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Abstract Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

Abstract The persistent SARS-CoV-2 pandemic, spanning over three years, has profoundly impacted daily life worldwide. Crucial measures like interpersonal distance (IPD) and mask-wearing have become paramount in preventing infection. With SARS-CoV-2 now resembling an endemic condition similar to influenza, it is vital to assess the changes in IPD influenced by relevant factors during and after the pandemic. This study concentrated on two specific stages (the pandemic stage and the post-pandemic era) and investigated variations in IPD with different test combinations. Variables taken into account encompassed the pandemic stage, participant gender, target gender, and mask-wearing status. We examined IPD data from 100 young individuals (50 males and 50 females) at each stage, with a one-year interval between tests. The results highlighted the substantial impact of all variables on perceived IPD during the pandemic phase (all p

Abstract Wedge-heeled shoes, which are formed by elevating both the forefoot and heel, have been popular among young women. However, research on the foot shape in wedge-heeled shoes is lacking. This study aimed to access the effects of forefoot height (10, 20, and 30 mm) and heel height (30, 50, 70, and 90 mm) on foot shape and perceived comfort when wearing wedge-heeled shoes. Three-dimensional (3D) foot scanning was performed on 35 females and the 14 foot dimensions were measured. Increased forefoot height generated larger lengths (foot, ball and out ball), smaller girths (ball and instep) and heights (instep and navicular) (p

Abstract The Arctic sea ice has been rapidly dwindling over the past four decades, significantly impacting the Arctic region and beyond. During the same period, the Atlantic meridional overturning circulation (AMOC) was also found in a declining trend. Here we investigate the role of the AMOC in the recent Arctic sea ice changes by comparing simulations from the Community Climate System Model version 4 with decelerated and stationary AMOCs under anthropogenic climate change. We find that the weakened AMOC can slow down the decline rates of Arctic sea ice area and volume by 36% and 22% between 1980 and 2020, respectively. The decelerated ocean circulation causes a reduction of northward Atlantic heat transport and hence a general interior ocean cooling in the Arctic Mediterranean, which helps alleviate the Arctic sea ice loss primarily through thermodynamic processes occurring at the base of the sea ice.

Climate change-induced prolonged water stress (WS) affects crassulacean acid metabolism photosynthesis in pitaya (Hylocereus), limiting crop productivity through insufficient photosynthate. To document how WS/rehydration affects diel photosynthesis, red-fleshed pitaya (H. polyrhizus) micropropagules were studied for 5 weeks in a mannitol-induced water potential gradient replaced with moderate (MWS; −1.0 MPa in week 2; −0.5 MPa for the rest) or intensified (IWS; −1.0 and −1.5 MPa in weeks 2 and 3; −0.5 MPa for the rest) WS in vitro. Net photosynthetic rate (Pn) and integrated net CO2 uptake (INCU) were measured using an Arduino-based photosynthesis system. Micropropagules under MWS had similar Pn in weeks 5 and 1, whereas the control (−0.5 MPa) increased. Pn recovery did not occur after IWS. The average relative INCU was similar in the control and MWS, but lower in IWS. The Pn difference increased with WS, becoming more evident at dawn (Phase II), evening (Phase IV), and predawn the next day (Phase I), and occurred earlier in Phases IV and I under IWS. MWS did not reduce photosynthesis, demonstrating that the photosynthetic regulation could respond to short-term WS in pitaya and indicating the potential of watering for Pn recovery at evening and predawn under IWS.

Prior research on interpersonal distance (IPD) has predominantly concentrated on specific nationalities or population groups within their respective regions. There is a dearth of studies investigating IPD differences among individuals of distinct nationalities coexisting in the same geographical location. This study aimed to examine the variances in IPD between 100 young Taiwanese participants (comprising 50 males and 50 females) and 100 Southeast Asian individuals (including 50 males and 50 females). This study also considered factors affecting IPD, including target genders and mask-wearing conditions. The results of the four-way ANOVA indicate that target gender and mask-wearing conditions had a significant impact on IPD (p < 0.001). While there were no significant main effects for region and participant gender, there was a noteworthy interactive effect between these two variables on IPD. In general, Southeast Asian participants exhibited lower sensitivity to changes in IPD in response to the independent variables in comparison to their Taiwanese counterparts; in certain instances, their IPD did not notably increase when confronted with targets not wearing masks. While prior research typically indicated that women tend to maintain larger IPD than men, the current study observed this gender difference only among young Taiwanese participants. However, such a gender gap was absent among young individuals from Southeast Asia.

