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Background Patients with large hemispheric infarction (LHI) are at risk of cerebral edema (CED). This study analyzed health resource use, costs, and outcomes during and after acute hospitalization for LHI in US patients with and without CED. Methods Using IBM® MarketScan® Commercial, Medicaid, and Medicare databases, patients with incident hospitalization for LHI (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes of I63.03x, I63.13x, I63.23x, I63.31x, I63.41x, I63.51x) from 31 March 2016 through 31 December 2018 were identified and further categorized by the presence or absence of CED based on related diagnosis codes or a procedure code of craniectomy. Health resource use, costs, and outcomes were compared in patients with and without CED during hospitalization and after discharge. Results Of 7336 Commercial, 1946 Medicaid, and 5015 Medicare patients with LHI, 7.8%, 6.9%, and 4.3% had CED, respectively. After adjusting for age, sex, and baseline comorbidities, differences (95% confidence intervals) in mean total costs of the index hospitalization in patients with CED versus without CED were $65,572 ($56,506–$76,335), $44,395 ($26,442–$63,495), and $31,417 ($18,982–$48,543) in the Commercial, Medicaid, and Medicare groups, respectively. Similarly, the adjusted differences (95% confidence intervals) in mean lengths of stay between patients with CED and without CED were 11.75 (10.17–13.48), 10.84 (7.59–14.17), and 3.69 (2.40–5.19) days, respectively. Mortality during index hospitalization was 10–20 times greater in patients with CED versus without CED (p

Background: Many employees experience high levels of stress in the workplace, which negatively impact their productivity and well-being. Effective stress management interventions exist, but are inaccessible due to insufficient numbers of mental health providers, long waiting times to initiate care, high out-of-pocket cost of care, and stigma related to receiving psychotherapy. Introduction: The purpose of this study was to test the efficacy, in real-world circumstances, of a structured, cognitive behavioral coaching (CBC) program delivered through video or telephone. Materials and Methods: Retrospective data on 289 subjects who had sought support for emotional health through a behavioral health benefit offered through employers were examined. Changes in perceived stress and well-being over the course of the program were measured using the Perceived Stress Scale (PSS) and Warwick–Edinburgh Mental Well-being Scale (WEMWBS), respectively. Rates of reliable change and satisfaction with the coaching program were also assessed. Results: Scores on both the PSS and WEMWBS improved between baseline and follow-up. Approximately 61.9% (n = 289) of participants demonstrated reliable improvement on either measure. Discussion: CBC is a promising intervention that has the potential to significantly expand access to effective and more affordable interventions for emotional health care. Conclusions: Coaching, when delivered by accredited professionals trained in cognitive behavioral theory and interventions and working in real-world settings, can be efficacious in decreasing perceived stress and increasing well-being when delivered through video or telephone.

Background Treatment recommendations suggest that suicidal ideation will decrease following successful psychotherapy for depression. However, findings from the empirical research are equivocal in this regard. It is possible suicidal ideation does not respond to empirically supported treatment (EST) for depression or that suicidal ideation limits the efficacy of ESTs for depression. Methods Data from 793 patients who sought EST for depression was analyzed using t-tests and multiple linear regression. Results Both patients with (n = 233) or without suicidal ideation (n = 560) were significantly less depressed following treatment. A significant reduction in suicidal ideation was also observed. At baseline, 233 (29.4%) patients reported suicidal ideation, whereas only 90 (11.3%) patients reported suicidal ideation at follow-up. The relationship between suicidal ideation at baseline and depression scores at follow-up was not significant. Conclusions Patients with suicidal ideation who receive short-term EST can experience significant reductions in both depressive symptoms and suicidal ideation. Findings suggest that suicidal ideation at baseline does not impact treatment efficacy, but additional research that directly tests moderation is needed.

Adult brains have limited regenerative capacity. Consequently, both brain damage and neurodegenerative diseases often cause functional impairment for patients. Mesenchymal stem cells (MSCs), one type of adult stem cells, can be isolated from various adult tissues. MSCs have been used in clinical trials to treat human diseases and the therapeutic potentials of the MSC-derived secretome and extracellular vesicles (EVs) have been under investigation. We found that blocking the prostaglandin E2/prostaglandin E2 receptor 4 (PGE2/EP4) signaling pathway in MSCs with EP4 antagonists increased EV release and promoted the sorting of specific proteins, including anti-inflammatory cytokines and factors that modify astrocyte function, blood–brain barrier integrity, and microglial migration into the damaged hippocampus, into the EVs. Systemic administration of EP4 antagonist-elicited MSC EVs repaired deficiencies of cognition, learning and memory, inhibited reactive astrogliosis, attenuated extensive inflammation, reduced microglial infiltration into the damaged hippocampus, and increased blood–brain barrier integrity when administered to mice following hippocampal damage. Stem Cells Translational Medicine 2019

Large hemispheric infarction (LHI) is associated with a high likelihood of the evolution of life-threatening edema. Few studies have assessed real-world clinical outcomes and management strategies among patients with LHI. The objective of this study was to describe the management, in-hospital outcomes, and direct healthcare resource burden of patients with LHI, as well as those of patients with subsequent cerebral edema.This observational, retrospective cohort study analyzed de-identified data from US adult patients using the IBM MarketScan Hospital Drug Database (Q4-2015 to Q4-2017). Patients were included in the "Possible LHI" or the "Other Ischemic Strokes" cohorts using ICD-10 diagnosis codes. Patients with possible LHI were further categorized into "LHI with Edema" and "LHI without Edema" subgroups using diagnosis and procedure codes. Select clinical and economic outcomes were compared between cohorts and subgroups using multivariable regressions.Of 79,201 eligible encounters with ischemic strokes, 11,772 unique patients were assigned to the Possible LHI cohort while 67,429 were assigned to the Other Ischemic Strokes cohort. Among patients with possible LHI, 869 (7%) were assigned to the LHI with Edema subgroup and 10,903 (93%) were assigned to the LHI without Edema subgroup. Patients in the Possible LHI cohort had longer hospital stays (mean difference [MD] [95%CI] = 2.6 [2.4;2.8] days), higher total facility charges (MD [95%CI] = $28,656 [26,794;30,524]), and higher odds of death (odds ratio [95%CI] = 2.2 [2.0;2.4]) than the Other Ischemic Strokes cohort. Among patients with possible LHI, the incremental clinical and resource burden was further exacerbated in the subgroup of patients with edema (hospital days: MD [95%CI] = 5.0 [3.9;6.2] days; total facility charges: MD [95%CI] = $59,585 [50,816;67,583]; mortality: odds ratio [95%CI] = 10.3 [8.5;12.4]).Among patients with ischemic strokes, LHI was associated with increased clinical management and direct healthcare resource burden in real-world hospital settings. The burden was substantially increased among patients who developed cerebral edema.

Introduction: Severe cerebral edema further compromises survival and functional outcomes in patients suffering from large hemispheric infarction (LHI). This study aims to compare the healthcare resource use and costs during the acute hospitalization and post-discharge, in a cohort of US patients with possible LHI with and without cerebral edema (CED). Methods: Using IBM MarketScan Commercial, Medicaid, and Medicare databases (2016Q1-2018Q4), a cohort of patients aged 18-85 were identified using ICD10 codes for hospitalization due to occlusion of the carotid or middle cerebral arteries, which are most closely associated with LHI. We classified patients with ICD10 codes G93.5 (compression of brain), G93.6 (cerebral edema), or a craniectomy procedure as having had CED. In addition to the inpatient resource use and outcomes, annualized frequency of resource utilization and costs during the follow-up period were reported in those who survived and continued to be enrolled in their health plan post-index hospitalization. Logistic regression was used to estimate the odds ratio of mortality, generalized linear models for mean in healthcare utilization and costs between those with and without CED, adjusting for age, sex, and comorbidity. Results: Of the 7,336 commercial, 1,946 Medicaid, and 5,015 Medicare patients with possible LHI, we found 7.8%, 6.9%, and 4.3% had CED, respectively. Those with CED had higher length of stay, mortality, and costs during the index hospitalization across the populations examined (Table). CED was also consistently associated with higher post-discharge resource utilization and costs in the commercially-insured population (Table). Conclusions: This real-world evidence from private and public health plans highlights the substantial clinical and economic burden during the index hospitalization and post-discharge in patients who develop cerebral edema after LHI.

