Rationale and protocol for a prospective cohort study of respiratory viral infections in patients admitted from emergency departments of community hospitals: Effect of respiratory Virus infection on EmeRgencY admission (EVERY) study.

INTRODUCTION: Respiratory syncytial virus (RSV) is a causative virus for the common cold worldwide and can result in hospitalisations and even death in patients with high-risk conditions and older adults. However, the relationship between RSV or other incidental respiratory infections and acute exacerbations of underlying conditions has not been well investigated. The primary objective of this study is to estimate RSV prevalence, risk factors for adverse outcomes or hospitalisation and their effect on the hospital course of patients with acute respiratory symptoms admitted from emergency departments. Furthermore, we evaluate the prevalence of other respiratory viruses associated with respiratory symptoms. METHODS AND ANALYSIS: We are conducting a multicentre prospective cohort study in Japan. We plan to enrol 3000 consecutive patients admitted from emergency departments with acute respiratory symptoms or signs from 1 July 2023 to 30 June 2024. A nasopharyngeal swab is obtained within 24 hours of admission and the prevalence of RSV and other respiratory viruses is measured using the FilmArray Respiratory 2.1 panel. Paired serum samples are collected from patients with suspected lower respiratory infections to measure RSV antibodies at admission and 30 days later. Information on patients' hospital course is retrieved from the electronic medical records at discharge, death or 30 days after admission. Furthermore, information on readmission to the hospital and all-cause mortality is collected 180 days after admission. We assess the differences in clinical outcomes between patients with RSV or other respiratory viruses and those without, adjusting for baseline characteristics. Clinical outcomes include in-hospital mortality, length of hospital stay, disease progression, laboratory tests and management of respiratory symptoms or underlying conditions. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review boards of participating hospitals. Our study reports will be published in academic journals as well as international meetings. TRIAL REGISTRATION NUMBER: NCT05913700.

Adverse Events in Pediatric Inpatients: The Japan Adverse Event Study.

OBJECTIVES: Adverse events (AEs) represent an important cause of morbidity and mortality for pediatric inpatients; however, reports on their epidemiology in pediatrics, especially outside Western countries, are scarce. We investigated the incidence and nature of AEs in pediatric inpatients in Japan. METHODS: Trained pediatrician and pediatric nurses reviewed all medical documents of 1126 pediatric inpatients in 2 tertiary care teaching hospitals in Japan, and potential incidents were collected with patients' characteristics. Age was categorized into 6 groups (neonates, infants, preschoolers, school-aged children, teenagers, and over-aged pediatric patients), and medical care when potential incidents occurred was classified into drug, operation, procedure/examinations, nursing, management, and judgment. Physician reviewers independently evaluated all collected incidents into AEs, potential AEs, medical errors, and exclusions and assessed their severity and preventability. RESULTS: A total of 1126 patients with 12,624 patient-days were enrolled, and 953 AEs, with an incidence of 76 (95% confidence interval, 71-80) per 1000 patient-days, were identified. Preventable AEs accounted for 23% (218/953) of AEs. The incidence of AEs tended to decrease with increasing age. The proportion of AEs that were preventable was highest in neonates (40%), and this proportion decreased as children aged. Both judgment and management-related AEs were considered preventable AEs, and judgment-related AEs were more severe AEs than no-judgment-related AEs; 43% were life-threatening. CONCLUSIONS: Adverse events were common in Japanese pediatric inpatients, and their preventability and severity varied considerably by age category and medical care. Further investigation is needed to address which strategies might most improve pediatric patient safety.

Monitoring for adverse drug events of high-risk medications with a computerized clinical decision support system: a prospective cohort study.