Summary: Autoimmunity-induced pancreatic beta cell failure is the main characteristic of type 1 diabetes (T1D). Here, we describe a protocol for genome-scale in vivo CRISPR-Cas9 screening for use in a mouse model of T1D. Using a non-obese-diabetic-derived mouse beta cell line, NIT-1, and a genome-wide CRISPR-Cas9 knockout library (GeCKO-v2), we describe how to identify genes that confer resistance to autoimmune killing. This protocol can be applied in other mouse models of autoimmunity.For complete details on the use and execution of this protocol, please refer to Cai et al. (2020).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events. Methods To address these limitations, TransCon™ TLR7/8 Agonist—an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod—was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice. Results Following a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8+ T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions. Conclusions Our findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054).

Background: Gastroesophageal reflux disease (GERD) affects a significant proportion of individuals, with life stress being a contributing factor. This study aimed to investigate the correlation between psychosomatic evaluations, heart rate variability (HRV), and GERD in a cohort of individuals. Additionally, the study aimed to analyze the sequencing changes following proton pump inhibitor (PPI) treatment and identify predictive factors associated with refractory GERD. Methods: A prospective cohort of 105 individuals with reflux esophagitis and a control group of 50 participants without acid reflux symptoms were enrolled. Psychosomatic evaluations, including GERDQ, GERDQLQ, RSI, BAI, BDI, and SSS-8, were assessed at baseline and during treatment. HRV parameters were also evaluated. Multivariate analysis was used to identify predictive factors for refractory GERD. PPIs were administered regularly for the initial 2 months and then used on-demand. Refractory GERD was defined as less than 50% improvement in symptom relief or GERDQLQ score ≥ 20 after 8 weeks of PPI treatment. Results: The GERD group had higher scores in all psychosomatic evaluations compared to the control group (all p-values < 0.001). There were no significant changes in any parameters of HRV before and after treatment in the GERD group. Strong and consistent correlations were observed between GERD symptoms and psychological scores (BAI, BDI, and SSS-8) across all time points (W0, W4, and W8). Sequential reductions in GERD symptom scores and psychosomatic evaluations were observed during the initial eight weeks of treatment. Higher GERDQ (≥10) and SSS-8 (≥12) scores were predictive of refractory GERD (p = 0.004 and p = 0.009, respectively). Conclusions: This study emphasizes the importance of considering physiological and psychological factors in the management of GERD. Psychosomatic evaluations provide valuable insights for assessing and treating GERD patients. Integrating stress management and comprehensive assessments into personalized treatment strategies is crucial.

Background: Many epigenetic loci have been associated with plasma triglyceride (TG) levels, but epigenetic connections between those loci and dietary exposures are largely unknown. This study aimed to characterize the epigenetic links between diet, lifestyle, and TG.Methods: We first conducted an epigenome-wide association study (EWAS) for TG in the Framingham Heart Study Offspring population (FHS, n = 2,264). We then examined relationships between dietary and lifestyle-related variables, collected four times in 13 years, and differential DNA methylation sites (DMSs) associated with the last TG measures. Third, we conducted a mediation analysis to evaluate the causal relationships between diet-related variables and TG. Finally, we replicated three steps to validate identified DMSs associated with alcohol and carbohydrate intake in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 993).Results: In the FHS, the EWAS revealed 28 TG-associated DMSs at 19 gene regions. We identified 102 unique associations between these DMSs and one or more dietary and lifestyle-related variables. Alcohol and carbohydrate intake showed the most significant and consistent associations with 11 TG-associated DMSs. Mediation analyses demonstrated that alcohol and carbohydrate intake independently affect TG via DMSs as mediators. Higher alcohol intake was associated with lower methylation at seven DMSs and higher TG. In contrast, increased carbohydrate intake was associated with higher DNA methylation at two DMSs (CPT1A and SLC7A11) and lower TG. Validation in the GOLDN further supports the findings.Conclusion: Our findings imply that TG-associated DMSs reflect dietary intakes, particularly alcoholic drinks, which could affect the current cardiometabolic risk via epigenetic changes. This study illustrates a new method to map epigenetic signatures of environmental factors for disease risk. Identification of epigenetic markers of dietary intake can provide insight into an individual’s risk of cardiovascular disease and support the application of precision nutrition.Clinical Trial Registration:www.ClinicalTrials.gov, the Framingham Heart Study (FHS), NCT00005121; the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), NCT01023750.

