37 research outputs found

    Phenotyping Diabetes Mellitus on Aggregated Electronic Health Records from Disparate Health Systems

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    Background: Identifying patients with diabetes mellitus (DM) is often performed in epidemiological studies using electronic health records (EHR), but currently available algorithms have features that limit their generalizability. Methods: We developed a rule-based algorithm to determine DM status using the nationally aggregated EHR database. The algorithm was validated on two chart-reviewed samples (n = 2813) of (a) patients with atrial fibrillation (AF, n = 1194) and (b) randomly sampled hospitalized patients (n = 1619). Results: DM diagnosis codes alone resulted in a sensitivity of 77.0% and 83.4% in the AF and random hospitalized samples, respectively. The proposed algorithm combines blood glucose values and DM medication usage with diagnostic codes and exhibits sensitivities between 96.9% and 98.0%, while positive predictive values (PPV) ranged between 61.1% and 75.6%. Performances were comparable across sexes, but a lower specificity was observed in younger patients (below 65 versus 65 and above) in both validation samples (75.8% vs. 90.8% and 60.6% vs. 88.8%). The algorithm was robust for missing laboratory data but not for missing medication data. Conclusions: In this nationwide EHR database analysis, an algorithm for identifying patients with DM has been developed and validated. The algorithm supports quantitative bias analyses in future studies involving EHR-based DM studies

    Sensitisation to recombinant Aspergillus fumigatus allergens and clinical outcomes in COPD

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    Background Variable clinical outcomes are reported with fungal sensitisation in chronic obstructive pulmonary disease (COPD), and it remains unclear which fungi and what allergens associate with the poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown. Methods A prospective multicentre assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non-Aspergillus allergens. Unsupervised clustering and topological data analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation subgroups exist and their related clinical outcomes. Results Aspergillus fumigatus sensitisation was associated with increased exacerbations in COPD. Unsupervised cluster analyses revealed two “fungal sensitisation” groups. The first was characterised by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group conferred even poorer outcome. The second group, characterised by Cladosporium sensitisation, was more symptomatic. Significant numbers of individuals demonstrated sensitisation responses to only recombinant (as opposed to crude) A. fumigatus allergens f 1, 3, 5 and 6, and exhibited increased exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a subgroup within Aspergillus-sensitised COPD of patients with frequent exacerbations. Conclusion Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remains overlooked by assessment of only crude Aspergillus allergens.Ministry of Education (MOE)Ministry of Health (MOH)National Medical Research Council (NMRC)Published versionThis research is supported by the Singapore General Hospital Research Grant (SRG-OPN-06-2021) (P.Y. Tiew) and the Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-000141) (S.H. Chotirmall) and Clinician-Scientist Award (MOH-000710) (S.H. Chotirmall). K. Tsaneva-Atanasova gratefully acknowledges the financial support of the EPSRC via grant EP/T017856/1. F.T. Chew (Singapore) received grants from the National University of Singapore (N-154-000-038-001), Singapore Ministry of Education Academic Research Fund (R-154-000-191-112, R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112, R-154-000-A08-592, R-154-000-A27-597, R-154-000-A91-592, R-154-000-A95-592, R154-000-B99-114), Biomedical Research Council (Singapore) (BMRC/01/1/21/18/077, BMRC/04/1/21/19/315, BMRC/APG2013/108), Singapore Immunology Network (SIgN-06-006, SIgN-08-020), National Medical Research Council (Singapore) (NMRC/1150/2008), and the Agency for Science Technology and Research (Singapore) (H17/01/a0/008 and APG2013/108). Funding information for this article has been deposited with the Crossref Funder Registry

    Determinants of Survival and Post-Progression Outcomes by Sorafenib–Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma

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    The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure

    Determinants of Survival and Post-Progression Outcomes by Sorafenib–Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma

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    The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure

    Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

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    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

    The Implementation of a Smart Sampling Scheme C2O Utilizing Virtual Metrology in Semiconductor Manufacturing