Monitoring is recommended to prevent severe adverse drug events, but such examinations are often missed. To increase the number of monitoring that should be ordered for high-risk medications, we introduced a clinical decision support system (CDSS) that alerts and orders the monitoring for high-risk medications in an outpatient setting. We conducted a 2-year prospective cohort study at a tertiary care teaching hospital before (phase 1) and after (phase 2) the activation of a CDSS. The CDSS automatically provided alerts for liver function tests for vildagliptin, thyroid function tests for immune checkpoint inhibitors (ICIs) and multikinase inhibitors (MKIs), and a slit-lamp examination of the eyes for oral amiodarone when outpatients were prescribed the medications but not examined for a fixed period. The order of laboratory tests automatically appeared if alert was accepted. The alerts were hidden and did not appear on the display before activation of the CDSS. The outcomes were the number of prescriptions with alerts and examinations. During the study period, 330 patients in phase 1 and 307 patients in phase 2 were prescribed vildagliptin, 20 patients in phase 1 and 19 patients in phase 2 were prescribed ICIs or MKIs, and 72 patients in phase 1 and 66 patients in phase 2 were prescribed oral amiodarone. The baseline characteristics were similar between the phases. In patients prescribed vildagliptin, the proportion of alerts decreased significantly (38% vs 27%, P < 0.0001), and the proportion of examinations increased significantly (0.9% vs 4.0%, P < 0.0001) after activation of the CDSS. In patients prescribed ICIs or MKIs, the proportion of alerts decreased significantly (43% vs 11%, P < 0.0001), and the proportion of examinations increased numerically, but not significantly (2.6% vs 7.0%, P = 0.13). In patients prescribed oral amiodarone, the proportion of alerts decreased (86% vs 81%, P = 0.055), and the proportion of examinations increased (2.2% and 3.0%, P = 0.47); neither was significant. The CDSS has potential to increase the monitoring for high-risk medications. Our study also highlighted the limited acceptance rate of monitoring by CDSS. Further studies are needed to explore the generalizability to other medications and the cause of the limited acceptance rates among physicians.

Low Serum Total Protein at Admission Predicts in-Hospital Mortality Among General Inpatients: Historical Cohort Study.

Purpose: Low total protein (TP) is associated with mortality among patients with specific diseases, but its association was uncertain among general patients. We evaluated the effects of low TP on in-hospital mortality among general inpatients. Patients and Methods: We used data from the Japan Adverse Drug Events study series. We enrolled adult inpatients (≥ 16 years) admitted to a tertiary care hospital between September 1 and November 30, 2013. We excluded patients with multiple myeloma, pregnant women, and bone marrow graft donors. Patient data were extracted from electronic medical records. All patients were stratified into those with and without malignancy and divided into the low and normal TP groups. Low TP was defined as < 6.5 g/dL. We compared the in-hospital mortality of the low and normal TP groups stratified by the presence of malignancy. Results: Among the 2235 enrolled patients (mean age, 67.8 years), the TP value was lower in 516 patients with malignancy than in 1719 patients without malignancy (6.6 g/dL vs 6.8 g/dL, P = 0.0002). Among patients without or with malignancy, 27% (462/1719) and 35% (183/516) were in the low TP group, respectively. Mortality was higher in the low TP group among patients without malignancy (23.2% vs 10.2%, P < 0.0001). Likewise, among patients with malignancy, mortality was higher in the low TP group (34.7% vs 11.3%, P = 0.0029). The adjusted hazard ratio of the low TP group was 1.75 (95% confidence interval, 1.04-2.96) in patients without malignancy and 2.45 (95% confidence interval, 1.12-5.37) in patients with malignancy, but the interaction was not significant (P = 0.23). Conclusion: Low TP values were associated with higher in-hospital mortality among general inpatients, and this association was observed among patients with and those without malignancy. Routinely measured TP should be utilized to risk stratification on admission.

Effectiveness of a computerized clinical decision support system for prevention of glucocorticoid-induced osteoporosis.

Glucocorticoids are widely used for a variety of diseases, but the prevention of glucocorticoid-induced osteoporosis is sometimes neglected. Therefore, the effectiveness of a computerized clinical decision support system (CDSS) to improve the performance rate of preventive care for glucocorticoid-induced osteoporosis was evaluated. We conducted a prospective cohort study of outpatients who used glucocorticoids for three months or longer and who met the indication for preventive care based on a guideline. The CDSS recommended bisphosphonate (BP) prescription and bone mineral density (BMD) testing based on the risk of osteoporosis. The observation period was one year (phase 1: October 2017-September 2018) before implementation and the following one year (phase 2: October 2018-September 2019) after implementation of the CDSS. Potential alerts were collected without displaying them during phase 1, and the alerts were displayed during phase 2. We measured BP prescriptions and BMD testing for long-term prescription of glucocorticoids. A total of 938 patients (phase 1, 457 patients; phase 2, 481 patients) were included, and the baseline characteristics were similar between the phases. The median age was 71 years, and men accounted for 51%. The primary disease for prescription of glucocorticoids was rheumatic disease (28%), followed by hematologic diseases (18%). The prevalence of patients who needed an alert for BP prescription (67% vs. 63%, P = 0.24) and the acceptance rate of BP prescription (16% vs. 19%, P = 0.33) were similar between the phases. The number of patients who had orders for BMD testing was significantly increased (4% vs. 24%, P < 0.001) after CDSS implementation. The number of patients who needed an alert for BMD testing was significantly decreased from 93% in phase 1 to 87% in phase 2 (P = 0.004). In conclusion, the CDSS significantly increased BMD testing in patients with a higher risk of glucocorticoid-induced osteoporosis, but did not increase BP prescription.

