Blood lipid profile, HbA1c, fasting glucose, and diabetes: a cohort study and a two-sample Mendelian randomization analysis.

PURPOSE: The prevalence of diabetes is increasing worldwide. The associations between the lipid profile and glycated hemoglobin (HbA1c), fasting glucose, and diabetes remain unclear, so we aimed to perform a cohort study and a two-sample Mendelian randomization (MR) study to investigate the causality between blood lipid profile and HbA1c, fasting glucose, and diabetes. METHODS: A total of 25,171 participants from the Taiwan Biobank were enrolled. We applied a cohort study and an MR study to assess the association between blood lipid profile and HbA1c, fasting glucose, and diabetes. The summary statistics were obtained from the Asian Genetic Epidemiology Network (AGEN), and the estimates between the instrumental variables (IVs) and outcomes were calculated using the inverse-variance weighted (IVW) method. A series of sensitivity analyses were performed. RESULTS: In the cohort study, high-density lipoprotein cholesterol (HDL-C) was negatively associated with HbA1c, fasting glucose, and diabetes, while the causal associations between HDL-C and HbA1c (ßIVW = - 0.098, p = 0.003) and diabetes (ßIVW = - 0.594, p < 0.001) were also observed. Furthermore, there was no pleiotropy effect in this study using the MR-Egger intercept test and MR-PRESSO global test. CONCLUSIONS: Our results support the hypothesis that a genetically determined increase in HDL-C is causally related to a reduction in HbA1c and a lower risk of diabetes.

[Advances in the use of bevacizumab for the treatment of respiratory papilloma].

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, randomized, multicenter, phase III trial.

BACKGROUND: Polymeric micellar paclitaxel (pm-Pac) is a novel Cremophor EL-free, nanoparticle micellar formulation of paclitaxel. We aimed to compare the efficacy and safety between pm-Pac plus cisplatin and solvent-based paclitaxel (sb-Pac) plus cisplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 448 stage IIIB to IV NSCLC patients were randomly assigned (2:1) to receive six 3-week cycles of either pm-Pac (230 mg/m2) plus cisplatin (70 mg/m2; n = 300), followed by dose escalation of pm-Pac to 300 mg/m2 from the second 3-week cycle if prespecified toxic effects were not observed after the first cycle, or sb-Pac (175 mg/m2) plus cisplatin (70 mg/m2; n = 148). The primary end point was objective response rate (ORR) assessed by independent review committees (IRCs). The secondary end points included IRC-assessed progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Patients in the pm-Pac-plus-cisplatin group showed significant improvements in IRC-assessed ORR compared with those in the sb-Pac-plus-cisplatin group (50% versus 26%; rate ratio 1.91; P < 0.0001). Additionally, subgroup analysis showed that a higher ORR was consistently observed in both squamous and nonsquamous histological types. IRC-assessed median PFS was significantly higher in the pm-Pac-plus-cisplatin group than in the sb-Pac-plus-cisplatin group (6.4-month versus 5.3-month; hazard ratio 0.63; P = 0.0001). Median OS was not significantly different between the two groups. The incidence of treatment-related serious adverse events (9% versus 18%; P = 0.0090) was significantly lower in the pm-Pac-plus-cisplatin group than in the sb-Pac-plus-cisplatin group. CONCLUSION: Pm-Pac plus cisplatin yielded superior ORR and PFS along with a favorable safety profile and should become an option for patients with advanced NSCLC. CLINICAL TRIAL IDENTIFIER: ClinicalTrials.gov NCT02667743; https://clinicaltrials.gov/ct2/show/NCT02667743.

The molecular functions of Biodentine and mineral trioxide aggregate in lipopolysaccharide-induced inflamed dental pulp cells.

