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Yi-Jan Wu,1,2 Shu-Sen Chang,3 Hsien-Yi Chen,4 Kai-Fan Tsai,2,5 Wen-Chin Lee,2,5 I-Kuan Wang,6,7 Chern-Horng Lee,8 Chao-Yu Chen,1,2 Shou-Hsuan Liu,1,2 Cheng-Hao Weng,1,2 Wen-Hung Huang,1,2 Ching-Wei Hsu,1,2 Tzung-Hai Yen1,2 1Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan City, Taiwan; 3Institute of Health Behaviors and Community Sciences, Department of Public Health, College of Public Health, National Taiwan University, Taipei City, Taiwan; 4Department of Emergency Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan; 5Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung City, Taiwan; 6Department of Nephrology, China Medical University Hospital, Taichung City, Taiwan; 7College of Medicine, China Medical University, Taichung City, Taiwan; 8Division of General Internal Medicine and Geriatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, TaiwanCorrespondence: Tzung-Hai Yen, Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, 5 Fu-Hsing Street, Kweishan, Taoyuan City, Taiwan, Tel +886 3 3281200 ext 8181, Fax +886 3 3282173, Email m19570@cgmh.org.twBackground and Purpose: There is an overall paucity of data regarding the human toxicity of chlorpyrifos and cypermethrin pesticide mixture. Both organophosphate and pyrethroid insecticides are metabolized by carboxylesterases. Thus, its pesticide combination, organophosphates may boost the toxicity of pyrethroids via inhibited its detoxification by carboxylesterases. This study examined the clinical course, laboratory tests, and outcomes of patients with chlorpyrifos, cypermethrin or their pesticide mixture poisoning, and to determine what association, if any, might exist between these findings.Patients and Methods: Between 2000 and 2021, 121 patients poisoned with chlorpyrifos, cypermethrin, or their pesticide mixture were treated at Chang Gung Memorial Hospital. Patients were categorized as chlorpyrifos (n=82), cypermethrin (n=27) or chlorpyrifos and cypermethrin (n=12) groups. Demographic, clinical, laboratory and mortality data were collected for analysis.Results: The patients experienced a broad range of clinical symptoms, including aspiration pneumonia (44.6%), salivation (42.5%), acute respiratory failure (41.3%), acute kidney injury (13.9%), seizures (7.5%), hypotension (2.6%), etc. Leukocytosis (12,700± 6600 /uL) and elevated serum C-reactive protein level (36.8± 50.4 mg/L) were common. The acute respiratory failure rate was 41.3%, comprising 48.8% in chlorpyrifos, 11.1% in cypermethrin as well as 58.3% in chlorpyrifos and cypermethrin poisoning. Patients with chlorpyrifos and cypermethrin pesticide mixture poisoning suffered higher rates of acute respiratory failure (P=0.001) and salivation (P=0.001), but lower Glasgow Coma Scale score (P=0.011) and serum cholinesterase level (P< 0.001) than other groups. A total of 17 (14.0%) patients expired. The mortality rate was 14.0%, including 17.1% in chlorpyrifos, 3.7% in cypermethrin as well as 16.7% in chlorpyrifos and cypermethrin poisoning. No significant differences in mortality rate were noted (P=0.214).Conclusion: Chlorpyrifos pesticide accounted for the major toxicity of the pesticide mixture. While the data show a higher rate of respiratory failure in the chlorpyrifos and cypermethrin pesticide mixture group than others, other measures of toxicity such as mortality and length of stay were not increased.Keywords: chlorpyrifos, cypermethrin, pesticide mixture, poisoning, acute respiratory failure, mortality

