Phenotypic Characterization of Congenital Hyperinsulinism Due to Novel Activating Glucokinase Mutations.

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. ARTICLE HIGHLIGHTS: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in ß-cells and α-cells to regulate glucose homeostasis.

A prognostic gene signature for gastric cancer and the immune infiltration-associated mechanism underlying the signature gene, PLG.

BACKGROUND: Globally, gastric cancer (GC) is a common and lethal solid malignant tumor. Identifying the molecular signature and its functions can provide mechanistic insights into GC development and new methods for targeted therapy. METHODS: Differentially expressed genes (DEGs) and prognostic genes (from univariate Cox regression analysis) were overlapped to obtain prognostic DEGs. Subsequently, molecular modules and the functions of these prognostic DEGs were identified by Metascape and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG)/Gene Set Enrichment Analysis (GSEA) enrichment analyses, respectively. Protein-protein interaction (PPI) networks of up- and down-regulated prognostic DEGs in GC were analyzed using the MCC algorithm of the Cytohubba plug-in in Cytoscape. The prognostic gene signature was defined on hub genes of the PPI networks by least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. Furthermore, the expressional level of PLG in our clinical GC samples was validated by quantitative PCR (qPCR), western blotting, and immunohistochemistry (IHC). Subsequently, the PLG expression-correlation analysis was performed to assess the role of PLG in GC progression. Immune infiltration analysis was performed by single-sample gene set enrichment analysis (ssGSEA) to assess the inhibitory effect of PLG on immune infiltration. RESULTS: Firstly, Up- and down-regulated prognostic DEGs and hub genes in protein-protein interaction (PPI) networks in GC were identified. A prognostic five-gene signature (i.e., PLG, SPARC, FGB, SERPINE1, and KLHL41) was identified. Among the five genes, the relationship between plasminogen (PLG) and GC remains largely unclear. Moreover, the functions of PLG-correlated genes in GC, like 'fibrinolysis', 'hemostasis', 'ion channel complex', and 'transporter complex' were identified. In addition, PLG expression correlated negatively with the infiltration of almost all immune cell types. Interestingly, the expression of PLG was significantly and highly correlated with that of CD160, an immune checkpoint inhibitor. CONCLUSION: Our findings defined a new five-gene signature for predicting GC prognosis, but more validation is required to assess the effects and mechanism of the five genes, especially PLG, for the development of new GC therapies.

Factores de riesgo de lesión de las arterias coronarias en niños con enfermedad de Kawasaki / Risk factors for coronary artery lesions in children with Kawasaki disease

Introducción. La enfermedad de Kawasaki (EK) es una vasculitis sistémica inespecífica que suele presentarse en los niños; la lesión de las arterias coronarias (LAC) es la complicación más grave.Objetivos. Nuestro objetivo fue investigar los factores de riesgo de LAC en niños con EK.Materiales y métodos. Se incluyó a niños con EK según los criterios diagnósticos, hospitalizados entre enero de 2014 y diciembre de 2017. Se realizaron análisis univariado y multivariado de regresión logística para investigar las relaciones entre LAC y género, edad, diagnóstico clínico, velocidad de sedimentación globular (VSG), recuento de trombocitos, concentración de hemoglobina, concentración de proteína C-reactiva, recuento de leucocitos, momento de inicio de la administración de inmunoglobulina intravenosa (IgIV) y duración de la fiebre.Resultados. Se dividió a los 982 niños con EK en un grupo con LAC (n = 104) y otro sin LAC (n = 878), según una ecocardiografía Doppler color. La tasa de incidencia de LAC fue del 10,6 % (104/982). En el análisis univariado, se observó una diferencia significativa entre ambos grupos en cuanto al género, la VSG, el recuento de trombocitos, el momento de inicio de la administración de IgIV y la duración de la fiebre (p < 0,05). Según el análisis multivariado de regresión logística, el sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC.Conclusiones. El sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC.

Introduction. Kawasaki disease (KD) is a non-specific systemic vasculitic disease that frequently occurs among children, and coronary artery lesion (CAL) is the most serious complication.Objectives. We aimed to study the risk factors for CAL in children with KD.Materials and methods. KD children in accordance with diagnostic criteria, who were hospitalized from January 2014 to December 2017, were selected as subjects. Univariate and multivariate logistic regression analyses were conducted to explore the relationships between CAL and gender, age, clinical diagnosis, erythrocyte sedimentation rate (ESR), platelet count, hemoglobin level, C reactive protein level, white blood cell count, initiation time of IVIG administration and duration of fever.Results. The enrolled 982 KD children were divided into a CAL group (n = 104) and an NCAL group (n = 878) according to cardiac color Doppler ultrasonography. The incidence rate of CAL was 10.6 % (104/982). Univariate analysis showed that the two groups had significantly different gender, ESR, platelet count, initiation time of IVIG administration and duration of fever (P < 0.05). Multivariate logistic regression analysis revealed that male gender, elevated ESR and delayed use of IVIG were independent risk factors for KD complicated with CAL.Conclusions:Male gender, increased ESR and delayed use of IVIG were independent risk factors for KD complicated with CA

Risk factors for coronary artery lesions in children with Kawasaki disease. / Factores de riesgo de lesión de las arterias coronarias en niños con enfermedad de Kawasaki.

