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Until recently, most genetic studies of headache have been conducted on participants with European ancestry. We therefore conducted a large-scale genome-wide association study of self-reported headache in individuals of East Asian ancestry (specifically those who were identified as Han Chinese). In this study, 108,855 participants were enrolled, including 12,026 headache cases from the Taiwan Biobank. For broadly-defined headache phenotype, we identified a locus on chromosome 17, with the lead single nucleotide polymorphism (SNP) rs8072917 (odds ratio 1.08, p = 4.49 × 10–8) mapped to two protein-coding genes RNF213 and ENDOV. For severe headache phenotype, we found a strong association on chromosome 8, with the lead SNP rs13272202 [odds ratio 1.30, p = 1.02 × 10–9], mapped to gene RP11-1101K5.1. We then conducted a conditional analysis and a statistical fine mapping of the broadly-defined headache-associated loci and identified a single credible set of loci with rs8072917 supporting that this lead variant was the true causal variant on RNF213 gene region. RNF213 replicated the result of previous studies and played important roles in the biological mechanism of broadly-defined headache. On the basis of the previous results found in the Taiwan biobank, we conducted phenome-wide association studies for the lead variants using data from the UK biobank, and found that the causal variant (SNP rs8072917) was associated with muscle symptoms, cellulitis and abscess of face and neck, and cardiogenic shock. Our findings foster the genetic architecture of headache in individuals of East Asian ancestry. Our study can be replicated using genomic data linked to electronic health records from a variety of countries, therefore affecting a wide range of ethnicities globally. Our genome-phenome association study may facilitate the development of new genetic tests and novel drug mechanisms.

STAT3 activation is important in the development of gastric cancer (GCA), but its role in DNA methylation is not fully understood. STAT3-mediated DNA methylation is controlled by K685 acetylation, we therefore hypothesized that distribution of acetyl-CoA could affect the role of STAT3 in DNA methylation. Here, by methylation microarray from GCA patients and cells depleted with STAT3, we identified a STAT3-related CpG island methylator phenotype (CIMP), located at neuronal genes (neuronal CIMP). Further TCGA RNA-Seq identified neuronal CIMP+ve to be positively associated with the expression and higher cyto/mito ratio of acetyl-CoA synthetase (ACSS2). Intriguingly, patients with neuronal-CIMP +ve or higher cyto/mito ratio of ACSS were associated with a better survival, suggesting a different role of acetyl-STAT3. As STAT3 pathway plays a key role in chemokine response, we also analyze whether neuronal-CIMP contributes to anti-tumor immune response. Surprisingly, CIMP +ve patients correlated with pro-inflammatory niche, including activated CD4 + T cells and M1 macrophages. In conclusion, neuronal-CIMP may be a biomarker to predict patient’s immune responses in GCA. Citation Format: Jie-Ting Low, Yu-Ming Chuang, Yu-Ting Lee, Michael Wing-Yan Chan. Acetyl-coA distribution devote STAT3 related neuronal methylation phenotype and pro-inflammatory niche in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1254.

Breast cancer is among the most frequently diagnosed cancer types and the leading cause of cancer-related death in women. The mortality rate of patients with breast cancer is currently increasing, perhaps due to a lack of early screening tools. In the present study, using The Cancer Genome Atlas (TCGA) breast cancer dataset (n=883), it was determined that methylation of the protocadherin β15 (

The impact of coronavirus disease 2019 (COVID-19) on economic and medical systems is significant, especially in the emergency department (ED). The patterns of ED visits have also changed significantly and may play a crucial role in rearranging medical resources to the most needed departments during the pandemic. This was a retrospective study conducted in hospitals of the Cathay Health System. All patients presented to the EDs between January 21, 2020 to April 30, 2020 (pandemic stage) and January 21, 2019 to April 30, 2019 (before the pandemic stage). Basic demographics, including visit characteristics, disposition, and chief complaints, of the patients visiting the ED between these 2 periods of time will be compared and analyzed. A total of 71,739 patients were included in the study. A reduction in ED visits was noted in 15.1% (32,950 ED visits) during the pandemic stage. ED visiting patients with the chief complaints of upper respiratory infection and social problems increased by 14.23% and 1.86%, respectively, during the pandemic period. Critical chief complaints such as cardiac arrest, chest pain and altered mental status decreased to less than the ED visits difference (−15.1%) between the pandemic and prepandemic stages, for 0%, −7.67%, and −13.8% respectively. Rearrangement of the ED pediatric staff to the COVID-19 special units and recruiting more social workers to the ED should be performed to respond to the COVID-19 pandemic.

