya theorem to all minimal nodal free fermion field theories protected by the time reversal, charge conservation, and charge conjugation symmetries. We prove that these massless field theories cannot be regularized on a lattice., 29 pages, 4 figures

Aim This study systematically reviewed evidence regarding the effectiveness of exercise in slowing breastfeeding-induced bone loss. Methods The evidence-based approach of a systematic review (PROSPERO registration No. CRD42019111623) was adopted. The inclusion criteria were randomized controlled trials or observational studies. Study samples were breastfeeding women, the intervention was any form of exercise, and bone mineral density (BMD) of the total body, lumbar spine and hip/femur neck before 6 months and at 1 year were the outcome measures. Meta-analyses were performed using a random effect model, and calculations of mean differences of BMD change and 95% confidence intervals (CIs) were carried out. Studies were further evaluated through trial sequential meta-analysis (TSA), and the 'Grading of Recommendations Assessment, Development and Evaluation' methodology was used to assess the certainty of evidence (CoE). Results A total of 1049 studies were screened, and 4 met the inclusion criteria. Weight-bearing aerobic exercise and resistance training before the 6-month evaluation slowed breastfeeding-induced bone loss in the lumbar spine (1.62% BMD change [95% CI = 0.53-2.71]; I2 = 8%). The TSA Z-curve revealed crossing of the TSA boundary and line of information size, indicating sufficient sampling and significance. The CoE of exercise benefit in the lumbar spine at 6 months was low, whereas the CoE for other areas ranged from low to very low. Conclusion This first systematic review and meta-analysis provided some evidence of the advantages of exercise for slowing breastfeeding-induced bone loss. However, additional randomized controlled trials are warranted to generate more conclusive evidence.

Additional file 14. GRADE Evidence and Summary of Findings Table.

Protocol for the network meta-analysis.

Objective: Tissue hypoperfusion during cardiopulmonary bypass (CPB) affects cardiac surgical outcomes. Lactate, an end product of anaerobic glycolysis from oxygen deficit, is a marker of tissue hypoxia. In this study, we aimed to identify the prognostic value of blood lactate level during CPB in predicting outcomes in adults undergoing cardiac surgeries. Materials and Methods: We retrospectively reviewed the medical records of patients who underwent cardiac surgeries with CPB from January 2015 to December 2015. Data about the characteristics of patients, preoperative status, type of surgery, and intraoperative lactate levels were collected. The outcomes were in-hospital mortality and complications. The receiver operating characteristics (ROC) curves were used to assess the ability of peak lactate level during CPB in predicting in-hospital mortality. Results: A total of 97 patients, including 61 who underwent emergent or urgent surgery, were enrolled. The types of surgery included coronary artery bypass grafting (CABG, n = 52), valve surgery (n = 27), combined surgery (CABG and valve surgery, n = 4), great vessel surgery (including aortic dissection, n = 9), and others (n = 5). The median CPB time was 139 min (interquartile range = 120–175). The median initial lactate and peak lactate levels during CPB were 0.9 and 4.2 mmol/L, respectively. In-hospital mortality was 14.4%, which was significantly associated with age and peak lactate level in the multivariate logistic regression model. When the peak lactate level during CPB reached 7.25 mmol/L, in-hospital mortality could be predicted with an area under the ROC curve of 0.75 (95% confidence interval: 0.59–0.90; P = 0.003), with a sensitivity of 57% and specificity of 93%. Conclusion: Hyperlactatemia during CPB was associated with increased in-hospital mortality. Thus, early detection of such conditions and aggressive postoperative care are important.

Background: Sinusitis-related intracranial abscess (ICA) is a rare but serious complication and is different from those of sinusitis-unrelated ICA. Purpose: This study aimed to analyze the differences in bacteriology, host factors, presentations, and prognoses between cases of sinusitis-related and sinusitis-unrelated ICA. Methods: This retrospective study was conducted at Buddhist Tzu Chi General Hospital (Hualien, Taiwan), during January 2010–August 2014, and enrolled patients with pathologically proven postsurgery ICA. P < 0.05 was considered statistically significant. Results: The number of patients with sinusitis-related and sinusitis-unrelated ICA was 10 and 17, respectively. Compared with sinusitis-unrelated ICA patients, significantly more patients with sinusitis-related ICA experienced cirrhosis, ophthalmic abnormalities, and frontal and cavernous sinus involvement. Among all ICA patients, diabetes mellitus (DM) was associated with an increased mortality risk. Patients with DM exhibited the highest positive culture rates for Klebsiella pneumoniae. Conclusion: Frontal sinusitis is associated with an increased risk of intracranial invasion. DM and liver cirrhosis patients exhibited the highest mortality rates among all ICA patients. Patient comorbidity should be considered when prescribing antibiotics for treatment.