Introduction: Kawasaki disease (KD) is a nonspecific systemic vasculitic disease that frequently occurs among children, and coronary artery lesion (CAL) is the most serious complication. Objectives: We aimed to study the risk factors for CAL in children with KD. Materials and methods: KD children in accordance with diagnostic criteria, who were hospitalized from January 2014 to December 2017, were selected as subjects. Univariate and multivariate logistic regression analyses were conducted to explore the relationships between CAL and gender, age, clinical diagnosis, erythrocyte sedimentation rate (ESR), platelet count, hemoglobin level, C reactive protein level, white blood cell count, initiation time of IVIG administration and duration of fever. Results: The enrolled 982 KD children were divided into a CAL group (n = 104) and an NCAL group (n = 878) according to cardiac color Doppler ultrasonography. The incidence rate of CAL was 10.6 % (104/982). Univariate analysis showed that the two groups had significantly different gender, ESR, platelet count, initiation time of IVIG administration and duration of fever (P < 0.05). Multivariate logistic regression analysis revealed that male gender, elevated ESR and delayed use of IVIG were independent risk factors for KD complicated with CAL. Conclusions: Male gender, increased ESR and delayed use of IVIG were independent risk factors for KD complicated with CAL.

Introducción. La enfermedad de Kawasaki (EK) es una vasculitis sistémica inespecífica que suele presentarse en los niños; la lesión de las arterias coronarias (LAC) es la complicación más grave. Objetivos. Nuestro objetivo fue investigar los factores de riesgo de LAC en niños con EK. Materiales y métodos. Se incluyó a niños con EK según los criterios diagnósticos, hospitalizados entre enero de 2014 y diciembre de 2017. Se realizaron análisis univariado y multivariado de regresión logística para investigar las relaciones entre LAC y género, edad, diagnóstico clínico, velocidad de sedimentación globular (VSG), recuento de trombocitos, concentración de hemoglobina, concentración de proteína C-reactiva, recuento de leucocitos, momento de inicio de la administración de inmunoglobulina intravenosa (IgIV) y duración de la fiebre. Resultados. Se dividió a los 982 niños con EK en un grupo con LAC (n = 104) y otro sin LAC (n = 878), según una ecocardiografía Doppler color. La tasa de incidencia de LAC fue del 10,6 % (104/982). En el análisis univariado, se observó una diferencia significativa entre ambos grupos en cuanto al género, la VSG, el recuento de trombocitos, el momento de inicio de la administración de IgIV y la duración de la fiebre (p < 0,05). Según el análisis multivariado de regresión logística, el sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC. Conclusiones. El sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC.

Outcomes after hepatectomy of patients with positive HBcAb Non-B Non-C hepatocellular carcinoma compared to overt hepatitis B virus hepatocellular carcinoma.

PURPOSE: Hepatitis B core antibody (HBcAb) positivity is regarded as a sensitive marker for occult and prior hepatitis B virus (HBV) infection. However, the prognosis of patients with HBcAb-positive in non-B, non-C hepatocellular carcinoma (NBNC-HCC) remains unclear. The study aimed to compare the clinicopathological characteristics of patients with HBcAb-positive NBNC-HCC to those with overt HBV (hepatitis B surface antigen positive) HCC. METHODS: 306 HCC patients underwent hepatectomy were divided into two groups: an overt HBV-HCC group and HBcAb-positive NBNC-HCC group. Then patients were analyzed using propensity score matching (PSM) to reduce selection bias. Clinicopathological characteristics and survival outcomes were compared between the two groups. Univariate and multivariate analysis for risk factors were also evaluated. RESULTS: HBcAb-positive NBNC-HCC group showed comparable survival outcomes to the overt HBV-HCC group (3-year overall survival rates 66% vs 62%, 69% vs 53%; 3-year recurrence-free survival rates 49% vs 40%, 47% vs 37%; P > 0.05) before and after PSM. Patients with HBcAb-positive NBNC-HCC were older, had more complications, higher proportions of vascular invasion, and larger tumor sizes but lower proportions of cirrhosis, elevated alanine aminotransferase and prothrombin time. CONCLUSIONS: HBcAb-positive NBNC-HCC group had more advanced tumors, but their prognosis was relatively comparable to that of the other group. Therefore, we believe that screening is also necessary in HBcAb-positive patients for early detection of HCC, especially in the elderly.