4-Mercapto-4-methyl-2-pentanone (4MMP), a high-impact aroma compound with the box tree and black currant flavors was first identified in wines and could be released by microbial cysteine-S-conjugate β-lyases from its precursors. In this study, various yeasts and bacteria encoding β-lyases were selected to examine their β-lyase activities. A thiol precursor of 4MMP, cysteine-conjugate of 4MMP (cys-4MMP), was synthesized with a purity of >95% in a relatively environmentally friendly approach, and its chemical structure was confirmed by nuclear magnetic resonance spectroscopy. The β-lyase activities of the crude cell extract from the bacteria and yeast strains for different substrates were examined using a colorimetric method. Shewanella putrefaciens cell extract exhibited the highest β-lyase activity for all tested substrates. Additionally, the optimum pH and temperature for their β-lyase activities were determined. To monitor the conversion efficiency of precursor cys-4MMP to 4MMP, liquid chromatography-mass spectrometry was used. Our data indicate that selected bacteria and yeasts could convert cys-4MMP into 4MMP, and S. putrefaciens exhibited the best conversion yield. This study demonstrated the potential use of microbial cell extracts to produce sulfur-containing aroma compounds such as 4MMP.

Background According to a WHO report, nearly 15% of adults aged 60 and over suffer from a mental disorder, constituting 6.6% of the total disability for this age group. Taipei City faces rapid transformation towards an aging society, with the proportion of elderly in the total population rising from 12% in 2008 to 16% in 2016. The aim of this study is to identify the prevalence of mental disorders among the elderly in Taipei City and to elucidate risk factors contributing to mental disorders. Methods The elderly health examination database was obtained from the Department of Health, Taipei City government, from 2005 to 2012. A total of 86,061 people underwent publicly funded health examinations, with 348,067 visits. Each year, there are around 43,000 elderly persons in Taipei City using this service. We used a mental health questionnaire including five questions to estimated relative risks among potential risk factors with the generalized estimating equations (GEE) model to measure the mental health status of the elderly. Mood disorders were measured with the Brief Symptom Rating Scale (BSRS-5) questionnaire. Age, education level, gender, marital status, living alone, drinking milk, eating vegetables and fruits, long-term medication, smoking status, frequency of alcohol consumption, frequency of physical activity, BMI, and number of chronic diseases were included as covariates. Results The results show that being male (odds ratio (OR) 0.57; 95% CI = 0.56, 0.59), higher education (OR 0.88; 95% CI = 0.82, 0.95), no long-term medication (OR 0.57; 95% CI = 0.56, 0.58), and exercising three or more times per week (OR 0.94; 95% CI = 0.91, 0.98) were all positively correlated with better emotional status. However, being divorced (OR = 1.22, 95% CI = 1.09, 1.36), not drinking milk (OR = 1.12, 95% CI = 1.09, 1.14), not eating enough vegetables and fruits every day (OR = 1.78, 95% CI = 1.73, 1.83), daily smoking (OR = 1.15, 95% CI = 1.01, 1.32), and having more chronic diseases (OR = 1.02, 95% CI = 1.01, 1.03) were all correlated with poor mental status among the elderly. Conclusions The findings of this research can both estimate the prevalence of mood disorders at the community level, and identify risk factors of mood disorders at the personal level.

Gastric cancer is one of the leading causes of cancer death worldwide. Previous studies demonstrated that activation of STAT3 is crucial for the development and progression of gastric cancer. However, the role of STAT3 in neuronal related gene methylation in gastric cancer has never been explored. In this study, by using DNA methylation microarray, we identified a potential STAT3 target, C11orf87, showing promoter hypomethylation in gastric cancer patients with lower STAT3 activation and AGS gastric cancer cell lines depleted with STAT3 activation. Although C11orf87 methylation is independent of its expression, ectopic expression of a constitutive activated STAT3 mutant upregulated its expression in gastric cancer cell line. Further bisulfite pyrosequencing demonstrated a progressive increase in DNA methylation of this target in patient tissues from gastritis, intestinal metaplasia, to gastric cancer. Intriguingly, patients with higher C11orf87 methylation was associated with better survival. Furthermore, hypermethylation of C11orf87 was also frequently observed in other GI cancers, as compared to their adjacent normal tissues. These results suggested that C11orf87 methylation may serve as a biomarker for diagnosis and prognosis of GI cancers, including gastric cancer. We further postulated that constitutive activation of STAT3 might be able to epigenetically silence C11orf87 as a possible negative feedback mechanism to protect the cells from the overactivation of STAT3. Targeted inhibition of STAT3 may not be appropriate in gastric cancer patients with promoter hypermethylation of C11orf87.

