Exploring the mechanism of PingTang No.5 capsule on nonalcoholic fatty liver disease through network pharmacology and experimental validation.

PingTang No.5 capsule (PT5), a modified Traditional Chinese Medicine (TCM) formula of Zexie Decoction, is used to treat patients with lipid metabolism disorders in our hospital. The present study was designed to investigate the mechanisms of PT5 in treating non-alcoholic fatty liver disease (NAFLD). PT5 information including ingredients, pharmacological properties, and potential targets was obtained from TCM databases. The candidate targets of PT5 were predicted by network pharmacological analysis, and the possible pathway and mechanism were obtained from DAVID database, followed by experimental validation in NAFLD mice model treated with PT5. Total 328 compounds were selected using the threshold oral bioactivity (OB) > 30% or drug-likeness (DL) > 0.1 of pharmacology characteristic, and 1033 candidate targets obtained to construct the network analysis. The 113 targets were selected from the intersection between candidate targets of PT5 and NAFLD relative gene. These targets were evaluated in diabetic complications, cancer, Hepatitis B, Fluid shear stress and atherosclerosis, and TNF signaling pathway. TNF-α was the important factor in protein interaction analysis of STRING and involved in the lipid regulation and oxidative stress in NAFLD. When administrated to the NAFLD mice, PT5 reduced weight, blood fatty acids, decreased the adipocyte size, and improved the metabolism. Besides, the molecular verification of lipid metabolism increased and oxidative stress reduced that interpreted the mechanism of PT5 preventing liver cell from lipid accumulation and injury of NAFLD. These results presented PT5 have the potential therapy as an alternative treatment for NAFLD.

An 'Ayurveda-Biology' platform for integrative diabetes management.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes is a multifactorial disease with complex multi-organ-multi-target crosstalk in the body. Currently, the theoretical assumptions framing the diabetes management strategies are reductionist and largely focus on reducing hyperglycemia through targeted molecular drugs. While they effectively reduce hyperglycemia, they are inadequate to address the multifactorial etiopathology, chronicity and systemic complications of diabetes. Therefore, a holistic and systemic approach is essential for its successful management. We hypothesize an integrative diabetes management strategy, combining holistic principles of diabetes management with its molecular understandings, would be more appropriate to fill this gap. The holistic disease management principles of Ayurveda, the Indian system of medicine, can play a pivotal role in this context. This narrative review discusses the scope of a trans-disciplinary ' Ayurveda-Biology ' approach for deepening the holistic understanding of the pathophysiology of diabetes as well as designing novel integrative strategies for managing diabetes and restoring whole body glucose homeostasis. METHODOLOGY: The article analyses the Ayurveda scheme of diabetes management and correlates it with the molecular understanding of its pathophysiology and management. The sources of information used in this article include classical texts of Ayurveda , medical books, published research articles and scientific databases like PubMed, Google Scholar, Science-Direct, etc. RESULTS: While Ayurveda and modern biomedicine uses different epistemology and ontology for describing diabetes, both the systems recognize the central role of gut and gut derived factors in postprandial glucose disposal and whole body glucose homeostasis. Essentially, the principles of both Ayurveda and modern biomedicine overlap at a gut centred view of diabetes management; and Gastro-intestinal mediated glucose disposal , a holistic concept of glucose metabolism, is emerging as a converging node for designing innovative integrative diabetes management strategies. CONCLUSIONS: An integrative disease management strategy, combining holistic and reductionist perspectives of traditional medicine and biology respectively, would be the prerogative for successful management of diabetes. Creating an ' Ayurveda-Biology' knowledge framework integrating the patient centred holistic management principles of Ayurveda and the molecular approaches of modern biology can give better insights into the biology of whole body glucose homeostasis and offer novel strategies for cost effective, holistic and multi-targeted management of diabetes.

Risk Factors for Pseudoaldosteronism with Yokukansan Use: Analysis Using the Japanese Adverse Drug Report (JADER) Database.

Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9-2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2-2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8-20; p < 0.01), dementia (OR 2.8, 95% CI 1.6-4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1-3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98-3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.

Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study.

BACKGROUND: Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. METHODS: We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. FINDINGS: Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017-19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48-53 mmol/mol (6·5-7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47-1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48-53 mmol/mol (HR 1·22 [95% CI 1·15-1·30, p<0·0001] for 59-74 mmol/mol [7·6-8·9%] and 1·36 [1·24-1·50, p<0·0001] for 75-85 mmol/mol [9·0-9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0-29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60-3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53-3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11-2·56, p<0·0001) and 1·60 (1·47-1·75, p<0·0001). INTERPRETATION: Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. FUNDING: None.