Humans are extensively exposed to organophosphate flame retardants (OPFRs), an emerging group of organic contaminants with potential nephrotoxicity. Nevertheless, the estimated daily intake (EDI) and prognostic impacts of OPFRs have not been assessed in individuals with chronic kidney disease (CKD). In this 2-year longitudinal study of 169 patients with CKD, we calculated the EDIs of five OPFR triesters from urinary biomonitoring data of their degradation products and analyzed the effects of OPFR exposure on adverse renal outcomes and renal function deterioration. Our analysis demonstrated universal OPFR exposure in the CKD population, with a median EDI ΣOPFR of 360.45 ng/kg body weight/day (interquartile range, 198.35-775.94). Additionally, our study revealed that high tris(2-chloroethyl) phosphate (TCEP) exposure independently correlated with composite adverse events and composite renal events (hazard ratio [95 % confidence interval; CI]: 4.616 [1.060-20.096], p = 0.042; 3.053 [1.075-8.674], p = 0.036) and served as an independent predictor for renal function deterioration throughout the study period, with a decline in estimated glomerular filtration rate of 4.127 mL/min/1.73 m 2 (95 % CI, -8.127--0.126; p = 0.043) per log ng/kg body weight/day of EDI TCEP . Furthermore, the EDI TCEP and EDI ΣOPFR were positively associated with elevations in urinary 8-hydroxy-2'-deoxyguanosine and kidney injury molecule-1 during the study period, indicating the roles of oxidative damage and renal tubular injury in the nephrotoxicity of OPFR exposure. To conclude, our findings highlight the widespread OPFR exposure and its possible nephrotoxicity in the CKD population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Organophosphate flame retardants (OPFRs) are emerging environmental pollutants that can be detected in water, dust, and biological organisms. Certain OPFRs can disrupt lipid metabolism in animal models and cell lines. However, the effects of OPFRs on human lipid metabolism remain unclear. We included 1,580 participants (≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the relationship between OPFR exposure and lipid metabolism biomarkers. After adjusting for confounding factors, results showed that one-unit increases in the log levels of diphenyl phosphate (DPhP) (regression coefficient = -5.755; S.E. = 2.289; p  = 0.023) and log bis-(1-chloro-2-propyl) phosphate (BCPP) (regression coefficient = -4.637; S.E. = 2.019; p  = 0.036) were negatively associated with the levels of total cholesterol (TC) in all participants. One-unit increases in the levels of DPhP (regression coefficient = -2.292; S.E. = 0.802; p  = 0.012), log bis (1,3-dichloro-2-propyl) phosphate (BDCPP) (regression coefficient = -2.046; S.E. = 0.825; p  = 0.026), and log bis-2-chloroethyl phosphate (BCEP) (regression coefficient = -2.604; S.E. = 0.704; p  = 0.002) were negatively associated with the levels of high-density lipoprotein cholesterol (HDL-C). With increasing quartiles of urine BDCPP levels, the mean TC levels significantly decreased in all participants ( p value for trend = 0.028), and quartile increases in the levels of DPhP ( p value for trend = 0.01), BDCPP ( p value for trend = 0.001), and BCEP ( p value for trend<0.001) were negatively corelated with HDL-C, with approximately 5.9, 9.9, and 12.5% differences between the upper and lower quartiles. In conclusion, DPhP, BDCPP, and BCEP were negatively related to HDL-C concentration, whereas DPhP and BCPP levels were negatively associated with TC level. Thus, exposure to OPFRs may interfere with lipid metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cheng, Tsai, Huang, Kung, Huang, You, Li, Wang, Lee and Pan.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Objective: Activity or expression of sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase (SERCA) is diminished in some disease states such as cardiac failure and diabetes mellitus. A newly developed activator of SERCA, CDN1163, reportedly rescued or alleviated pathological conditions attributed to dysfunctional SERCA. We examined whether CDN1163 could relieve mouse neuronal N2A cell growth inhibition caused by cyclopiazonic acid (CPA, SERCA inhibitor). We also examined how CDN1163 affected cytosolic Ca 2+ , mitochondrial Ca 2+ and mitochondrial membrane potential., Methods: Cell viability was measured by MTT assay and trypan blue exclusion test. Cytosolic Ca 2+ , mitochondrial Ca 2+ and mitochondrial membrane potential were measured using fura 2, Rhod-2 and JC-1, respectively, as fluorescent probes., Results: CDN1163 (10 μM) itself suppressed cell proliferation, and did not alleviate CPA's inhibitory effect (and vice versa). Cell cycle was arrested at the G1 phase after CDN1163 treatment. CDN1163 treatment caused a slow yet persistent cytosolic [Ca 2+ ] elevation partly due to Ca 2+ release from an internal store other than the CPA-sensitive endoplasmic reticulum (ER). Treatment with CDN1163 for 3 h raised mitochondrial Ca 2+ level and such increase was suppressed by MCU-i4 (an inhibitor of mitochondria Ca 2+ uniporter, MCU), suggesting Ca 2+ entered the mitochondrial matrix through MCU. Treatment of cells with CDN1163 up to 2 days resulted in mitochondrial hyperpolarization., Conclusion: CDN1163 caused internal Ca 2+ leak, cytosolic Ca 2+ overload, mitochondrial Ca 2+ elevation and hyperpolarization, cell cycle arrest and cell growth inhibition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Organophosphate flame retardants (OPFRs) are ubiquitous in the environment. The compositions and concentrations of different OPFRs metabolites vary in different environments depending on different human activities. The objective of the present study was to evaluate the exposure of different age groups to OPFRs in Taiwan., Methods: Volunteers provided urine samples and responded to questionnaires including demographic factors, underlying disease, lifestyle information, and occupation from October 2021 to January 2022. OPFR measurements were performed using a Waters Acquity Ultra-Performance Liquid Chromatography system coupled with a Waters Xevo TQ-XS mass spectrometer., Results: A total of 391 volunteers (74 children and 317 adults) were enrolled in this study. The concentrations (presented as μg/g creatinine) of bis(1,3-dichloro-2-propyl) phosphate (BDCPP, p  = 0.029) and tri-n-butyl phosphate (TNBP, p  = 0.008) were higher in the adult group, while the concentrations of bis-2-chloroethyl phosphate (BCEP, p  = 0.024), diphenyl phosphate (DPHP, p  < 0.001), tris(1,3-dichloro-2-propyl) phosphate (TDCPP, p  = 0.009), and Tris(2-butoxyethyl) phosphate (TBEP, p  = 0.007) were higher in the child group. Compared with school age children (>6 years), the concentration of di(2-n-butoxyethyl) phthalate (DBEP, 1.14 vs. 0.20 μg/g creatinine, p  = 0.001), DPHP (1.23 vs. 0.54 μg/g creatinine, p  = 0.036), TBEP (1.63 vs. 0.29 μg/g creatinine, p  < 0.001), and the sum of OPFR metabolites (ΣOPFRs, 6.58 vs. 2.04 μg/g creatinine, p  < 0.001) were statistically higher in preschool-aged children. After adjusting for confounding factors, pre-school age [odds ratio (OR): 4.579, 95% confidence interval (CI): 1.389-13.115] and current smoker (OR: 5.328, 95%CI: 1.858-14.955) were independently associated with the risk of ΣOPFRs higher than 90 percentile., Conclusion: This study revealed the distribution of different OPFRs metabolites in children and adults. DBEP, DPHP, TBEP, and ΣOPFR were higher in preschool-aged children. Pre-school age and current smoking status were independent risk factors for ΣOPFRs higher than 90 percentile., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cheng, Wang, Pan, Chen, Huang, Li, Wang, Wang, Lee, Tsai, Ou and Kung.)

Background: Molnupiravir is an essential oral antiviral agent against coronavirus disease 2019 (COVID-19); however, its real-world effectiveness has not been evaluated in patients undergoing haemodialysis (HD)., Methods: This multi-centre retrospective study, involving 225 patients undergoing HD with initially mild or asymptomatic COVID-19, was conducted to compare the risks of 30-day COVID-19-related acute care visits between patients receiving and not receiving molnupiravir. Patients who received molnupiravir were stratified by rapid antigen detection (RAD) test results on day 7 after disease onset to assess whether rapid molnupiravir introduction accelerated viral clearance., Results: Thirty-day COVID-19-related acute care visits were reported in 9.41% and 21.74% of the molnupiravir and control groups, respectively, and use of molnupiravir markedly reduced the risk of acute care visits after adjusting for baseline characteristics via propensity score weighting [hazard ratio 0.218, 95% confidence interval (CI) 0.074-0.642; P=0.006]. The tolerability of molnupiravir in the enrolled patients was generally acceptable, with only 11.88% of molnupiravir users reporting mild adverse events. Moreover, rapid initiation of molnupiravir within 1 day of COVID-19 onset was an independent predictor of conversion to a negative RAD test result on day 7 after disease onset (odds ratio 6.207, 95% CI 2.509-15.358; P<0.001)., Conclusions: Molnupiravir is well tolerated and decreases the medical needs in patients with COVID-19 undergoing HD. Furthermore, the rapid initiation of molnupiravir accelerates viral clearance in patients with COVID-19 undergoing HD. These findings highlight the therapeutic role of molnupiravir for this vulnerable population., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Organophosphate flame retardants (OPFRs) are widely distributed in the environment and their metabolites are observed in urine, but little is known regarding OPFRs in a broad-spectrum young population from newborns to those aged 18 years., Objectives: Investigate urinary levels of OPFRs and OPFR metabolites in Taiwanese infants, young children, schoolchildren, and adolescents within the general population., Methods: Different age groups of subjects (n=136) were recruited from southern Taiwan to detect 10 OPFR metabolites in urine samples. Associations between urinary OPFRs and their corresponding metabolites and potential health status were also examined., Results: The mean level of urinary Σ 10 OPFR in this broad-spectrum young population is 2.25 μg/L (standard deviation (SD) of 1.91 μg/L). Σ 10 OPFR metabolites in urine are 3.25 ± 2.84, 3.06 ± 2.21, 1.75 ± 1.10, and 2.32 ± 2.29 μg/L in the age groups comprising of newborns, 1-5 year-olds, 6-10 year-olds, and 11-18 year-olds, respectively, and borderline significant differences were found in the different age groups ( p =0.125). The OPFR metabolites of TCEP, BCEP, DPHP, TBEP, DBEP, and BDCPP predominate in urine and comprise more than 90% of the total. TBEP was highly correlated with DBEP in this population (r=0.845, p <0.001). The estimated daily intake (EDI) of Σ 5 OPFRs (TDCPP, TCEP, TBEP, TNBP, and TPHP) was 2,230, 461, 130, and 184 ng/kg bw/day for newborns, 1-5 yr children, 6-10 yr children, and 11-17 yr adolescents, respectively. The EDI of Σ 5 OPFRs for newborns was 4.83-17.2 times higher than the other age groups. Urinary OPFR metabolites are significantly correlated with birth length and chest circumference in newborns., Conclusion: To our knowledge, this is the first investigation of urinary OPFR metabolite levels in a broad-spectrum young population. There tended to be higher exposure rates in both newborns and pre-schoolers, though little is known about their exposure levels or factors leading to exposure in the young population. Further studies should clarify the exposure levels and factor relationships., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Chen, Tsai, Lu, You, Chen, Huang, Tsai, Cheng, Kung, Li, Wang, Ou, Lee, Chang, Hashim, Chao and Wang.)