Aging kidneys are characterized by an increased vulnerability to glomerulosclerosis and a measurable decline in renal function. Evidence suggests that renal and systemic klotho and sirtuin 1 (SIRT1) deficiencies worsen kidney damage induced by exogenous stresses. The aim of this study was to explore whether resveratrol would attenuate concanavalin A (Con A)-induced renal oxidative stress and advanced glomerulosclerosis in aged mice. Aged male C57BL/6 mice were treated orally with resveratrol (30 mg/kg) seven times (12 h intervals) prior to the administration of a single tail-vein injection of Con A (20 mg/kg). The plasma and urinary levels of kidney damage markers were evaluated. The kidney histopathology, renal parameters, and oxidative stress levels were measured. Furthermore, klotho was downregulated in mouse kidney mesangial cells that were pretreated with 25 &micro, M resveratrol followed by 20 &micro, g/mL Con A. The urinary albumin/creatinine ratio, blood urea nitrogen, kidney mesangial matrix expansion, tubulointerstitial fibrosis, and renal levels of &alpha, smooth muscle actin, transforming growth factor beta, fibronectin, procollagen III propeptide, and collagen type I significantly increased in Con A-treated aged mice. Aged mice kidneys also showed markedly increased levels of 8-hydroxydeoxyguanosine (8-OH-dG) and reactive oxygen species (ROS), with reduced superoxide dismutase activity and levels of glutathione, klotho, and SIRT1 after Con A challenge. Furthermore, in kidney mesangial cells, klotho silencing abolished the effects of resveratrol on the Con A-mediated elevation of the indices of oxidative stress and the expression of glomerulosclerosis-related factors. These findings suggest that resveratrol protects against Con A-induced advanced glomerulosclerosis in aged mice, ameliorating renal oxidative stress via the SIRT1-mediated klotho expression.

Introduction: Patients with large hemispheric infarction (LHI) may suffer from life-threatening complications, including cerebral edema. Published data among these patients in real-world settings are limited. This study describes inpatient outcomes and resource utilization associated with cerebral edema among hospitalized patients with LHI. Methods: A retrospective cohort study was conducted using the MarketScan Hospital Drug Database (2015Q3-2017Q4). As infarct volume is not captured in the data, patients were included based on diagnosis codes for infarction of the middle cerebral artery or carotid artery, which are most closely associated with LHI. Within this group, cerebral edema was determined based on a diagnosis code of cerebral edema (ICD-10-CM G93.6) or herniation (G93.5), or a craniectomy procedure. Logistic regressions, comparing patients with edema vs. those without edema, were used to estimate the odds ratio of death, ICU admission, and tracheostomy/intubation during the hospital stay. Linear regression models were used to estimate the mean difference in length of hospital stay, length of ICU stay, and hospital charges. All models controlled for age, sex, and admission type. Results: A total of 11,772 patients were designated as likely LHI cases; 869 (7%) were identified with cerebral edema. Table 1 compares inpatient outcomes and resource utilization in patients with vs. without cerebral edema. Patients with cerebral edema had significantly higher odds of death, ICU admission and tracheostomy/intubation. They also had longer hospital stays, longer stays in the ICU, and higher hospital charges. Conclusion: This study provides evidence in a real-world setting, highlighting the substantial clinical and economic burden associated with cerebral edema among patients hospitalized with LHI. Given the unmet needs, management strategies and interventions focusing on reducing cerebral edema among patients with LHI are warranted.

Cells expressing mesenchymal/basal phenotypes in tumors have been associated with stem cell properties. Cancer stem cells (CSCs) are often resistant to conventional chemotherapy. We explored overcoming mesenchymal CSC resistance to chemotherapeutic agents. Our goal was to reduce CSC numbers in vivo, in conjunction with chemotherapy, to reduce tumor burden. Analysis of clinical samples demonstrated that COX-2/PGE2 /EP4 signaling is elevated in basal-like and chemoresistant breast carcinoma and is correlated with survival and relapse of breast cancer. EP4 antagonism elicts a striking shift of breast cancer cells from a mesenchymal/CSC state to a more epithelial non-CSC state. The transition was mediated by EP4 antagonist-induced extracellular vesicles [(EVs)/exosomes] which removed CSC markers, mesenchymal markers, integrins, and drug efflux transporters from the CSCs. In addition, EP4 antagonism-induced CSC EVs/exosomes can convert tumor epithelial/non-CSCs to mesenchymal/CSCs able to give rise to tumors and to promote tumor cell dissemination. Because of its ability to induce a CSC-to-non-CSC transition, EP4 antagonist treatment in vivo reduced the numbers of CSCs within tumors and increased tumor chemosensitivity. EP4 antagonist treatment enhances tumor response to chemotherapy by reducing the numbers of chemotherapy-resistant CSCs available to repopulate the tumor. EP4 antagonism can collaborate with conventional chemotherapy to reduce tumor burden.

Parkinson’s disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.

// Yu-Chuen Huang 1, 8, * , Wen-Ling Liao 2, 9, * , Jane-Ming Lin 3, 8 , Ching-Chu Chen 4, 8 , Shih-Ping Liu 5, 10, 14 , Shih-Yin Chen 1, 8 , Yu-Ning Lin 1 , Yu-Jie Lei 1 , Huan-Ting Liu 1 , Yu-Jen Chen 1, 11, 12, 13 and Fuu-Jen Tsai 1, 6, 7, 15 1 Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan 2 Center for Personalized Medicine, China Medical University Hospital, Taichung 404, Taiwan 3 Department of Ophthalmology, China Medical University Hospital, Taichung 404, Taiwan 4 Division of Endocrinology and Metabolism, China Medical University Hospital, Taichung 404, Taiwan 5 Center for Translational Medicine, China Medical University Hospital, Taichung 404, Taiwan 6 Children's Hospital of China Medical University, Taichung 404, Taiwan 7 Department of Medical Genetics, China Medical University Hospital, Taichung 404, Taiwan 8 School of Chinese Medicine, China Medical University, Taichung 404, Taiwan 9 Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan 10 Graduate Institute of Biomedical Science, China Medical University, Taichung 404, Taiwan 11 Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan 12 Department of Medical Research, Mackay Memorial Hospital, New Taipei City 251, Taiwan 13 Institute of Traditional Medicine, National Yang-Ming University, Taipei 112, Taiwan 14 Department of Social Work, Asia University, Taichung 413, Taiwan 15 Department of Biotechnology, Asia University, Taichung 413, Taiwan * These authors contributed equally to this work Correspondence to: Fuu-Jen Tsai, email: d0704@mail.cmuh.org.tw Yu-Jen Chen, email: chenmdphd@gmail.com Keywords: type 2 diabetes; diabetic retinopathy; circulating endothelial progenitor cells; ARHGAP22 Received: July 03, 2017 Accepted: September 21, 2017 Published: April 03, 2018 ABSTRACT Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Circulating endothelial progenitor cells (EPCs) are derived from bone marrow and are characterized by pathological retinal neovascularization. Rho GTPase Activating Protein 22 ( ARHGAP22 ) is a DR susceptibility gene that interacts with its downstream regulatory protein ras-related C3 botulinum toxin substrate 1 (Rac1), to assist in endothelial cell angiogenesis and increasing capillary permeability. The aim of this study was to elucidate the relationship between ARHGAP22 expression and EPC levels in type 2 diabetes (T2D) patients with DR. Fifty T2D patients with DR were recruited. Circulating EPCs were characterized as CD31 + /vascular endothelial growth factor-2 + /CD45 dim /CD133 + and were quantified using triple staining flow cytometry. Real-time polymerase chain reaction tests were used to quantify ARHGAP22 expression. We found that T2D patients with proliferative DR had significantly lower EPC levels than those with non-proliferative DR ( P = 0.028). T2D patients with EPC levels above the median value (> 4 cells/10 5 events) had higher levels of ARHGAP22 expression ( P = 0.002). EPC levels were positively correlated with ARHGAP22 expression ( r = 0.364, P = 0.009). Among T2D patients with DR, a higher expression of ARHGAP22 was associated with higher levels of EPCs. ARHGAP22 may be involved in the mobilization or active circulation of EPCs, thus contributing to neovascularization during DR development.