Increased risk of tinnitus following a trigeminal neuralgia diagnosis: a one-year follow-up study.

BACKGROUND: Tinnitus due to hyperactivity across neuronal ensembles along the auditory pathway is reported. We hypothesized that trigeminal neuralgia patients may subsequently suffer from tinnitus. Using nationwide, population-based data and a retrospective cohort study design, we investigated the risk of tinnitus within 1 year following trigeminal neuralgia. METHODS: We used the Taiwan National Health Insurance Research Dataset, a claims database, to identify all patients diagnosed with trigeminal neuralgia from January 2001 to December 2014, 12,587 patients. From the remaining patients, we identified 12,587 comparison patients without trigeminal neuralgia by propensity score matching, using sex, age, monthly income, geographic region, residential urbanization level, and tinnitus-relevant comorbidities (hyperlipidemia, diabetes, coronary heart disease, hypertension, cervical spondylosis, temporomandibular joint disorders and injury to head and neck and index year). All study patients (n = 25,174) were tracked for a one-year period to identify those with a subsequent diagnosis of tinnitus over 1-year follow-up. RESULTS: Among total 25,174 sample patients, the incidence of tinnitus was 18.21 per 100 person-years (95% CI = 17.66 ~ 18.77), the rate being 23.57 (95% CI = 22.68 ~ 24.49) among patients with trigeminal neuralgia and 13.17 (95% CI = 12.53 ~ 13.84) among comparison patients. Furthermore, the adjusted Cox proportional hazard ratio for tinnitus in the trigeminal neuralgia group was 1.68 (95% CI = 1.58 ~ 1.80) relative to the comparison cohort. CONCLUSIONS: We found a significantly increased risk of tinnitus within 1 year of trigeminal neuralgia diagnosis compared to those without the diagnosis. Further studies in other countries and ethnicities are needed to explore the relationship between trigeminal neuralgia and subsequent tinnitus.

Mechanisms for the reduction of caffeine consumption: What, how and why.

BACKGROUND: Anecdotal evidence suggests consumers of caffeine self-administer strategies to reduce consumption, but little is known of what these strategies are or how they are implemented. This study aimed to understand the lived experience of reducing caffeine consumption including specific techniques (what) and implementation strategies (how), harm and withdrawal symptoms (why). METHODS: We developed a classification system through an inductive and deductive approach and applied it to a large dataset derived from online sources. RESULTS: A total of 112 internet sources were identified, containing 2,682 different strategies. The classification system identified 22 categories of Behaviour Change Techniques (BCT): 10 categories were directly aligned with a BCT, one was split into two categories (substance and behavioural substitution), six represented a cluster of BCT's (e.g., withdrawal management and maintaining momentum) and four appeared to uniquely represent a consumer perspective (e.g., realisation of a problem). The most common techniques were substance substitution, seek knowledge and information, avoidance of caffeine and identify prompts for change. The most frequently perceived benefit was the stimulating effects of caffeine and a feeling of mental alertness. The most frequently cited harms were sleep problems including insomnia and concerns about dependence (or addiction) to caffeine. We found 16 categories of withdrawal symptoms. The most frequently endorsed symptom was headaches, followed by fatigue, exhaustion and low energy. CONCLUSIONS: Consumers use a wide range of techniques when attempting to reduce caffeine consumption. Treatment approaches are focused on fading, but the current study found consumers most frequently focus on substance and behavioural substitution.

Does Diabetes Increase the Risk of Contracting COVID-19? A Population-Based Study in Korea.

