Independent insulin signaling modulators govern hot avoidance under different feeding states.

Thermosensation is critical for the survival of animals. However, mechanisms through which nutritional status modulates thermosensation remain unclear. Herein, we showed that hungry Drosophila exhibit a strong hot avoidance behavior (HAB) compared to food-sated flies. We identified that hot stimulus increases the activity of α'ß' mushroom body neurons (MBns), with weak activity in the sated state and strong activity in the hungry state. Furthermore, we showed that α'ß' MBn receives the same level of hot input from the mALT projection neurons via cholinergic transmission in sated and hungry states. Differences in α'ß' MBn activity between food-sated and hungry flies following heat stimuli are regulated by distinct Drosophila insulin-like peptides (Dilps). Dilp2 is secreted by insulin-producing cells (IPCs) and regulates HAB during satiety, whereas Dilp6 is secreted by the fat body and regulates HAB during the hungry state. We observed that Dilp2 induces PI3K/AKT signaling, whereas Dilp6 induces Ras/ERK signaling in α'ß' MBn to regulate HAB in different feeding conditions. Finally, we showed that the 2 α'ß'-related MB output neurons (MBONs), MBON-α'3 and MBON-ß'1, are necessary for the output of integrated hot avoidance information from α'ß' MBn. Our results demonstrate the presence of dual insulin modulation pathways in α'ß' MBn, which are important for suitable behavioral responses in Drosophila during thermoregulation under different feeding states.

Calibration improves the agreement in grading oral epithelial dysplasia-Findings from a National Workshop in Malaysia.

INTRODUCTION: A major pitfall of many of the established oral epithelial dysplasia (OED) grading criteria is their lack of reproducibility and accuracy to predict malignant transformation. The main objective of this study was to determine whether calibration of practicing oral pathologists on OED grading could improve the reproducibility of the WHO 2017 and the binary OED grading systems. METHODS: A nationwide online exercise was carried out to determine the influence of calibration on the reproducibility of the WHO 2017 and the binary OED grading systems. RESULTS: A significant improvement was observed in the inter-observer agreement for the WHO 2017 OED grading system (K 0.196 vs. 0.448; Kw 0.357 vs. 0.562) after the calibration exercise. The significant difference (p = 0.027) in the level of agreement between those with five or more years and less than 5 years of experience was no more observed (p = 0.426) after the calibration exercise. The percent agreement for binary grading was significantly higher (91.8%) for buccal mucosal lesions as compared to lesions on the tongue after the calibration exercise. CONCLUSION: This study validates the significance of calibration in improving the reproducibility of OED grading. The nationwide exercise resulted in a statistically significant improvement in the inter-observer agreement for the WHO 2017 OED grading system among a large number of oral pathologists. It is highly recommended that similar exercises should be organized periodically by professional bodies responsible for continuing education among oral pathologists to improve the reliability of OED grading for optimal treatment of oral potentially malignant disorders.

Urban-Rural Disparity in Birth Cohort Effects on Breast Cancer Incidence.

Breast cancer is the most commonly diagnosed cancer among women worldwide. Studies have reported minimal birth cohort effects on the incidence rates of breast cancer in Western countries but have reported notable birth cohort effects in some Asian countries. The risks of breast cancer may also vary within a country. In the present study, we abstracted female invasive breast cancer data from the Taiwan Cancer Registry for the period 1997-2016. We used the age-period-cohort model to compare birth cohort effects on breast cancer incidence rates between urban and rural regions in Taiwan. We identified a notable urban-rural disparity in birth cohort effects on breast cancer incidence rates in women in Taiwan. The incidence rates in the urban regions were higher than those in the rural regions across all cohorts. However, the incidence rates rose faster in the rural regions than in the urban regions across the cohorts. The risks of breast cancer observed for women born in 1992 were approximately 22 and 11 times than those observed for women born in 1917 in rural and urban regions, respectively. The observed gap in breast cancer incidence rates between the urban and rural regions gradually disappeared across the cohorts. Accordingly, we speculate that urbanization and westernization in Taiwan may be the drivers of female breast cancer incidence rates across birth cohorts.

Ambulatory uniportal versus biportal endoscopic unilateral laminotomy with bilateral decompression for lumbar spinal stenosis-cohort study using a prospective registry.