Background Depression and anxiety are leading causes of disability worldwide, but access to quality mental health care is limited by myriad factors. Cognitive-behavioral coaching is rooted in evidence-based principles and has the potential to address some of these unmet care needs. Harnessing technology to facilitate broader dissemination within a blended care model shows additional promise for overcoming barriers to care. Objective The aim of this study is to evaluate the outcomes of a blended care coaching (BCC) program for clients presenting with moderate levels of anxiety and depression in real-world settings. Methods This study examined retrospective data from US-based individuals (N=1496) who presented with moderate levels of depression and anxiety symptoms and who received blended care coaching services. Using a short-term framework, clients met with coaches via a secure video conference platform and also received digital video lessons and exercises. To evaluate the effectiveness of the BCC program, mixed effects modeling was used to examine growth trajectories of anxiety and depression scores over the course of care. Results Out of the total sample of 1496 clients, 75.9% (n=1136) demonstrated reliable improvement, and 88.6% (n=1326) recovered based on either the Generalized Anxiety Disorder-7 scale (anxiety) or Patient Health Questionnaire-9 (depression). On average, clients exhibited a significant decline in anxiety and depression symptoms during the initial weeks of coaching, with a continued decline over subsequent weeks at a lower rate. Engaging in a coaching session was associated with lower anxiety (b=–1.04) and depression (b=–0.79) symptoms in the same week, as well as lower anxiety (b=–0.74) and depression (b=–0.91) symptoms the following week (P Conclusions The BCC program demonstrated strong outcomes in decreasing symptomology for clients presenting with moderate levels of anxiety and depression. When clients received coaching sessions, significant decreases in symptoms were observed, reflecting the importance of session attendance. Additionally, the steepest declines in symptoms tended to occur during the initial weeks of coaching, emphasizing the importance of client buy-in and early engagement. Collectively, these findings have implications for addressing unmet mental health care needs in a more accessible, cost-effective manner.

PURPOSE: Type-2 diabetes mellitus (T2D) is a metabolic disorder that can progress to a serious chronic disease and frequently develops in obese individuals in association with various pathogenic complications that shorten the lifespan of these patients. The liver is an important organ regulating lipid metabolism, which is damaged in both obesity and T2D; however, the specific pathways involved in these pathogenic effects remain unclear. Establishing a suitable animal model that effectively mimics the human biological condition is a critical factor to allow for precise identification of T2D-related genes. METHODS: The KK.Cg-A(y) mouse strain is one such model that has offered insight into obesity-related T2D pathogenesis. To comprehensively assess the association between obesity and T2D, in the present study, we performed microarray analysis on liver tissue samples of KK.Cg-A(y) and KK-α/α wild-type mice to examine differences in gene expression and methylation patterns and their related biological processes and pathways. RESULTS: We found that inflammation accompanied by abnormal lipid metabolism led to the spontaneous mechanism of obesity-induced diabetes, resulting in differential expression of some genes related to the terms of insulin resistance and glucose tolerance. Surprisingly, disruption of steroid biosynthesis strongly facilitated the diabetic pathogenesis. To support these findings, we highlighted some candidate genes and determined their relationships in biological networks of obesity-induced T2D. CONCLUSION: These findings provide valuable reference data that can facilitate further detailed investigations to elucidate the pathogenic mechanism of obesity-induced diabetes in mice, which can be associated with the human condition to inform new prevention and treatment strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40200-019-00453-8) contains supplementary material, which is available to authorized users.

Background/Aim: Diabetic retinopathy (DR) is a type of retinal damage caused by a complication of diabetes and is a major cause of blindness in working-age adults. Ecto-NOX disulfide-thiol exchanger 1 (ENOX1) is a member of the ecto-NOX family involved in the plasma membrane electron transport pathway. This study aimed to investigate the role of ENOX1 in the development of DR. Materials and Methods: Human retinal endothelial cells (HRECs) and human retinal pigment epithelial cells (HREpiCs) exposed to a high concentration (25 mM) of D-glucose and type 2 diabetes (T2D) mice (+Lepr(db)/+Lepr(db), db/db) with retinopathy were used as models to determine the ENOX1 expression levels there. Results: Our results showed that ENOX1 expression levels did not significantly change in both HRECs and HREpiCs under hyperglycemic conditions for 48 h. Nevertheless, ENOX1 expression increased significantly in T2D mouse retinas, particularly in the photoreceptor layer, compared to the control mouse retinas. Conclusion: Different retinal ENOX1 expression in T2D mice and control mice suggested that ENOX1 may be involved in DR development.

Diabetic retinopathy (DR) is a severe and recurrent microvascular complication in diabetes. The multifunctional response gene to complement 32 (RGC-32) is involved in the regulation of cell cycle, proliferation, and apoptosis. To investigate the role of RGC-32 in the development of DR, we used human retinal microvascular endothelial cells under high-glucose conditions and type 2 diabetes (T2D) mice (+Leprdb/ + Leprdb, db/db). The results showed that RGC-32 expression increased moderately in human retinal endothelial cells under hyperglycemic conditions. Histopathology and RGC-32 expression showed no significant changes between T2D and control mice retina at 16 and 24 weeks of age. However, RGC-32 expression was significantly decreased in T2D mouse retina compared to the control group at 32 weeks of age, which develop features of the early clinical stages of DR, namely reduced retinal thickness and increased ganglion cell death. Moreover, immunohistochemistry showed that RGC-32 was predominantly expressed in the photoreceptor inner segments of control mice, while the expression was dramatically lowered in the T2D retinas. Furthermore, we found that the level of anti-apoptotic protein Bcl-2 was decreased (approximately 2-fold) with a concomitant increase in cleaved caspase-3 (approximately 3-fold) in T2D retina compared to control. In summary, RGC-32 may lose its expression in T2D retina with features of DR, suggesting that it plays a critical role in DR pathogenesis.

This study investigates the use of Deep Neural Learning to predict propensity for disease from demographic information alone, with thyroid disease as the test application. The imbalanced dataset of 747,301 samples contained 13 demographic predictor variables that were not known to be associated with the disease, and had much missing information. A TensorFlow feed-forward neural network was trained to predict thyroid disease. Different activation functions and a variety of up-sampling and down-sampling methods were employed. The lift statistic was used to evaluate success in identifying patients with a propensity for thyroid disease. The DNN model outperformed the Random Forest model with a 36.63% improvement in the lift statistic. These results suggest that deep learning may be successfully employed to select candidates for early intervention for improved health outcomes, utilizing a large dataset with only minimal demographic variables, similar to datasets that are held by the marketing arms of healthcare providers.

Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis, exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.

Intensive glycemic control has not shown consistent findings in stroke prevention for diabetes patients, particularly for those with microvascular complications. This case-control study evaluates the risks of stroke in Asian diabetic population with microvascular complications. From the insurance claims of Taiwan, we identified 67,426 type 2 diabetic mellitus (DM) patients with newly diagnosed stroke in 2000–2011 and 134,852 randomly selected controls with DM but without stroke, matched by sex, age, and number of years since diagnosis of DM. Conditional logistic regression analysis measured crude odds ratios (OR) and adjusted odds ratio (aOR) of stroke and 95% confidence intervals (CI) for associations with demographic status, comorbidities, and microvascular complications: retinopathy (RetP), neuropathy (NeuP) or nephropathy (NepP). The aOR of stroke increased significantly associated with each complication: 1.47 with RetP, 1.73 with NeuP and 1.23 with NepP. The risk increased further when there was a combination of complications. The overall aOR of stroke was 2.83 (95% CI 2.58–3.09) for stroke patients with 3 microvascular complications. The corresponding aOR of ischemic stroke was 2.64 (95% CI 2.39–2.91) and that of hemorrhagic stroke was 4.12 (95% CI 3.25–5.22). The number of microvascular complications positively correlated to the prevalence of comorbidity (p < 0.01). This study suggests that microvascular complications are significant stroke predictors, with a greater involvement for ischemic stroke than for hemorrhagic stroke. Multiple microvascular complications interactively increase the stroke risk. Our study contributes to the identification of high-risk subjects for stroke prevention and adequate glycemic control.