IntroductionPositive fluid balance is a prognostic factor for mortality in patients with sepsis; however, the association between cumulated fluid balance (CFB) and sepsis-induced multi-organ dysfunction syndrome (MODS) has yet to be elucidated. In this study, we sought to determine whether CFB is correlated with MODS and mortality in cases of septic shock.MethodsThe study retrospectively recruited patients with septic shock from the intensive care unit of a tertiary care hospital. Multiple organ dysfunction syndrome (MODS) was identified as sequential organ failure assessment (SOFA) score ≥ 2 in more than one organ system. The CFB is the sum of all daily intake and output. An independent t-test, single and multivariate logistic regression, the receiver operating characteristic (ROC) curves, and the Pearson correlation coefficient were used to determine whether a relationship exists between CFB and the development of MODS and mortality.ResultsAmong the 104 patients enrolled in the study, 58 (55.8%) survived more than 28 days, and 73 (70.2%) developed MODS on day 3. The values of CFB in the first 24 hours and 72 hours after diagnosis of septic shock in patients with MODS were higher than these in patients without MODS (1086.6 ± 176.3 vs. 325.5 ± 205.7 ml, p = 0.013 and 2408 ± 361 vs. 873.1 ± 489 ml, p < 0.0001). In a multivariate logistic regression, the independent factors associated with the development of MODS on day 3 were APACHE II score at ICU admission (27.6 ± 7.6 in patients with MODS vs. 20.5 ± 6.4 in those without; O.R. 1.18; 95% C.1 I. 1.08-1.30; p < 0.001), disseminated intravascular coagulopathy (DIC) (n = 28; 38.4% vs. n = 2; 6.5%; O.R. 23.67; 95% C.I. 3.58-156.5; p = 0.001), and CFB in the first 72 hours (72-hr CFB) > median (1767.50ml) (n = 41; 56.2% vs. n = 11; 35.5%; O.R. 3.67; 95% C.I., 1.18-11.40; p = 0.024). Moreover, a multivariate logistic regression also identified neoplasm (n = 25; 54.3% vs. n = 17; 29.3%; O.R. 3.45; 95% C.I. 1.23-10.0; p = 0.019) and 72-hr CFB > median (n = 30; 65.2% vs. n = 21; 36.2%; O.R. 4.13; 95% C.I. 1.34-12.66; p = 0.013) as independent factors associated with 28-day mortality. 72-hr CFB values were strongly correlated with the SOFA score (r = 0.445, p < 0.0001). The area under the ROC curve revealed that 72-hr CFB has good discriminative power in associating the development of MODS (0.644, p = 0.002) and predicting subsequent 28-day mortality (0.704, p < 0.0001).Conclusions72-hr CFB appears to be correlated with the likelihood of developing MODS and mortality in patients with septic shock. Thus, it appears that 72-hr CFB could perhaps be used as an indicator for MODS and a predictor for mortality in those patients.

Background Bladder cancer is a disease frequently seen in the elderly. Frail and elderly patients with muscle-invasive bladder cancer (MIBC) are often unfit for surgery. While concurrent chemoradiotherapy (CCRT) is a well-established alternative treatment modality, only a small proportion of elderly patients receive CCRT. The purpose of this article is to review our experience with CCRT in elderly MIBC patients. Methods Between January 1, 2007 and December 31, 2013, we retrospectively reviewed patients aged >75 who were treated with CCRT at Taipei Veterans General Hospital. Patients' characteristics, therapeutic strategy, clinical outcomes, and treatment-related toxicities were assessed. Results Nineteen patients (4 females and 15 males) were identified. The median age was 79.5 years (range, 78.5–84.0 years) and the median follow-up was 33.7 months (interquartile range, 19.1–51.8 months). The major adverse event was grade 3 or grade 4 neutropenia, which developed in 10 of the 19 patients. No treatment-related mortality occurred. We found no association between prognosis and the chemotherapy regimen. Chemotherapy with a conventional dose of gemcitabine (800–1000 mg/m2) was well tolerated. The two-year and three-year estimated overall survival rates were 74% and 60%, respectively. Conclusion CCRT after complete transurethral resection of the bladder tumor is feasible for elderly patients with MIBC. The conventional dose of gemcitabine as a chemosensitizer is adequate in the elderly population, but further investigation is needed.