BACKGROUND: Endoscopic spine surgery has been established as a practical, minimally invasive technique for decompression in patients with lumbar spinal stenosis. However, there remains a paucity of studies prospective cohort study comparing uniportal lumbar endoscopic unilateral laminotomy with bilateral decompression and unilateral biportal endoscopic unilateral laminotomy with bilateral decompression with open spinal decompression-both viable techniques with satisfactory clinical outcomes in the treatment of lumbar spinal stenosis. OBJECTIVE/AIM: To compare the efficacy of UPE and BPE lumbar decompression surgery for patients with lumbar spinal stenosis. METHODS: A prospective registry of patients who had undergone spinal decompression for lumbar stenosis via UPE or BPE under a single fellowship trained spine surgeon was studied. Baseline characteristics, initial clinical presentation, and operative details including complications were recorded for all included patients. Clinical outcomes, such as visual analogue scale and Oswestry Disability Index, were recorded at preoperative, immediate postoperative, 2-week, 3-, 6-, and 12-month follow-up periods. RESULTS: A total of 62 patients underwent endoscopic decompression surgery for lumbar spinal stenosis (29 UPE, 33 BPE). No significant baseline differences were found between uniportal and biportal decompression, when comparing operative duration (130 vs. 140 min; p = 0.30), intraoperative blood loss (5.4 vs. 6mLs; p = 0.05), and length of hospital stay (23.6 vs. 20.3 h; p = 0.35). Two patients (7%) who underwent uniportal endoscopic decompression required conversion to open surgery due to inadequate decompression. Intraoperative complication rates were significantly higher in the UPE group (13.4% vs. 0%, p < 0.05). VAS score (leg & back) and ODI improved significantly (p < 0.001) in both endoscopic decompression groups across all follow-up time points, with no appreciable statistical differences between both groups. CONCLUSION: UPE has the same efficacy as BPE in the treatment of lumbar spinal stenosis. While UPE surgery enjoys added aesthetic benefits of only one wound, BPE had potentially lower risks of intraoperative complication, inadequate decompression, and conversion to open surgery during early period of learning curve.

Rare presentations of primary amyloidosis as ptosis: a case report.

BACKGROUND: Amyloidosis is a rare, progressive and variable group of diseases characterized by extracellular deposits of amyloid protein in different tissues and organs. It is a protein-misfolding disease in which small proteins of about 10 to 15 kDa acquire an alternative and relatively misfolded state at minimum energy and subsequently aggregate into oligomers and polymers. It mimics other eyelid diseases, such as involutional ptosis, eyelid granulomatous or cancerous lesions. Misdiagnosis of eyelid amyloidosis is usual when the lesion grows slowly and insidiously. Definite diagnosis depends on clinical suspicion and tissue-proven biopsy. CASE PRESENTATION: A 50-year-old female had painless progressive ptosis in both eyes for 6 months. She presented with limited upward gaze due to swelling of the upper eyelids OU. She complained of mild foreign body sensation. Upon examination, we observed an infiltrated irregular yellowish mass on the surface of her upper palpebral conjunctiva in both eyes. The mass was non-movable without tenderness. We performed excisional biopsy for the masses and subsequent histopathology of the biopsy specimens revealed amyloidosis. Systemic workup showed no other lesions. Unfortunately, her ptosis and upward gaze restriction was not improved after the operation. However, the masses did not enlarge in the following 3 months. CONCLUSIONS: The varied presentations of ocular adnexal and orbital amyloidosis often lead to a significant delay between first symptoms and diagnosis. Immediate confirmatory biopsy and subsequent systemic workup should be performed whenever amyloidosis is highly suspected.