Epidemiology of adverse drug events and medication errors in four nursing homes in Japan: the Japan Adverse Drug Events (JADE) Study.

BACKGROUND: Worldwide, the emergence of super-ageing societies has increased the number of older people requiring support for daily activities. Many elderly residents of nursing homes (NHs) take drugs to treat chronic conditions; however, there are few reports of medication safety in NHs, especially from non-western countries. OBJECTIVE: We examined the incidence and nature of adverse drug events (ADEs) and medication errors (MEs) in NHs for the elderly in Japan. DESIGN, SETTING, AND PARTICIPANTS: The Japan Adverse Drug Events Study for NHs is a prospective cohort study that was conducted among all residents, except for short-term admissions, at four NHs for older people in Japan for 1 year. MEASUREMENTS: Trained physicians and psychologists, five and six in number, respectively, reviewed all charts of the residents to identify suspected ADEs and MEs, which were then classified by the physicians into ADEs, potential ADEs and other MEs after the exclusion of ineligible events, for the assessment of their severity and preventability. The kappa score for presence of an ADE and preventability were 0.89 and 0.79, respectively. RESULTS: We enrolled 459 residents, and this yielded 3315 resident-months of observation time. We identified 1207 ADEs and 600 MEs (incidence: 36.4 and 18.1 per 100 resident-months, respectively) during the study period. About one-third of ADEs were preventable, and MEs were most frequently observed in the monitoring stage (72%, 433/600), with 71% of the MEs occurring due to inadequate observation following the physician's prescription. CONCLUSION: In Japan, ADEs and MEs are common among elderly residents of NHs. The assessment and appropriate adjustment of medication preadmission and postadmission to NHs are needed to improve medication safety, especially when a single physician is responsible for prescribing most medications for the residents, as is usually the case in Japan.

Incidence of atrial fibrillation in elderly patients with type 2 diabetes mellitus.

INTRODUCTION: The incidence of atrial fibrillation (AF), a significant risk factor for cardiovascular disease (CVD), is increasing worldwide. Type 2 diabetes mellitus (T2D) and advanced age are recognized as major risk factors for AF, but herein, we evaluated the incidence of AF in elderly patients with T2D and compared the prognosis between these patients with/without AF. RESEARCH DESIGN AND METHODS: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD2) study is a follow-up cohort study of the JPAD trial, a randomized controlled clinical trial initiated in 2002 in 2535 Japanese patients with T2D, to examine whether low-dose aspirin prevents CVD. After completion of that trial, we followed up the patients until 2019 and evaluated the incidence of AF. We also compared the incidence of cerebral cardiovascular events in elderly patients with T2D with/without AF. RESULTS: During the median follow-up period of 10.9 years, 132 patients developed AF (incidence rate: 5.14/1000 person-years). The adjusted HRs for cerebral cardiovascular events, stroke, coronary artery disease, heart failure, and all-cause death in elderly patients with T2D with versus without AF were 1.65 (95% CI 1.03 to 2.66), 1.54 (95% CI 0.81 to 2.93), 1.96 (95% CI 1.03 to 3.73), 5.17 (95% CI 2.46 to 10.89), and 1.82 (95% CI 1.24 to 2.67), respectively. CONCLUSIONS: Annually, 1 in 200 elderly Japanese patients with T2D are estimated to develop AF. Because elderly patients with T2D with AF are at an elevated risk for CVD, careful follow-up of this patient subgroup is necessary. TRIAL REGISTRATION NUMBER: NCT00110448.