AIM: To explore the proliferation, adhesion and differentiation response and the underlying mechanisms that occur in lipopolysaccharide (LPS)-induced inflamed dental pulp cells (DPCs) in contact with Biodentine and mineral trioxide aggregate (MTA). METHODOLOGY: The DPCs were isolated from three healthy donors and named DPC-H1 to DPC-H3. The DPCs were pre-cultured with 2 or 5 µg mL-1 LPS for 24 h to induce inflammation. The expression of inflammation marker miR-146a was detected by q-PCR. The normal and LPS-induced DPCs were further treated with 0.14 mg mL-1 Biodentine or 0.13 mg mL-1 MTA for 24 h. MTT assay and adhesion assay were used to analyse the changes of cell phenotypes. DSPP, AKT and ERK expressions were detected by Western blotting. The data were analysed by Mann-Whitney test or two-way anova. Differences were considered statistically significant when P < 0.05. RESULTS: In LPS-induced DPCs, Biodentine and MTA treatment neither induced nor aggravated LPS-induced inflammation, but their presence did increase the expression of the odontogenic differentiation marker DSPP. Under 2 or 5 µg mL-1 LPS-induced inflammation, Biodentine and MTA promoted the proliferation of DPC cells, and significantly in DPC-H2 (P < 0.0001 for both reagents). With the treatment of 2 µg mL-1 LPS, the cell adhesion of DPCs on the fibronectin-coated culture plates was increased significantly by Biodentine (P = 0.0413) and MTA (P < 0.0001). Biodentine and MTA regulated cell adhesion on the fibronectin-coated culture plates (P < 0.0001 for both reagents) and proliferation (P < 0.0001 for both reagents) via the AKT pathway. However, the AKT pathway was not involved in the expression of DSPP induced by Biodentine and MTA. CONCLUSION: Biodentine and MTA enhanced the proliferation, adhesion and differentiation of LPS-induced DPCs. The proliferation and adhesion process induced by Biodentine and MTA was via the AKT pathway. However, the cellular differentiation process might not use the same pathway, and this needs to be explored in future studies.

Association between psoriasis, psoriatic arthritis and gout: a nationwide population-based study.

BACKGROUND: Psoriasis is a common skin disease that has been recently found to be associated with various systemic inflammatory disorders. However, the association between psoriasis and gout has not been well defined. OBJECTIVE: We investigated whether there is an association between psoriasis, psoriatic arthritis and gout in a large population of patients in Taiwan. METHODS: A nationwide population-based cross-sectional study was performed using the Taiwanese National Health Insurance Research Database (NHIRD). A total of 114 623 patients with gout and 114 623 patients without gout (1 : 1 propensity score-matched according to age, sex, income category and urbanization level) were identified. The prevalence of psoriasis, psoriatic arthritis and other comorbid diseases in these two groups of patients was compared. Adjusted odds ratios (OR) were calculated using conditional logistic regression. RESULTS: There was an increased prevalence of psoriasis in patients with gout compared with patients without gout (1.6% vs. 1.1%, P < 0.0001). Subgroup analysis showed an increased prevalence of psoriatic arthritis (0.3% vs. 0.1%, P < 0.0001) in patients with gout compared with patients without gout. In addition, multiple conditional logistic regression analysis showed that gout was significantly associated with psoriasis (adjusted OR 1.30, 95% CI 1.20-1.42) and psoriatic arthritis (adjusted OR 2.50, 95% CI 1.95-3.22). After stratification by age and sex, it was found that the strength of the association between gout and psoriasis was similar among males and females but varied according to age group, with patients aged 41-50 years having the strongest association. CONCLUSION: Gout is significantly associated with psoriasis and psoriatic arthritis in the Taiwanese population, and the strength of the association varies with the patient's age. Further studies are warranted to elucidate the molecular mechanisms underlying this association.

Increased incidence of ischaemic heart disease and cerebrovascular disease in psoriasis patients with depression: a nationwide retrospective cohort study.

BACKGROUND: Psoriasis is known to confer a higher risk of cardiovascular and cerebrovascular diseases. However, very few studies have investigated whether the development of depression in psoriasis patients may further increase this vascular risk. OBJECTIVE: We investigated the risk of ischaemic heart disease and cerebrovascular disease in Taiwanese psoriasis patients with and without depression. METHODS: A nationwide population-based retrospective cohort study was performed using the National Health Insurance Research Database. We included 604 psoriasis patients with depression, who were matched to 2416 psoriasis patients without depression (1 : 4 ratio). Relative risks (RR) with 95% confidence intervals (CI) were determined using the Cox proportional hazards regression model, with adjustment for demographic characteristics and comorbidities. RESULTS: Compared with psoriasis patients without depression, psoriasis patients with depression had greater risk of developing incident ischaemic heart disease (19.5% vs. 8.3%, adjusted RR 1.98, 95% CI 1.57-2.49), cerebrovascular disease (15.6% vs. 5.9%, adjusted RR 2.29, 95% CI 1.76-2.98), and either ischaemic heart disease or cerebrovascular disease (28.3% vs. 12.5%, adjusted RR 1.94, 95% CI 1.60-2.35). Subgroup analysis showed that in psoriasis patients with depression, a higher risk of incident ischaemic heart disease or cerebrovascular disease was present in age groups 30-100 years, in both males and females, and in both lower and higher income categories. CONCLUSION: Depression is an independent risk factor for incident ischaemic heart disease and cerebrovascular disease in patients with psoriasis. Therefore, clinicians need to be vigilant for the increased vascular risk in psoriasis patients with depression.