There is limited literature analyzing the outcome of human poisoning with methomyl and cypermethrin pesticide mixture. Between 2002 and 2018, a total of 63 patients intoxicated with methomyl, cypermethrin, or their pesticide mixture were treated at Chang Gung Memorial Hospital. The patients were categorized into three groups based on the type of pesticide, as methomyl (n = 10), cypermethrin (n = 31), or methomyl and cypermethrin (n = 22). Demographic, clinical, laboratory, and mortality data were obtained for analysis. The patients were aged 54.9 ± 18.9 years. Following ingestion, the patients experienced a wide range of clinical symptoms, including aspiration pneumonia (50.8%), acute respiratory failure (41.3%), acute kidney injury (33.3%), multiple organ failure (19.0%), emesis (19.0%), acute hepatitis (12.7%), diarrhea (7.9%), seizures (4.8%), lacrimation (4.8%), etc. After analysis, it was found that patients with methomyl and cypermethrin poisoning suffered higher incidences of acute respiratory failure ( p < 0.001), aspiration pneumonia ( p = 0.004), acute kidney injury ( p = 0.011), and multiple organ failure ( p < 0.001) than the other groups. Laboratory analyses revealed that patients with methomyl and cypermethrin poisoning had a higher creatinine level ( p = 0.011), white blood cell count ( p < 0.001), and neutrophil count ( p = 0.019) than the other groups. A total of seven (11.1%) patients died. The average duration of hospitalization was 9.8 ± 10.0 days. In a multivariate logistic regression model, it was revealed that methomyl pesticide ( p = 0.045) or methomyl and cypermethrin pesticide mixture ( p = 0.013) were significant risk factors for acute respiratory failure. Nevertheless, no mortality risk factor could be identified. Therefore, the analytical results suggest that methomyl pesticide is the major contributor to the toxicity of methomyl and cypermethrin pesticide mixture poisoning. More research is needed.

Patients undergoing cardiac catheterization are at high risk of post-procedure acute kidney injury (AKI) and may experience persistent renal damage after an initial insult, a state known as acute kidney disease (AKD). However, the association between AKD and urinary renal biomarkers has not yet been evaluated in this population. We enrolled 94 patients who underwent elective cardiac catheterization to investigate patterns of urinary renal biomarkers and their associations with post-procedure AKD. Serial urinary renal biomarker levels were measured during pre-procedure, early post-procedure (12-24 h), and late post-procedure (7-10 days) periods. In our investigation, 42.55% of the enrolled patients developed AKD during the late post-procedure period. While the liver-type free-fatty-acid-binding protein level increased sharply during the early post-procedure period, it returned to baseline during the late post-procedure period. In contrast, interleukin-18 (IL-18) levels increased steadily during the post-procedure period. Early post-procedure ratios of IL-18 and gelsolin (GSN) were independently associated with subsequent AKD (odds ratio (95% confidence interval), 4.742 (1.523-14.759) for IL-18 ratio, p = 0.007; 1.812 (1.027-3.198) for GSN ratio, p = 0.040). In conclusion, post-procedure AKD is common and associated with early changes in urinary IL-18 and GSN in patients undergoing cardiac catheterization.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine booster is one of the most essential strategies against coronavirus disease 2019 (COVID-19) in the era of emerging variants. However, the effectiveness of SARS-CoV-2 vaccine boosters has not much been investigated in hemodialysis (HD) patients receiving oral antiviral agents. In this retrospective study involving 258 HD patients with COVID-19 receiving molnupiravir, we stratified the study cohort according to vaccination status and compared the baseline characteristics and risks of 30-day composite events (COVID-19-related acute care visits, hospitalization, or mortality) among groups. Our analysis demonstrated that the SARS-CoV-2 vaccine boosters markedly decreased the risk of composite events in HD patients (hazard ratio (95% confidence interval), 0.163 (0.063-0.423) for three vs. ≤ two doses of vaccination, p < 0.001; 0.309 (0.115-0.830) for four vs. ≤ two doses of vaccination, p = 0.020). The benefits of vaccine boosters were similar between patients receiving mRNA-based and protein-based boosters and between those with post-booster intervals of ≤ 120 and > 120 days. In conclusion, for HD patients with initially mild or asymptomatic COVID-19 receiving molnupiravir, the benefits of SARS-CoV-2 vaccine boosters are prominent, irrespective of booster vaccine types.