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Low levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of type 2 diabetes (T2D). This study investigated CETP gene variants to assess the risk of T2D and specific complications of diabetic kidney disease (DKD) and diabetic retinopathy. Towards this, a total of 3023 Taiwanese individuals (1383 without T2D, 1640 with T2D) were enrolled in this study. T2D mice (+Leprdb/+Leprdb, db/db) were used to determine CETP expression in tissues. The A-alleles of rs3764261, rs4783961, and rs1800775 variants were found to be independently associated with 2.86, 1.71, and 0.91 mg/dL increase in HDL-C per allele, respectively. In addition, the A-allele of rs4783961 was significantly associated with a reduced T2D risk (odds ratio (OR), 0.82, 95% confidence interval (CI), 0.71‒0.96)), and the A-allele of rs1800775 was significantly related to a lowered DKD risk (OR, 0.78, 95% CI, 0.64‒0.96). CETP expression was significantly decreased in the T2D mice kidney compared to that in the control mice (T2D mice, 0.16 0.01 vs. control mice, 0.21 0.02, p = 0.02). These collective findings indicate that CETP variants in the promoter region may affect HDL-C levels. Taiwanese individuals possessing an allele associated with higher HDL-C levels had a lower risk of T2D and DKD.

Objective To investigate the determinants of health care utilization and costs with use of glucocorticoid (GC) drugs among adult systemic lupus erythematosus (SLE) patients. Methods This cross-sectional study analyzed established SLE patients identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes from a large US insurance claims database in 2007–2011. Five patient groups were defined by their oral GC use during a 1-year period: non-GC users, 7.5 to ≤15 mg/day), or higher dosage (>15 mg/day). Annual health care utilization and costs were compared across these groups. Incremental costs of GC groups, calculated as the difference in total health care costs compared with those of the non-GC group, were estimated from multivariable regressions adjusting for demographic/clinical characteristics and stratified by concomitant immunosuppressant use. Results A total of 50,230 SLE patients were identified (52% non-GC users, 20%

Autophagy, a double-edged sword for cell survival, is the research object on 2016 Nobel Prize in Physiology or Medicine. Autophagy is a molecular mechanism for maintaining cellular physiology and promoting survival. Defects in autophagy lead to the etiology of many diseases, including diabetes mellitus (DM), cancer, neurodegeneration, infection disease and aging. DM is a metabolic and chronic disorder and has a higher prevalence in the world as well as in Taiwan. The character of diabetes mellitus is hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and failure of producing insulin on pancreatic beta cells. In T2DM, autophagy is not only providing nutrients to maintain cellular energy during fasting, but also removes damaged organelles, lipids and miss-folded proteins. In addition, autophagy plays an important role in pancreatic beta cell dysfunction and insulin resistance. In this review, we summarize the roles of autophagy in T2DM.

Objective We have previously described the association of rheumatoid arthritis (RA) prevalence and two epidermal growth factor receptor (EGFR) SNPs (rs17337023 and rs2227983) among the Taiwanese population. This present study aimed to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. Methods The cohort study included 366 Taiwan's Han Chinese RA patients and 326 age and gender matched healthy controls. Blood samples collected from the participants were analyzed to determine their serum EGFR levels and to identify EGFR SNPs from their genomic DNA. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. The relationship between EGFR SNP and the clinical manifestations of RA was evaluated. Results Our results showed that a statistically significant difference in genotype frequency distributions at rs17337023 SNP for RA patients and controls (p ˂ 0.05). In addition, compared with the haplotype frequencies between case and control groups, the RA patient with the GT haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.73, 95% CI: 0.59-0.91; p = 0.005). Furthermore, the increased serum level of EGFR was also observed in RA patients (p ˂ 0.001). Conclusion Our study showed that RA is associated with rs17337023 SNP in EGFR gene and increased serum level of the EGFR protein. These findings suggest EGFR is worthy of further investigation as a therapeutic target for RA.

Summary Background Published data for the epidemiology of idiopathic pulmonary fibrosis in the USA are scarce. We sought to estimate the incidence, prevalence, and mortality risk of idiopathic pulmonary fibrosis among US Medicare beneficiaries. Methods We used administrative claims from a 5% random sample of Medicare beneficiaries (aged 65 years and older) from the years 2000–11 as a data source. Idiopathic pulmonary fibrosis was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. We estimated annual incidence and cumulative prevalence of idiopathic pulmonary fibrosis, median survival time of patients, and potential risk factors for diagnosis of idiopathic pulmonary fibrosis and death between 2001 and 2011. We also estimated incidence and prevalence using more restrictive algorithms for diagnosis. Findings The annual incidence of idiopathic pulmonary fibrosis in the Medicare population remained stable between 2001 and 2011, with an overall estimate of 93·7 cases per 100 000 person-years (95% CI 91·9–95·4) across the study period. The annual cumulative prevalence increased steadily from 202·2 cases per 100 000 people in 2001 to 494·5 cases per 100 000 people in 2011. Among newly diagnosed patients with Medicare (mean age 79·4 years [SD 7·2], 54% female, 91% white), the median survival time was 3·8 years (95% CI 3·5–3·8). Older age and male sex were associated with a higher incidence of disease and shorter survival time after diagnosis. Mortality risk was lower in patients diagnosed in more recent years (median survival time 3·3 years [95% CI 3·0–3·8] in 2001 vs 4·0 years [3·8–4·5] in 2007). Interpretation The incidence and prevalence of idiopathic pulmonary fibrosis in people aged 65 years and older in the USA are substantially higher than previously reported, and prevalence is increasing annually, even in the subgroups based on more restrictive algorithms for diagnosis. Patients with idiopathic pulmonary fibrosis aged 65 years and older were living longer in 2011 than they were 10 years before, which could partly account for the steady increase in prevalence. Funding Biogen Idec.

Background Kawasaki disease (KD) patients who experience a cardiovascular complication known as a coronary artery aneurysm (CAA) are at high risk of developing ischemic heart disease, which may lead to sudden death. The etiology of CAA in KD patients is unclear, and this study aims to clarify the relationship between steroid receptor coactivator-1 (SRC-1) gene polymorphisms and CAA pathogenesis. Methods We investigated four SRC-1 gene polymorphisms (rs11894248, rs17791703, rs7572475, and rs9309308) and their correlation with KD with CAA susceptibility in 327 Taiwanese people (279 KD patients without CAA and 48 KD patients with CAA). Results The results indicated a statistically significant difference in genotype and allele frequency distributions at the SRC-1 four single nucleotide polymorphisms (SNPs) between KD patients with and without CAA (P < 0.01). Additionally, Smad3 gene polymorphism (rs12901071) is well known to be associated with KD patients. In our results, Smad3 SNP did not provide a statistically significant difference between KD patients with and without CAA. Conclusion Our data show that SRC-1 polymorphisms may be the underlying cause of CAA; therefore, the polymorphisms examined in this study warrant further investigation.

Background Acromegaly is a rare, debilitating condition for which data on the associated treatment patterns and economic burden are limited. Objective Our objective was to examine patient characteristics, treatment patterns, and healthcare resource utilization (HRU)/costs for individuals with acromegaly treated with surgical and/or medical therapy in the USA. Methods Using a large US claims database, adults with new episodes of acromegaly between 1 July 2007 and 31 December 2010 were identified (the first observed diagnosis being the index date). Patients had 6-month pre-index and 12-month post-index continuous enrollment and surgical and/or medical treatment during the 12-month post-index period. Descriptive analysis was performed to observe demographic/clinical characteristics, treatment patterns, HRU, and monthly healthcare costs between two mutually exclusive surgically and medically treated cohorts. Results This study included 228 acromegalic individuals treated with surgical therapy and 169 treated with medical therapy. During the 12-month follow-up, compared with the medical cohort, the surgical cohort were more likely to have hypertension (50.4 vs. 32.0 %), sleep apnea (31.6 vs. 15.8 %), cardiac dysrhythmia (16.7 vs. 7.0 %), hospitalizations (98.3 vs. 13.6 %), and emergency room visits (29.8 vs. 20.7 %), and had more outpatient visits (10.2 vs. 5.2) and physician office visits (21.2 vs. 15.0) (all differences, p