Background: Infection-induced inflammatory response might be aggravated by surgery insults. The clinical presentation of Surgical Intensive Care Unit (SICU) patients might be different from medical critically ill patients. Purpose: To evaluate the diagnostic and prognostic values of procalcitonin (PCT) to predict bacterial infection in SICU patients. Methods: We retrospectively analyzed the 2-year (2013 and 2014) records of 342 adult SICU cases with suspected bacterial infection in SICU of Hualien Tzu Chi Hospital. The past histories, the first infection-related parameters when SICU admission, culture results, infection-related laboratory examinations, and outcomes were collected. Results: Median of PCT level in patients with negative and any positive culture was 0.84 (interquartile range [IQR] 0.18–6.21) and 2.27 (IQR 0.54–9.93) ng/ml, respectively. Infection from blood, urine, and skin/soft tissue elicited significantly higher PCT levels. PCT in receiver operating characteristic (ROC) curve demonstrated the most accurate to predict bacterial infection (area under the ROC curve [AUC]: 0.61; 95% confidence interval [CI]: 0.54–0.63) and bacteremia (AUC: 0.73; 95% CI: 0.66–0.80) compared to white blood cell count, ratio of neutrophils, and neutrophil-to-lymphocyte count ratio (NLCR). Significantly higher PCT levels (4.12 ng/ml, 1.12–19.99; median, IQR) were observed in mortality cases. Higher PCT levels were significantly accompanied with higher NLCR, as well as higher incidence of leukopenia and bandemia. Using Kaplan–Meier analysis, significantly higher intrahospital mortality was observed in cases with above the cutoff PCT levels of 0.5 and 2 ng/ml cases, respectively. Conclusion: PCT is a relatively more useful tool to predict bacterial and particularly bloodstream infection compared to other infection-related parameters in routinely clinical practice. Initial PCT levels may be a prognostic factor of SICU patients with bacterial infection.

Nonlinear optical effects play key roles to communication, sensing, imaging, and so on. Recently, nonlinear scattering (saturation and reverse saturation) was discovered in gold nanospheres, providing a novel approach to nonbleaching super-resolution microscopy. However, the nonlinearity was previously limited to green-orange plasmonic band. It is highly desirable to extend the applicable wavelength range. In this work, we demonstrated nonlinear scattering in near-infrared with gold nanorods and in blue-violet with silver nanospheres. Besides, the nonlinear mechanism is clarified via different material/geometry. By spectrally decoupling the contributions of plasmonic absorption/scattering and interband/intraband transitions, we have verified plasmonic absorption, and the subsequent thermal effects to be the dominating source of nonlinearity. Our work not only provides the physical mechanism of the nonlinear scattering, but also paves the way toward multicolor super-resolution imaging based on plasmonic sc...