Organophosphate flame retardants (OPFRs) are emerging and widespread environmental pollutants with potential health hazards, including nephrotoxicity. However, the exposure patterns and nephrotoxic potential of OPFRs are yet to be investigated in patients with chronic kidney disease (CKD). We conducted a cross-sectional study involving 166 patients with CKD stratified by estimated glomerular filtration rate (eGFR) and severity of proteinuria. The urinary concentrations of 10 OPFR compounds were measured to evaluate the exposure patterns. Clinical and urinary OPFR profiles were compared among subgroups to identify whether the OPFR compounds were independently correlated with eGFR and proteinuria. Additionally, lifestyle factors were compared among subgroups stratified by median concentrations of urinary OPFR compounds associated with renal disease severity. This study revealed universal exposure to OPFRs in the CKD population, with an overall urinary detection rate of 98.80 %. Furthermore, after adjusting for covariates, the urinary concentration of bis(2-chloroethyl) phosphate (BCEP) was identified as an independent predictor of lower eGFR (low vs high eGFR, odds ratio (OR) (95 % confidence interval (CI)), 1.761 (1.032-3.005) per log μg/g creatinine, p = 0.038), and the urinary concentration of bis(2-butoxyethyl) phosphate (BBOEP) was independently correlated with overt proteinuria in CKD patients (with vs without overt proteinuria, OR (95 % CI), 1.813 (1.065-3.086) per log μg/g creatinine, p = 0.028). Moreover, frequent seafood consumption was negatively correlated with urinary BCEP concentration (high vs low BCEP, OR (95 % CI), 0.455 (0.228-0.908), p = 0.025), and age was inversely associated with urinary BBOEP concentration (high vs low BBOEP, OR (95 % CI), 0.968 (0.937-0.999) per year, p = 0.048). In conclusion, our investigation highlights the extensive exposure to OPFRs and the independent association between renal disease severity and urinary BCEP/BBOEP concentrations in the CKD population, indicating the nephrotoxic potential of these pollutants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Video 1Endoscopic full thickness resection with retroperitoneal dissection for duodenal myogenic cyst with adjustable traction from an independently controlled snare., (© 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Competing Interests: The authors declare that they have no conflict of interest.

Hemodialysis (HD) patients are vulnerable to coronavirus disease 2019 (COVID-19) and have a high mortality rate. We evaluated the anti-SARS-CoV-2 spike protein antibody (ACOV2S) levels in 385 HD patients before and 4 and 8 weeks after the second dose of vector-based ChAdOx1 nCoV-19 vaccine. For study control, week 4 ACOV2S levels after the second vaccination dose were measured in 66 healthcare workers (HCWs). The seroconversion rate of HD patients was 98.96% 4 weeks after the second vaccination. Despite low antibody levels before the second dose (week 0), week 4 ACOV2S levels after the second vaccine dose in HD patients increased prominently and were compatible with those in HCWs (p = 0.814 for HCWs vs. HD patients). The ACOV2S levels in HD patients waned significantly 8 weeks after the second vaccination dose (p < 0.001 at week 8 vs. 4). Older age and immunosuppressant use were negative predictors, while higher C-reactive protein (CRP) levels were positive predictors of ACOV2S waxing after the second vaccine dose in HD patients. Higher CRP levels and platelet counts were independently associated with decreased ACOV2S waning. The ChAdOx1 nCoV-19 vaccine is effective and safe for primary vaccination in HD patients and a booster dose is necessary.

Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming growth factor β receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer tissues, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn causes differentiation of cell aggregates, conferring a low-adhesion phenotype, and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Hemodialysis is often recommended to treat severe lithium poisoning. Nevertheless, the application rate of hemodialysis in patients with lithium poisoning is varied across different groups and the effect of hemodialysis is still undetermined. Therefore, this study aimed to analyze the hemodialysis rate of patients with lithium poisoning and to explore the clinical features of lithium-poisoned-patients treated or untreated with hemodialysis., Methods: Between 2001 and 2019, 36 patients treated at the Chang Gung Memorial Hospital for the management of lithium poisoning were stratified according to whether they were treated with hemodialysis ( n = 7) or not ( n = 29)., Results: The patients were aged 50.7 ± 18.1 years. The poisoning patterns were acute on chronic (61.1%), chronic (25.0%) and acute (13.9%). The precipitating factors of dehydration and infection were noted in 36.1% and 25.0% of patients, respectively. Bipolar disorder (72.2%), depressive disorder (27.8%) and psychotic disorder (11.1%) were the top three psychiatric comorbidities. The hemodialysis group not only had a lower Glasgow Coma Scale (GCS) score ( p = 0.001) but also had a higher respiratory failure rate ( p = 0.033), aspiration pneumonia rate ( p = 0.033) and acute kidney injury network (AKIN) score ( p = 0.002) than the non-hemodialysis group. Although none of the patients died of lithium poisoning, the hemodialysis group required more endotracheal intubation ( p = 0.033), more intensive care unit admission ( p = 0.033) and longer hospitalization ( p = 0.007) than the non-hemodialysis group., Conclusion: The analytical results revealed zero mortality rate and low hemodialysis rate (1.9%). Compared with patients without hemodialysis, patients receiving hemodialysis suffered severer lithium-associated complications and needed a more intensive care unit admission and longer hospital stay.

Background: Colorectal endoscopic submucosal dissection is technically demanding, and the traction offered by gravity, cap, or clip-with-line during conventional endoscopic submucosal dissection remains unsatisfactory. Robotic systems are still under development and are expensive. We proposed double-scope endoscopic submucosal dissection with strong and adjustable traction offered by snaring the lesion with additional scope., Objective: This study aimed to test the novel double-scope endoscopic submucosal dissection with snare-based traction., Design: This was a retrospective study that reviewed double-scope endoscopic submucosal dissection compared with matched conventional endoscopic submucosal dissection, and size, location, morphology, and pathology between groups were compared., Settings: This study was conducted in a referral endoscopy center in a local hospital., Patients: This study included patients with colorectal lesions receiving double-scope endoscopic submucosal dissection and matched conventional endoscopic submucosal dissection., Main Outcome Measures: The pathological completeness, procedure time, and complications were analyzed., Results: Fifteen double-scope endoscopic submucosal dissection procedures, with 11 lesions located in the proximal colon with a median size of 40 mm, were performed. The median procedure time of double-scope endoscopic submucosal dissection was 32.45 (interquartile range, 16.03-38.20) minutes. The time required for second scope insertion was 2.57 (interquartile range, 0.95-6.75) minutes; for snaring, 3.03 (interquartile range, 2.12-6.62) minutes; and for actual endoscopic submucosal dissection, 28.23 (interquartile range, 7.90-37.00) minutes. All lesions were resected completely. No major complication was encountered. The procedure time was significantly shorter than that of 14 matched conventional endoscopic submucosal dissections (54.61 [interquartile range, 33.11-97.25] min; p = 0.021)., Limitations: This was a single-center, single-operator, retrospective case-controlled study with limited cases., Conclusions: This study confirmed the feasibility of double-scope endoscopic submucosal dissection with snare-based traction to shorten procedure time and to simplify endoscopic submucosal dissection. Additional trials are required., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.)