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    Virtual metrology (VM) is an enabling technology capable of performing virtual inspection on the metrology quality of wafers. Instead of physically acquiring the metrology measurements, VM applies conjecture models on the process data of wafers to estimate the measurements of the targeted metrology variables. Prior works on overlay VM system utilized fault detection and classification (FDC) data as the process data for the conjecture models. Hence, when FDC data are unavailable owing to FDC system enhancement works, FDC-based VM models would be rendered inefficacious. During such events, a competent VM system using a different modeling approach is required to sustain the production line until FDC data resumes availability and FDC-based VM reaches production state. Motivated by a real-world production environment of a 200mm semiconductor manufacturing plant (fab), a novel wafer lot-level modeling approach for overlay VM was proposed in our prior work. Using the proposed modeling, a smart sampling scheme was also designed in the same work. The smart sampling scheme consists of two conjecture tasks, with the first task classifies the overlay quality of the wafers, and the second task estimates the overlay errors of the wafers classified with normal overlay quality. The abnormal ones are diverted to the physical metrology station. In this paper, the implementation of a smart sampling system, C2O, using the designed scheme and its experimental results are presented. The experimental results showed that C2O is capable to achieve a true positive rate (TPR) of 71.34% for the classification task and mean absolute scaled error (MASE) of 9.59 for the regression task. The obtained results set the baseline to measure the efficacy of future enhancement works, which have been enlisted and underway to augment the performance of the system so that its competency meets the requirements of real fab

    "High-Risk" Clinical and Inflammatory Clusters in COPD of Chinese Descent

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    COPD is a heterogeneous disease demonstrating inter-individual variation. A high COPD prevalence in Chinese populations is described, but little is known about disease clusters and prognostic outcomes in the Chinese population across Southeast Asia. We aim to determine if clusters of Chinese patients with COPD exist and their association with systemic inflammation and clinical outcomes.Ministry of Education (MOE)Nanyang Technological UniversityNational Medical Research Council (NMRC)This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Research Training Fellowship [NMRC/Fellowship/0049/2017 to P. Y. T.] and a Clinician-Scientist Individual Research Grant [MOH-000141 to S. H. C.]; the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 [2016-T1-001-050 to S. H. C.]; the NTU Integrated Medical, Biological and Environmental Life Sciences (NIMBELS), Nanyang Technological University , Singapore [NIM/03/2018 to S. H. C.]; the Ageing Research Institute for Society and Education (ARISE), Nanyang Technological University , Singapore [ARISE/2017/6 to S. H. C.]; and Engineering and Physical Sciences Research Council (EPSRC) grant, United Kingdom [EP/N014391/1] to K. T. A

    The Changeless Core in a Changing Business Environment

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    Rapid change in business environment poses threat to business survival. It is crucial to examine the core of business sustainability. This paper proposes changeless factors in response to today’s business environment. Specifically, it addresses (1) the people factor (2) the purpose factor and (3) the principle factor as the pillars through which an organization finds its stability in the sea of business change. This paper demonstrates the unchanged factors to ensure business sustainability and to achieve long term objectives. After mapping the conceptual model, the paper devotes particular attention to conceptualizing the changeless cores of business. This research contributes practical insights for managers to further understand the cores of business sustainability. Specifically, it will assist managers to have clear goals in making decisions and managing change to enhance competitiveness in the business environment

    Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models

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    Background: Given that aberrant activation of epidermal growth factor receptor family receptors (ErbB) is a common event in oral squamous cell carcinoma, and that high expression of these receptor proteins is often associated with poor prognosis, this rationalizes the approach of targeting ErbB signaling pathways to improve the survival of patients with oral squamous cell carcinoma. However, monotherapy with the ErbB blocker afatinib has shown limited survival benefits. Objectives: This study was performed to identify mechanisms of afatinib resistance and to explore potential afatinib-based combination treatments with other targeted inhibitors in oral squamous cell carcinoma. Methods: We determined the anti-proliferative effects of afatinib on a panel of oral squamous cell carcinoma cell lines using a crystal violet-growth inhibition assay, click-iT 5-ethynyl-2′-deoxyuridine staining, and cell-cycle analysis. Biochemical assays were performed to study the underlying mechanism of drug treatment as a single agent or in combination with the MEK inhibitor trametinib. We further evaluated and compared the anti-tumor effects of single agent and combined treatment by using oral squamous cell carcinoma xenograft models. Results: In this study, we showed that afatinib inhibited oral squamous cell carcinoma cell proliferation via cell-cycle arrest at the G0/G1 phase, and inhibited tumor growth in xenograft mouse models. Interestingly, we demonstrated reactivation of the mitogen-activated protein kinase (ERK1/2) pathway in vitro, which possibly reduced the effects of ErbB inhibition. Concomitant treatment of oral squamous cell carcinoma cells with afatinib and trametinib synergized the anti-tumor effects in oral squamous cell carcinoma-bearing mouse models. Conclusions: Our findings provide insight into the molecular mechanism of resistance to afatinib and support further clinical evaluation into the combination of afatinib and MEK inhibition in the treatment of oral squamous cell carcinoma. © 2019, Springer Nature Switzerland AG

    The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors

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    Abstract The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted
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