Survivin is overexpressed in transitional cell carcinoma (TCC), the most common type of bladder cancer. Previous reports demonstrated that knockdown of survivin by siRNA induced apoptosis of TCC cells. The present study evaluated the therapeutic effects of sepantronium bromide (YM155), a novel small molecule survivin inhibitor under clinical trials, on TCC cells in vitro. BFTC905, a grade III TCC cell line derived from a patient of blackfoot disease in Taiwan, was the most gemcitabine-resistant cell line when compared to BFTC909, TSGH8301 and T24 in cytotoxicity assay, resulting from upregulation of securin and bcl-2 after gemcitabine treatment. YM155 caused potent concentration‑dependent cytotoxicity in 4 TCC cell lines (IC50s ≤20 nM), but exhibited no cytotoxicity in survivin-null primary human urothelial cells. For BFTC905 cells, addition of gemcitabine and/or cisplatin, the standard TCC chemotherapy regimen, to YM155 did not exert additive cytotoxic effects. Molecular analyses indicated that YM155 inhibited the proliferation of BFTC905 cells by increasing p27kip1, suppressing Ki-67, and inducing quiescence. In addition, YM155 elicited apoptosis manifested with DNA fragmentation through suppressing the expression of survivin, securin and bcl-2. Furthermore, YM155 induced autophagy in BFTC905 cells as autophagic inhibitor, 3-methyladenine, attenuated YM155-induced LC3B-II levels and reversed the cytotoxicity of YM155. mTOR inhibitors sirolimus and everolimus did not increase YM155-induced expression of LC3B-II nor augment YM155-induced cytotoxicity. These results indicate that YM155 exerts its lethal effect on BFTC905 cells via apoptotic and autophagic death pathways and suggest that YM155 may be a potential drug for the therapy of gemcitabine-resistant bladder cancer.

Nonlinear optical interaction is crucial to all-optical signal processing. In metallic nanostructures, both linear and nonlinear optical interactions can be greatly enhanced by surface plasmon resonance (SPR). In the last few decades, saturation and reverse saturation of absorption in plasmonic materials have been unraveled. It is known that scattering is one of the fundamental light–matter interactions and is particularly strong in metallic nanoparticles due to SPR. However, previous methods measure response from ensemble of nanoparticles and did not characterize scattering on a single particle basis. Here we report that backscattering from an isolated gold nanoparticle exhibits not only saturation, but also reverse saturation. Wavelength-dependent and intensity-dependent studies reveal that nonlinear scattering is dominated by SPR and shares a similar physical origin with nonlinear absorption. The reversibility and repeatability of saturable scattering (SS) and reverse saturable scattering (RSS) are val...

Objective The attempt to block one type of receptor tyrosine kinase (RTK) signaling has been considered a main strategy for cancer therapy; however, cancer cells may survive using alternative RTK signaling. Thus, targeting multiple RTKs simultaneously may be a better treatment strategy. Previously, we demonstrated that brain-derived neurotrophic factor (BDNF) via activating tropomyosin receptor kinase B (TrkB) is a survival factor for transitional cell carcinoma (TCC). Others have reported that autocrine vascular endothelial growth factor (VEGF) pathways also play a crucial role in TCC growth. We aim to examine the in vitro and in vivo effects of BDNF plus VEGF on the TCC cell line BFTC905 derived from the bladder cancer of a Taiwanese patient with black foot disease. Materials and Methods Cell numbers were counted after administration of 50 nM BDNF and/or VEGF to the BFTC905 or primary human urothelial cell (HUC) cultures for 96 hours. The volumes of the xenograft tumors were measured 6 weeks after weekly injections of 100 ng BDNF and/or VEGF into the cancer cell-loading site of NOD.CB17-Prkdc scid /Tcu mice. The expression of TrkB in HUCs and VEGF receptor FLT-1 in BFTC905 cells and HUCs, as well as CD34 and Ki-67 in the xenograft tumors was determined by Western blotting. Results The effects of increasing BFTC905 cell numbers were as follows: BDNF + VEGF > BDNF > VEGF > control after 96 hours of treatment. The VEGF receptor FLT-1 was expressed in BFTC905 cells. Exogenous BDNF and/or VEGF did not promote the proliferation of HUCs. In addition, TrkB and FLT-1 were very weakly expressed in HUCs. After treatment for 5 weeks, the effects of exogenously administered BDNF and/or VEGF on the xenograft tumor volume were as follows: BDNF + VEGF > BDNF > VEGF > control. However, similar tumor sizes with few metastases were found in the four groups of mice after treatment for 6 weeks. The expression levels of the angiogenic marker CD34 and proliferative marker Ki-67 were also similar among these four groups of xenograft tumors. Conclusion Exogenous BDNF plus VEGF additively promotes the early growth of BFTC905 in vitro and in vivo without affecting the normal urothelium. Targeted blockade of both TrkB and VEGF signaling might be an effective treatment for adjuvant bladder cancer therapy or in the early stage of high-grade TCC.