With improved living conditions, the demand for wearable products has increased, particularly for headwear. Traditionally, the dimensions of headwear products are designed according to 1D anthropometric data, such as head length, width, and eye width. However, this design method, applied to fit the 3D human head, results in differences in adaptability, which affect the wearing comfort of the user. Hence, this study aimed to develop an aided design platform based on a three-dimensional standard head shape to evaluate the virtual wearing of headwear products and adaptability testing. Specifically, a WebGL-based service, named the Chinese Headwear Adaptability Testing (CHAT) platform, was established. Validation and user studies were then conducted using an eye massager device. After the product was redesigned according to evaluation by the proposed system, the results show that the comfort and adaptability of the redesigned eye massager were significantly improved. The findings suggest that using the CHAT platform to design headwear products can help achieve a better wearing fit for the products.

Abstract Sorafenib is the recommended first‐line treatment option for patients with advanced hepatocellular carcinoma (HCC). Hepatitis C virus (HCV)‐related advanced HCC (HCV–HCC) seemed to have a better response than hepatitis B virus (HBV)‐related HCC (HBV–HCC) in sorafenib use, but it was undetermined. Hence, we aimed to investigate the effect of sorafenib between HBV–HCC and HCV–HCC patients in Taiwan. From August 2012 to December 2016, 575 consecutive advanced HCC patients received sorafenib under the reimbursement of Taiwan national health insurance in our hospital. Radiologic assessment was performed at a 2‐month interval. Those patients with tumor progression or liver function deterioration were disallowed for further sorafenib use. Patients with HBV or HCV infection were, retrospectively, enrolled and followed till December 2018. There were 277 (62.4%) HBV–HCC patients and 167 (37.6%) HCV–HCC patients. Before sorafenib, 192 (69.3%) HBV–HCC patients who had used nucleoside analogs (NAs) for HBV management, whereas only 5 (3%) HCV–HCC patients received interferon‐based antiviral therapy. Overall survival (OS) of HCV–HCC patients was significantly superior to HBV–HCC patients without NAs (8.8 months vs. 4.9 months, p = 0.006), but was noninferior to HBV–HCC patients with NAs (8.8 months vs. 10.7 months, p = 0.54). Using propensity score matching, progression‐free survival (2.0 months vs. 2.1 months, p = 0.374) and OS (10.5 months vs. 9.6 months, p = 0.746) between HBV–HCC and HCV–HCC groups were not different. Antiviral therapy might increase survival benefits of advanced HBV–HCC patients underwent sorafenib use, leading to a comparable OS to HCV–HCC patients in Taiwan.

Background Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rβ/γ+ natural killer (NK) cells and CD8+, CD4+ and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα+ regulatory T cells (Tregs) and IL-2Rα+ eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα+ cells and suboptimal pharmacokinetics with high Cmax and short half-life.Methods TransCon IL-2 β/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rβ/γ activity, IL-2 β/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 β/γ, with sustained release of IL-2 β/γ. IL-2 β/γ was characterized in binding and primary cell assays while TransCon IL-2 β/γ was studied in tumor-bearing mice and cynomolgus monkeys.Results IL-2 β/γ demonstrated selective and potent human IL-2Rβ/γ binding and activation without IL-2Rα interactions. TransCon IL-2 β/γ showed slow-release pharmacokinetics with a low Cmax and a long (>30 hours) effective half-life for IL-2 β/γ in monkeys. In mouse tumor models, TransCon IL-2 β/γ promoted CD8+ T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 β/γ induced robust activation and expansion of CD8+ T cells, NK cells and γδ T cells, relative to CD4+ T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 β/γ enhanced proliferation and cytotoxicity of primary human CD8+ T cells, NK cells and γδ T cells.Summary TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 β/γ is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609).

This study aims to characterize the interhemispheric teleconnection pattern, which is established by the South America (SA) summer monsoon over the Atlantic Ocean during January and February, and referred it as the Atlantic symmetric pattern (ASP). The ASP is characterized using the leading mode of interannual sea surface temperature (SST) variability of the Southwest Atlantic Ocean, where strong convection-SST coupling occurs. The pattern is manifested as two anomalous cyclonic-anticyclonic-cyclonic circulation trains aligned meridionally over the Atlantic Ocean, with a distinct SST dipole of the Southwest Atlantic Ocean and a tripole of the North Atlantic Ocean. The interhemispheric wave trains of the ASP are excited as a Gill-type response to convective activity in the SA summer monsoon, as confirmed in linear baroclinic model. Complementing previous studies on observed interhemispheric connection in the Atlantic, our findings highlight the importance of characterizing the ASP and its role in linking the South Atlantic SST, the SA summer monsoon, and North Atlantic climate. Further research is warranted to explore the impacts of the ASP on the Northern Hemisphere and its interactions with other climatic modes.