Jeffrey Scott Andrews,1 Ning Wu,2 Shih-Yin Chen,2 Xia Yu,2 Xiaomei Peng,1 Diego Novick1 1Global Health Outcomes, Eli Lilly and Company, Indianapolis, IN, USA; 2Evidera, Lexington, MA, USA Abstract: To describe the use of pain medications in patients with chronic low back pain (CLBP) after initiating duloxetine or standard of care (SOC [muscle relaxants, gabapentin, pregabalin, venlafaxine, and tricyclic antidepressants]) for pain management, pharmacy and medical claims from Surveillance Data, Inc (SDI) Health were analyzed. Adult patients with CLBP who initiated duloxetine or SOC between November 2010 and April 2011 were identified. Treatment initiation was defined as no pill coverage for duloxetine or SOC in the previous 90 days. Included patients had no opioid use in the 90 days before initiation. Propensity score matching was used to select patients with similar baseline demographic and clinical characteristics for duloxetine and SOC cohorts. Compliance with index medication was assessed via medication possession ratio (MPR) and proportion of days covered (PDC) for 6 months after initiation. The proportion of patients receiving opioids and days on opioids after index date were assessed, and regression models were estimated to compare opioid use between cohorts. A total of 766 patients initiated duloxetine and 6,206 patients initiated SOC. After matching, 743 patients were selected for the duloxetine (mean age 57 years; female 74%) and SOC (mean age 57 years; female 75%) cohorts, respectively. Of the duloxetine cohort, 92% started on or below recommended daily dose (≤60 mg). The duloxetine cohort had significantly higher MPR (0.78 versus [vs] 0.60) and PDC (0.50 vs 0.31), were less likely to use opioids (45% vs 61%), and had fewer days on opioids (median 0 vs 7 days) than the SOC cohort (all P < 0.001). After adjusting for demographic and clinical characteristics, the duloxetine cohort initiated opioids later than the SOC cohort (hazard ratio 0.77, 95% confidence interval 0.66–0.89). CLBP patients initiating duloxetine had better compliance with initiated medication and were less likely to use opioids than those initiating SOC. Keywords: medications, duloxetine, low back pain, opioid

The purpose of this study was to determine whether toll-like receptors 9 (TLR9) gene polymorphisms (rs352139 and rs352140) were markers of susceptibility to the development and progression of membranous nephropathy (MGN) in Taiwanese patients. The polymorphisms were investigated by polymerase chain reaction in 397 Taiwanese individuals (134 MGN patients and 263 controls). Patients with malignancy, chronic infectious diseases, lupus nephritis, or drug-induced secondary MGN were excluded from the study. Data showed AA genotype at rs352139 SNP or GG genotype at rs352140 SNP may indicate higher risk for MGN (odds ratio [OR] = 1.55; 95% confidence interval [CI] = 1.02-2.35, at rs352139 SNP; OR = 1.57; 95% CI = 1.03-2.39, at rs352140 SNP). However, MGN patients with A-G haplotype were susceptible for decreased creatinine clearance rate and for seriously tubule-interstitial fibrosis. The result suggests for the first time that TLR9 (rs352139 and rs352140) polymorphisms may contribute to the development and progression of MGN.

Background Kawasaki disease (KD) is a pediatric systemic vasculitis, for which both genetic and environmental factors are suspected. HLA gene clusters within the major histocompatibility complex (MHC) region at chromosome 6p21.3 have been recently linked to KD. However, little was known about the roles of non-MHC genes during KD development. This study examines the association of psoriasis susceptibility 1 (PSORS1) genetic variants at the MHC region with KD development. Methods A total of 93 KD patients and 680 healthy children were enrolled. Three unique single nucleotide polymorphisms (SNPs) that cover PSORS1C1, PSORS1C2, and CDSN genes were genotyped by Taqman genotyping assay. The frequency of genetic variants was assessed by χ2 analysis. Results Polymorphism rs1064190 located at the promoter region of PSORS1C1 is found to be associated with KD development (p = 0.026) with higher T/T genotype frequency (p = 0.006) the T-A-T haplotype is more frequent in KD patients than normal controls (p = 0.033). In addition, T allele at rs1064190 shows a protective allele for coronary artery aneurysm (CAA) formation in KD patients (p = 0.015). The plasma activity of GOT/GPT, the indicators for KD heart damage, are significantly lower in patients with T/T genotype than in those with non-T/T genotype. Conclusion Results suggest pivotal roles of polymorphisms within the PSORS1 region in KD pathogenesis. Since this region has been linked to psoriasis, this finding provides molecular evidence to suggest the possible linkage between KD and psoriasis.

Background We have previously described the association between rheumatoid arthritis (RA) prevalence and the two mutY Homolog (E. coli) (MUTYH) SNPs (rs3219463 and rs3219476) among the Taiwanese population. This present study will aim to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. Methods The cohort study included 368 Taiwan’s Han Chinese RA patients and 364 healthy controls. Blood samples collected from the participants were analyzed to determine their serum MUTYH levels and to identify rs3219463 SNP of MUTYH from their genomic DNA. Results Our data resulted in a statistically significant difference in genotype frequency distributions at rs3219463 for RA patients and controls (p

Systemic lupus erythematosus (SLE) is a multi-organ chronic autoimmune disease that can negatively affect patients’ health-related quality of life (HRQOL). This study evaluated HRQOL of SLE patients using questionnaires from the Patient-Reported Outcomes Measurement Information System (PROMIS) and Quality of Life in Neurological Disorders (Neuro-QoL). Individuals with SLE completed an online survey consisting of the PROMIS-29 health profile, PROMIS Psychosocial Illness Impact-Negative, and Neuro-QoL Applied Cognition. PROMIS and Neuro-QoL scores have a mean of 50 in the US general population. Patients self-rated SLE disease severity as negligible, mild, moderate, or severe. Of the 333 participants (mean age 45 years; 92% female; 26% Black; mean SLE disease duration 12 years, 56% with SLE disease severity as moderate or severe), mean HRQOL scores were worse than those of the general population by ≥0.5 SD with the greatest deficits observed in the domains of fatigue, applied cognition, psychosocial illness impact-negative, pain interference, and physical function. Greater SLE disease severity was associated with worse mean HRQOL scores (all p

Diabetic retinopathy (DR) is one of the most feared complications of diabetes and is a leading cause of acquired blindness in working adults. The prevalence of undiagnosed diabetes in Taiwan is about 4%, and the annual incidence of T2D (Type 2 Diabetes) in Taiwan is 1.8% following the 1985 WHO criteria. Multiple mechanisms have been shown in T2DR with some signaling pathways, including the polyol pathway, PKC pathway, AGEs pathway, and MAPK pathway. However, the cause of vision loss in diabetic retinopathy is complex and remains incompletely understood. Herein, we try to fully understand the new concepts regarding hyperglycemia-induced biochemical pathways contributing to DR pathophysiology. Our work may be able to provide new strategies for the prevention and treatment of diabetic vascular complications.

Among patients with common immune-compromised (IC) conditions in the United States, the healthcare cost associated with herpes zoster (HZ) was sizable and occurred mainly during the first quarter after diagnosis. And HZ-associated costs varied by age and underlying IC conditions., Background. This retrospective study investigates the healthcare costs of herpes zoster (HZ) in patients with selected immune-compromised (IC) conditions in the United States (US). Methods. Patients with incident HZ diagnosis (index date) were selected from nationwide administrative claims databases from 2005 to 2009. Baseline IC groups, analyzed separately, included adults aged 18–64 years with the following: human immunodeficiency virus infection (HIV), solid organ transplant (SOT), bone marrow or stem cell transplant (BMSCT), or cancer; and older adults (aged ≥65 years) with cancer. Herpes zoster patients (n = 2020, n = 1053, n = 286, n = 13 178, and n = 9089, respectively) were 1-to-1 matched to controls without HZ (with randomly selected index date) in the same baseline group. The healthcare resource utilization and costs (2014 US dollars) during the first 2 postindex quarters were compared between matched cohorts with continuous enrollment during the quarter. Results. Herpes zoster patients generally had greater use of inpatient, emergency room and outpatient services, and pain medications than matched controls (P < .05). The incremental costs of HZ during the first postindex quarter were $3056, $2649, $13 332, $2549, and $3108 for HIV, SOT, BMSCT, cancer in adults aged 18–64 years, and cancer in older adults, respectively (each P < .05). The incremental costs of HZ during the second quarter were only significant for adults aged 18–64 years with cancer ($1748, P < .05). The national incremental costs of HZ were projected to be $298 million annually across the 5 IC groups. Conclusions. The healthcare cost associated with HZ among patients with studied IC conditions was sizable and occurred mainly during the first 90 days after diagnosis.