Over Half of Falls Were Associated with Psychotropic Medication Use in Four Nursing Homes in Japan: A Retrospective Cohort Study.

Medication use can increase the risk of falls and injuries in nursing homes, creating a significant risk for residents. We performed a retrospective cohort study over one year to identify the incidence of drug-related falls with and without injury among four Japanese nursing homes with 280 beds. We evaluated the relationship between potential risk factors for falls and fall-related injuries while considering well-known risks such as ADLs and chronic comorbidities. By collaboratively reviewing care records, we enrolled 459 residents (mean age, 87) and identified 645 falls, including 146 injurious falls and 16 severe injurious falls requiring inpatient care, incidence: 19.5, 4.4, 0.5 per 100 resident-months, respectively. Medication influenced around three-quarters of all falls, >80% of which were psychotropic drugs. Regularly taking ≥5 medications was a risk factor for the initial falls (HR 1.33: CI 1.00−1.77, p = 0.0048) and injuries after falls (OR 2.41: CI 1.30−4.50, p = 0.006). Our findings on the incidence of falls with and without injury were similar to those in Western countries, where the use of psychotropic medication influenced >50% of falls. Discontinuing unnecessary medication use while simultaneously assessing patient ADLs and comorbidities with physicians and pharmacists may help to avoid falls in nursing homes.

Effect of Anagliptin versus Sitagliptin on Renal Function: Subanalyzes from the REASON Trial.

Purpose: The effects of two types of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function remain unclear. Thus, we investigated the effect of anagliptin (ANA) and sitagliptin (SITA) on renal function in patients with type 2 diabetes who participated in the randomized evaluation of ANA versus SITA on low-density lipoprotein-cholesterol (LDL-C) in diabetes (REASON) trial. Patients and methods: We measured the estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) before and after the REASON trial. ANA 200 mg/day was administered to 177 patients for 52 weeks, while SITA 50 mg/day was given to 176 patients. We investigated the relationship between differences in renal function and differences in hemoglobin A1c (HbA1c) levels, LDL-C levels, and blood pressure (BP). Results: No significant differences were found in baseline eGFR and UACR between the two groups. The eGFR levels were significantly decreased in both groups; however, the UACR level was unchanged in the ANA group but elevated in the SITA group, although the difference did not reach significance between the two groups. The difference in eGFR was affected by the differences in HbA1c level and BP, and the difference in the UACR was affected by the differences in LDL-C level and BP, which were reduced only in the ANA group. Conclusion: These findings imply that the effects of DPP-4 inhibitors on renal function, especially on UACR, may be different between the types of DPP-4 inhibitors.

Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy.

AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. METHODS: PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. RESULTS: Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07). CONCLUSIONS: PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.

Experience and awareness of research integrity among Japanese physicians: a nationwide cross-sectional study.

OBJECTIVES: To explore the awareness and practice of clinical research integrity among Japanese physicians. DESIGN: A nationwide cross-sectional study conducted in March 2020. SETTING: All hospitals in Japan. PARTICIPANTS: Physicians aged <65 years who work at hospitals participated in clinical research over the past 5 years. The sample was stratified according to geographical location and subspecialty, and 1100 physicians were proportionally selected. PRIMARY AND SECONDARY OUTCOME MEASURES: Knowledge and awareness of research integrity. RESULTS: Among the 1100 participants, 587 (53%) had the experience of being the first author, 299 (27%) had been co-authors only and 214 (19%) had no authorship. A total of 1021 (93%) had experienced learning research integrity, and 555 (54%) became aware of research integrity. The experience of learning about research integrity was highest among those with first authorship (95%) and lowest among those without authorship (89%) (p=0.003). The majority of participants learnt about research integrity for passive reasons such as it being 'required by the institution' (57%) or it being 'required to obtain approval of institutional review board (IRB)' (30%). Potentially inappropriate research behaviours were observed in participants, with 11% indulging in copying and pasting for writing the paper, 11% for gifted authorship and 5.8% for the omission of IRB approval. Factors significantly associated with copying and pasting were being below 40 years old (OR: 1.84; 95% CI: 1.05 to 3.26), being the first presenter (OR: 1.64; 95% CI: 1.05 to 2.57) or having passive reasons for learning research integrity (OR: 2.96; 95% CI: 1.57 to 5.59). Furthermore, gifted authorship was significantly associated with being a co-author only (OR: 1.84; 95% CI: 1.18 to 2.87) and having passive reasons for learning about research integrity (OR: 1.79; 95% CI: 1.03 to 3.12). CONCLUSIONS: Most physicians conducting clinical research have learnt about research integrity, but potentially inappropriate research behaviours are associated with passive reasons for learning.