The study aims to provide the decision support for airfreight forwarders regarding the air-land intermodal operation, for which shipments are transported to gateway airports by air transportation and then delivered to final destinations by trucking service. A mixed integer programming model has been formulated to tackle the integrated routing and consolidation decision, given the various types of air containers. This study has designed an approximate solution algorithm based on Lagrangian Relaxation. In the numerical experiment, the solution algorithm can achieve an objective function value very close to optimality or the Lagrangian lower bound within an acceptable computation time.

Y1-xEuxMn2O5 nanorod samples (x = 0, 0.5, and 1) were prepared and crystallized in an orthorhombic structure with the Pbam space group. Magnetic susceptibility experiments revealed that the size effect reduced the effective magnetic moment and interaction among magnetic moments. All six samples exhibited AFM ordering and canted AFM domain below 50 K, and adjustable by varying the size of the nanorods. Hysteresis experiments revealed the size effect induced exchange bias. Room-temperature Raman spectra revealed a red-shift in all of x = 0 and x = 1 samples in an applied magnetic field, indicating that a spin-phonon interaction existed at room temperature.

The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (K(i) values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates.

BACKGROUND Patients with colorectal cancer (CRC) who undergo cancer surgeries with higher-volume providers may have better outcomes. The current debate focuses on whether it is hospital volume or surgeon volume that matters more. METHODS The authors conducted a nationwide population-based study in Taiwan that enrolled all patients who underwent definitive surgery for newly diagnosed CRC between 2005 and 2011. All patients were divided into 4 quartiles according to hospital and surgeon volume. The main outcome was the 5-year mortality rate, which was analyzed using a frailty model for Cox regression. The authors also conducted fixed and random effects multivariate regression models to examine short-term outcomes and resource use, including operative mortality, hospital stay, emergency department visits within 30 days, and medical expenses. Analyses were adjusted for patient and provider characteristics. RESULTS A total of 61,728 patients with CRC were included in the current study. The 5-year mortality rates were 38.7%, 32.8%, 32.0%, and 29.1% in descending order of hospital volume quartiles and were 41.4%, 34.1%, 29.8%, and 27.4% in descending order of surgeon volume quartiles. After adjustment for the individual and provider characteristics, surgeon volume, but not hospital volume, remained a significantly predictive factor of death (P

This study proposes a novel framework to monitor the rankings of public companies that are released periodically by worldwide business organizations. With different ranking rationales and diverse indicators, the released reports may not be comparable or suited to investment objectives. Therefore, this study introduces the DuPont model to derive well-recognized common investment indicators and then employs the data envelopment analysis (DEA) ranking method and the grey entropy (GE) ranking method to re-rank the listed companies. Both DEA and GE re-rankings are compared with the released rankings to generate a map of the DEA-gap versus the GE-gap to advise stock investors of undervalued or overvalued companies. As a demonstration, the proposed framework is applied to the case of Taiwan Info Tech 100 released by Business Next. It is thought that continual monitoring of public company rankings may promote business opportunities in the long run; hence, application of the proposed framework to develop favorable business models is further addressed in this study.

This paper presents evidence that household energy use in Uganda conforms to the energy ladder theory. As household income increases, solid and transitional fuel use evolves in an inverse U manner, while electricity consumption shows a direct relationship with income. Public infrastructure provision, income, and education are the key variables which can be targeted to reduce household dependence on solid-fuels while increasing non-solid fuel use. While education and public infrastructure have varying impacts on rural and urban households' energy mix, these variables generally reduce rudimentary fuel use and increase modern fuel consumption. Timely investment in electricity infrastructure is necessary to cater for burgeoning electricity demand as households become affluent. Strategies for reforestation, dissemination of improved cookstoves, relieving supply side constraints for modern fuels, and staggered payment options to lower the cost of entry for modern fuels can improve Ugandan households' energy security.