BACKGROUND: This study aimed to determine the infection risk of coronavirus disease 2019 (COVID-19) in patients with diabetes (according to treatment method). METHODS: Claimed subjects to the Korean National Health Insurance claims database diagnosed with COVID-19 were included. Ten thousand sixty-nine patients with COVID-19 between January 28 and April 5, 2020, were included. Stratified random sampling of 1:5 was used to select the control group of COVID-19 patients. In total 50,587 subjects were selected as the control group. After deleting the missing values, 60,656 subjects were included. RESULTS: Adjusted odds ratio (OR) indicated that diabetic insulin users had a higher risk of COVID-19 than subjects without diabetes (OR, 1.25; 95% confidence interval [CI], 1.03 to 1.53; P=0.0278). In the subgroup analysis, infection risk was higher among diabetes male insulin users (OR, 1.42; 95% CI, 1.07 to 1.89), those between 40 and 59 years (OR, 1.66; 95% CI, 1.13 to 2.44). The infection risk was higher in diabetic insulin users with 2 to 4 years of morbidity (OR, 1.744; 95% CI, 1.003 to 3.044). CONCLUSION: Some diabetic patients with certain conditions would be associated with a higher risk of acquiring COVID-19, highlighting their need for special attention. Efforts are warranted to ensure that diabetic patients have minimal exposure to the virus. It is important to establish proactive care and screening tests for diabetic patients suspected with COVID-19 for timely disease diagnosis and management.

Radiographic progression can still occur in individual patients with low or moderate disease activity in the current treat-to-target paradigm: real-world data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry.

BACKGROUND: The aim of this retrospective study was to examine the longitudinal association between disease activity and radiographic damage in a cohort of patients with early RA (symptom onset < 1 year) treated according to treat-to-target (T2T) therapy. METHODS: Baseline to 3-year follow-up data were used from patients included in the DREAM remission induction cohort. Patients received protocolized T2T treatment, aimed at 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission. Disease activity (DAS28-ESR and C-reactive protein, CRP) were assessed at least every 3 months; X-rays of the hand and feet at inclusion, 6 months, and 1, 2, and 3 years were scored using modified Sharp/van der Heijde scoring (SHS). Between and within-person associations between time-integrated disease activity and radiographic progression over time were examined. RESULTS: A subset of 229 out of 534 included patients were available for analysis. At the between-patient level, time-integrated DAS28-ESR scores were not significantly correlated with progression at the 6 month and 2-year follow-up and only weakly at the 1-year (Pearson's correlation coefficient r = 0.17, P < 0.05) and 3-year follow-up (r = 0.21, P < 0.05). Individual slopes of the relationship between DAS28-ESR and progression scores in each time interval were significantly correlated over time and the slope of the first 6 months was moderately associated with this slope at later time points (r between 0.39 and 0.59; P values < 0.001). Between 15.9 to 22.7% and 16.7 to 38.5% of patients with low and moderate time-integrated disease activity, respectively, experienced relevant (ΔSHS ≥ 3) radiographic progression at the different time intervals. Analyses using CRP showed similar results. CONCLUSIONS: In early RA patients treated according to T2T, radiographic progression appears to be an individually determined disease process, driven by factors other than consistent high disease activity. For individual patients, the intra-patient relation between disease activity and cumulative radiographic damage during the first 6 months is a good indicator for this relation in later years. TRIAL REGISTRATION: Netherlands Trial Register NTR578, 12 January 2006.

Health of Spanish centenarians: a cross-sectional study based on electronic health records.

BACKGROUND: With the number of centenarians increasing exponentially in Spain, a deeper knowledge of their socio-demographic, clinical, and healthcare use characteristics is important to better understand the health profile of the very elderly. METHODS: We conducted a retrospective, cross-sectional observational study in the EpiChron Cohort (Aragón, Spain) aimed at analyzing the socio-demographic, clinical, drug use and healthcare use characteristics of 1680 centenarians during 2011-2015, using data from electronic health records and clinical-administrative databases. RESULTS: Spanish centenarians (79.1% women) had 101.6 years on average. Approximately 80% of centenarians suffered from multimorbidity, with an average of 4.0 chronic conditions; 50% were exposed to polypharmacy, with an average of 4.8 medications; only 6% of centenarians were free of chronic diseases and only 7% were not on medication. Centenarians presented a cardio-cerebrovascular pattern in which hypertension, heart failure, cerebrovascular disease and dementia were the most frequent conditions. Primary care was the most frequently visited healthcare level (79% of them), followed by medical specialist consultations (23%), hospitalizations (13%), and emergency service use (9%). CONCLUSIONS: Multimorbidity is the rule rather than the exception in Spanish centenarians. Addressing medical care in the very elderly from a holistic geriatric view is critical in order to preserve their health, and avoid the negative effects of polypharmacy.

What Are the Costs of Cervical Radiculopathy Prior to Surgical Treatment?