Event-Based Surveillance at Community and Healthcare Facilities, Vietnam, 2016-2017.

Surveillance and outbreak reporting systems in Vietnam required improvements to function effectively as early warning and response systems. Accordingly, the Ministry of Health of Vietnam, in collaboration with the US Centers for Disease Control and Prevention, launched a pilot project in 2016 focusing on community and hospital event-based surveillance. The pilot was implemented in 4 of Vietnam's 63 provinces. The pilot demonstrated that event-based surveillance resulted in early detection and reporting of outbreaks, improved collaboration between the healthcare facilities and preventive sectors of the ministry, and increased community participation in surveillance and reporting.

Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy.

Background: Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM. Patients and methods: Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled. Results: A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P < 0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P = 0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression. Conclusion: CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.

Hepatitis B virus and risk of non-Hodgkin lymphoma: An updated meta-analysis of 58 studies.

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV-infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20-2.83) regardless of the study design (case-control studies: sOR: 2.47; 95% CI: 2.16-2.82; cohort studies: sOR: 2.64; 95% CI: 1.78-3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta-regression: P < .05). Overall, B-cell NHL (sOR: 2.46; 95% CI: 1.97-3.07) presented a stronger association with HBV infection than T-cell NHL (sOR: 1.67; 95% CI: 1.34-2.10). Within the B-cell NHL subtypes, HBV infection was significantly associated with diffuse large B-cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48-2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11-2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta-analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV-induced NHL are warranted.

Characterization of the B-cell receptor repertoires in peanut allergic subjects undergoing oral immunotherapy.

B-cell receptors (BCRs) play a critical role in adaptive immunity as they generate highly diverse immunoglobulin repertoires to recognize a wide variety of antigens. To better understand immune responses, it is critically important to establish a quantitative and rapid method to analyze BCR repertoire comprehensively. Here, we developed "Bcrip", a novel approach to characterize BCR repertoire by sequencing millions of BCR cDNA using next-generation sequencer. Using this method and quantitative real-time PCR, we analyzed expression levels and repertoires of BCRs in a total of 17 peanut allergic subjects' peripheral blood samples before and after receiving oral immunotherapy (OIT) or placebo. By our methods, we successfully identified all of variable (V), joining (J), and constant (C) regions, in an average of 79.1% of total reads and 99.6% of these VJC-mapped reads contained the C region corresponding to the isotypes that we aimed to analyze. In the 17 peanut allergic subjects' peripheral blood samples, we observed an oligoclonal enrichment of certain immunoglobulin heavy chain alpha (IGHA) and IGH gamma (IGHG) clones (P = 0.034 and P = 0.027, respectively) in peanut allergic subjects after OIT. This newly developed BCR sequencing and analysis method can be applied to investigate B-cell repertoires in various research areas, including food allergies as well as autoimmune and infectious diseases.

The era of immunogenomics/immunopharmacogenomics.

Although germline alterations and somatic mutations in disease cells have been extensively analyzed, molecular changes in immune cells associated with disease conditions have not been characterized in depth. It is clear that our immune system has a critical role in various biological and pathological conditions, such as infectious diseases, autoimmune diseases, drug-induced skin and liver toxicity, food allergy, and rejection of transplanted organs. The recent development of cancer immunotherapies, particularly drugs modulating the immune checkpoint molecules, has clearly demonstrated the importance of host immune cells in cancer treatments. However, the molecular mechanisms by which these new therapies kill tumor cells are still not fully understood. In this regard, we have begun to explore the role of newly developed tools such as next-generation sequencing in the genetic characterization of both cancer cells and host immune cells, a field that is called immunogenomics/ immunopharmacogenomics. This new field has enormous potential to help us better understand changes in our immune system during the course of various disease conditions. Here we report the potential of deep sequencing of T-cell and B-cell receptors in capturing the molecular contribution of the immune system, which we believe plays critical roles in the pathogenesis of various human diseases.

[The spatial distribution and epidemic trend of silicosis in Guangdong province].