Antipsychotic Polypharmacy Is Associated With Adverse Drug Events in Psychiatric Inpatients: The Japan Adverse Drug Events Study.

BACKGROUND: Antipsychotic (AP) polypharmacy (APP), the coprescription of more than 1 AP, is frequently practiced in psychiatric inpatients and is considered to be a risk factor for adverse drug events (ADEs). However, the association between APP and ADEs among psychiatric inpatients has not been well investigated. METHODS: The Japan Adverse Drug Events (JADE) study was a series of cohort studies conducted in several clinical settings. In particular, the JADE study for psychiatric inpatients was a retrospective cohort study of 448 psychiatric inpatients with a cumulative 22,733 patient-days. We investigated the relationship between APP, defined as a concurrent prescription of 2 or more APs and ADEs. We also assessed the relationship between potential risk factors for ADEs due to APs. RESULTS: Among the 448 patients included in this study, 106 patients (24%) had APP and the remaining 342 patients were prescribed 1 AP or none. Risperidone was the most frequent drug (25%, 109/442 AP prescriptions) used, and levomepromazine was most frequently prescribed as a concurrent medication with other APs (91%, 29/32). The median number of ADEs among the patients with APP was significantly higher than in those without APP (P = 0.001). Antipsychotic polypharmacy was a risk factor for the occurrence of first (adjusted hazard ratio, 1.54; 95% confidence interval, 1.15-2.04) and second (adjusted hazard ratio, 1.99; 95% confidence interval, 1.40-2.79) ADEs. CONCLUSIONS: Antipsychotic polypharmacy was a risk factor for the occurrence of single and multiple ADEs. Antipsychotic polypharmacy should be conservatively and minimally practiced.

The Burden of Preventable Adverse Drug Events on Hospital Stay and Healthcare Costs in Japanese Pediatric Inpatients: The JADE Study.

BACKGROUND: Adverse drug events (ADEs) are a burden to the healthcare system. Preventable ADEs, which was ADEs due to medication errors, could be reduced if medication errors can be prevent or ameliorate. OBJECTIVE: We investigated the burden of preventable ADEs on the length of hospital stay (LOS) and costs, and estimated the national burden of preventable ADEs in pediatric inpatients in Japan. METHODS: We analyzed data from the Japan Adverse Drug Events (JADE) study on pediatric patients and estimated the incidence of preventable ADEs and associated extended LOS. Costs attributable to extended LOS by preventable ADEs were calculated using a national statistics database and we calculated the effect of preventable ADEs on national cost excess. RESULTS: We included 907 patients with 7377 patient-days. Among them, 31 patients (3.4%) experienced preventable ADEs during hospitalization. Preventable ADEs significantly increased the LOS by 14.1 days, adjusting for gender, age, ward, resident physician, surgery during hospitalization, cancer, and severe malformation at birth. The individual cost due to the extended LOS of 14.1 days was estimated as USD 8258. We calculated the annual extra expense for preventable ADEs in Japan as USD 329 676 760. Sensitivity analyses, considering the incidence of preventable ADEs and the length of hospital stay, showed that the expected range of annual extra expense for preventable ADEs in Japan is between USD 141 468 968 and 588 450 708. CONCLUSION: Preventable ADEs caused longer hospitalization and considerable extra healthcare costs in pediatric inpatients. Our results would encourage further efforts to prevent and ameliorate preventable ADEs.

Association Between Statins and Cancer Incidence in Diabetes: a Cohort Study of Japanese Patients with Type 2 Diabetes.