Obesity is associated with many chronic diseases that impair healthy aging and is governed by genetic, epigenetic, and environmental factors and their complex interactions. This study aimed to develop a model that predicts an individual’s risk of obesity by better characterizing these complex relations and interactions focusing on dietary factors. For this purpose, we conducted a combined genome-wide and epigenome-wide scan for body mass index (BMI) and up to three-way interactions among 402,793 single nucleotide polymorphisms (SNPs), 415,202 DNA methylation sites (DMSs), and 397 dietary and lifestyle factors using the generalized multifactor dimensionality reduction (GMDR) method. The training set consisted of 1,573 participants in exam 8 of the Framingham Offspring Study (FOS) cohort. After identifying genetic, epigenetic, and dietary factors that passed statistical significance, we applied machine learning (ML) algorithms to predict participants’ obesity status in the test set, taken as a subset of independent samples (n = 394) from the same cohort. The quality and accuracy of prediction models were evaluated using the area under the receiver operating characteristic curve (ROC-AUC). GMDR identified 213 SNPs, 530 DMSs, and 49 dietary and lifestyle factors as significant predictors of obesity. Comparing several ML algorithms, we found that the stochastic gradient boosting model provided the best prediction accuracy for obesity with an overall accuracy of 70%, with ROC-AUC of 0.72 in test set samples. Top predictors of the best-fit model were 21 SNPs, 230 DMSs in genes such as CPT1A, ABCG1, SLC7A11, RNF145, and SREBF1, and 26 dietary factors, including processed meat, diet soda, French fries, high-fat dairy, artificial sweeteners, alcohol intake, and specific nutrients and food components, such as calcium and flavonols. In conclusion, we developed an integrated approach with ML to predict obesity using omics and dietary data. This extends our knowledge of the drivers of obesity, which can inform precision nutrition strategies for the prevention and treatment of obesity.Clinical Trial Registration: [www.ClinicalTrials.gov], the Framingham Heart Study (FHS), [NCT00005121].

Abstract Background Decreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS). Methods Systemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25–0.8 Hz) and high-frequency (HF; 0.8–2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump. Results The suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline. Conclusion These results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.

Wearing face masks and maintaining social distancing of 1.5m are two common preventive measures against the spread of COVID-19. However, the interaction of these preventive measures in interpersonal space (IPS) perception remains unknown. This study evaluated the effects of wearing surgical masks, sex dyads, and approaching patterns on IPS judgment. Data were collected from participants from Mainland China (n=100) and Taiwan (n=100) through an online survey. Therefore, the regional differences were also examined. A smaller IPS was observed when participants faced confederates wearing surgical masks than in the no-mask condition. Female dyads tended to maintain a smaller IPS than did both male and mixed-sex dyads, and Taiwanese participants maintained a significantly larger IPS than did Mainland Chinese participants. No significant difference was observed between the active and passive pattern. Moreover, the interaction between region and mask had a significant influence on IPS perception. Among all test combinations, only the IPS perceived by Taiwanese participants facing confederates without surgical masks exceeded 1.5m. This study revealed that the wearing of surgical masks for health protection during the pandemic influences IPS perception in different regions. The current findings may provide useful information for social interaction and environmental design during the COVID-19 pandemic.