Objective: To investigate the characteristics, temporal trend of silicosis, and provide basis for risk assessment and precise prevention and control of occupational diseases. Methods: Using descriptive statistics to analyze the reported cases of silicosis by SPSS 20.0 software. Reported silicosis cases, the constituent ratio, the incidence age and the working age at onset were analyzed by a linear trend test. Analyzing the variation trends of regional, industry, economic type and enterprise scale distributions by the chi-square trend test. Moreover, using Moran's I method for spatial autocorrelation analysis and trend-surface analysis. Results: (1) During 2006 to 2015, Guangdong province had reported 1, 428 cases of silicosis, mainly gathered in Foshan, Zhongshan, Guangzhou, Shenzhen, which included 1391 male cases accounting for 97.41%. And the average incidence age was 45 (39, 51) . The average working age of onset was 9 (5.5, 15) . In economic type distribution, the private economy took the main part, accounting for 59.1%. In enterprise scale distribution, it was dominated by small and medium enterprises (SMEs) , accounting for 32.4% and 37.3% respectively. In industry distribution, most cases were gathered in materials and mining industry, accounting for 32.1% and 22.9% respectively. (2) The number of silicosis cases, the incidence age and the working age of onset showed a rising trend (P<0.01) . Meanwhile, the constituent ratios of medium-sized enterprises and building materials industry were increasing (P<0.05) . The annual variation trends of regional, economic type and age distributions were not statistically significant (P> 0.05) . (3) The spatial distribution trend showed an inverted U type, which was firstly raised and then declined from south to north and from east to west. The distribution characteristic demonstrated some high-high cluster areas, including Chancheng, Nanhai, Shunde, Panyu, Dongguan, Pengjiang, and Zhongshan. While Wuhua showed a high-low outlier form (P<0.01) . Conclusion: Silicosis cases, age and working age of onset were on the rise, as well as the industry and enterprise scale distributions of occupational diseases presented a certain trend in Guangdong province from 2006 to 2015. There were high-high cluster and high-low outlier phenomena in spatial distribution with spatial correlation. Therefore, our work of silicosis epidemic trend and distribution may provide some bases for the occupational disease risk assessment and control.

A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations.

BACKGROUND: A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21. METHODS: Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival. RESULTS: A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62-1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172). CONCLUSIONS: The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities.

MicroRNA-related genetic variants in iron regulatory genes, dietary iron intake, microRNAs and lung cancer risk.

Background: Genetic variations in MicroRNA (miRNA) binding sites may alter structural accessibility of miRNA binding sites to modulate risk of cancer. This large-scale integrative multistage study was aimed to evaluate the interplay of genetic variations in miRNA binding sites of iron regulatory pathway, dietary iron intake and lung cancer (LC) risk. Patients and methods: The interplay of genetic variant, dietary iron intake and LC risk was assessed in large-scale case-control study. Functional characterization of the validated SNP and analysis of target miRNAs were performed. Results: We found that the miRNA binding site SNP rs1062980 in 3' UTR of Iron-Responsive Element Binding protein 2 gene (IREB2) was associated with a 14% reduced LC risk (P value = 4.9×10 - 9). Comparing to AA genotype, GG genotype was associated with a 27% reduced LC risk. This association was evident in males and ever-smokers but not in females and never-smokers. Higher level of dietary iron intake was significantly associated with 39% reduced LC risk (P value = 2.0×10 - 8). This association was only present in individuals with AG + AA genotypes with a 46% reduced risk (P value = 1.0×10 - 10), but not in GG genotype. The eQTL-analysis showed that rs1062980 significantly alters IREB2 expression level. Rs1062980 is predicted to alter a miR-29 binding site on IREB2 and indeed the expression of miR-29 is inversely correlated with IREB2 expression. Further, we found that higher circulating miR-29a level was significantly associated with 78% increased LC risk. Conclusion: The miRNA binding site SNP rs1062980 in iron regulatory pathway, which may alter the expression of IREB2 potentially through modulating the binding of miR-29a, together with dietary iron intake may modify risk of LC both individually and jointly. These discoveries reveal novel pathway for understanding lung cancer tumorigenesis and risk stratification.

Comparison of exome-based HLA class I genotyping tools: identification of platform-specific genotyping errors.