BACKGROUND: The antitumor effect of statins has been highlighted, but clinical study results remain inconclusive. While patients with diabetes are at high risk of cancer, it is uncertain whether statins are effective for cancer chemoprevention in this population. OBJECTIVE: This study evaluated the association between statins and cancer incidence/mortality in patients with type 2 diabetes. DESIGN: This study was a follow-up observational study of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, which was a randomized controlled trial of low-dose aspirin in Japanese patients with type 2 diabetes. PARTICIPANTS: This study enrolled 2536 patients with type 2 diabetes, age 30-85 years, and no history of atherosclerotic cardiovascular disease, from December 2002 until May 2005. All participants recruited in the JPAD trial were followed until the day of any fatal event or July 2015. We defined participants taking any statin at enrollment as the statin group (n = 650) and the remainder as the no-statin group (n = 1886). MAIN MEASURES: The primary end point was the first occurrence of any cancer (cancer incidence). The secondary end point was death from any cancer (cancer mortality). KEY RESULTS: During follow-up (median, 10.7 years), 318 participants developed a new cancer and 123 died as a result. Cancer incidence and mortality were 10.5 and 3.7 per 1000 person-years in the statin group, and 16.8 and 6.3 per 1000 person-years in the no-statin group, respectively. Statin use was associated with significantly reduced cancer incidence and mortality after adjustment for confounding factors (cancer incidence: adjusted hazard ratio [HR], 0.67; 95% CI, 0.49-0.90, P = 0.007; cancer mortality: adjusted HR, 0.60; 95% CI, 0.36-0.98, P = 0.04). CONCLUSIONS: Statin use was associated with a reduced incidence and mortality of cancer in Japanese patients with type 2 diabetes.

Effect of Anagliptin versus Sitagliptin on Inflammatory Markers: Sub-Analysis from the REASON Trial.

PURPOSE: Experimental evidence has suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors have an anti-inflammatory effect as well as a glucose-lowering effect, but this has yet to be confirmed in diabetic patients. Therefore, we examined the anti-inflammatory effects of two kinds of DPP-4 inhibitors in patients who participated in the randomized evaluation of anagliptin (ANA) vs sitagliptin (SITA) on low-density lipoprotein cholesterol in diabetes (REASON) Trial, which compared low-density lipoprotein-cholesterol lowering effects between (ANA) and SITA in patients with type 2 diabetes, dyslipidemia, and atherosclerotic vascular lesions. PATIENTS AND METHODS: The studied patients consisted of 177 patients who received ANA 200 mg per day and 176 patients who received SITA 50 mg per day for 52 weeks. We measured high-sensitivity C-reactive protein (hs-CRP), white blood cells (WBC), and interleukin-6 (IL-6) before and after treatment for 52 weeks, and the changes in inflammatory markers were measured as the differences between baseline and 52 weeks. Furthermore, we checked the relationship between the change in hs-CRP and several clinical factors such as the baseline hs-CRP level, use of a moderate-intensity statin, presence of coronary artery disease (CAD) and taking a previous DDP-4 inhibitor. RESULTS: The levels of the inflammatory markers hs-CRP, WBC, and IL-6 were determined to have not significantly changed from baseline to the final follow-up in each arm; furthermore, the changes in these markers were not significantly different between the two groups. The change in hs-CRP level was not affected by the baseline hs-CRP level, use of a moderate-intensity statin, presence of coronary artery disease, and absence of prior DPP-4 inhibitor use. CONCLUSION: In this sub-analysis from the REASON Trial, taking a DPP-4 inhibitor, either ANA or SITA, for 52 weeks did not affect the levels of inflammatory markers.

Clinical Decision Support System with Renal Dose Adjustment Did Not Improve Subsequent Renal and Hepatic Function among Inpatients: The Japan Adverse Drug Event Study.

BACKGROUND: Medication dose adjustment is crucial for patients with renal dysfunction (RD). The assessment of renal function is generally mandatory; however, the renal function may change during the hospital stay and the manual assessment is sometimes challenging. OBJECTIVE: We developed the clinical decision support system (CDSS) that provided a recommended dose based on automated calculated renal function. METHODS: We conducted a prospective cohort study in a single teaching hospital in Japan. All hospitalized patients were included except for obstetrics/gynecology and pediatric wards between September 2013 and February 2015. The CDSS was implemented on December 2013. Renal and hepatic dysfunction (HD) were defined as changes in the estimated glomerular filtration rate (eGFR) and alanine aminotransferase or alkaline phosphatase levels based on these measurements during hospital stay. These measurements were obtained before (phase I), after (phase II), and 1 year after (phase III) the CDSS implementation. RESULTS: We included 6,767 patients (phase I: 2,205; phase II: 2,279; phase III: 2,283). The patients' characteristics were similar among phases. Changes in eGFR were similar among phases, but the incidence of RD increased in phase III (phase I: 228 [10.3%]; phase II: 260 [11.4%]; phase III: 296 [13.0%], p = 0.02). However, the differences in incidences of RD were not statistically significant after adjusting for eGFR at baseline and age. The incidences of HD were also similar among phases (phase I: 175 [13.2%]; phase II: 171 [12.9%]; phase III: 167 [12.2%], p = 0.72). CONCLUSION: The CDSS implementation did not affect the incidence of renal and HD and changes in renal and hepatic function among hospitalized patients. The effectiveness of the CDSS with renal-guided doses should be investigated with respect to other endpoints.