Acute kidney disease (AKD) forms part of the continuum of acute kidney injury (AKI) and worsens clinical outcomes. Currently, the predictors of AKD severity have yet to be established. We conducted a retrospective investigation involving 310 hospitalized patients with AKI and stratified them based on the AKD stages defined by the Acute Dialysis Quality Initiative criteria. Demographic, clinical, hematologic, and biochemical profiles, as well as 30-day outcomes, were compared between subgroups. In the analysis, the use of offending drugs (odds ratio, OR (95% confidence interval, CI), AKD stage 3 vs. non-AKD, 3.132 (1.304−7.526), p = 0.011, AKD stage 2 vs. non-AKD, 2.314 (1.049−5.107), p = 0.038), high AKI severity (OR (95% CI), AKD stage 3 vs. non-AKD, 6.214 (2.658−14.526), p < 0.001), and early dialysis requirement (OR (95% CI), AKD stage 3 vs. non-AKD, 3.366 (1.008−11.242), p = 0.049) were identified as independent predictors of AKD severity. Moreover, a higher AKD severity was associated with higher 30-day mortality and lower dialysis-independent survival rates. In conclusion, our study demonstrated that offending drug use, AKI severity, and early dialysis requirement were independent predictors of AKD severity, and high AKD severity had negative impact on post-AKI outcomes.

Background and Objectives : Direct-acting antiviral agents (DAA) are a safe and highly effective treatment for hepatitis C virus (HCV) infection. However, the uptake of DAA treatment remains a challenge. This study aims to examine the reasons for DAA refusal among HCV patients covered by the Taiwan National Health Insurance system. Materials and Methods : This retrospective observational study covered the period from January 2009 to December 2019 and was conducted at a single hepatitis treatment center in Taiwan. This study involved chart reviews and phone-based surveys to confirm treatment status and refusal causes. To confirm treatment status, subjects with HCV without treatment records were phone-contacted to confirm treatment status. Patients who did not receive treatment were invited back for treatment. If the patient refused, the reason for refusal was discussed. Results : A total of 3566 patients were confirmed with DAA treatment; 418 patients (179 patients who were lost to contact or refused the survey and 239 patients who completed the survey of DAA refusal) were included in the no-DAA-therapy group. Factors associated with receiving DAAs were hemoglobin levels, hepatitis B virus co-infection, and regular gastroenterology visits. Meanwhile, male sex, platelet levels, and primary care physician visits were associated with DAA refusal. The leading causes of treatment refusal were multiple comorbidities, low health literacy, restricted access to hospitals, nursing home residence, and old age. The rate of DAA refusal remains high (10%). Conclusions : The reasons for treatment refusal are multifactorial, and addressing them requires complex interventions.

Background. This retrospective observational study attempted to examine the prevalence of abnormal blood aluminum levels in dialysis patients, and to explore the association of pathogenic factors, such as demographic, clinical, laboratory as well as the use of phosphate binding drugs, drugs for secondary hyperparathyroidism and erythropoiesis-stimulating drugs with the blood aluminum levels. Methods. The study included 1175 patients (874 hemodialysis and 301 peritoneal dialysis), recruited from Chang Gung Memorial Hospital in November 2020. Patients were stratified into two groups by their blood aluminum levels, as normal (<2 µg/dL, n = 1150) or abnormal (≥2 µg/dL, n = 25). Results. The patients aged 60.4 ± 13.2 years and were dialyzed for 8.6 ± 8.1 years. The average blood aluminum level was 1.0 ± 0.4 µg/dL. Patients with abnormal blood aluminum levels received more sevelamer than patients with normal blood aluminum level (p = 0.014). Patients with abnormal blood aluminum levels had higher platelet count (p = 0.001), triglyceride (p < 0.001) and total iron binding capacity (p = 0.003) than patients with normal blood aluminum levels. Moreover, the cardiothoracic ratio was higher in patients with abnormal blood aluminum levels than patients with normal blood aluminum levels (p = 0.003). Conclusions. The prevalence of abnormal blood aluminum levels was low at 2.2%. Nevertheless, the linking of cardiothoracic ratio of more than 0.5 as well as elevated blood platelet count and triglyceride level with blood aluminum levels are interesting, and warranted more researches in this area.

Background and Objectives: Hepatitis C virus (HCV) is a major cause of liver disease worldwide. People who inject drugs (PWIDs) constitute the majority of patients with HCV infection in the United States and Central Asia. There are several obstacles to treating HCV infection in PWIDs because PWIDs are often accompanied by concurrent infection, low compliance, substance abuse, and risky behavior. The aim of the study is to compare the efficacies of direct-acting antiviral (DAA) therapy for HCV infection in PWIDs and those without opioid injection. Materials and Methods: In this retrospective cohort study, we included 53 PWIDs with HCV infections treated on site in a methadone program and 106 age- and sex-matched patients with HCV infections who had no history of opioid injection (ratio of 1:2). All eligible subjects received anti-HCV treatment by DAA agents in our hospital from March 2018 to December 2020. The charts of these patients were carefully reviewed for demographic data, types of DAA agents, and treatment outcomes. The primary outcome measure was sustained virological response (SVR). Results: PWIDs and non-drug users had different HCV genotype profiles (p = 0.013). The former had higher proportions of genotype 3 (18.9% vs. 7.5%) and genotype 6 (24.5% vs. 14.2%) than the latter. The two patient groups had comparable rates of complete drug refilling (100.0% vs. 91.1%) and frequency of loss to follow-up (3.8% vs. 0.9%). However, PWIDs had a lower SVR rate of DAA treatment than non-drug users (92.2% vs. 99.0%; p = 0.04). Further analysis showed that both human immunodeficiency virus (HIV) coinfection and history of PWID were risk factors associated with treatment failure. The subjects with coinfection with HIV had lower SVR rates than those without HIV infection (50.0% vs. 96.5%; p = 0.021). Conclusions: PWIDs with HCV infections have higher proportions of HCV genotype 3 and genotype 6 than non-drug users with infections. DAA therapy can achieve a high cure rate (>90%) for HCV infection in PWID, but its efficacy in PWID is lower than that in non-drug users.

Cadmium exposure is associated with chronic kidney disease (CKD), but the optimal biomarker for early cadmium-associated nephrotoxicity in low-level exposure has not yet been established. We conducted a cross-sectional investigation involving 167 CKD patients stratified according to tertiles of urinary cadmium levels (UCd), in which enzyme-linked immunosorbent assay (ELISA)-measured novel renal biomarkers were utilized to assess the extent of renal injury associated with cadmium burden. In the analyses, urinary kidney injury molecule-1 (KIM-1) levels and age were the independent factors positively correlated with UCd after adjusting for covariates in non-dialysis-dependent CKD patients (high vs. low UCd, odds ratio (95% confidence interval), 1.0016 (1.0001-1.0032), p = 0.043, and 1.0534 (1.0091-1.0997), p = 0.018). Other conventional and novel renal biomarkers, such as serum creatinine, estimated glomerular filtration rate, CKD staging, urinary protein/creatinine ratio, urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), and urinary epidermal growth factor (EGF) were not independently correlated with UCd in the analyses. In conclusion, our study found that the ELISA-measured urinary KIM-1 level could serve as an early renal injury marker in low-level cadmium exposure for non-dialysis-dependent CKD patients. In addition, age was an independent factor positively associated with UCd in this population.