This paper proposes an integrative framework for network-structured analytic network process (ANP) modeling. The underlying rationales include: 1) creating the measuring items for the complex decision problems; 2) applying factor analysis to reduce the complex measuring items into fewer constructs; 3) employing Bayesian network classifier technique to discover the causal directions among constructs; 4) using partial least squares path modeling to test the causal relationships among the items-constructs. The proposed framework is implemented for knowledge discovery to a case of high-tech companies’ enterprise resource planning (ERP) benefits and satisfaction in Hsinchu Science Park,Taiwan. The results show that the proposed framework for ANP modeling can reach a satisfactory level of convergent reliability and validity. Based on the findings, pragmatic implications to the ERP venders are discussed. This study has shed new light on the long neglected, yet critical, issue on decision structures and knowledge discovery for ANP modeling.

The World Economic Forum employs Travel & Tourism Competitiveness Indexes (TTCI) to measure the travel & tourism (T&T) global competitiveness of a country. The TTCI overall scores are calculated with an arithmetic mean aggregation from the scores of the fourteen composite pillars with a subjective assumption of all the pillars having the same weights. This paper attempts to release such a subjective assumption by proposing a new solution framework to explore an objective weighting system for the pillars. The proposed solution framework employs the Expectation Maximization (EM) clustering algorithm to group the 139 ranked countries into three classes and then performs the Artificial Neural Network (ANN) analysis to explore the objective weighting system for the fourteen pillars. The results show that tourism infrastructure, ground transport infrastructure, air transport infrastructure, cultural resources, health and hygiene, and ICT infrastructure are the six most critical pillars contributing to the TTCI overall scores. Accordingly, the policy makers should allocate limited resources with priority to improve these six pillars to frog leap the T&T global competitiveness.

A new highly efficient three-component reaction of alkyl acrylate, aldehyde and dialkyl malonate using ethyl diphenylphosphine as organocatalyst has been described. Various highly functional compounds bearing hydroxyl groups and the ester functions can be easily prepared in moderate to good yields according to our one-step procedure. The reactions are believed to proceed via Morita-Baylis-Hillman reactions of alkyl acrylate and aldehydes, followed by the Michael addition reactions of dialkyl malonates. Our reactions indicated that the intermediate species formed in the phosphine-catalyzed MBH reaction are an effective organic base to catalyze the Michael addition reactions of dialkyl malonates to the preformed MBH adducts.

Factoring the most affective elements into a tangible product is the core of Kansei design. Accordingly, one promising means to innovate the local food is to incorporate essential features of renowned international cuisine into the local gastronomy to serve as a destination marketing enabler. This paper proposes an evaluation framework by employing Analytic Network Process (ANP) and Borda count method to select an icon dish of innovative Hakka-Kaiseki hybrid cuisine for a local Hakka restaurant in Taiwan. The decision group has selected “Shrimp Tofu” as the icon dish to promote food tourism. The results show that the Kaiseki features have surpassed the Hakka features; among which, the foremost feature is shape, followed by color, material, and savory. The findings provide useful culinary guides to facilitate the chefs to develop more Kansei cuisine dishes.

Software as a Service (SaaS) is regarded as a favorable solution to enhance a modern organization's IT performance and competitiveness; however, many organizations may still be reluctant to introduce SaaS solutions mainly because of the trust concern—they may perceive more risks than benefits. This paper presumes that an organization will augment the trust of adopting SaaS solutions when perceived risks decrease and/or perceived benefits increase. To gain insights into this issue, a solution framework using a modified Decision Making Trial and Evaluation Laboratory (DEMATEL) approach is proposed. The core logic is to treat perceived benefits and perceived risks as two distinct themes so that a visible cause-effect diagram can be developed to facilitate the decision makers. A case study is conducted on a Taiwanese company—one of the world's leading manufacturers in the niche and specialized resistor markets. The findings suggest that the case company concern more about strategic-oriented benefits than economic- oriented benefits and more about subjective risks than technical risks. Some implications are addressed accordingly.