Because of their exceptional local-field enhancement and ultrasmall mode volume, plasmonic components can integrate photonics and electronics at nanoscale and active control of plasmons is the key. However, all-optical modulation of plasmonic response with nanometer mode volume and unity modulation depth is still lacking. Here we show that scattering from a plasmonic nanoparticle, whose volume is smaller than 0.001 μm3, can be optically switched off with less than 100 μW power. Over 80% modulation depth is observed and shows no degradation after repetitive switching. The spectral bandwidth approaches 100 nm. The underlying mechanism is suggested to be photothermal effects and the effective single-particle nonlinearity reaches nearly 10−9 m2/W, which is to our knowledge the largest record of metallic materials to date. As a novel application, the non-bleaching and unlimitedly switchable scattering is used to enhance optical resolution to λ/5 (λ/9 after deconvolution), with 100-fold less intensity requirement compared to similar superresolution techniques. Our work not only opens up a new field of ultrasmall all-optical control based on scattering from a single nanoparticle, but also facilitates superresolution imaging for long-term observation.

Objective Securin, the product of PTTG (pituitary tumor transforming gene), is overexpressed in several tumors, and plays important roles in cancer progression and invasion. In our previous report, securin expression was observed in transitional cell carcinoma (TCC; the most common pathological pattern of bladder cancer) cell lines, including BFTC905, T24, and TSGH8301. However, the existence of securin in human bladder cancer specimens has not been established. Materials and Methods Commercial bladder cancer tissue arrays (BL208 & BLC661) were used. Slides of paraffin-fixed human bladder tissues included all grades of TCC (18, 22 and 29 tissue samples for grades I, II, and III, respectively), 21 superficial and 41 invasive TCC specimens, and 11 normal urothelial tissue samples. The intensities of securin immunostaining were graded as background, mild, and strong (scored as 0, 1, and 2, respectively), and scores from the nucleus and cytosol were analyzed separately. Results We have demonstrated, for the first time, the expression of securin in bladder tissues. Securin was overexpressed in the cytosol and nucleus of all TCC samples compared to normal urothelium, but only cytosolic localization revealed statistical significance. There were no differences in securin immunoreactivity among the different grades of TCC. Significant over-expression of cytosolic but not nuclear securin was found in both superficial and invasive TCC samples compared to normal urothelium. No difference in immunoreactive staining for nuclear and cytosolic securin between superficial and invasive TCC was noted. Conclusion Significant enhanced expression of cytosolic securin protein was found in human bladder cancer specimens, suggesting that the level of tissue securin may be a potential biomarker for the diagnosis of bladder cancer. Studies that investigate the relationship between securin expression and the outcomes of bladder cancer patients could be conducted in the future.

Plasmonics, which are based on the collective oscillation of electrons due to light excitation, involve strongly enhanced local electric fields and thus have potential applications in nonlinear optics, which requires extraordinary optical intensity. One of the most studied nonlinearities in plasmonics is nonlinear absorption, including saturation and reverse saturation behaviors. Although scattering and absorption in nanoparticles are closely correlated by the Mie theory, there has been no report of nonlinearities in plasmonic scattering until very recently. Last year, not only saturation, but also reverse saturation of scattering in an isolated plasmonic particle was demonstrated for the first time. The results showed that saturable scattering exhibits clear wavelength dependence, which seems to be directly linked to the localized surface plasmon resonance (LSPR). Combined with the intensity-dependent measurements, the results suggest the possibility of a common mechanism underlying the nonlinear behaviors of scattering and absorption. These nonlinearities of scattering from a single gold nanosphere (GNS) are widely applicable, including in super-resolution microscopy and optical switches. In this paper, it is described in detail how to measure nonlinearity of scattering in a single GNP and how to employ the super-resolution technique to enhance the optical imaging resolution based on saturable scattering. This discovery features the first super-resolution microscopy based on nonlinear scattering, which is a novel non-bleaching contrast method that can achieve a resolution as low as l/8 and will potentially be useful in biomedicine and material studies.