Development of an enterprise risk inventory for healthcare.

BACKGROUND: The first phase of an enterprise risk management (ERM) program is the identification of risks. Accurate identification is essential to a proactive and effective ERM function. The authors identified a lack of such risk identification in the literature and in practical cases when interviewing the chief risk officers from healthcare organizations. A risk inventory specific to healthcare organizations that includes detailed risk scenarios and risk impacts currently does not exist. Thus, the objective of this research is to develop an enterprise risk inventory for healthcare organizations to create a common understanding of how each type of risk impacts a healthcare organization. METHOD: ERM guidelines and data from 15 interviews with chief risk officers were analyzed to create the risk inventory. The identified risks were confirmed through a survey of risk managers from a range of global healthcare organizations during the ASHRM conference in 2017. Descriptive statistics were developed and cluster analysis was performed using the survey results. RESULTS: The risk inventory includes 28 risks and their specific risk scenarios. Cyberattack was ranked as the principal risk by the participants, followed by sentinel events and risks associated with human capital management (organizational culture, use of electronic medical records and physician wellness). The data analysis showed that the specific characteristics of the survey participants, such as the length of time working in risk management, the size of the organization, and the presence of a school of medicine, do not impact an individual's opinion of the importance of the risks identified. A personal background in risk management (clinical or enterprise) was a characteristic that showed a small difference in the perceived importance of the risks from the proposed risk inventory. CONCLUSIONS: In addition to defining specific risk scenarios, the enterprise risk inventory presented in this research can contribute to guiding the risk identification phase of an ERM program and thereby support the development of a risk culture. Patient data security in hospitals that operate with high levels of technology is fundamental to delivering high quality and safe care to patients. At the top of the risk ranking, the identification of cyberattacks reflects the importance that healthcare risk managers place on this risk by allocating time and other resources. Exploring opportunities to improve cyber risk management and evaluating the benefits of using the risk inventory at the beginning of the risk identification phase in an ERM program are suggestions for future studies.

Screening Circulating Tumor Cells as a Noninvasive Cancer Test in 3388 Individuals from High-Risk Groups (ICELLATE2).

Cancer is known to spread up to 12 years before clinical symptoms occur, but few screening tests exist. Early detection would give the opportunity for early treatment, potentially improving prognosis. To this end, 3388 subjectively healthy individuals of age 45 to 80 who had been exposed to cancer risk factors were screened for the occurrence of circulating tumor cells in their blood. Presence of circulating tumor cells is a suspicious finding indicative of spreading cancer, since cancer metastasizes by way of the blood and offers the opportunities to (a) follow up the individual clinically based on established guidelines for early detection of cancer and (b) evaluate the cells further analytically. 107 individuals showed one or more circulating tumor cells in a 7.5 ml blood sample, which constitutes a positive circulating tumor cell test, based on the iCellate IsoPic™ laboratory test. That number compares favorably with the cancer incidence per 100,000 people/year that is 157.1 in Peru, given that a high-risk group of individuals was screened and that the screening results would be expected to correspond to an accumulated incidence of up to 12 years. The present findings therefore identify screening for circulating tumor cells as a promising new test.

Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study.

OBJECTIVE: Rheumatoid arthritis (RA) is a costly and crippling autoimmune disease that can lead to the development of depression, contributing to suboptimal clinical outcomes. However, no longitudinal studies have identified an association between rheumatoid arthritis and subsequent depression. This study aimed to investigate the incidence and risk factors of depression among RA patients in Taiwan. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 3,698 newly diagnosed RA patients aged 18 years or older, together with 7,396 subjects without RA matched by sex, age and index date, between 2000 and 2004. The incidence of depression and the risk factors among RA cases were evaluated using Cox proportional-hazard regression. RESULTS: The incidence of depression was 1.74-fold greater in the RA cohort than in the non-RA cohort (11.80 versus 6.89 per 1,000 person-years; p<0.01). Multivariate analysis showed that RA subjects who were female, were older, or had comorbidities such as stroke, chronic kidney disease, or cancer had a significantly greater risk of depression compared with those without these conditions. CONCLUSION: This population-based cohort study showed a strong relationship between RA and a subsequent risk of depression. The findings could be beneficial to healthcare providers for identifying individuals with a higher predisposition for depression, thereby possibly facilitating the provision of an appropriate rehabilitation intervention after RA onset to support the patient's adaptation.

Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study

OBJECTIVE: Rheumatoid arthritis (RA) is a costly and crippling autoimmune disease that can lead to the development of depression, contributing to suboptimal clinical outcomes. However, no longitudinal studies have identified an association between rheumatoid arthritis and subsequent depression. This study aimed to investigate the incidence and risk factors of depression among RA patients in Taiwan. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 3,698 newly diagnosed RA patients aged 18 years or older, together with 7,396 subjects without RA matched by sex, age and index date, between 2000 and 2004. The incidence of depression and the risk factors among RA cases were evaluated using Cox proportional-hazard regression. RESULTS: The incidence of depression was 1.74-fold greater in the RA cohort than in the non-RA cohort (11.80 versus 6.89 per 1,000 person-years; p<0.01). Multivariate analysis showed that RA subjects who were female, were older, or had comorbidities such as stroke, chronic kidney disease, or cancer had a significantly greater risk of depression compared with those without these conditions. CONCLUSION: This population-based cohort study showed a strong relationship between RA and a subsequent risk of depression. The findings could be beneficial to healthcare providers for identifying individuals with a higher predisposition for depression, thereby possibly facilitating the provision of an appropriate rehabilitation intervention after RA onset to support the patient's adaptation. .

Spin Brazil-nut effect and its reverse in a rotating double-walled drum.

The segregation of binary mixtures in a filled rotating double-walled drum is explored by simulations. Based on the characteristics of self-gravity and the centrifugal force, we argue that both percolation and buoyancy effects dominate the segregation process. The simulational results show that up to long enough times the segregation state is controlled by the rotational speed, the particle radius and density. At low rotational speeds, the smaller and heavier particles tend to accumulate towards the inner drum wall and the bigger and lighter ones towards the outer drum wall, while the segregation pattern reverses completely at higher rotational speeds. Two typical phase diagrams in the space of the density and radius ratio of bigger particles to smaller particles further confirm the predictions.

Analysis of the nuclear localization signal of TRF1 in non-small cell lung cancer.

Several studies revealed a similar down-regulation of telomeric repeat binding factor 1 (TRF1) in tumors. We have previously reported the TRFl expression levels were down-regulation in non-small cell lung cancer (NSCLC). The regulation of TRFl localization is proposed to be important for the function and expression. The nuclear localization signal (NLS) and nuclear export signal (NES) are often important clues to localization of protein. The objective of the present study was to investigate the NLS and NES of TRFl in NSCLC patients. Thirty (30) patients with NSCLCs had undergone radical operations in The First Affiliated Hospital, College of Medicine, Zhejiang University. DNA sequences of NLSs and NESs were amplified by PCR. The PCR products were analyzed by DNA sequencing. There were four NLSs of the TRFl protein, including two monopartite and two bipartite NLSs. The NLSs sequences were included in 337KKERRVGTPQSTKKKKESRR356. The exon 8 and exon 9 of TRFl DNA were covered the NLS sequences. The sequences of predicted NESs were 11WMLDFLCLSL86 and 174NLLKLQALAV183, respectively. The exon 1, exon 3 and exon 4 of TRFl were covered the NES sequences. In NSCLCs, there was no a mutation, deletion, or substitution in NLS and NES of TRFl. We conclude that the NLS and NES sequences in NSCLCs patients did not have mutations. Down-expression of TRFl does not indicate gene mutation of NLS and NES in NSCLCs.

Analysis of the nuclear localization signal of TRF1 in non-small cell lung cancer

Several studies revealed a similar down-regulation of telomeric repeat binding factor 1 (TRF1) in tumors. We have previously reported the TRFl expression levels were down-regulation in non-small cell lung cancer (NSCLC). The regulation of TRFl localization is proposed to be important for the function and expression. The nuclear localization signal (NLS) and nuclear export signal (NES) are often important clues to localization of protein. The objective of the present study was to investigate the NLS and NES of TRFl in NSCLC patients. Thirty (30) patients with NSCLCs had undergone radical operations in The First Affiliated Hospital, College of Medicine, Zhejiang University. DNA sequences of NLSs and NESs were amplified by PCR. The PCR products were analyzed by DNA sequencing. There were four NLSs of the TRFl protein, including two monopartite and two bipartite NLSs. The NLSs sequences were included in 337KKERRVGTPQSTKKKKESRR356. The exon 8 and exon 9 of TRFl DNA were covered the NLS sequences. The sequences of predicted NESs were 11WMLDFLCLSL86 and 174NLLKLQALAV183, respectively. The exon 1, exon 3 and exon 4 of TRFl were covered the NES sequences. In NSCLCs, there was no a mutation, deletion, or substitution in NLS and NES of TRFl. We conclude that the NLS and NES sequences in NSCLCs patients did not have mutations. Down-expression of TRFl does not indicate gene mutation of NLS and NES in NSCLCs.