Non-alcoholic fatty liver disease among patients with sleep disorders: a Nationwide study of Taiwan.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. Studies have shown that sleep apnea is associated with NAFLD. However, studies on the association between sleep disorders in general and NAFLD are limited. We conducted a nationwide population-based longitudinal study to evaluate this potential association. METHODS: We identified patients diagnosed with sleep disorders in the years 2000 through 2005 in Taiwan using the National Health Insurance Research Database and selected an equal number of patients without sleep disorders from the same database as the comparison cohort. The patients were followed from the index date to the diagnosis of NAFLD or the end of 2013. We used Cox proportional hazards models to estimate the risk of NAFLD associated with sleep disorders. RESULTS: A total of 33,045 patients with sleep disorders were identified. The incidence of NAFLD was 14.0 per 10,000 person-year in patients with sleep disorders and 6.2 per 10,000 person-year in the comparison cohort. The adjusted hazard ratio (AHR) of NAFLD associated with sleep disorders was 1.78 (95% confidence interval [95%CI]: 1.46-2.16), and other independent risk factors included male sex (AHR = 1.31, 95%CI: 1.12-1.54), age 40-59 years (AHR = 1.49, 95%CI: 1.21-1.82), and dyslipidemia (AHR = 2.51, 95%CI: 2.08-3.04). In the subgroup analyses, both patients with (AHR = 2.24, 95%CI: 1.05-4.77) and without (AHR = 1.77, 95%CI: 1.46-2.15) sleep apnea had an increased risk of NAFLD. CONCLUSIONS: Sleep disorders are associated with NAFLD, even in patients without sleep apnea. Further studies are warranted to explore the mechanisms of the association.

Chronic ileitis with transmural migration of ingested foreign body treated by laparoscopy.

BACKGROUND: Ingestion of foreign bodies such as fish bone or chicken bone is relatively common in adults; however, resultant transmural migration is extremely rare. METHODS: We present a case of a 79-year-old woman with chronic low-grade abdominal pain, worsening over the last 4 days. Computed tomography revealed segmental small bowel wall thickening with chronic inflammation suggestive of Crohn's ileitis and oral steroids were commenced; only later, ingestion of a foreign body was suspected. RESULTS AND CONCLUSION: At diagnostic laparoscopy, a linear foreign body resembling a wooden splinter was identified. It had partly migrated through the chronically inflamed bowel wall without causing perforation or abdominal contamination. It was removed laparoscopically without an enterotomy or bowel resection. Microscopy revealed non-viable bone, likely fish or chicken bone. The patient made an uneventful recovery and was discharged 3 days later. Herein we emphasise on the differential diagnosis and presentation of chronically ingested foreign bodies, as well as the feature of chronic ileitis with uncomplicated transmural migration of the ingested foreign body that was treated laparoscopically without an enterotomy.

Influence of job demands and job control on work-life balance among Taiwanese nurses.

AIM: This study investigated the extent to which the job demands and job control of nurses were related to their work-life balance. BACKGROUND: The inability to achieve work-life balance is one of the major reasons for the declining retention rate among nurses. Job demands and job control are two major work domain factors that can have a significant influence on the work-life balance of nurses. METHOD: The study measured the job demands, job control and work-life balance of 2040 nurses in eight private hospitals in Taiwan in 2013. RESULTS: Job demands and job control significantly predicted all the dimensions of work-life balance. Job demands increased the level of work-life imbalance among nurses. While job control showed positive effects on work/personal life enhancement, it was found to increase both work interference with personal life and personal life interference with work. CONCLUSION: Reducing the level of job demands (particularly for psychological demands) between family and career development and maintaining a proper level of job control are essential to the work-life balance of nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Flexible work practices and team-based management could be considered by nursing management to lessen job demand pressure and to facilitate job engagement and participation among nurses, thus promoting a better balance between work and personal life.

Induction of autoimmune response to the extracellular loop of the HERG channel pore induces QTc prolongation in guinea-pigs.