Objective Recombinant activated factor VII (rFVIIa) is a novel hemostatic agent originally developed to treat hemophilia patients who had developed inhibitors with bleeding. Its role in treating uncontrolled bleeding in patients without pre-existing coagulation abnormalities has not been well established. We herein report our experiences with its use in non-hemophilic patients. Patients and Methods Four patients, aged 33 to 94 years, with different underlying diseases were treated with rFVIIa for uncontrolled, life-threatening hemorrhage. rFVIIa was initially administered by intravenous bolus injection at 80–100 mg/kg. Doses were adjusted according to clinical response. Results Clinical response with significant hemostasis was evident in three patients after initial treatment. One patient was unresponsive to rFVIIa treatment and died of uncontrolled bleeding. Of those who achieved initial hemostasis, two died of their underlying diseases. One had recurrent bleeding controlled by subsequent multiple doses of rFVIIa, but she died of acute myocardial infarction, a thromboembolic complication that probably arose from the use of rFVIIa. Conclusion Our results suggest that rFVIIa could play a role in the management of bleeding other than congenital coagulation disorder. However, clinical hemostatic effects that do not translate into a survival benefit require further study, especially with regard to appropriate timing for clinical use. Its potential risk, especially that of thromboembolism when treating bleeding in elderly patients, warrants further investigation.

Organophosphate poisoning is not uncommon in Taiwan. However, no case of intermediate syndrome (IMS) has been published. We report a case of delayed-onset IMS presenting with abrupt respiratory failure following the acute cholinergic crisis of phenthoate poisoning. Based on electrophysi-ological studies from the literature, IMS results from an excess amount of acetylcholine at neuromuscular junction nicotinic acetylcholine receptors due to prolonged inhibition of acetylcholinesterase. This phenomenon leads to downregulation of the acetylcholine receptor and promotes muscle weakness. There are still no appropriate parameters to predict the development of IMS. Perhaps electrophysiological studies can be applied in the future. Ventilatory support is the most important treatment; the benefits of pra-lidoxime treatment are still controversial. IMS is still a challenging complication of organophosphate poisoning. Physicians should not overlook IMS.

Radiocontrast-induced nephropathy (RIN) is one of the leading causes of hospital-acquired acute kidney injury (AKI). The clinical strategies currently available for the prevention of RIN are insufficient. In this study, we aimed to determine whether resveratrol, a polyphenol phytoalexin, can be used to prevent RIN. For this purpose, in vitro experiments were performed using a human renal proximal tubule epithelial cell line (HK-2 cells). Following treatment for 48 h, the highly toxic radiocontrast agent, ioxitalamate, exerted cytotoxic effects on the HK-2 cells in a concentration-dependent manner, as shown by MTT assay. The half maximal inhibitory concentration (IC50) was found to be approximately 30 mg/ml. Flow cytometry also revealed a marked increase in the number of apoptotic cells following exposure to ioxitalamate. In addition, the number of necrotic, but not necroptotic cells was increased. However, treatment with resveratrol (12.5 µM) for 48 h significantly alleviated ioxitalamate (30 mg/ml)-induced cytotoxicity, by reducing cytosolic DNA fragmentation, increasing the expression of the anti-apoptotic protein, Bcl-2 (B-cell lymphoma 2), and survivin, activating caspase-3, preventing autophagic death and suppressing the production of reactive oxygen species (ROS). Resveratrol also suppressed the ioxitalamate-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage. N-acetylcysteine (NAC), a ROS scavenger commonly used to prevent RIN, also reduced ioxitalamate-induced cytotoxicity, but at a high concentration of 1 mM. Sirtuin (SIRT)1 and SIRT3 were not found to play a role in these effects. Overall, our findings suggest that resveratrol may prove to be an effective adjuvant therapy for the prevention of RIN.

We demonstrated novel non-bleaching contrast for super-resolution imaging based on saturation and on/off switching of scattering from plasmonic particles, for the first time. Our study opens up new paradigms for both plasmonics and super-resolution microscopy.

Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

Nonlinear plasmonics has attracted a lot of interests due to its wide applications. Recently, we demonstrated saturation and reverse saturation of scattering from a single plasmonic nanoparticle, which exhibits extremely narrow side lobes and central peaks in scattering images [ACS Photonics 1(1), 32 (2014)]. It is desirable to extract the reversed saturated part to further enhance optical resolution. However, such separation is not possible with conventional confocal microscope. Here we combine reverse saturable scattering and saturated excitation (SAX) microscopy. With quantitative analyses of amplitude and phase of SAX signals, unexpectedly high-order nonlinearities are revealed. Our result provides greatly reduced width in point spread function of scattering-based optical microscopy. It will find applications in not only nonlinear material analysis, but also high-resolution biomedical microscopy.