STUDY DESIGN: Retrospective, observational study. OBJECTIVE: To examine the costs associated with nonoperative management (diagnosis and treatment) of cervical radiculopathy in the year prior to anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: While the costs of operative treatment have been previously described, less is known about nonoperative management costs of cervical radiculopathy leading up to surgery. METHODS: The Humana claims dataset (2007-2015) was queried to identify adult patients with cervical radiculopathy that underwent ACDF. Outcome endpoint was assessment of cumulative and per-capita costs for nonoperative diagnostic (x-rays, computed tomographic [CT], magnetic resonance imaging [MRI], electromyogram/nerve conduction studies [EMG/NCS]) and treatment modalities (injections, physical therapy [PT], braces, medications, chiropractic services) in the year preceding surgical intervention. RESULTS: Overall 12,514 patients (52% female) with cervical radiculopathy underwent ACDF. Cumulative costs and per-capita costs for nonoperative management, during the year prior to ACDF was $14.3 million and $1143, respectively. All patients underwent at least one diagnostic test (MRI: 86.7%; x-ray: 57.5%; CT: 35.2%) while 73.3% patients received a nonoperative treatment. Diagnostic testing comprised of over 62% of total nonoperative costs ($8.9 million) with MRI constituting the highest total relative spend ($5.3 million; per-capita: $489) followed by CT ($2.6 million; per-capita: $606), x-rays ($0.54 million; per-capita: $76), and EMG/NCS ($0.39 million; per-capita: $467). Conservative treatments comprised of 37.7% of the total nonoperative costs ($5.4 million) with injections costs constituting the highest relative spend ($3.01 million; per-capita: $988) followed by PT ($1.13 million; per-capita: $510) and medications (narcotics: $0.51 million, per-capita $101; gabapentin: $0.21 million, per-capita $93; NSAIDs: 0.107 million, per-capita $47), bracing ($0.25 million; per-capita: $193), and chiropractic services ($0.137 million; per-capita: $193). CONCLUSION: The study quantifies the cumulative and per-capital costs incurred 1-year prior to ACDF in patients with cervical radiculopathy for nonoperative diagnostic and treatment modalities. Approximately two-thirds of the costs associated with cervical radiculopathy are from diagnostic modalities. As institutions begin entering into bundled payments for cervical spine disease, understanding condition specific costs is a critical first step. LEVEL OF EVIDENCE: 3.

Variability in Palliative Care Use after Intracerebral Hemorrhage at US Hospitals: A Multilevel Analysis.

BACKGROUND: Palliative care (PC) is an essential component of comprehensive care of patients with intracerebral hemorrhage (ICH). In the present study, we sought to characterize the variability of PC use after ICH among US hospitals. METHODS: ICH admissions from hospitals with at least 12 annual ICH cases were identified in the Nationwide Inpatient Sample between 2008 and 2011. We used multilevel logistic regression modeling to estimate between-hospital variance in PC use. We calculated the intraclass correlation coefficient (ICC), proportional variance change, and median OR after accounting for individual-level and hospital-level covariates. RESULTS: Among 26,791 ICH admissions, 12.5% received PC (95% CI 11.5-13.5). Among the 629 included hospitals, the median rate of PC use was 9.1 (interquartile range 1.5-19.3) per 100 ICH admissions, and 150 (23.9%) hospitals had no recorded PC use. The ICC of the random intercept (null) model was 0.274, suggesting that 27.4% of the overall variability in PC use was due to between-hospital variability. Adding hospital-level covariates to the model accounted for 25.8% of the between-hospital variance observed in the null model, with 74.2% of between-hospital variance remaining unexplained. The median OR of the fully adjusted model was 2.62 (95% CI 2.41-2.89), indicating that a patient moving from 1 hospital to another with a higher intrinsic propensity of PC use had a 2.63-fold median increase in the odds of receiving PC, independent of patient and hospital factors. CONCLUSIONS: Substantial variation in PC use after ICH exists among US hospitals. A substantial proportion of this between-hospital variability remains unexplained even after accounting for patient and hospital characteristics.

Ethnobotanic, phytochemical uses and ethnopharmacological profile of genus Cnidoscolus spp. (Euphorbiaceae): A comprehensive overview.