Background A significant percentage of Taiwanese neonatal HB immunization recipients have subsequently exhibited low anti-HB titers at non-protective or undetectable levels. Several mechanisms have been proposed to explain this phenomenon, including low vaccination responsiveness, deficient lymphocyte function, inappropriate antigen processing and presentation, and abnormal cytokine secretion. Methods To determine genetic influences resulting in high anti-HB titers, we divided a study cohort of 183 individuals into an anti-HBs ≥ 1000 mIU/mL group and a 10–1000 mIU/mL anti-HBs titer group. Chi-square tests were used to compare genotype and allelic frequencies between the two groups. Results Data from univariate and multivariate regression analyses of cytokine and cytokine receptor gene variants indicate (a) increased potential of high anti-HB titers in the presence of the TT genotype of the IL - 4 rs2243250 SNP (OR = 3.19; p = 0.012) and the AA genotype of the IL - 4R rs1805010 SNP (OR = 2.25; p = 0.048), and (b) individuals carrying the TT genotype of the IL - 4 rs2243250 SNP had anti-HB titers at levels that were almost twice as high as those in individuals carrying the CC genotype (478.8 mIU/mL and 290.3 mIU/mL, respectively; p = 0.033). Conclusion Genetic determinants, especially IL - 4 and IL - 4R , may contribute to high anti-HB titers in immune responses to HB vaccinations.

To assess outcomes associated with oral anti-diabetic drug (OAD) treatment concordant with guidelines from the National Kidney Foundation (NKF) among type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD).Electronic health record data between 1/1/2005 and 10/31/2010 provided by an integrated health system were analyzed. T2DM patients were selected based on diagnosis from the health record. Patients with stages 3-5 CKD based on diagnosis or lab results were further identified with the date of first indicated CKD set as index date. Patients who had a medication order of OADs within three months of the index date were included. Patients were considered non-guideline-concordant if prescribed OADs that were recommended to be avoided or if they required dosage adjustment, but were unadjusted. Glycemic control, hospital admissions, and costs of encounters were assessed over a 12-month post-index period, and hypoglycemic events were evaluated until loss of follow-up. Regression analyses were performed, adjusting for patient demographic and clinical characteristics.Among 6058 patients (mean age: 70; 42% male), 45% were not [corrected] guideline-concordant. After adjusting for patient characteristics, guideline-concordant patients had a lower risk for hypoglycemic events (HR: 0.72; 95% CI: 0.62-0.83), were less likely to have a hospital admission (OR: 0.87; 95% CI: 0.77-0.98), and more likely to have glycemic control (OR: 1.64, 95% CI: 1.46-1.84). Non-guideline-concordant patients had annual encounter costs of 1.10 times those of guideline-concordant patients (marginal cost = $731; P = 0.04).Unobservable confounders may still exist and bias the results; therefore, findings should be interpreted as associations instead of causations. Findings were based on a single integrated health system and may not be generalizable to larger populations.The findings of this exploratory study suggest that guideline-concordant treatment may yield better clinical and economic outcomes. Future research with a better controlled design is warranted to confirm these preliminary findings.

Idiopathic pulmonary fibrosis (IPF) produces symptoms and activity limitations that impair health-related quality of life (HRQOL). The Patient-Reported Outcomes Measurement Information System(®) (PROMIS(®)) includes measures of self-reported health and HRQOL for a range of conditions. This study evaluated the HRQOL of individuals with IPF using PROMIS measures and examined associations between HRQOL and key symptoms or supplemental oxygen need.Individuals who reported being told by a doctor that they have IPF completed an online battery of measures at baseline and 7-10 days later (for test-retest reliability). Measures included a brief survey of demographic and health-related questions, the PROMIS-29 profile, the Modified Medical Research Council Dyspnea Scale (MMRC), PROMIS dyspnea severity short form, A Tool to Assess Quality of life in IPF (ATAQ-IPF) and one cough item from the Functional Assessment of Chronic Illness Therapy (FACIT).220 individuals were included in the final sample. Except for sleep disturbance, all PROMIS domain scores significantly (p .01) differed by MMRC level. Supplemental oxygen users were more impaired than non-users in fatigue, physical function, and social role participation (p 0.01). The test-retest reliability was acceptable to excellent (0.7) for all scales, but was lower for sleep disturbance (0.64).People with IPF report substantial deficits in HRQOL across a range of PROMIS domains, and deficits vary by dyspnea and cough severity. These deficits warrant monitoring in clinical practice and consideration when investigating new therapies. Further research is required to further evaluate the psychometric performance of the PROMIS-29 in IPF.

We sought to present the epidemiology of idiopathic pulmonary fibrosis (IPF) in adults 18–64 years old in the USA.From adults aged 18–64 years in a large administrative claims data in 2004–2010, patients with IPF were identified using diagnosis codes. We estimated annual incidence and cumulative prevalence of IPF over time, and examined potential risk factors for the IPF diagnosis.The annual cumulative prevalence increased steadily in the first few years (from 13.4 cases per 100 000 persons in 2005 to 18.2 cases in 2010 per 100 000 persons), which is likely due to a methodological reason, while the annual incidence of IPF decreased over time (from 7.9 cases per 100 000 person-years in 2005 to 5.8 cases in 2010 per 100 000 person-years). The overall decrease was mainly driven by a decreasing trend in the younger patients (aged 18–44 years), while the incidence in older patients remained stable. Consistent trends were observed in subgroups defined by previously published more restrictive algorithms for diagnosis. Older age and male sex were associated with a higher incidence of disease (pIn US adults younger than 65 years, we observed a decreasing incidence of IPF over time which may partially explain the plateau of cumulative prevalence in the last few years of our data.

Objectives: Several pharmacologic therapies have been recommended for managing fibromyalgia. However, the factors associated with each treatment initiation have not been well established. This study assessed factors that were associated with the use of duloxetine vs. other pain medications among patients with fibromyalgia. Research Design and Methods: Administrative claims from a large, U.S. commercially insured population were analyzed using a retrospective cohort design. Patients with fibromyalgia who were 18 to 64 years old and initiated duloxetine vs. selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), venlafaxine, gabapentin, pregabalin, tramadol, or nontramadol opioids between January 1, 2007 and December 12, 2008 were selected. Treatment initiation was defined as no access to the same medication over the previous 90 days, with the most recent initiation date as the index date. All patients selected had at least one fibromyalgia diagnosis (ICD-9-CM: 729.1) in the 12 months prior to initiation of each study medication. Multiple logistic regression models were estimated to assess the predictors of initiating duloxetine vs. each of the other medications. Results: The study included 117,305 patients with fibromyalgia (48 years of age on average; 76% women) who initiated duloxetine (n = 5,827), SSRIs (n = 8,620), TCAs (n = 5,424), venlafaxine (n = 2,038), gabapentin (n = 5,733), pregabalin (n = 11,152), tramadol (n = 7,312), or nontramadol opioids (n = 71,199). Common fibromyalgia-related comorbidities were low back pain (31% to 49%), osteoarthritis (14% to 21%), and sleep disturbance (10% to 15%). Controlling for demographic and clinical characteristics, patients who received pregabalin in the prior 12-month period were more likely to initiate duloxetine. Patients from other treatment cohorts, except for those in the pregabalin and nontramadol opioid cohorts, were more likely to re-initiate the same prior medication than to begin treatment with duloxetine. Other predictors of duloxetine initiation included history of rheumatoid and sleep disturbance. Conclusions: The presence of select comorbidities and prior use of certain medications were associated with the duloxetine initiation among working-age, commercially insured patients with fibromyalgia.