Recently, we discovered, for the first time, reverse saturable scattering in a single gold nanoparticle. When incident intensity increases, the scattering intensity dependence of 80-nm gold nanoparticles evolves from linear, to saturation, and to reverse saturation sequentially. The intensity dependence in reverse saturable scattering region is significantly steeper than that in the linear region. With the aid of a confocal microscope, the full width half maximum of the single-particle point spread function can be reduced down to 80 nm, which is beyond the diffraction limit. Our finding shows great potential for superresolution imaging application without bleaching.

The wavelength and size dependencies of nonlinear scattering by a single gold nanosphere immersed in oil are presented. We show that the wavelength dependency fits well with the scattering spectrum by Mie solution, reflecting that the nonlinear scattering is dominated by the field enhancement from plasmonic effects. The tendency for different sizes is consistent with the results of degenerate four-wave mixing in the literature, showing that the saturation behavior is governed by the Kerr nonlinearity resonantly enhanced via intraband transition. Thus we conclude that the saturable scattering in our case is attributed to intraband χ( 3) , with nonlinear behavior enhanced by LSPR.

We show that scattering from a single gold nanoparticle is saturable for the first time. Wavelength-dependent study reveals that the saturation behavior is governed by depletion of surface plasmon resonance, not the thermal effect. We observed interesting flattening of the point spread function of scattering from a single nanoparticle due to saturation. By extracting the saturated part of scattering via temporal modulation, we achieve λ/8 point spread function in far-field imaging with unambiguous separation of adjacent particles.

Recently, we reported that the localized surface plasmon resonance (LSPR) could strongly affect to the nonlinear light scattering from a single gold nanoparticle. The saturation and reverse satiation effect of light scattering were observed under the laser irradiation at the resonance [1, 2], but not under the off-resonance conditions.

Nowadays, nonlinear optics plays an unprecedented role in research not only because of its intriguing physical mechanisms but the wide range of photonic functionalities, such as frequency generation, ultrafast signal processing, microscopy, etc. [1]. However, optical nonlinearities are usually weak. One of the most promising candidates is the nonlinearity of localized surface plasmon resonance (LSPR) in noble metal nanostructure. The strongly enhanced nonlinearity is usually attributed to the strong surface field enhancement due to the nanometer scale and the interband transitions near visible light. Many examples had been discovered, such as Kerr effect [2], saturable and reverse-saturable absorption (SA and RSA) [3].

BDNF (brain-derived neurotrophic factor) and TrkB (tropomyosin receptor kinase B) are expressed in several tumor types. However, the existence of BDNF and TrkB in human bladder cancer, especially transitional cell carcinoma (TCC), has not been established. In this study, commercial TCC tissue arrays were used. Slides of paraffin-fixed human bladder tissues included all grades of TCC (13, 30 and 22 tissue samples in grade I, II and III, respectively), superficial and invasive TCC (31 and 34 tissue samples, respectively), paired malignancy-uninvolved urothelium (35 tissue samples) and normal urothelial tissues (12 tissue samples). The intensities of BDNF and TrkB immunostaining were graded as background, mild and strong (score as 0, 1 and 2, respectively). The results showed significantly overexpressed BDNF and TrkB in TCC samples compared to normal urothelium. According to grade assignment of TCC samples, BDNF in grade III and TrkB in grade I and III appeared to be overexpressed. BDNF and TrkB were overexpressed in superficial TCC samples according to staging classification. The score between the paired TCC and its uninvolved urothelium was not statistically different. In conclusion, the existence of overexpressed BDNF and TrkB in human TCC has been demonstrated in our study. A strategy involving BDNF/TrkB blockade may be a new hope for TCC target therapy.