Background: Evidence supporting the feasibility of single-stage stone removal in patients with a moderate grade of acute cholangitis remains insufficient. The maximal size of a common bile-duct stone suitable for removal during a single-stage ERCP in a moderate grade of acute cholangitis is unknown. Methods: We prospectively enrolled 196 endoscopic retrograde cholangiopancreatography (ERCP)-naïve patients diagnosed with acute cholangitis and choledocholithiasis. For eligible patients, single-stage treatment involved stone removal at initial ERCP. Results: A total of 123 patients were included in the final analysis. The success rate of complete stone extraction was similar between patients with mild and moderate grades of acute cholangitis (89.2% vs. 95.9%; p = 0. 181). Complication rates were comparable between the two groups. In the moderate grade of the cholangitis group, among patients who underwent early single-stage ERCP, the length of hospitalization declined as short as the patients in the mild grade of cholangitis (10.6 ± 6.2 vs. 10.1 ± 5.1 days; p = 0.408). In the multivariate analysis, early ERCP indicated shorter hospitalization times (≤10 days) (odds ratio (OR), 3.981; p = 0.001). A stone size less than 1.5 cm presented a high success rate (98.0%) for complete stone removal. Conclusions: Single-stage retrograde endoscopic stone removal in mild and moderate grades of acute cholangitis may be safe and effective, which can obviate the requirement for a second session, thus reducing medical expenses. ClinicalTrials.gov: NCT03754491.

To prevent vehicle crashes, studies have proposed the use of flashing signals (brake lights or other light indicators) to improve the driver’s response time when the leading vehicle is braking. However, there are no consistent results on the ideal flashing frequency of the brake lights. This study aimed to investigate different brake light flashing frequencies to assess their impact on braking response time. Twenty-four participants aged 25 to 30 were recruited. Two driving speed environments (50 and 80 km/h), three deceleration rates (0.25, 0.6, and 1 g), and four brake light flashing frequencies (0, 2, 4, and 7 Hz) were examined. Braking response time, average braking force, and braking response time ratio were used to evaluate the driving behavior. The results showed that the braking response time and average braking force were affected by the deceleration rate in the 50 km/h driving environment. In the 50 and 80 km/h driving environments, although there were no significant differences among the three deceleration rates, the braking response time decreased by 3–7% under the flashing brake light condition. These findings can be used as a reference for safety designs as well as future studies on driving behavior.

Abstract This study evaluates the performance of the Taiwan Earth System Model version 1 (TaiESM1) in simulating the observed climate variability in the historical simulation of the Coupled Model Intercomparison Phase 6 (CMIP6). TaiESM1 is developed on the basis of the Community Earth System Model version 1.2.2, with the inclusion of several new physical schemes and improvements in the atmosphere model. The new additions include an improved triggering function in the cumulus convection scheme, a revised distribution‐based formula in the cloud fraction scheme, a new aerosol scheme, and a unique scheme for three‐dimensional surface absorption of shortwave radiation that accounts for the influence of complex terrains. In contrast to the majority of model evaluation processes, which focus mainly on the climatological mean, this evaluation focuses on climate variability parameters, including the diurnal rainfall cycle, precipitation extremes, synoptic eddy activity, intraseasonal fluctuation, monsoon evolution, and interannual and multidecadal atmospheric and oceanic teleconnection patterns. A series of intercomparisons between the simulations of TaiESM1 and CMIP6 models and observations indicate that TaiESM1, a participating model in CMIP6, can realistically simulate the observed climate variability at various time scales and are among the leading CMIP6 models in terms of many key climate features.

Micropropagation protocols for red-fleshed Hylocereus species (Cactaceae) have been developed; however, these methods prolong the sprout duration from areoles and produce irregular micro-propagules in ‘Da Hong’ pitaya. Thus, the present study aimed to establish an improved micropropagation protocol for this cultivar. Shoot regeneration and root induction of self-pollinating seedling segments were evaluated in response to combinations of activated charcoal (AC; 200 mg/L), α-naphthaleneacetic acid (NAA; 0.05, 0.10, and 0.20 mg/L), and 6-benzylaminopurine (BAP; 1.00, 2.00, and 4.00 mg/L). The correlations among plantlet growth characteristics and plantlet survival rate after transplantation under field conditions were calculated. Increasing the NAA concentration increased the number of roots but reduced root length. The addition of AC enhanced shoot length and prevented the regeneration of dried-out, clustered, and abnormal shoots. Plantlets treated with 200 mg/L AC and 0.10 mg/L NAA produced the highest number of shoots, i.e., 4.1 shoots, which however, were shorter and lighter than those cultured with AC alone. Plantlets grown on medium supplemented with BAP showed no advantage in shoot number, shoot weight, plantlet surface area, or plantlet volume. The weight and shoot surface area of plantlets were strongly correlated. All plantlets grew well at 4 weeks post-transplantation. Overall, these results support this improved micropropagation method to regenerate robust ex vitro plantlets.