The application of medicinal plants are the most important biotechnological alternative in the treatment of numerous diseases, especially in developing countries, such as Brazil. Among them, we specified some specimens of the genus Cnidoscolus used as phytotherapies, with healing properties, analgesic, anti-inflammatory, antibiotic and diuretic, anticancer, among others. Such effects are possibly associated with the presence of terpenoids, alkaloids, coumarins, flavonoids phenolic compounds, among others. Thus, the objective of this work was to evaluate in the literature the studies on the phytochemical, ethnopharmacological and biotechnological applications of this genus, from 1998 to 2017. Among the sixty-one studies reported in this review, ten species are popularly utilized to pharmacological and/or biotechnological applications. Cnidoscolus aconitifolius and Cnidoscolus chayamansa are the most cited species, which were also supported by either animal or cellular investigations indicating some beneficial pharmacological actions like antioxidant, anti-inflammatory and potential cytotoxic activity. The plant parts of this genus under study are important as sources for the isolation and identification of bioactive molecules with biotechnological applications, among the many diseases treated with this phytotherapy. Given these verdicts, ethnopharmacological approaches are significant systematic tools in the determination of plant species that exhibit medicinal and nutritional purposes. The results presented here should further stimulate the development of validation studies to ensure the safe and effective use of these plant species.

Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib.

BACKGROUND: Before the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib. METHODS: A database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model. RESULTS: Forty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 - 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3-4 in 44.4% of the patients. CONCLUSION: In accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.

Trends in anemia care in non-dialysis-dependent chronic kidney disease (CKD) patients in the United States (2006-2015).

BACKGROUND: The objective of the study was to examine overall anemia management trends in non-dialysis patients with chronic kidney disease (CKD) from 2006 to 2015, and to evaluate the impact of Trial to Reduced Cardiovascular Events with Ananesp Therapy (TREAT)'s study results (October 2009) and the US Food and Drug Administration (FDA)'s (June 2011) safety warnings and guidelines on the use of ESA therapy in the current treatment of anemia. METHODS: A retrospective cohort analysis of anemia management in CKD patients using Truven MarketScan Commercial and Medicare Supplemental databases was conducted. Monthly rates and types of anemia treatment for post-TREAT and post-FDA safety warning periods were compared to pre-TREAT period. Anemia management included ESA, intravenous iron, and blood transfusion. A time-series analysis using Autoregressive Integrated Moving Average (ARIMA) model and a Generalized Estimating Equation (GEE) model were used. RESULTS: Between 2006 and 2015, CKD patients were increasingly less likely to be treated with ESAs, more likely to receive intravenous iron supplementation, and blood transfusions. The adjusted probabilities of prescribing ESAs were 31% (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.67-0.71) and 59% (OR = 0.41, 95% CI: 0.40, 0.42) lower in the post-TREAT and post-FDA warning periods compared to pre-TREAT period. The probability of prescribing intravenous iron was increased in the post-FDA warning period (OR = 1.11, 95% CI: 1.03-1.19) although the increase was not statistically significant in the post-TREAT period (OR = 1.03, 95% CI: 0.94-1.12). The probabilities of prescribing blood transfusion during the post-TREAT and post-FDA warning periods increased by 14% (OR = 1.14, 95% CI: 1.06-1.23) and 31% (OR = 1.31, 95% CI: 1.22-1.39), respectively. Similar trends of prescribing ESAs and iron supplementations were observed in commercially insured CKD patients but the use of blood transfusions did not increase. CONCLUSIONS: After the 2011 FDA safety warnings, the use of ESA continued to decrease while the use of iron supplementation continued to increase. The use of blood transfusions increased significantly in Medicare patients while it remained stable in commercially insured patients. Results suggest the TREAT publication had effected treatment of anemia prior to the FDA warning but the FDA warning solidified TREAT's recommendations for anemia treatment for non- dialysis dependent CKD patients.

Signal Detection Between Fluoroquinolone Use and the Risk of Rhegmatogenous Retinal Detachment: Sequence Symmetry Analysis Using Nationwide South Korean Healthcare Database Between 2004 and 2015.