KEY POINTS: Channelopathies of autoimmune origin are novel and are associated with corrected QT (QTc) prolongation and complex ventricular arrhythmias. We have recently demonstrated that anti-SSA/Ro antibodies from patients with autoimmune diseases and with QTc prolongation on the ECG target the human ether-à-go-go-related gene (HERG) K+ channel by inhibiting the corresponding current, IKr , at the pore region. Immunization of guinea-pigs with a peptide (E-pore peptide) corresponding to the extracellular loop region connecting the S5 and S6 segments of the HERG channel induces high titres of antibodies that inhibit IKr , lengthen the action potential and cause QTc prolongation on the surface ECG. In addition, anti-SSA/Ro-positive sera from patients with connective tissue diseases showed high reactivity to the E-pore peptide. The translational impact is the development of a peptide-based approach for the diagnosis and treatment of autoimmune-associated long QT syndrome. ABSTRACT: We recently demonstrated that anti-SSA/52 kDa Ro antibodies (Abs) from patients with autoimmune diseases and corrected QT (QTc) prolongation directly target and inhibit the human ether-à-go-go-related gene (HERG) K+ channel at the extracellular pore (E-pore) region, where homology with SSA/52 kDa Ro antigen was demonstrated. We tested the hypothesis that immunization of guinea-pigs with a peptide corresponding to the E-pore region (E-pore peptide) will generate pathogenic inhibitory Abs and cause QTc prolongation. Guinea-pigs were immunized with a 31-amino-acid peptide corresponding to the E-pore region of HERG. On days 10-62 after immunization, ECGs were recorded and blood was sampled for the detection of E-pore peptide Abs. Serum samples from patients with autoimmune diseases were evaluated for reactivity to E-pore peptide by enzyme-linked immunosorbent assay (ELISA), and histology was performed on hearts using Masson's Trichrome. Inhibition of the HERG channel was assessed by electrophysiology and by computational modelling of the human ventricular action potential. The ELISA results revealed the presence of high titres of E-pore peptide Abs and significant QTc prolongation after immunization. High reactivity to E-pore peptide was found using anti-SSA/Ro Ab-positive sera from patients with QTc prolongation. Histological data showed no evidence of fibrosis in immunized hearts. Simulations of simultaneous inhibition of repolarizing currents by anti-SSA/Ro Ab-positive sera showed the predominance of the HERG channel in controlling action potential duration and the QT interval. These results are the first to demonstrate that inhibitory Abs to the HERG E-pore region induce QTc prolongation in immunized guinea-pigs by targeting the HERG channel independently from fibrosis. The reactivity of anti-SSA/Ro Ab-positive sera from patients with connective tissue diseases with the E-pore peptide opens novel pharmacotherapeutic avenues in the diagnosis and management of autoimmune-associated QTc prolongation.

IL-1ß induces IL-6 production in retinal Müller cells predominantly through the activation of p38 MAPK/NF-κB signaling pathway.

IL-6 plays an important role in various inflammatory ocular diseases, including diabetic retinopathy. Müller cells are the major source of inflammatory mediators, including IL-6, in the retina. However, the mechanism of regulating IL-6 production in these cells remains unclear. Examination of signaling pathways in human retinal Müller cells (MIO-M1 cell line) cultured with IL-1ß, TNF-α, IL-6, IL-8, VEGF, IFN-γ, glucose or mannitol showed that IL-1ß was the most potent stimulator of IL-6 production. In addition, IL-1 ß also increased NF-κB p50 protein level and phosphorylation of p38 MAPK, ERK1/2 and c-Jun. Induction of IL-6 production by IL-1ß was significantly reduced by addition of p38 MAPK (SB203580), MEK1/2 (U0126) or NF-κB (BAY11-7082) inhibitors, with the highest effect being observed with SB203580. To explore the specific elements in IL-6 promoter responsible for IL-1ß-induction of IL-6 expression, a series of plasmids bearing various IL-6 promoter mutations were transiently expressed in MIO-MI cells cultured in the presence or absence of IL-1ß (10ng/ml) and/or SB203580 (10µM). Results showed that IL-6 promoter activity of the parent pIL-6-Luc651 was significantly enhanced by IL-1ß, but the level was significantly attenuated by SB203580. Furthermore, the IL-6 promoter activity was also reduced upon deletion of NF-κB, AP-1 or C/EBP binding sites, with NF-κB deletion being the greatest. These results are the first demonstration that IL-1ß induces IL-6 production in Müller cells by activation of IL-6 promoter activity predominantly through the p38 MAPK/NF-κB pathway.

Revisiting the streptavidin-biotin binding by using an aptamer and displacement isothermal calorimetry titration.

The association constant of a well-known streptavidin-biotin binding has only been inferred from separately measured kinetic parameters. In a single experiment, we obtained Ka 1 × 10(12) M(-1) by using a streptavidin-binding aptamer and ligand-displacement isothermal titration calorimetry. This study explores the challenges of determining thermodynamic parameters and the derived equilibrium binding affinity of tight ligand-receptor binding.

Stromal androgen receptor in prostate development and cancer.