This study explores the interpersonal space (IPS) and peripersonal space (PPS) of Chinese people and evaluates the relationship between the two spaces for different directions and genders. Seventy-one participants were recruited for this study. Participants were required to determine their IPS in eight directions (0°, 45°, 90°, 135°, 180°, 225°, 270°, 315°) when approached by male or female confederates in the comfort distance task. Each participant was also asked to judge their PPS in five directions (0°, 45°, 90°, 270°, 315°) following the same procedure. Results showed that their IPS was significantly influenced by direction (p < 0.05), with the largest distance in the front (0°) and the closest distance in the rear (135°, 180°, 225°), indicating non-circular IPS among Chinese subjects. Moreover, the PPS on the right side (90°) was larger than in other directions (0°, 45°, 270°, 315°). Participants maintained larger IPS than PPS in the front, but the IPS was closer than PPS on the right and left sides. When facing a female confederate, larger IPS was preferred than PPS, whereas the opposite held true when facing a male confederate. Comparison of participants’ arm length and PPS showed that the reachability distance was overestimated in the front but underestimated laterally. The findings of this study can be applied to environmental design, space utilization, and social interaction.

The aim of this study was to analyze and provide an in-depth improvement priority for medication adverse events. Thus, the Human Factor Analysis and Classification System with subfactors was used in this study to analyze the adverse events. Subsequently, the improvement priority for the subfactors was determined using the hybrid approach in terms of the Analytical Hierarchy Process and the fuzzy Technique for Order of Preference by Similarity to Ideal Solution. In Of the 157 medical adverse events selected from the Taiwan Patient-safety Reporting system, 25 cases were identified as medication adverse events. The Human Factor Analysis and Classification System and root cause analysis were used to analyze the error factors and subfactors that existed in the medication adverse events. Following the analysis, the Analytical Hierarchy Process and the fuzzy Technique for Order of Preference by Similarity to Ideal Solution were used to determine the improvement priority for subfactors. The results showed that the decision errors, crew resource management, inadequate supervision, and organizational climate contained more types of subfactors than other error factors in each category. In the current study, 16 improvement priorities were identified. According to the results, the improvement priorities can assist medical staff, researchers, and decisionmakers in improving medication process deficiencies efficiently.

Background and aimTransient elastography and fibrosis-4 index (FIB-4) have been proposed to access hepatic fibrosis and steatosis for patients with chronic liver disease. This study was to determine the changes of liver stiffness (LS), controlled attenuation parameter (CAP) value and FIB-4 and their associated factors for chronic hepatitis C (CHC) patients who underwent direct-acting antivirals (DAAs).Patients and methodsConsecutive patients with CHC in advanced fibrosis or compensated cirrhosis undergoing paritaprevir/ritonavir/ombitasvir plus dasabuvir therapy and with LS and CAP before and 12 weeks after treatment were enrolled. The demographics, clinical characteristics and treatment outcomes were reviewed. The changes of LS, FIB-4, CAP and their associated factors were analyzed.ResultsA total of 213 patients (mean age: 63.7 years) with complete recommended treatment were enrolled. All patients achieved sustained virological response at 12 weeks (SVR12) of follow-up. The mean values of LS, CAP and FIB-4 index before treatment were 18.5kPa, 283dB/m and 5.05 respectively. While there was no significant change in CAP, LS and FIB-4 decreased significantly at the time of SVR12 (pConclusionFor CHC patients in advanced fibrosis or compensated cirrhosis, DAAs improved LS and FIB-4 index at SVR12. Higher baseline LS and FIB-4 contributed to greater reductions. However, there was no significant change in CAP value.

Background: The aim of this study was to evaluate the effect of a newly designed foam cushion on the air leakage and pressure when applied to the face. Methods: A teaching manikin connected to a bilevel positive airway pressure ventilator attached to four different brands of oronasal masks (Amara, Mirage, Forma, and Wizard) was used. The foam cushions of 5-mm and 10-mm-thickness were attached to the masks, and each mask was tested without a cushion. Six pressure sensors were placed on the manikin’s face, and data were recorded. Inspiratory volume and air leak flow from the ventilator were observed. Results: Air leakage was influenced by both the mask brand and the presence of a cushion. The presence of a cushion did not affect the Wizard mask in terms of leakage (p = 0.317) or inspiratory volume (p = 0.726). The Wizard and Amara masks generated the lowest contact pressure on the frontal forehead (p < 0.001) compared to the other five points. Conclusions: Utilisation of a cushion reduces air leakage and maintains greater inspiratory volume regardless of its thickness. The contact pressure varies depending on the brand of the mask, which would require a difference in the thickness of the cushion for pressure reduction.