BACKGROUND AND OBJECTIVES: The association between fluoroquinolone and rhegmatogenous retinal detachment (RRD) has been controversial as a result of inconsistent findings. We set out to detect a possible association of fluoroquinolone use and risk of RRD, using sequence symmetry analysis (SSA). METHODS: We conducted an SSA, case-only design, using a Korean nationwide healthcare database between 2004 and 2015. Exposure was defined as new fluoroquinolone use and outcome as an incident RRD, defined by a diagnosis of RRD (ICD-10: "H33.0") or surgery for RRD. Pairs of exposure and RRD within a 1-year time-window were included. The sequence ratio (SR) was calculated by the ratio of the number of patients prescribed with exposure first and diagnosed with RRD second divided by the number of patients diagnosed with RRD first and prescribed with exposure second. SR was adjusted (aSR) for underlying trends and 95% confidence intervals (CIs) were calculated. In order to observe whether the estimated ratio stabilized over time, we did repeated time-sequential analyses with the cumulative data starting from the 3-year period 2004-2006 to 2015. RESULTS: Fluoroquinolone use had a greater association with RRD as compared with other antibiotics [fluoroquinolone: 5234 pairs; aSR = 1.70 (95% CI 1.61-1.80), first-generation cephalosporin: 4139 pairs; aSR = 1.39 (95% CI 1.31-1.80), second-generation cephalosporin: 5914 pairs; aSR = 1.31 (95% CI 1.24-1.38), third-generation cephalosporin: 3650 pairs; aSR = 0.88 (95% CI 0.83-0.95), extended-spectrum penicillin: 4823 pairs; aSR = 1.29 (95% CI 1.31-1.47), macrolides: 4115 pairs; aSR = 1.31 (95% CI 1.24-1.39)]. Time-sequential analyses supported the association between fluoroquinolone and RRD. CONCLUSIONS: Our detection suggests a possible association between fluoroquinolone use and RRD. However, possible overestimation and reverse causality bias may have influenced our findings due to the limitation of an SSA design.

Evaluation of the HealthImpact Diabetes Risk Model in the Veterans Health Administration.

BACKGROUND: HealthImpact is a novel algorithm using administrative health care data to stratify patients according to risk for incident diabetes. OBJECTIVES: To (a) independently assess the predictive validity of HealthImpact and (b) explore its utility in diabetes screening within a nationally integrated health care system. METHODS: National Veterans Health Administration data were used to create 2 cohorts. The replication cohort included patients without diagnosed diabetes as of October 1, 2012, to determine if HealthImpact scores were significantly associated with diabetes (type 1 or 2) incidence within the subsequent 3 years. The utility cohort included patients without diagnosed diabetes as of August 1, 2015, and assessed diabetes screening rates in the 2 years surrounding this index date, stratified by HealthImpact scores. RESULTS: The 3-year incidence of diabetes in the replication cohort (n = 3,287,240) was 9.1%. Of 100,617 (3.1%) patients with HealthImpact scores > 90, 30,028 developed diabetes, yielding a positive predictive value of 29.8%. These patients accounted for 9.9% of all incident diabetes cases (sensitivity). Sensitivity and negative predictive value improved with descending HealthImpact threshold scores (e.g., > 75, > 50), whereas specificity and positive predictive value declined. Of 3,499,406 patients in the utility cohort, 85.3% received either a blood glucose or hemoglobin A1c test during the 2-year observation period. Among 101,355 patients with a HealthImpact score > 90, nearly all (98.3%) were screened, and 86.3% had an A1c test. CONCLUSIONS: Our independent analysis corroborates the validity of HealthImpact in stratifying patients according to diabetes risk. However, its practical utility to enhance diabetes screening in a real-world clinical environment will be strongly dependent on the pattern and frequency of existing screening practices. DISCLOSURES: This work was supported by the Iowa City VA Health Care System and by the Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service (Lund, CIN 13-412). The authors have no conflicts of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.

Effectiveness and Safety of Standard- and Low-Dose Rivaroxaban in Asians With Atrial Fibrillation.

BACKGROUND: Low-dose rivaroxaban (10 mg/day) has been widely used in Asia for patients with atrial fibrillation (AF), although there is a lack of evidence regarding its effectiveness. In Asians, it is unclear whether low-dose rivaroxaban is equally effective as that of the standard dose or is associated with less bleeding risk. OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of standard-dose (15 or 20 mg/day) and low-dose (10 mg/day) rivaroxaban in Asians with AF. METHODS: Using data files from the National Health Insurance Research Database between May 1, 2014, and September 30, 2015, a retrospective population-based cohort study was conducted in patients diagnosed with AF or atrial flutter and treated with low- or standard-dose rivaroxaban. Patients were followed up until the first occurrence of the study outcome or the end of the observation period (December 31, 2015). RESULTS: Among 6,558 eligible patients, a total of 2,373 and 4,185 patients took low- and standard-dose rivaroxaban, respectively. Compared to standard-dose rivaroxaban, low-dose rivaroxaban was associated with a significantly higher risk of myocardial infarction (subdistribution hazard ratio: 2.26; 95% confidence interval: 1.13 to 4.52), with similar risk of ischemic stroke, systemic embolism, major bleeding, and nonmajor clinically relevant bleeding. CONCLUSIONS: Compared to standard-dose rivaroxaban, low-dose rivaroxaban in Asian patients with AF was associated with similar risks of thromboembolism and bleeding except myocardial infarction.