A highly chemoselective PPh(3)-catalyzed three-component reaction of an imine, alkyl vinyl ketone, and phthalimide or succinimide is developed. Various highly functional adducts with high diastereoselectivities can be generated via aza-Morita-Baylis-Hillman reactions of aryl-substituted imines and alkyl vinyl ketones followed by Michael additions of imides and then epimerization.

This paper presents a robust global router called NTHU-Route 2.0 that improves the solution quality and runtime of NTHU-Route by the following enhancements: 1) a new history based cost function; 2) new ordering methods for congested region identification and rip-up and reroute; and 3) two implementation techniques. We report convincing experimental results to show the effectiveness of each individual enhancement. With all these enhancements together, NTHU-Route 2.0 solves all ISPD98 benchmarks with very good quality. Moreover, NTHU-Route 2.0 routes 7 of 8 ISPD07 benchmarks and 12 of 16 ISPD08 benchmarks without any overflow. Compared with other state-of-the-art global routers, NTHU-Route 2.0 is able to produce better solution quality and/or run more efficiently.

Competency development and management are widely regarded as vital tools to enhance competitiveness for organizations. A number of studies have suggested a variety of competency models, including a list of required competencies for use by organizations that wish to enrich their employees' competencies. However, all these required competencies do not necessarily share the same importance. To effectively implement competency development, it is desirable to distinguish the differences of perceived competency levels between high-performers and others. In doing so, a large number of required competencies can be reduced into a compact set that focuses on significant competencies of high-performers. To this end, this paper proposes a method based on the rough set theory to explore high-performers' required competencies. An empirical study is presented to illustrate the application of the proposed method. Based on our findings, conclusions and implications for management are presented.

Head and neck squamous cell carcinoma (HNSCC) has a high prevalence and is a major cause of cancer deaths in Taiwan. However, there is still no effective salvage therapy that prolongs the life expectancy of patients with recurrent/metastatic (R/M) HNSCC. Immune checkpoint therapy that targets the programmed cell death protein 1 (PD-1) may provide clinical benefit for these patients. We analyzed 22 R/M HNSCC patients who received pembrolizumab, a monoclonal antibody against PD-1, as salvage therapy. Intravenous pembrolizumab was given at a fixed dosage of 100 or 200 mg every 3 weeks. Three patients also received local palliative radiotherapy, but no patients received chemotherapy or targeted drugs. Seventeen patients (77.3%) received at least 3 cycles of pembrolizumab. Based on Response Evaluation Criteria in Solid Tumors criteria (ver. 1.1), 2 patients (9.1%) had complete response, 5 (22.7%) had partial response, and 6 (27.3%) had stable disease, corresponding to a disease control rate of 59.1%. Four patients had confirmed disease progression, 2 of whom had continuous progression over the target lesion after shrinkage of other metastases. One patient developed immune-related pneumonitis that resolved quickly after steroid treatment. Another patient developed itchy skin rashes immediately after administration of pembrolizumab, and this was controlled by an antihistamine. There were no other severe adverse effects. Pembrolizumab is beneficial and well-tolerated for some patients with refractory R/M HNSCC. However, it is important to identify biomarkers to identify the most responsive patients when designing future trials.

For ensuring the successful implementation of knowledge management, here raises a critical issue of how companies can better evaluate and select a favorable knowledge management strategy before that implementation. However, selecting a proper knowledge management strategy is a kind of multiple criteria decision-making (MCDM) problem required to consider a large number of complex factors. Unlike many traditional MCDM methods that are based on the independence assumption, the analytic network process (ANP) is a relative new MCDM method which can deal with all kinds of dependences systematically. Since the ANP has these advantages, in this paper, we develop an effective method based on the ANP to help companies that need to evaluate and select knowledge management strategies. Additionally, an empirical study is presented to illustrate the application of the proposed method.

Modern global managers are required to possess a set of competencies or multiple intelligences in order to meet pressing business challenges. Hence, expanding global managers’ competencies is becoming an important issue. Many scholars and specialists have proposed various competency models containing a list of required competencies. But it is hard for someone to master a broad set of competencies at the same time. Here arises an imperative issue on how to enrich global managers’ competencies by way of segmenting a set of competencies into some portions in order to facilitate competency development with a stepwise mode. To solve this issue involving the vagueness of human judgments, we have proposed an effective method combining fuzzy logic and Decision Making Trial and Evaluation Laboratory (DEMATEL) to segment required competencies for better promoting the competency development of global managers. Additionally, an empirical study is presented to illustrate the application of the proposed method.