Colorectal cancer (CRC) is one of the most common cancers worldwide and its incidence is increasing; therefore, an understanding of its oncogenic mechanisms is critical for improving its treatment and management. Methylglyoxal (MGO) has a highly reactive aldehyde group and has been suggested to play a role in oncogenesis. However, no standardized data are currently available on MGO levels in colorectal precancerous and cancerous lesions. We collected 40 matched colorectal tumor and peritumor tissues from patients with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive cancer (IC). MGO levels increased between LGD, HGD, and IC tumor tissues (215.25 ± 39.69, 267.45 ± 100.61, and 587.36 ± 123.19 μg/g protein, respectively; p = 0.014). The MGO levels in peritumor tissue increased and were significantly higher than MGO levels in tumor tissue (197.99 ± 49.40, 738.09 ± 247.87, 933.41 ± 164.83 μg/g protein, respectively; p = 0.002). Tumor tissue MGO levels did not correlate with age, sex, underlying disease, or smoking status. These results suggest that MGO levels fluctuate in progression of CRC and warrants further research into its underlying mechanisms and function in tumor biology.

Low-level cadmium exposure has adverse effects on chronic kidney disease (CKD); however, the risk factors for elevated blood cadmium levels (BCLs) have not been studied in CKD. We conducted a cross-sectional investigation in 200 CKD patients and stratified them by the tertiles of BCL to compare their demographic, environmental, and biochemical data. The factors associated with BCL were identified, and their effects were examined in subgroups. In the analyses, female sex, smoking, and CKD stage 5D were associated with high BCL, and statin was inversely correlated with BCL (odds ratio [95% confidence interval, CI], 6.858 [2.381-19.746], p < 0.001, 11.719 [2.843-48.296], p = 0.001, 30.333 [2.252-408.520], p = 0.010, and 0.326 [0.122-0.873], p = 0.026; deviations of BCL [nmol/L, 95% CI], 2.66 [1.33-4.00], p < 0.001, 3.68 [1.81-5.56], p < 0.001, 3.38 [0.95-5.82], p = 0.007, and -2.07 [-3.35--0.78], p = 0.002). These factors were also independently correlated with BCL in subgroups, including non-dialysis CKD, hypertensive patients, non-smokers, and male patients. In conclusion, female sex, smoking, and CKD stage 5D were the major risk factors for elevated BCL; additionally, statins were negatively associated with BCL in CKD.

Palmitic acid (PA) is a saturated free fatty acid which, when being excessive, accounts for lipotoxicity. Using human lung A549 cells as a model for lung alveolar type 2 epithelial cells, we found that challenge of A549 cells with PA resulted in apoptotic cell death, as reflected by positive annexin V and PI staining, and also appearance of cleaved caspase-3. PA treatment also caused depletion of intracellular Ca 2+ store, endoplasmic reticulum (ER) stress, and oxidative stress. Tannic acid (TA), a polyphenol present in wines and many beverages, alleviated PA-induced ER stress, oxidative stress and apoptotic death. Thus, our results suggest PA lipotoxicity in lung alveolar type 2 epithelial cells could be protected by TA., Competing Interests: None

Cytokine-mediated inflammation is involved in the pathophysiology of paraquat toxicity. Nevertheless, few human studies have examined fluctuations in circulating cytokine levels. Blood samples were obtained from 21 patients with paraquat poisoning and compared to those of 18 healthy controls. All paraquat patients received a standard detoxification protocol composed of hemoperfusion, pulse therapies of methylprednisolone and cyclophosphamide, followed by dexamethasone therapy. Nonsurvivors not only had higher scores for the severity index of paraquat poisoning (P=0.004) but also presented with higher white blood cell counts (P=0.046) than survivors. Multiplex immunoassays revealed higher circulating levels of interleukin 2 (IL-2), interleukin 9 (IL-9), interleukin 10 (IL-10) and macrophage inflammatory protein-1 beta (MIP-1β) in survivors than in healthy controls. Furthermore, the circulating levels of interleukin 1 beta (IL-1β), IL-2, interleukin 5 (IL-5), interleukin 8 (IL-8), IL-9, IL-10, interleukin 12 (IL-12 p70), interleukin 17A (IL-17A), eotaxin, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein 10 (IP-10) and MIP-1β were higher in nonsurvivors than in healthy controls. Finally, the circulating levels of IL-1β and MCP-1 were higher in nonsurvivors than in survivors. Therefore, the observation of cytokine-mediated inflammation is in line with the detoxification protocol because glucocorticoids and cyclophosphamide are potent anti-inflammatory agents. Additionally, circulating levels of IL-1β and MCP-1 could serve as promising prognostic markers for patients with paraquat poisoning., Competing Interests: None., (AJTR Copyright © 2021.)

Background and Objectives : To evaluate the effectiveness of hepatic arterial infusion chemotherapy (HAIC) followed by lipiodol infusion in advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Materials and Methods : Thirty-two patients with advanced HCC and PVTT who received HAIC with regimens of cisplatin, mitomycin-C, and 5-fluorouracil followed by lipiodol infusion were enrolled. The primary efficacy endpoint was tumor response rate. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used for assessment of treatment response. The secondary endpoints were overall survival (OS) and progression free survival (PFS). Prognostic factors for survival also were evaluated. Results : The median OS and PFS were 11.9 and 9.5 months, respectively. Seventeen patients (53.1%) achieved objective response, and 23 patients (71.9%) achieved disease control. The length of survival in the responder and disease control groups was longer than in the non-responder and progressive disease groups after two cycles of HAIC (responder vs. non-responder: 16.5 vs. 7.9 months, p = 0.001; disease control vs. progressive disease: 12.3 vs. 5.6 months, p < 0.001) and after completing HAIC (responder vs. non-responder: 15.7 vs. 6.9 months, p = 0.001; disease control vs. progressive disease: 13.6 vs. 6.9 months, p < 0.001). Better survival was associated with Child-Pugh A liver function ( p = 0.013), with early response to two HAIC cycles ( p = 0.009), and with response ( p = 0.02) and disease control ( p = 0.001) after completing HAIC treatment. Conclusion: HAIC followed by lipiodol infusion is a safe and feasible treatment for advanced HCC with PVTT. Patients with early response could continue HAIC treatment with expected prolonged survival.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral glucose-lowering agents. Apart from their glucose-lowering effects, large clinical trials assessing certain SGLT2 inhibitors have revealed cardiac and renal protective effects in non-diabetic patients. These excellent outcomes motivated scientists and clinical professionals to revisit their underlying mechanisms. In addition to the heart and kidney, redox homeostasis is crucial in several human diseases, including liver diseases, neural disorders, and cancers, with accumulating preclinical studies demonstrating the therapeutic benefits of SGLT2 inhibitors. In the present review, we aimed to update recent advances in the antioxidant roles of SGLT2 inhibitors in common but debilitating human diseases. We anticipate that this review will guide new research directions and novel therapeutic strategies for diabetes, cardiovascular diseases, nephropathies, liver diseases, neural disorders, and cancers in the era of SGLT2 inhibitors.