BDNF (brain-derived neurotrophic factor) and its receptor TrkB (tropomyosin receptor kinase B) play important roles in the progression of cancer, including transitional cell carcinoma (TCC) cells reported in our previous investigation. In this study, we used a specific TrkB antibody (Ab) to evaluate its effects on survival, proliferation and migration/invasion in three TCC cell lines (BFTC905, T24 and TSGH8301) in vitro. The TrkB Ab at 1 and 3 microg/ml, but not the TrkA or TrkC Abs, significantly elicited cytotoxicity in TCC cells. The TrkB Ab at 3 microg/ml also induced apoptosis of TCC cells, which may result from up-regulation of phospho-p38 plus down-regulation of survivin and securin expression. The TrkB Ab at 0.5 microg/ml, which did not show cytotoxicity, suppressed migration of TCC cells and invasion of BFTC905 cells, possibly mediated through increased E-cadherin, decreased BDNF-stimulated phospho-PLCgamma1 and reduced MMP-9 activity. These results indicate that TrkB blockade may be a new strategy for TCC therapy.

An overproduction of proinflammatory mediators in severe acute pancreatitis contributes to the systemic inflammatory response, which may lead to multiorgan damage and even death. Thus, inflammatory cytokines, e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β, may be novel targets for the treatment of acute pancreatitis. The aim of this study was to investigate the therapeutic effects of pomalidomide (or CC-4047), a thalidomide analog and immunomodulatory agent, in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by intraperitoneal administration of cerulein (100 μg/kg/h × 8). Pomalidomide was administered (0.5 mg/kg orally) 1 h before the first or 1 h after the last cerulein administration. The severity of the acute pancreatitis was evaluated biochemically and morphologically. Pretreatment with pomalidomide significantly reduced the plasma levels of amylase and lipase; the histological injury; and the expression of TNF-α, IL-1β, monocyte chemotactic protein-1 (MCP-1), and inducible nitric oxide synthase (iNOS) in cerulein-induced acute pancreatitis. Post-treatment with pomalidomide also decreased the cerulein-induced elevation of plasma amylase and lipase and decreased the pancreatic damage. Treatment with pomalidomide ameliorated the severity of cerulein-induced acute pancreatitis in mice. Our data suggest that pomalidomide may become a new therapeutic agent in future clinical trials for the treatment of acute pancreatitis.

Pathologically, >90% of bladder cancer is transitional cell carcinoma (TCC). Previously, brain-derived neurotrophic factor (BDNF) but not tropomyosin-related kinase B (TrkB) was found in normal urothelium. TrkB activation by BDNF has been shown to promote the progression of several cancers, however, the existence and functional roles of both BDNF and TrkB in TCC have not been elucidated. In this study, three human TCC cell lines, BFTC905, TSGH8301, and T24 were used for the investigation. Both BDNF and TrkB but not TrkA or TrkC identified by RT-PCR and Western blotting were found in these cell lines. Immunostaining demonstrated the cytosolic expression of BDNF and TrkB, as well as membranous expression of TrkB in these cells. BDNF released from three cell lines was also detected in culture medium by ELISA. The proliferation of BFTC905 cells was enhanced by recombinant human BDNF (rhBDNF) in vitro, which was associated with increased phospho-TrkB and phospho-ERK levels. In contrast, TrkB-Fc chimeric protein served as BDNF scavenger eliciting cytotoxicity. Addition of rhBDNF in these cell lines cultured in poly-HEMA [Poly(2-hydroxyethyl methacrylate)] coated dishes for 48 h did not confer resistance to anoikis. Increased phospho-Akt expression was observed transiently within an hour after rhBDNF administration but disappeared 24 h later. Weekly injections of 100 ng rhBDNF into the cancer cell-loading site for 6 weeks promoted BFTC905 xenograft growth in SCID mice. Daily injection of 5 microg TrkB-Fc chimeric protein into the tumor 2 weeks after tumor cell implantation delayed tumor growth concomitant with phospho-TrkB suppression in xenografts. These results indicate that BDNF binding to TrkB receptor is a survival signal for TCC cells. Drugs that block BDNF or TrkB may provide a new and potential approach for TCC therapy.

Lactated Ringer (L/R) for resuscitation of hemorrhagic shock is suggested by the ATLS program. However, prior studies showed that resuscitation with L/R was associated with more kidney damage in rats with severe hemorrhagic shock. The direct effects of L/R on human renal tubule cells have not been reported.