The androgen receptor (AR) in stromal cells contributes significantly to the development and growth of prostate during fetal stages as well as during prostate carcinogenesis and cancer progression. During prostate development, stromal AR induces and promotes epithelial cell growth, as observed from tissue recombinant and mouse knockout studies. During prostate carcinogenesis and progression, the stromal cells begin to lose AR expression as early as at the stage of high-grade prostatic intraepithelial neoplasia. The extent of loss of stromal AR is directly proportional to the degree of differentiation (Gleason grade) and progression of prostate cancer (PCa). Co-culture studies suggested that stromal AR inhibits the growth of malignant epithelial cells, possibly through expression of certain paracrine factors in the presence of androgens. This functional reversal of stromal AR, from growth promotion during fetal prostate development to mediating certain growth-inhibiting effects in cancer, explains to some extent the reason that loss of AR expression in stromal cells may be crucial for development of resistance to androgen ablation therapy for PCa. From a translational perspective, it generates the need to re-examine the current therapeutic options and opens a fundamental new direction for therapeutic interventions, especially in advanced PCa.

Collagen Triple Helix Repeat Containing-1 (CTHRC1) Expression in Oral Squamous Cell Carcinoma (OSCC): Prognostic Value and Clinico-Pathological Implications.

BACKGROUND: Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC. METHODS: In this study, mRNA and protein expression of CTHRC1 in OSCCs were determined by quantitative PCR and immunohistochemistry, respectively. The association between CTHRC1 and clinico-pathological parameters were evaluated by univariate and multivariate binary logistic regression analyses. Correlation between CTHRC1 protein expressions with survival were analysed using Kaplan-Meier and Cox regression models. RESULTS: Current study demonstrated CTHRC1 was significantly overexpressed at the mRNA level in OSCC. Univariate analyses indicated a high-expression of CTHRC1 that was significantly associated with advanced stage pTNM staging, tumour size ≥ 4 cm and positive lymph node metastasis (LNM). However, only positive LNM remained significant after adjusting with other confounder factors in multivariate logistic regression analyses. Kaplan-Meier survival analyses and Cox model demonstrated that patients with high-expression of CTHRC1 protein were associated with poor prognosis and is an independent prognostic factor in OSCC. CONCLUSION: This study indicated that over-expression of CTHRC1 potentially as an independent predictor for positive LNM and poor prognosis in OSCC.

BRD4 inhibitor inhibits colorectal cancer growth and metastasis.

Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.

Biobanking of derivatives from radical retropubic and robot-assisted laparoscopic prostatectomy tissues as part of the prostate cancer biorepository network.

BACKGROUND: The goal of the Prostate Cancer Biorepository Network (PCBN) is to develop a biorepository with high-quality, well-annotated specimens obtained in a systematic, reproducible fashion using optimized and standardized protocols, and an infrastructure to facilitate the growth of the resource and its wide usage by the prostate cancer research community. An emerging area of concern in the field of prostate cancer biobanking is an apparent shift in the proportion of surgical procedures performed for prostate cancer treatment from radical retropubic prostatectomy (RRP) to robot-assisted laparoscopic prostatectomy (RALP). Our study aimed to determine the potential impact of the RALP procedure on the detection of known prostate cancer biomarkers, and the subsequent suitability of RALP-derived specimens for prostate cancer biomarker studies. METHODS: DNA and RNA were extracted from RRP and RALP specimens. Quality assessment was conducted using spectrophotometric analysis and RNA was analyzed for RNA integrity number (RIN) and by real-time reverse-transcription PCR (qRT-PCR) for racemase, hepsin, ERG, TMPRSS2-ERG gene fusions, and the microRNAs miR-26a, miR-26b, miR-141, and miR-221. RESULTS: We demonstrate that extraction of derivatives from frozen tissues from RRP and RALP specimens yields samples of equally high quality as assessed by spectrophotometric and RIN analysis. Likewise, expression levels of genes analyzed by qRT-PCR did not differ between RRP and RALP-derived tissues. CONCLUSIONS: Our studies indicate that samples obtained from RALP specimens may be suitable for prostate cancer biomarker studies-an important finding given the current shift in surgical procedures for prostate cancer treatment.

Calcium-dependent dynamics of cadherin interactions at cell-cell junctions.