Background: Low-dose aspirin is widely used in the prevention of cardiovascular diseases. However, the use of aspirin is associated with an increased risk of gastrointestinal injury., Methods: Low-dose aspirin users with a history of peptic ulcers who did not have gastroduodenal mucosal breaks at initial endoscopy were randomly assigned to receive famotidine (20 mg bid) or omeprazole (20 mg qd) for 6 months. Follow-up endoscopy was performed at the end of the sixth month and whenever epigastric discomfort, hematemesis, or melena occurred. The primary end point was the occurrence of gastroduodenal mucosal breaks. The secondary end points were (1) the occurrence of gastroduodenal ulcers and (2) the occurrence of gastroduodenal bleeding., Result: Between November 2013 and June 2018, 170 patients were randomly assigned to receive either famotidine (n = 84) or omeprazole (n = 86). The incidence of gastroduodenal mucosal breaks was 33.8% among the patients receiving famotidine, and 19.8% among those receiving omeprazole (95% CI: 0.4%-27.5%; p = 0.045). The two patient groups had comparable incidence rates of gastroduodenal ulcers (20.0% vs 9.8%; p = 0.071), and gastroduodenal bleeding (2.5% vs 0%; p = 0.243). Multivariate analysis showed that use of the proton pump inhibitor was an independent protective factor (odds ratio: 0.47; 95% CI: 0.23-0.99; p = 0.047), and that smoking was a risk factor for mucosal breaks (odds ratio: 3.84; 95% CI: 1.52-9.71; p = 0.004)., Conclusion: Proton pump inhibitor was superior to histamine-2 receptor antagonist in the prevention of gastroduodenal mucosal breaks in high-risk users of low-dose aspirin, and smoking was an independent risk factor for developing gastroduodenal mucosal breaks., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2020, the Chinese Medical Association.)

Mammalian targets of rapamycin inhibitors (mTORIs), including sirolimus and everolimus, are used for minimizing calcineurin inhibitors after liver transplantation. However, head-to-head randomized comparisons of these 2 mTORIs are lacking. We assessed the differences in renoprotection and possible mechanisms between sirolimus and everolimus in liver transplant recipients. For this prospective cohort study, we recruited liver transplant recipients whose regimens were switched from tacrolimus to sirolimus or everolimus at a Taiwan medical center. Serial changes in estimated glomerular filtration rate (eGFR), urinary N-acetyl-β-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-hydroxy-2'-deoxyguanosine, and transforming growth factor-β1 during 1 year after mTORI conversion were compared within and between groups. In the 61 patients analyzed, no significant change in eGFR occurred within 12 months after conversion in both mTORI groups. Among patients with baseline eGFR <60 mL/min/1.73 m 2 , eGFR improved at 6 months and 1 year after conversion (+12.3 and +12.0 mL/min/1.73 m 2 , both P < .05). Urinary N-acetyl-β-D-glucosaminidase decreased in both sirolimus and everolimus groups at 6 months (-68.7 ± 137.6 and -62.0 ± 92.4 U/g creatinine, both P < .05), and the reduction of urinary neutrophil gelatinase-associated lipocalin was significant in the sirolimus group (-4345.1 ± 7763.5 ng/g creatinine; P < .05). Neither transforming growth factor-β1 nor 8-hydroxy-2´-deoxyguanosine changed significantly. In conclusion, the renoprotective effect of mTORI conversion was significant in liver transplant recipients with renal insufficiency, which was similar for sirolimus and everolimus, in the first year and may be associated with ameliorated tubular injury. Available evidence remains insufficient to determine which mTORI conversion therapy is more effective in renoprotection in the long run., (© 2018, The American College of Clinical Pharmacology.)

Q fever (QF) is a worldwide zoonosis associated with outbreaks. Only a few nationwide studies regarding the surveillance and epidemiology of human QF have been reported. Although QF is endemic in Taiwan, a nationwide database investigation of the epidemiology and characteristics of QF and its associations with scrub typhus (ST), murine typhus (MT) and leptospirosis (LS) has never been reported. We analysed nationwide databases of suspected QF, ST, MT and LS cases from October 2007 to December 2014 obtained from the Centers for Disease Control, Taiwan. A total of 468 (4.2%) QF cases were identified among 11 109 suspected QF cases. QF cases were mainly distributed in the southern and Kaohsiung-Pingtung regions but rarely in the eastern region. Compared to non-QF cases, QF cases had significantly higher percentages of males (88.7 versus 66.2%) and high-risk occupations (farming, animal husbandry or veterinary medicine) (16.2 versus 10.5%). But the percentages of specific animal contact, including cattle (0.6 versus 0.8%) and goats (0.9 versus 1.0%), were low in both. The majority of suspected QF cases (89.4%) were simultaneously suspected with ST, MT or LS, and the combinations of suspected diseases differed between regions. The number of suspected QF cases from the eastern region decreased since 2009, which was not observed in other regions. A total of 1420 (12.8%) cases had confirmed diseases, including QF (453, 4.1%), QF+ST (7, 0.06%), QF+MT (4, 0.04%), QF+LS (4, 0.04%), MT (186, 1.7%), ST (545, 4.9%), ST+LS (11, 0.1%) and LS (210, 1.9%). Compared to cases of unknown disease, QF cases had larger percentages of high-risk occupations (16.2 versus 9.6%) but similar histories of animal contact (29.8 versus 25.1%). QF is an endemic disease in southern Taiwan. It is difficult to differentiate QF from ST, MT or LS only by high-risk occupations and history of animal contact, and co-infection of QF with these diseases should be considered., (© 2016 Blackwell Verlag GmbH.)