Determining the potential risks of musculoskeletal disorders through working postures in a workplace is expensive and time-consuming. A novel intelligent rapid entire body assessment (REBA) system based on convolutional pose machines (CPM), entitled the Quick Capture system, was applied to determine the risk levels. The aim of the study was to validate the feasibility and reliability of the CPM-based REBA system through a simulation experiment. The reliability was calculated from the differences of motion angles between the CPM-based REBA and a motion capture system. Results show the data collected by the Quick Capture system were consistent with those of the motion capture system; the average of root mean squared error (RMSE) was 4.77 and the average of Spearman’s rho (ρ) correlation coefficient in the different 12 postures was 0.915. For feasibility evaluation, the linear weighted Cohen’s kappa between the REBA score obtained by the Quick Capture system and those from the three experts were used. The result shows good agreement, with an average proportion agreement index (P0) of 0.952 and kappa of 0.738. The Quick Capture system does not only accurately analyze working posture, but also accurately determines risk level of musculoskeletal disorders. This study suggested that the Quick Capture system could be applied for a rapid and real-time on-site assessment.

Abstract Background Foot dimension information on different user groups is important for footwear design and clinical applications. Foot dimension data collected using different measurement methods presents accuracy problems. This study compared the precision and accuracy of the 3D foot scanning method with conventional foot dimension measurement methods including the digital caliper, ink footprint and digital footprint. Methods Six commonly used foot dimensions, i.e. foot length, ball of foot length, outside ball of foot length, foot breadth diagonal, foot breadth horizontal and heel breadth were measured from 130 males and females using four foot measurement methods. Two‐way ANOVA was performed to evaluate the sex and method effect on the measured foot dimensions. In addition, the mean absolute difference values and intra‐class correlation coefficients (ICCs) were used for precision and accuracy evaluation. The results were also compared with the ISO 20685 criteria. Results The participant's sex and the measurement method were found (p < 0.05) to exert significant effects on the measured six foot dimensions. The precision of the 3D scanning measurement method with mean absolute difference values between 0.73 to 1.50 mm showed the best performance among the four measurement methods. The 3D scanning measurements showed better measurement accuracy performance than the other methods (mean absolute difference was 0.6 to 4.3 mm), except for measuring outside ball of foot length and foot breadth horizontal. The ICCs for all six foot dimension measurements among the four measurement methods were within the 0.61 to 0.98 range. Conclusions Overall, the 3D foot scanner is recommended for collecting foot anthropometric data because it has relatively higher precision, accuracy and robustness. This finding suggests that when comparing foot anthropometric data among different references, it is important to consider the differences caused by the different measurement methods.

While genome-wide association studies (GWAS) and candidate gene approaches have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, a tool for Genome-wide Complex Trait Analysis (GCTA) was used to examine GxE variance contribution of 15 macronutrients and lifestyle to the total phenotypic variance of diabetes-related traits at the genome-wide level in a European American population. GCTA identified two key environmental factors making significant contributions to the GxE variance for diabetes-related traits: carbohydrate for fasting insulin (25.1% of total variance, P-nominal = 0.032) and homeostasis model assessment of insulin resistance (HOMA-IR) (24.2% of total variance, P-nominal = 0.035), n-6 polyunsaturated fatty acid (PUFA) for HOMA-β-cell-function (39.0% of total variance, P-nominal = 0.005). To demonstrate and support the results from GCTA, a GxE GWAS was conducted with each of the significant dietary factors and a control E factor (dietary protein), which contributed a non-significant GxE variance. We observed that GxE GWAS for the environmental factor contributing a significant GxE variance yielded more significant SNPs than the control factor. For each trait, we selected all significant SNPs produced from GxE GWAS, and conducted anew the GCTA to estimate the variance they contributed. We noted the variance contributed by these SNPs is higher than that of the control. In conclusion, we utilized a novel method that demonstrates the importance of genome-wide GxE interactions in explaining the variance of diabetes-related traits.