This study evaluated the national trends in prescribing pharmacologic treatments for pediatric depression before and after a 2003 U.S. Food and Drug Administration advisory linking an increased risk of suicidality with antidepressants among pediatric patients with major depressive disorder.National estimates on outpatient visits between 1998 and 2007 with a diagnosis of depression, a prescription for an antidepressant, or both among children ages 5 to 17 and adults were obtained from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.Among children, depression visits increased from 1998-1999 to 2002-2003 (3.2 and 4.3 million, respectively) but decreased to 3.2 million in 2006-2007. Antidepressant visits increased from 1998-1999 to 2002-2003 (3.4 and 7.6 million, respectively) but dropped to 6.7 million in 2006-2007. Depression visits with an antidepressant prescribed rose from 1998-1999 to 2002-2003 (1.7 and 2.8 million, respectively) but dropped in 2004-2005 and 2006-2007 (2.4 and 2.1 million, respectively). Nevertheless, the proportion of depression visits with an antidepressant prescribed, having risen from 54% in 1998-1999 to 66% in 2002-2003, remained stable in 2004-2005 (65%) and in 2006-2007 (64%), the result, seemingly, of more prescribing of antidepressants for major depressive disorder and less for other depression. Utilization patterns among adults were not interrupted.Children's depression visits and visits with an antidepressant prescribed dropped after the advisory, but children with major depressive disorder appeared no less likely to be prescribed antidepressants.

The involvement of the epidermal growth factor receptor (EGFR) in the pathogenesis of cancer is well documented. In contrast, its role in rheumatoid arthritis (RA) development is not that well defined although previous studies suggested the possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between the EGFR genetic polymorphisms and the RA. Our study gauged the effects of EGFR (rs11543848 and rs17337023) single-nucleotide polymorphisms (SNPs) on RA among Taiwan’s Han Chinese population. Polymorphism of EGFR gene was analyzed in 188 RA patients and 128 control subjects. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. Our data confirmed statistically significant increased risk of RA development in subjects with A carrier at rs17337023 SNP (P

Objective: This retrospective cohort study assessed subsequent opioid utilization and health-care costs among patients with diabetic peripheral neuropathic pain (DPNP) who initiated duloxetine vs. other standard of care (SOC) treatments. Methods: Medical and pharmacy claims were analyzed for commercially-insured individuals aged 18–64. Two study cohorts were constructed from DPNP patients who initiated duloxetine or SOC medications (tricyclic antidepressants, venlafaxine, gabapentin, pregabalin) between March 1, 2005 and December 31, 2005. Initiation was defined as a prior 90-day period without access of the medication. The dispense date of the first initiation was denoted as the index date. Patients with opioids dispensed in the prior 90 days were excluded. Opioid utilization including total days, number of prescriptions filled, and morphine equivalent dosage was assessed for overall, long-acting, and short-acting opioids. Health-care costs and opioid use in the 12-month post-index period were examined via multivariate regression analyses. Results: Four hundred and ninety-nine DPNP patients (272 duloxetine, 227 SOC) were identified. SOC patients had higher prevalence of comorbidities and pre-index health-care costs than duloxetine patients. Controlling for cross-cohort differences, duloxetine patients were significantly less likely to use any opioids than SOC patients. Also, duloxetine patients had 20 fewer adjusted opioid supply days (largely due to the use of short-acting opioids, P

To assess the demographic and clinical characteristics associated with initiation of duloxetine therapy compared with other pharmacologic therapies for treatment of diabetic peripheral neuropathic pain (DPNP).This study used administrative claims databases for commercially-insured individuals aged 18-64 years to examine factors associated with treatment among DPNP patients who initiated duloxetine versus tricyclic antidepressants (TCAs), venlafaxine, gabapentin, pregabalin, or opioids between 7/1/2005 and 12/31/2007. Treatment initiation was defined as no pill coverage of the same medication over the previous 90 days. Multiple logistic regression models were estimated to assess factors associated with initiating duloxetine versus each of the other DPNP therapies.The study included 11,060 DPNP patients with average age of 55 years old. Cardiovascular disease (63-70%), cerebrovascular/peripheral vascular disease (26-33%), low back pain (24-39%), and osteoarthritis (17-26%) were the most common diabetes- and pain-related comorbidities. Controlling for demographic and clinical characteristics, patients who received duloxetine or pregabalin in the prior 12-month period were more likely to initiate duloxetine. Patients from other DPNP treatment cohorts, except for those in the pregabalin cohort, were more likely to re-initiate the same prior therapy than begin treatment with duloxetine (all p0.05). A history of anxiety disorder was significantly associated with initiation of all DPNP treatments other than duloxetine (all p0.05), except for TCAs. Patients with low back pain were more likely to initiate duloxetine than TCAs or venlafaxine, but less likely to initiate duloxetine than pregabalin or opioids. Patients with infections related to diabetes were less likely to initiate duloxetine than venlafaxine, gabapentin, or opioids.Because a retrospective administrative claims database was used, this study is subject to selection bias due to unobservable confounders, inability to measure prescriber preferences or characteristics or disease severity.Among commercially-insured DPNP patients, those with prior use of duloxetine or pregabalin were more likely to initiate duloxetine than other treatments. The presence of select comorbidities was also associated with specific medication initiation.

Objective: The study aims to examine predictors associated with duloxetine adherence and its association with healthcare costs among fibromyalgia patients. Methods: Administrative claims from both commercially and Medicare supplemental-insured fibromyalgia patents aged 18+ who initiated duloxetine in 2006 were analyzed. Initiation was defined as a 90-day clean period without duloxetine. The dispense date of the first duloxetine prescription was denoted as the index date. Two cohorts were constructed based on duloxetine adherence over the 12-month postindex period (high adherence as medication possession ratio ≥ 0.8). Predictors of high adherence were examined via logistic regression. Generalized linear regressions were performed to estimate the association between duloxetine adherence and healthcare costs. Results: A total of 4,869 commercially and 566 Medicare supplemental-insured fibromyalgia patients were identified. Two-thirds of patients had low adherence. Higher duloxetine average daily dose (ADD) was associated with increased adherence (reference group = 30 mg; Commercial: Odds ratio [OR] = 3.03, 2.40, and 3.73 for 31 to 59 mg, 60 mg, and > 60 mg, respectively, all P 60 mg, respectively, all P

Objective: Patient nonadherence and early discontinuation of antidepressant treatment are common. Pharmaceutical promotion to consumers and physicians may influence this behavior. The objectives of this study were to explore whether promotional spending is related to early antidepressant switching, acute-phase adherence, and continuationphase adherence. Methods: A retrospective cohort study was conducted with national promotional expenditure data merged with medical and prescription claims data from a large national health plan affiliated with i3 Innovus. Included were records for continuously insured adults with major depression who received a new prescription for an antidepressant: 5,010 were in the cohort assessed for switching, 4,457 were in the cohort assessed for acute-phase adherence, and 1,772 were in the cohort assessed for continuation-phase adherence. National promotional efforts were estimated by examining inflation-adjusted spending on direct-toconsumer advertising (DTCA) and physician detailing. Clinical guidelines were used to create proxies for aspects of treatment outcomes, including antidepressant switching and adherence in the acute phase and adherence in the continuation phase. Logistic regression models estimated the association between promotional variables and these outcomes. Results: Patients taking medications that were more highly promoted to physicians were less likely to switch medications (odds ratio [OR]=.61) and were more likely to be adherent during the acute phase of treatment (OR=1.13). DTCA had little effect on switching or antidepressant adherence. Conclusions: Detailing to physicians was associated with lower rates of medication switching and had a positive relationship with patient adherence during early antidepressant treatment. This finding indicates that certain aspects of promotion may have beneficial effects on antidepressant use. (Psychiatric Services 61:1232–1238, 2010)

To examine whether prescriber specialty and guideline-concordant follow-up visits were associated with antidepressant treatment completion among patients with major depressive disorder (MDD).This study analyzed medical and prescription claims from a large national health plan. Patients were grouped based on initial prescriber specialty. Receipt of guideline-concordant follow-ups was defined as havingor =3 visits during the treatment phase. Completion of acute phase (first 90 days) and continuation phase (Days 91-270) was defined by adherenceor = 80% without significant gaps in treatment. Logistic regressions were used to examine factors associated with treatment completion.Forty-seven percent of the 4102 newly diagnosed patients completed the acute phase, 45% of whom also completed the continuation phase. Among those initially prescribed by primary care providers (PCPs), patients with guideline-concordant follow-ups were more likely (13.1 percentage points, P.0001) to complete acute phase than patients without guideline-concordant follow-ups. Receipt of guideline-concordant follow-ups increased the probability of acute phase completion by an additional 6.8 percentage points if initially treated by psychiatrists. Patients prescribed by psychiatrists were less likely to complete acute phase treatment (-4.6 percentage points, P=.04) if they did not have guideline-concordant follow-ups.A large gap remains between guideline recommendations and actual antidepressant treatment. Frequent follow-up corresponds with better antidepressant adherence.