Background: Whether the characteristics and prognosis of gastric cancer (GC) are different in patients with and without Helicobacter pylori (HP) remains controversial. The definitions of HP status in patients with atrophic gastritis but negative tests for HP are heterogeneous. We aimed to assess the impact of HP on the prognosis of GC using different definitions., Methods: From 1998 Nov to 2011 Jul, five hundred and sixty-seven consecutive patients with GC were included. HP status was determined by serology and histology. Patients with any positive test were defined as HP infection. Patients without HP infection whose serum pepsinogen (PG) I <70 ng/dl and PG I/II ratio < 3.0 were defined as atrophic gastritis and they were categorized into model 1: HP positive; model 2: HP negative; and model 3: exclusion of these patients., Results: We found four characteristics of HP negative GC in comparison to HP positive GC: (1) higher proportion of the proximal tumor location (24.0%, P = 0.004), (2) more diffuse histologic type (56.1%, p = 0.008), (3) younger disease onset (58.02 years, p = 0.008) and (4) more stage IV disease (40.6%, p = 0.03). Patients with negative HP had worse overall survival (24.0% vs. 35.8%, p = 0.035). In Cox regression models, the negative HP status is an independent poor prognostic factor (HR: 1.34, CI:1.04-1.71, p = 0.019) in model 1, especially in stage I, II and III patients (HR: 1.62; CI:1.05-2.51,p = 0.026)., Conclusion: We found the distinct characteristics of HP negative GC. The prognosis of HP negative GC was poor., Competing Interests: The authors have declared that no competing interests exist.

The one-time ray-tracing optimization method is a fast way to design LED illumination systems [Opt. Express22, 5357 (2014)10.1364/OE.22.005357]. The method optimizes the performance of LED illumination systems by modifying the LEDs' luminous intensity distribution curve (LIDC) with a freeform lens, instead of modifying the illumination system structure. In finding the LEDs' LIDC for optimizing the illumination system's performance, the LEDs' LIDC found by means of a general gradient descent method can be trapped in a local solution. This study develops a matrix operation method to directly find the global solution of the LEDs' LIDC for the optimization of the illumination system's performance for any initial design of an illumination system structure. As compared with the gradient descent method, using the proposed characteristic matrix operation method to find the best LEDs' LIDC reduces the cost in time by several orders of magnitude. The proposed characteristic matrix operation method ensures that the one-time ray-tracing optimization method is an efficient and reliable method for designing LED illumination systems.

Background & Aims: Metabolic syndrome is associated with increased risk of colorectal neoplasm, but little is known about its effects on the occurrence of neoplasm after colonoscopy. We investigated the effects of metabolic syndrome on the risk of advanced neoplasm after colonoscopy., Methods: We performed a prospective study of 4483 subjects age 50 years and older who underwent screening and surveillance colonoscopies as part of an annual health check-up at National Taiwan University Hospital. Baseline demographic data and colonoscopic findings were recorded. Subjects with either advanced adenoma or 3 or more adenomas detected at baseline were classified as high risk; those with fewer than 3 nonadvanced adenomas were classified as low risk; and those without any neoplastic lesions were classified as normal. The cumulative risk of detecting an advanced neoplasm during surveillance colonoscopies (3 and 5 years later) was correlated with risk group and metabolic syndrome. Hazard ratios (HRs) were calculated for occurrence of neoplasm according to baseline colonoscopic findings and clinical risk factors, including metabolic syndrome., Results: Advanced neoplasms were detected during the surveillance colonoscopies in 1.3% of subjects in the normal group and in 2.4% of those in the low-risk group at 5 years, and in 8.5% of subjects in the high-risk group at 3 years. Subjects with metabolic syndrome had a significantly higher risk for subsequent advanced neoplasms (P < .0001). After stratification based on findings from baseline colonoscopies, the risk for neoplasm was significant in the normal (P < .001) and low-risk groups (P = .04), but not in the high-risk group (P = .48). In Cox regression analysis, metabolic syndrome had significant effects on the risk for advanced neoplasms in the normal (HR, 2.07; 95% confidence interval, 1.13-3.81) and low-risk groups (HR, 2.34; 95% confidence interval, 1.01-5.41), but not in the high-risk group., Conclusions: Metabolic syndrome is a significant risk factor for occurrence of an advanced adenoma after a negative or low-risk finding from a baseline colonoscopy. Metabolic syndrome should be considered in risk stratification for surveillance intervals., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

This study reports the first systematic approach to the excitation of all high-order Hermite-Gaussian modes (HGMs) in end-pumped solid-state lasers. This study uses a metal-wire-inserted laser resonator accompanied with the "off axis pumping" approach. This study presents numerical analysis of the excitation of HGMs in end-pumped solid-state lasers and experimentally generated HGM patterns. This study also experimentally demonstrates the generation of an square vortex array laser beams by passing specific high-order HGMs (HGn,n + 1 or HGn + 1,n modes) through a Dove prism-embedded unbalanced Mach-Zehnder interferometer [Optics Express 16, 19934-19949]. The resulting square vortex array laser beams with embedded vortexes aligned in a square array can be applied to multi-spot dark optical traps in the future.

This study reports a possible first systematic approach to the selective excitations of all Mathieu-Gauss modes (MGMs) in end-pumped solid-state lasers with a new kind of axicon-based stable laser resonator. The study classifies MGMs into two categories, and explores and verifies the approach to excite each MGM category using numerical simulations. Controlling both the "cavity mode gain" and the "cavity conical asymmetry" of the axicon-based stable laser resonator achieves the proposed selective MGM-excitation approach.

Previous studies have demonstrated that naturally phosphorylated PRL antagonizes the growth-promoting effects of unmodified PRL in two different PRL-responsive cell lines. In this study our aim was to produce a molecular mimic of phosphorylated PRL by substituting a fairly bulky, negatively charged amino acid (glutamate or aspartate) for the normally phosphorylated serine [serine 179 in human PRL (hPRL)]. In addition, because of the marked effect of phosphorylation on biological activity, we investigated the importance of the unmodified serine in the growth-promoting activity of PRL. hPRL complementary DNA was obtained from the American Type Culture Collection and subcloned into pT7-SCII after site-directed mutagenesis using the deoxyuridine approach. Proteins were expressed in Escherichia coli BL21 (DE3) and were primarily found in inclusion bodies. Agonist and antagonist activities of each serine 179 mutant were assessed using the Nb2 bioassay. Compared with standard hPRL, the recombinant wild-type was more active in the Nb2 assay, attesting to both the absence, or low level, of endotoxin contamination in preparations from these cells and the appropriate folding of the molecule. The aspartate and glutamate mutants had no intrinsic agonist activity, but both antagonized the growth-promoting activity of wild-type PRL, with the aspartate mutant proving to be a very effective antagonist. Two hundred picograms per ml of the aspartate mutant negated 75% of the growth response to 400 pg/ml wild-type PRL. When serine 179 was mutated to alanine or valine, mutant PRLs with 0% and 14% of the biological activity of wild-type PRL, respectively, were produced. These results demonstrate 1) that molecular mimicry of the phosphorylated hormone does produce a PRL antagonist, and 2) that the serine at position 179 is crucial to the growth-promoting activity of PRL. The aspartate mutant can now be used to study many aspects of the physiology of PRL.