Independent and Distinct Associations of FABP4 and FABP5 With Metabolic Parameters in Type 2 Diabetes Mellitus.

Objective: Among fatty acid-binding proteins (FABPs), secreted forms of FABP4 and FABP5, which are expressed in adipocytes and macrophages, act as bioactive molecules. We investigated concentrations of FABP4 and FABP5 in patients with type 2 diabetes mellitus. Methods: As a sub-analysis study of the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial, 256 patients (male/female: 146/110, age: 68 ± 10 years) with type 2 diabetes mellitus and dyslipidemia who were receiving statin therapy were recruited. Patients who had been treated with a thiazolidinedione were excluded. Results: Several drugs which may modulate FABP4 levels including statins, dipeptidyl peptidase-4 inhibitors and angiotensin II receptor blockers had been administered in 100, 81, and 51% of the recruited patients, respectively. The level of FABP4, but not that of FABP5, was significantly higher in females than in males. Multivariable linear regression analysis demonstrated that waist circumference (ß = 0.21), estimated glomerular filtration rate (ß = -0.31), triglycerides (ß = 0.16), and FABP5 (ß = 0.39) were independent predictors of FABP4 level after adjusting age and sex. On the other hand, FABP5 level was independently associated with levels of FABP4 (ß = 0.57) and high-density lipoprotein (HDL) cholesterol (ß = -0.12). Conclusions: Concentrations of FABP4 and FABP5 are independent predictors of each other in patients with type 2 diabetes mellitus. There are distinct independent associations of FABP4 with renal dysfunction, adiposity and hypertriglyceridemia and there is a distinct independent association of FABP5 with a low HDL cholesterol level in type 2 diabetic patients with dyslipidemia at high risks for cardiovascular disease who are receiving statin therapy.

Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. AIM AND METHODS: As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. RESULTS: The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. CONCLUSION: Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406.

Adverse Drug Events due to Central Nervous System Depressant Drugs in Pediatric Patients With or Without Surgery.

OBJECTIVES: To identify differences in the incidence and severity of adverse drug events (ADEs) due to CNS depressant drugs among pediatric patients with and without surgery. METHODS: The Japan Adverse Drug Events Study was a cohort study enrolling pediatric inpatients. Potential ADEs were identified by onsite review of medical charts, incident reports, and prescription queries. Two independent physicians classified ADEs and severity. We compared the incidence and characteristics of ADEs between pediatric patients with surgery (surgery group) and without surgery (non-surgery group). We evaluated severity of ADEs due to CNS depressant drugs among both groups. RESULTS: We enrolled 944 patients, 234 in surgery group and 710 in non-surgery group. A total of 480 ADEs due to any drugs occurred in 225 patients. Among 81 ADEs due to CNS depressant drugs, 42 ADEs were in surgery group, whereas 39 were in non-surgery group. The risk of fatal or life-threatening ADEs due to CNS depressant drugs was significantly higher than other drugs (12% vs. 2%, p < 0.001). In the surgery group, anesthetics led to 2 fatal or life-threatening, 8 serious, and 30 significant ADEs, whereas in the non-surgery group anesthetics led to 2 fatal or life-threatening, 5 serious, and 4 significant ADEs. Anesthetics were higher risk in the non-surgery group (p = 0.049). CONCLUSIONS: The risks of fatal and life-threatening ADEs were significantly higher with CNS depressant drugs than other drugs. Pediatric patients without surgery have higher risks of fatal or life-threatening ADEs due to anesthetics than those with surgery.