Accurate human leukocyte antigen (HLA) genotyping is critical in studies involving the immune system. Several algorithms to estimate HLA genotypes from whole-exome data were developed. We compared the accuracy of seven algorithms, including Optitype, Polysolver and PHLAT, as well as investigated patterns and possible causes of miscalls using 12 clinical samples and 961 individuals from the 1000 Genomes Project. Optitype showed the highest accuracy of 97.2% for HLA class I alleles at the second field resolution, followed by 94.0% in Polysolver and 85.6% in PHLAT. In Optitype, 34 (21.1%) of 161 miscalls were across different serological types, and common miscalls were HLA-A*26:01 to HLA-A*25:01, HLA-B*45:01 to HLA-B*44:15 and HLA-C*08:02 to HLA-C*05:01 with error rates of 4.1%, 10.0% and 4.1%, respectively. In Polysolver, 193 (55.9%) of 345 miscalls occurred across different serological alleles, and a specific pattern of genotyping error from HLA-A*25:01 to HLA-A*26:01 was observed in 93.3% of HLA-A*25:01 carriers, due to dropping of HLA-A*25:01 sequence reads during the extraction process of HLA reads. In PHLAT, 147 (59.8%) of 246 miscalls in HLA-A were due to erroneous assignment of multiple alleles to either HLA-A*01:22 or HLA-A*01:81. These results suggest that careful considerations needed to be taken when using exome-based HLA class I genotyping data and applying these results in clinical settings.

Strengthening Multipayer Collaboration: Lessons From the Comprehensive Primary Care Initiative.

Policy Points: Collaboration across payers to align financial incentives, quality measurement, and data feedback to support practice transformation is critical, but challenging due to competitive market dynamics and competing institutional priorities. The Centers for Medicare & Medicaid Services or other entities convening multipayer initiatives can build trust with other participants by clearly outlining each participant's role and the parameters of collaboration at the outset of the initiative. Multipayer collaboration can be improved if participating payers employ neutral, proactive meeting facilitators; develop formal decision-making processes; seek input on decisions from practice representatives; and champion the initiative within their organizations. CONTEXT: With increasing frequency, public and private payers are joining forces to align goals and resources for primary care transformation. However, sustaining engagement and achieving coordination among payers can be challenging. The Comprehensive Primary Care (CPC) initiative is one of the largest multipayer initiatives ever tested. Drawing on the experience of the CPC initiative, this paper examines the factors that influence the effectiveness of multipayer collaboration. METHODS: This paper draws largely on semistructured interviews with CPC-participating payers and payer conveners that facilitated CPC discussions and on observation of payer meetings. We coded and analyzed these qualitative data to describe collaborative dynamics and outcomes and assess the factors influencing them. FINDINGS: We found that several factors appeared to increase the likelihood of successful payer collaboration: contracting with effective, neutral payer conveners; leveraging the support of payer champions, and seeking input on decisions from practice representatives. The presence of these factors helped some CPC regions overcome significant initial barriers to achieve common goals. We also found that leadership from the Centers for Medicare & Medicaid Services (CMS) was key to achieving broad payer engagement in CPC, but CMS's dual role as initiative convener and participating payer at times made collaboration challenging. CMS was able to build trust with other payers by clarifying which parts of CPC could be adapted to regional contexts, deferring to other payers for these decisions, and increasing opportunities for payers to meet with CMS representatives. CONCLUSIONS: CPC demonstrates that when certain facilitating factors are present, payers can overcome competitive market dynamics and competing institutional priorities to align financial incentives, quality measurement, and data feedback to support practice transformation. Lessons from this large-scale, multipayer initiative may be helpful for other multipayer efforts getting under way.

Effect of high glucose, Porphyromonas gingivalis lipopolysaccharide and advanced glycation end-products on production of interleukin-6/-8 by gingival fibroblasts.

BACKGROUND AND OBJECTIVE: It is known that chronic periodontal infection can magnify the cytokine responses in patients with diabetes. Hyperglycemia increases the proinflammatory status, including the levels of advanced glycation end-products (AGEs), in patients with periodontitis. However, whether AGEs have additional effects on the production of those proinflammatory cytokines in diabetic patients with periodontitis is still unknown. To examine in vitro the effect of hyperglycemia and AGEs on the amounts of interleukin (IL)-6 and IL-8 produced in periodontally infected gingiva, human gingival fibroblasts (HGFs) were stimulated with glucose, AGE-modified bovine serum albumin (AGE-BSA) and Porphyromonas gingivalis LPS in the present study. MATERIAL AND METHODS: Primary culture of HGFs was incubated with various concentrations of AGE-BSA (0, 50, 100 and 200 µg/mL) and LPS (0, 10, 100 or 1000 ng/mL) at two different glucose concentrations - normal glucose (5 mm) and high glucose (25 mm). The amounts of IL-6 and IL-8 produced by HGFs were evaluated using ELISA. Expression of the AGE receptor on HGFs was determined by flow cytometry. RESULTS: High glucose stimulated a significant increase in the production of IL-6 and IL-8 by HGFs compared with normal glucose. This enhanced production of IL-6 and IL-8 could also be observed in the presence of LPS and/or AGE-BSA. When both LPS and AGE-BSA were present, especially at high concentrations (≥ 500 µg/mL of LPS and ≥ 25 µg/mL of AGE-BSA), a synergistic effect on IL-8 production was found in the high-glucose condition. CONCLUSIONS: A synergistic effect of the production of IL-8 could be induced in HGFs with the combination of high glucose, LPS and AGEs.