Isoleucine, leucine and valine are synthesized via a common pathway in which the first reaction is catalysed by AHAS (acetohydroxyacid synthase; EC 2.2.1.6). This heterotetrameric enzyme is composed of a larger subunit that contains the catalytic machinery and a smaller subunit that plays a regulatory role. The RSU (regulatory subunit) enhances the activity of the CSU (catalytic subunit) and mediates end-product inhibition by one or more of the branched-chain amino acids, usually valine. Fungal AHAS differs from that in other organisms in that the inhibition by valine is reversed by MgATP. The fungal AHAS RSU also differs from that in other organisms in that it contains a sequence insert. We suggest that this insert may form the MgATP-binding site and we have tested this hypothesis by mutating ten highly conserved amino acid residues of the yeast AHAS RSU. The modified subunits were tested for their ability to activate the yeast AHAS CSU, to confer sensitivity to valine inhibition and to mediate reversal of the inhibition by MgATP. All but one of the mutations resulted in substantial changes in the properties of the RSU. Unexpectedly, four of them gave a protein that required MgATP in order for strong stimulation of the CSU and valine inhibition to be observed. A model to explain this result is proposed. Five of the mutations abolished MgATP activation and are suggested to constitute the binding site for this modulator.

Enterovesical fistula (EVF) is a rare complication of diverticulitis, as well as Crohn's disease, intestinal malignancy, radiotherapy and trauma. EVF formation is associated with inflammation of the involved bowel segments. The current study presents the case of a 35-year-old man with non-Hodgkin's lymphoma who developed pneumaturia, fecaluria and recurrent urinary tract infections following chemotherapy, accompanied by regressive change of the lymphoma. Abdominal computed tomography scans revealed that the terminal ileum had adhered to the bladder wall. The patient underwent exploratory laparotomy and partial resection of the terminal ileum, and EVF was confirmed. Histological examination revealed an inflammatory response but no evidence of residual lymphoma. The diagnosis of EVF is occasionally difficult and requires appropriate radiographic examination. Surgical treatment is recommended.

Acetohydroxyacid synthase (AHAS; EC 4.1.3.18) contains catalytic and regulatory subunits, the latter being required for sensitivity to feedback regulation by leucine, valine and isoleucine. The regulatory subunit of Arabidopsis thaliana AHAS possesses a sequence repeat and we have suggested previously that one repeat binds leucine while the second binds valine or isoleucine, with synergy between the two sites. We have mutated four residues in each repeat, based on a model of the regulatory subunit. The data confirm that there are separate leucine and valine/isoleucine sites, and suggest a complex pathway for regulatory signal transmission to the catalytic subunit.

Acetohydroxyacid synthase (EC 4.1.3.18, also known as acetolactate synthase) isoenzyme II from Escherichia coli is inhibited by sulphonylurea and imidazolinone herbicides, although it is much less sensitive than the plant enzyme. This isoenzyme is also unusual in that it is not inhibited by valine. Mutating S100 (Ser100 in one-letter amino acid notation) of the catalytic subunit to proline increases its sensitivity to sulphonylureas, but not to imidazolinones. Mutating P536 to serine, as found in the plant enzyme, had little effect on the properties of the enzyme. Mutating E14 of the regulatory subunit to glycine, either alone or in combination with the H29N (His29 → Asn) change, did not affect valine-sensitivity.

The paper appraises the myriad of Murray-Darling Basin-related policies since the early 1990s. It contends that significant environmental improvements could have been achieved at substantially lower cost had decisive action been taken earlier. If the total expenditures in the last two decades had been put solely towards water entitlement buy-backs, an amount of water several times that necessary to significantly improve the health of the Basin would have been acquired.

There has now been almost two decades of natural resource management by signatory states under the Murray-Darling Basin Agreement Despite significant public expense, the success of initiatives to improve the Basin’s environmental remains ambiguous. This confusion is partly due to poorly distinguished investment outcomes, a blurring of the transparency of public spending and a lack of accountability of decision makers. The aim of this study is to demonstrate that significant environmental improvements could have been achieved at a much lower cost if decisive action been taken early. The research report outlines the myriad of Murray-Darling Basin related policies and its funding. It also notes the achievements and impediments to program success.