Background ABILHAND, a manual ability patient-reported outcome instrument originally developed for stroke patients, has been used in multiple sclerosis clinical trials; however, psychometric analyses indicated the measure’s limited measurement range and precision in higher-functioning multiple sclerosis patients. Objective The purpose of this study was to identify candidate items to expand the measurement range of the ABILHAND-56, thus improving its ability to detect differences in manual ability in higher-functioning multiple sclerosis patients. Methods A step-wise mixed methods design strategy was used, comprising two waves of patient interviews, a combination of qualitative (concept elicitation and cognitive debriefing) and quantitative (Rasch measurement theory) analytic techniques, and consultation interviews with three clinical neurologists specializing in multiple sclerosis. Results Original ABILHAND was well understood in this context of use. Eighty-two new manual ability concepts were identified. Draft supplementary items were generated and refined with patient and neurologist input. Rasch measurement theory psychometric analysis indicated supplementary items improved targeting to higher-functioning multiple sclerosis patients and measurement precision. The final pool of Early Multiple Sclerosis Manual Ability items comprises 20 items. Conclusion The synthesis of qualitative and quantitative methods used in this study improves the ABILHAND content validity to more effectively identify manual ability changes in early multiple sclerosis and potentially help determine treatment effect in higher-functioning patients in clinical trials.

Objective: To examine the relationship between average daily dose (ADD) of duloxetine, adherence to therapy, and health-care costs among patients with diabetic peripheral neuropathic pain (DPNP). Methods: A retrospective analysis of commercially insured DPNP patients was conducted among those aged 18 to 64 years who initiated duloxetine therapy between Ocotober 1, 2004 and December 31, 2006. The dispense date of the first duloxetine prescription was defined as the index date. All duloxetine prescriptions over the 12-month post-index period were used to assess ADD and adherence. Four study cohorts were constructed based on ADD: 30 mg, 31 to 59 mg, 60 mg; and >60 mg. High adherence was defined as having a medication possession ratio for duloxetine of ≥0.8. Health-care costs over 12-month post-index period were estimated. Multiple regression models were used to examine the association between ADD, adherence, and health-care costs. Results: The study sample included 1,351 DPNP patients (mean age: 55 years; male: 41%). Twelve percent of patients had a duloxetine ADD of 30 mg, 17% of 31 to 59 mg, 56% of 60 mg, and 15% of >60 mg. Patients with ADD of 30 mg (>60 mg) were significantly less (more) likely to adhere to duloxetine therapy compared with those in the 60 mg cohort. Controlling for cross-cohort demographic and clinical differences, patients with ADD of 30 mg, 31 to 59 mg, or >60 mg had significantly higher total health-care costs than those with ADD of 60 mg (adjusted differences: $6,090, $6,320, $6,466 for 30 mg, 31 to 59 mg, >60 mg, respectively, all P

Tumour necrosis factor-α (TNF-α), an important proinflammatory cytokine, exerts a variety of physiological and pathogenic effects that lead to tissue destruction. Studies on the association of TNF-α genetic polymorphisms with systemic lupus erythematosus (SLE) have yielded inconclusive results. We investigated the association of TNF-α genetic polymorphisms (−1031T/C, −863C/A, −857T/C, −308A/G and +489A/G) with SLE in Taiwanese patients and controls. Our results indicate that 1) the frequency of the A-allele at −863 position was significantly higher in SLE patients (odds ratio = 1.46; 95% CI = 1.02–2.08); 2) the frequency of the A-allele at +489 position was significantly higher in SLE patients (odds ratio = 1.79; 95% CI = 1.21–2.65); 3) the AA or GA genotype frequencies at +489 position were significantly increased in SLE patients (AA genotype: odds ratio = 11.20; 95% CI = 1.36–92.55; GA genotype: odds ratio = 1.63; 95% CI = 1.03–2.58); 4) no significant association of TNF-α haplotypic distributions was observed, except for the haplotypes TCCGA, CACGA and CCCGG; and 5) the genotype frequency of the polymorphisms at −1031 was significantly different in patients with antinuclear antibodies ( P = 0.022). The allele and genotype frequencies of the polymorphisms at −863 were not significantly different. The genotype frequency of the polymorphisms at −857 was significantly different in patients with haematological disorder ( P = 0.025). The frequency of A allele of the polymorphisms at −308 was significantly increased in patients with malar rash ( P = 0.033), discoid rash ( P = 0.023), photosensitivity ( P = 0.037), oral ulcers ( P = 0.002) and serositis ( P = 0.029). The genotype frequency of the polymorphisms at +489 was significantly different in patients with discoid rash and photosensitivity (data not shown; discoid rash, P = 0.031; photosensitivity, P = 0.044). These results suggest that TNF-α genetic polymorphisms contribute to SLE susceptibility in the Taiwanese population.

Introduction: Managing ARDS is resource-intensive, but published quantitative data are limited. Objective: To examine the healthcare resource utilization (HRU) and costs of patients hospitalized with ARDS. Methods: US administrative claims between 2009 and 2013 of commercially-insured individuals and Medicare beneficiaries were analyzed. Patients with ARDS who received mechanical ventilation during the index hospitalization were selected. Each ARDS patient was demographically matched to 10 non-ARDS hospitalized controls. HRU, costs, and comorbidities during one-year prior (baseline), were compared, as were characteristics of the index hospitalization. One-year HRU and costs of a subgroup who were discharged alive and had at least one year follow-up were also examined. Results: Commercially-insured hospitalized ARDS patients had greater comorbid conditions and prior hospitalizations than matched controls. During the index hospitalization, ARDS patients had longer stays (16.7 vs. 4.6 days), higher mortality (11.9% vs. 0.8%), and incurred higher costs than controls ($117,137 vs. $25,199; all p Conclusion: Patients hospitalized with ARDS incurred significantly higher resource utilization and costs than non-ARDS hospitalizations during and prior to the stay. The pattern persists for one year after hospital discharge.

Management of idiopathic pulmonary fibrosis (IPF) is resource-intensive. Because an increasing prevalence of IPF was found among the elderly in the United States, it is important to understand the economic burden associated with the disease in this population.To compare health care resource utilization and costs between patients with IPF and matched control subjects without IPF in Medicare, the largest U.S. payer covering the elderly.Administrative claims from a 5% random sample of Medicare beneficiaries (aged 65+) from years 2000 to 2011 were analyzed. Incident patients with IPF were identified on the basis of International Classification of Diseases, ninth revision, Clinical Modification diagnosis codes, with at least 1 year of enrollment before (preindex) and after (postindex) the first diagnosis (index date). Up to five beneficiaries without IPF were matched to each patient with IPF, based on age, sex, race, and region. Annual health care resource utilization and medical costs (excluding outpatient drug costs) during the preindex and postindex periods were compared between patients with IPF and matched control subjects.A total of 7,855 patients with IPF were matched to 38,856 control subjects. Compared with matched control subjects during the preindex period, patients with IPF had an 82% higher risk of hospitalization (28.8 vs. 15.8%), and 72% higher total medical costs ($10,124 vs. $5,888). Compared with matched control subjects during the postindex period, patients with IPF had a 134% higher risk of hospitalization (48.7 vs. 20.8%), similar increased risk of emergency room visits (39.6 vs. 17.5%), and 134% higher total medical costs ($20,887 vs. $8,932).In the U.S. Medicare population, patients with IPF incurred substantial health care resource utilization. The annual IPF-attributable medical cost to the U.S. health care system, excluding medication costs, is estimated at close to $2 billion.