Bipolar resistive switching with negative differential resistance effect in a Cu/BaTiO3/Ag device.

We demonstrate that a bipolar non-volatile resistive switching behaviour with negative differential resistance (NDR) effect is realized in a Cu/BaTiO3/Ag device, which was deposited on a Si substrate via magnetron sputtering equipment. We suggest that the bipolar resistive switching is dominated by the trapping/detrapping of electrons at the BaTiO3-Cu interface. In addition, we demonstrate that the device exhibits good performance, including a large on/off ratio, high reliability and long retention time. Therefore, BaTiO3 may become a good candidate for application in resistive switching random access memory (RRAM) devices.

Risk of developing psoriasis in patients with schizophrenia: a nationwide retrospective cohort study.

BACKGROUND: Schizophrenia is a complex disease which proceeds from an interaction between genetic background and environmental factors. Recent studies showed T helper 17 (Th17) signalling, which is the main downstream immune response of psoriasis, is activated in schizophrenia. OBJECTIVE: To investigate whether patients with schizophrenia have higher risk of psoriasis. METHODS: In this nationwide retrospective cohort study, we analysed the 1 million enrollees' cohort from Taiwan's National Health Insurance Research Database. Psoriasis and schizophrenia were ascertained by International Classification of Diseases, 9th revision, Clinical Modification coding. The study cohort was comprised of enrollees diagnosed with schizophrenia during the period from 1 January 1996 through 31 December 2010, while the comparison population consisted of enrollees who had not been diagnosed with schizophrenia during the study period. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for the risk of psoriasis associated with schizophrenia using Cox proportional hazard regression. RESULTS: The adjusted HR of psoriasis associated with schizophrenia was 2.32 (95% CI = 1.81-2.98). After 15 years, the cumulative incidence of psoriasis in patients with schizophrenia and comparison population was 2.82% and 1.17%, respectively. The Kaplan-Meier curves for the cumulative incidence of psoriasis in individuals with and without schizophrenia differed significantly (P < 0.0001, log-rank test). CONCLUSIONS: Patients with schizophrenia have higher risk of psoriasis, which may be due to common genetic susceptibilities and/or immunologic mechanisms in both diseases. Th17 signalling and pro-inflammatory cytokines may act as a link between these two diseases and are potential therapeutic targets for schizophrenia.

Clinical analysis of hyperkalemic renal tubular acidosis caused by calcineurin inhibitors in solid organ transplant recipients.

WHAT IS KNOWN AND OBJECTIVE: Calcineurin inhibitor (CNI)-based immunosuppressive regimen is widely used for preventing rejection in solid organ transplantation. Hyperkalemic renal tubular acidosis (RTA) caused by CNI is uncommon and potentially underappreciated. We reported four such cases to increase awareness of this risk and to provide recommendations for its management based on our experience. CASE SUMMARY: Four middle-aged males underwent solid organ transplant (two kidneys, one liver, one heart) and were treated with CNI-based immunosuppressive regimen (one cyclosporine A, three tacrolimus). On post-operative day 13-35, hyperkalemic hyperchloremic non-gap metabolic acidosis developed. All patients had relatively preserved renal function, normal urine output and plasma aldosterone level. Reduction in CNI dosage was partly effective; the patient on cyclosporine A was treated with fludrocortisone, and two others temporarily switched to sirolimus (SRL). WHAT IS NEW AND CONCLUSION: We should alert for CNI-induced hyperkalemic RTA in transplant recipients. By CNI dosage reduction or adding low dose fludrocortisone, or temporarily switching to SRL, the prognosis of CNI-induced hyperkalemic RTA is favourable.