Cadherins play a key role in the dynamics of cell-cell contact formation and remodeling of junctions and tissues. Cadherin-cadherin interactions are gated by extracellular Ca(2+), which serves to rigidify the cadherin extracellular domains and promote trans junctional interactions. Here we describe the direct visualization and quantification of spatiotemporal dynamics of N-cadherin interactions across intercellular junctions in living cells using a genetically encodable FRET reporter system. Direct measurements of transjunctional cadherin interactions revealed a sudden, but partial, loss of homophilic interactions (τ = 1.17 ± 0.06 s(-1)) upon chelation of extracellular Ca(2+). A cadherin mutant with reduced adhesive activity (W2A) exhibited a faster, more substantial loss of homophilic interactions (τ = 0.86 ± 0.02 s(-1)), suggesting two types of native cadherin interactions--one that is rapidly modulated by changes in extracellular Ca(2+) and another with relatively stable adhesive activity that is Ca(2+) independent. The Ca(2+)-sensitive dynamics of cadherin interactions were transmitted to the cell interior where ß-catenin translocated to N-cadherin at the junction in both cells. These data indicate that cadherins can rapidly convey dynamic information about the extracellular environment to both cells that comprise a junction.

Overexpression of MMP13 is associated with clinical outcomes and poor prognosis in oral squamous cell carcinoma.

Matrix metalloproteinase 13 (MMP13) plays a central role in the MMP activation cascade that enables degradation of the extracellular matrix and basement membranes, and it is identified as a potential driver in oral carcinogenesis. Therefore, this study aims to determine the copy number, mRNA, and protein expression of MMP13 in oral squamous cell carcinoma (OSCC) and to associate these expressions with clinicopathological parameters. Copy number, mRNA, and protein expression analysis of MMP13 were determined using real-time quantitative PCR and immunohistochemistry methods in OSCC samples. The correlations between MMP13 expressions and clinicopathological parameters were evaluated, and the significance of MMP13 as a prognostic factor was determined. Despite discrepancies between gene amplification and mRNA and protein overexpression rates, OSCC cases showed high amplification of MMP13 and overexpression of MMP13 at both mRNA and protein levels. High level of MMP13 protein expression showed a significant correlation with lymph node metastasis (P = 0.011) and tumor staging (P = 0.002). Multivariate Cox regression model analysis revealed that high level of mRNA and protein expression of MMP13 were significantly associated with poor prognosis (P < 0.050). Taken together, these observations indicate that the MMP13 protein overexpression could be considered as a prognostic marker of OSCC.

Diabetic foot ulcer is associated with cardiovascular-related mortality and morbidity - a systematic review and meta-analysis of 8062 patients.

OBJECTIVES: To conduct a systematic review and meta-analysis of prevalence of cardiovascular-related morbidity and mortality in patients with diabetic foot ulcers (DFU), as well as compare risks of cardiovascular-related morbidity and mortality between diabetic patients with and without DFU. METHODS: A systematic search was conducted on Medline, Embase, and Cochrane databases for randomized controlled trials and observational studies which explored the association between DFU and cardiovascular-related morbidity & mortality, or compared differences in hazard ratios of cardiovascular diseases between diabetics with and without DFU. Frequentist, pairwise meta-analysis was performed on studies with two comparator arms, whereas single-arm studies reporting pooled incidences of cardiovascular-related mortality and morbidity were calculated based on exact binomial distributions. A random-effect meta-analysis model was used with heterogenicity of studies assessed using I2, τ2, and χ2 statistics. RESULTS: 10 studies were identified and included in the systematic review & meta-analysis of 8602 patients. DFU was consistently found to have significant association with cardiovascular-related morbidity and mortality, with pooled prevalences of all cause cardiovascular-related morbidity (37.1%), IHD (44.7%), CHF (25.1%), CAD (11.7%), and CVA (10.9%), and all cause cardiovascular-related mortality (14.6%), fatal IHD (6.2%), fatal CHF (3.67%), fatal CAD (7.92%), and fatal CVA (1.99%). Diabetic patients with DFU were found to have significantly increased risk of IHD (RR 1.25), CVA (RR 2.03), and all-cause cardiovascular-related mortality (RR 2.59) compared to those without DFU. CONCLUSIONS: The presence of DFU is associated with major adverse cardiac events. The alarming rates of cardiovascular-related morbidity and mortality in DFU patients highlight its potential role as a marker of cardiovascular complications and should prompt early clinical investigation and management.

Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study.

INTRODUCTION: There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome. MATERIAL AND METHODS: A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors. RESULTS: There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862). CONCLUSIONS: Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.