Cortico-thalamic hypo- and hyperconnectivity extend consistently to basal ganglia in schizophrenia.

Schizophrenia is characterized by hypoconnectivity or decreased intrinsic functional connectivity (iFC) between prefrontal-limbic cortices and thalamic nuclei, as well as hyperconnectivity or increased iFC between primary-sensorimotor cortices and thalamic nuclei. However, cortico-thalamic iFC overlaps with larger, structurally defined cortico-striato-pallido-thalamo-cortical (CSPTC) circuits. If such an overlap is relevant for intrinsic hypo-/hyperconnectivity, it suggests (i) that patterns of cortico-subcortical hypo-/hyperconnectivity extend consistently from thalamus to basal ganglia nuclei; and (ii) such consistent hypo-/hyperconnectivity might link distinctively but consonant with different symptom dimensions, namely cognitive and psychotic impairments. To test this hypothesis, 57 patients with schizophrenia and 61 healthy controls were assessed by resting-state functional magnetic resonance imaging (fMRI) and clinical-behavioral testing. IFC from intrinsic cortical networks into thalamus, striatum, and pallidum was estimated by partial correlations between fMRI time courses. In patients, the salience network covering prefrontal-limbic cortices was hypoconnected with the mediodorsal thalamus and ventral parts of striatum and pallidum; these iFC-hypoconnectivity patterns were correlated both among each other and specifically with patients' impaired cognition. In contrast, the auditory-sensorimotor network covering primary-sensorimotor cortices was hyperconnected with the anterior ventral nucleus of the thalamus and dorsal parts of striatum and pallidum; these iFC-hyperconnectivity patterns were likewise correlated among each other and specifically with patients' psychotic symptoms. The results demonstrate that prefrontal-limbic hypoconnectivity and primary-sensorimotor hyperconnectivity extend consistently across subcortical nuclei and specifically across distinct symptom dimensions. Data support the model of consistent cortico-subcortical hypo-/hyperconnectivity within CSPTC circuits in schizophrenia.

Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis.

IMPORTANCE: While psoriasis (Ps) is mainly characterized as an adult disease, it can also develop during childhood. However, prevalence estimates of pediatric psoriasis in the United States (US) are lacking. OBJECTIVE: To assess the 2015 annual prevalence of Ps and moderate-to-severe Ps in pediatric individuals in the US. DESIGN: This is a retrospective study based on a large administrative insurance claims database in the US. SETTING: Data were extracted from the Truven Health Analytics MarketScan® Commercial Claims and Encounters database, which covers over 60 million individuals with employer-provided health insurance across the US. PARTICIPANTS: Over 4.3 million of individuals continuously enrolled in their healthcare plan in 2015 and under 18 years of age were included in the study. Intervention(s) for Clinical Trials or Exposure(s) for Observational Studies: Not applicable. Main Outcome(s) and Measure(s): Ps was defined based on medical claims with a diagnosis of Ps (ICD-9-CM: 696.1); moderate-to-severe Ps was defined based on medical or pharmacy claims for a systemic treatment (biologic, conventional systemic, or phototherapy) for Ps. Overall and age- and gender-stratified prevalence was estimated for both Ps and moderate-to-severe Ps. RESULTS: The prevalence of Ps was estimated at 128 cases per 100,000 individuals (95% CI: 124-131), that of moderate-to-severe Ps at 16 cases per 100,000 individuals (95% CI: 15-17) in 2015. For both Ps and moderate-to-severe Ps, prevalence estimates were numerically higher in females than in males (146 per 100,000 vs. 110 per 100,000 and 17 per 100,000 vs. 15 per 100,000) and increased with age, ranging from 30 per 100,000 in the 0-3 year old group to 205 per 100,000 in the 12-17 year old group. CONCLUSION AND RELEVANCE: This study provides robust estimates of the prevalence of pediatric Ps that can inform decisions pertaining to the management of pediatric patients with Ps. J Drugs Dermatol. 2018;17(2):187-194.