BACKGROUND:Neighboring genes PIK3CA and KCNMB3 are both important for insulin signaling and β-cell function, but their associations with glucose-related traits are unclear. OBJECTIVE:The objective was to examine associations of PIK3CA-KCNMB3 variants with glucose-related traits and potential interaction with dietary fat. DESIGN:We first investigated genetic associations and their modulation by dietary fat in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820). Nine single-nucleotide polymorphisms (SNPs) were selected for analysis, covering more than 80% of the SNPs in the region. We then sought to replicate the findings in the Boston Puerto Rican Health Study (BPRHS) (n = 844). RESULTS:For KCNMB3 missense mutation rs7645550, meta-analysis indicated that homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower in minor allele T homozygotes compared with major allele C carriers (pooled P-value = 0.004); for another SNP rs1183319, which is in moderate LD with rs7645550, minor allele G carriers had higher HOMA-IR compared with non-carriers in both populations (pooled P-value = 0.028). In GOLDN, rs7645550 T allele homozygotes had lower HOMA-IR only when dietary n-3: n-6 PUFA ratio was low (≤0.11, P = 0.001), but not when it was high (>0.11, P-interaction = 0.033). Similar interaction was observed between rs1183319 and n-3: n-6 PUFA ratio on HOMA-IR (P-interaction = 0.001) in GOLDN. Variance contribution analyses in GOLDN confirmed the genetic association and gene-diet interaction. In BPRHS, dietary n-3: n-6 PUFA ratio significantly modulated the association between rs1183319 and HbA1c (P-interaction = 0.034). CONCLUSION:PIK3CA-KCNMB3 variants are associated with insulin resistance in populations of different ancestries, and are modified by dietary PUFA.

Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could explain the previously reported association between the CLOCK 3111T/C SNP and weight loss.We recruited 1495 overweight/obese subjects (BMI: 25-40 kg/m(2)) of 20-65 y. who attended outpatient obesity clinics in Murcia, in southeastern Spain. We detected an association between the CLOCK 3111T/C SNP and weight loss, which was particularly evident after 12-14 weeks of treatment (P = 0.038). Specifically, carriers of the minor C allele were more resistant to weight loss than TT individuals (Mean±SEM) (8.71±0.59 kg vs 10.4±0.57 kg) C and TT respectively. In addition, our data show that minor C allele carriers had: 1. shorter sleep duration Mean ± SEM (7.0±0.05 vs 7.3±0.05) C and TT respectively (P = 0.039), 2. higher plasma ghrelin concentrations Mean ± SEM (pg/ml) (1108±49 vs 976±47)(P = 0.034); 3. delayed breakfast time; 4. evening preference and 5. less compliance with a Mediterranean Diet pattern, as compared with TT homozygotes.Sleep reduction, changes in ghrelin values, alterations of eating behaviors and evening preference that characterized CLOCK 3111C carriers could be affecting weight loss. Our results support the hypothesis that the influence of the CLOCK gene may extend to a broad range of variables linked with human behaviors.

Apolipoprotein C3 (APOC3) modulates triglyceride metabolism through inhibition of lipoprotein lipase, but is itself regulated by insulin, so that APOC3 represents a potential mechanism by which glucose metabolism may affect lipid metabolism. Unfavorable lipoprotein profiles and impaired glucose metabolism are linked to cognitive decline, and all three conditions may decrease lifespan. Associations between apolipoprotein C3 (APOC3) gene polymorphisms and impaired lipid and glucose metabolism are well-established, but potential connections between APOC3 polymorphisms, cognitive decline and diabetes deserve further attention.We examined whether APOC3 single nucleotide polymorphisms (SNPs) m482 (rs2854117) and 3u386 (rs5128) were related to cognitive measures, whether the associations between cognitive differences and genotype were related to metabolic differences, and how diabetes status affected these associations. Study subjects were Hispanics of Caribbean origin (n = 991, aged 45-74) living in the Boston metropolitan area.Cognitive and metabolic measures differed substantially by type II diabetes status. In multivariate regression models, APOC3 m482 AA subjects with diabetes exhibited lower executive function (P = 0.009), Stroop color naming score (P = 0.014) and Stroop color-word score (P = 0.022) compared to AG/GG subjects. APOC3 m482 AA subjects with diabetes exhibited significantly higher glucose (P = 0.032) and total cholesterol (P = 0.028) compared to AG/GG subjects. APOC3 3u386 GC/GG subjects with diabetes exhibited significantly higher triglyceride (P = 0.004), total cholesterol (P = 0.003) and glucose (P = 0.016) compared to CC subjects.In summary, we identified significant associations between APOC3 polymorphisms, impaired cognition and metabolic dysregulation in Caribbean Hispanics with diabetes. Further research investigating these relationships in other populations is warranted.