Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan.

PURPOSE: To estimate the incidence of lactic acidosis (LA) and role of metformin in Japanese patients with type 2 diabetes mellitus (T2DM) treated with anti-diabetes drugs. METHODS: This retrospective propensity score matched cohort study was conducted using the Japanese Medical Data Vision claims database. T2DM patients aged 18 or above who received diabetes drugs during January 2010 through August 2014 were identified. Cases of LA were identified based on reimbursement codes and confirmed by lactic acid test and subsequent treatment by hemodialysis or intravenous sodium bicarbonate. Poisson regression and Cox proportional hazard models were used to estimate the incidence and assess if metformin use was associated with increased risk of LA. RESULTS: Thirty cases of LA were identified among 283 491 treated T2DM patients with 504 169 patient-years of follow-up. Crude incidence of LA was 5.95 per 100 000 patient-years. T2DM patients with chronic kidney disease (CKD) were seven-fold more likely to develop LA than those without CKD (adjusted hazard ratio (aHR), 7.33, 95%CI, 3.17-16.96). Use of metformin was not associated with risk of LA in the study population (aHR, 0.92, 95%CI, 0.33-2.55), and in the propensity score matched cohort (aHR, 0.90, 95%CI, 0.26-3.11). Similar findings were observed among diabetes patients with chronic liver disease (CLD) and CKD. The age-sex adjusted incidence rates in metformin users and non-users were 5.80 and 5.78 per 100 000 person-years, respectively (Incidence rate ratio, 1.00, p = 0.99). CONCLUSIONS: This study found that use of metformin was not associated with increased risk of LA in diabetic patients including those with CKD or CLD. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

A compact 3D-printed interface for coupling open digital microchips with Venturi easy ambient sonic-spray ionization mass spectrometry.

Digital microfluidics (DMF) based on the electrowetting-on-dielectric phenomenon is a convenient way of handling microlitre-volume aliquots of solutions prior to analysis. Although it was shown to be compatible with on-line mass spectrometric detection, due to numerous technical obstacles, the implementation of DMF in conjunction with MS is still beyond the reach of many analytical laboratories. Here we present a facile method for coupling open DMF microchips to mass spectrometers using Venturi easy ambient sonic-spray ionization operated at atmospheric pressure. The proposed interface comprises a 3D-printed body that can easily be "clipped" at the inlet of a standard mass spectrometer. The accessory features all the necessary connections for an open-architecture DMF microchip with T-shaped electrode arrangement, thermostatting of the microchip, purification of air (to prevent accidental contamination of the microchip), a Venturi pump, and two microfluidic pumps to facilitate transfer of samples and reagents onto the microchip. The system also incorporates a touch-screen panel and remote control for user-friendly operation. It is based on the use of popular open-source electronic modules, and can readily be assembled at low expense.

Colorimetric microchip assay using our own whole blood collected by a painless needle for home medical care.

We have developed a colorimetric measurement chip that measures triglycerides, total cholesterol, and high-density lipoprotein in 6 µL of whole blood collected with a painless needle. The chip can be used by patients to self-monitor certain health conditions at home. This chip contains a sharp 150 µm diameter stainless steel (SUS) needle that collects blood painlessly. The chip consists of three layers of injection-molded poly(methyl methacrylate) bonded together with two double-sided tapes. Two commercial reagents are used, and the volume ratio of plasma to reagent is doubled from the reagent specification to reduce the optical absorption length (and chip mass) by half. Centrifugal force separates the plasma from the blood, and then weighs out and mixes the plasma and reagents. A zigzag channel allows mixing of the plasma with the reagents mainly by vortex motion due to the centrifugal force generated at the corners of the channel. The measured values correlated well with conventionally tested values.

Acute urinary retention increases the risk of complications after transurethral resection of the prostate: a population-based study.

UNLABELLED: Study Type--Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Higher mortality and morbidity rates in men presenting with AUR have been reported in previous studies. This study has comprehensive comparisons of post-TURP complications between patients with and without AUR. Furthermore, it shows that AUR is associated with increased risk of complications after TURP. OBJECTIVE: • To assess the association between a history of acute urinary retention (AUR) and complications after transurethral resection of prostate (TURP). PATIENTS AND METHODS: • We conducted a retrospective, national, population-based study using Taiwan's National Health Insurance Research Database. • We included men > 50 years old, diagnosed with benign prostatic hyperplasia (BPH) and divided these into two groups: an AUR(+) group--those with AUR who underwent TURP between 2002 and 2004; and an AUR(-) group--those without AUR who underwent TURP between those dates. • Prostate cancer, Parkinsonism and multiple sclerosis were exclusion criteria. • Postoperative complications, e.g. re-catheterization, haematuria or urinary tract infection (UTI), were compared using crude odds ratios (ORs), 95% confidence intervals (CIs), and Student's t-test. • A chi-squared test was used for potential confounding factors: preoperative UTI and anticoagulant use. • Univariate and multivariate analysis on medical expenses were conducted. RESULTS: • The AUR(+) group contained 3305 men; the AUR(-) group contained 1062. • Re-catheterization (13.8%), septicaemia (1.1%) and shock (0.3%) were found only in the AUR(+) group. • The AUR(+) group had more UTIs (18.9% vs. 15.6%, OR: 1.26, 95% CI: 1.05-1.52), more lower urinary tract symptoms (22.8% vs. 16.9%, OR: 1.45, 95% CI: 1.21-1.73), fewer blood transfusions (3.2% vs. 1.5%, OR: 2.19, 95% CI: 1.29-3.72) and higher medical expenses. • There were no significant differences in haematuria, lower urinary tract stricture, or re-surgical intervention of the prostate and second-line antibiotic use. CONCLUSION: • Patients in Taiwan with BPH with AUR who were treated by TURP were associated with a higher risk of complications, longer hospital stay and more comorbidities than those without AUR and a preoperative warning is warranted for these patients.

Prevalence and incidence of cyclic vomiting syndrome in Japan: A study using Japanese claims data.

Cyclic vomiting syndrome (CVS) is a gastrointestinal disorder that is characterized by recurrent episodes of vomiting. Previous studies have provided reliable data on the prevalence of CVS among children in Japan; however, neither prevalence data nor incidence of CVS is available for adults. Hence, we obtained detailed prevalence and incidence data for CVS and estimated the total number of CVS cases in Japan. This retrospective cross-sectional study was conducted using the JMDC (JMDC, Inc.; formerly known as Japan Medical Data Center Co., Ltd.,) database, which is a de-identified Japanese claims database. Individuals enrolled between January 2017 and December 2017 were included in this study. Longitudinal data for eligible populations were used to identify patients who displayed CVS symptoms throughout the follow-up period. Due to the lack of a specific diagnosis code for CVS in 2017, the Rome IV criteria were applied to identify CVS cases in the pediatric and adult populations. The prevalence was standardized to the 2017 Japanese census and extrapolated to estimate the number of CVS cases. A total of 2,093 patients with CVS were identified from 3,506,144 individuals. The overall age-and-sex-standardized prevalence was 0.32 per 1,000 population (95% confidence interval [CI]: 0.30-0.34), projected to approximately 49,000 patients with CVS across Japan. The pediatric age-and-sex-standardized prevalence was 2.10 per 1,000 population (95% CI: 2.01-2.19), and the adult prevalence was 0.05 per 1,000 population (95% CI: 0.04-0.06). Marked sex differences were observed before and after 12 years of age. Thus our study provides the first large-population-based estimates of CVS prevalence and incidence in Japan, and currently, the only estimates for adult CVS in Japan.

Microscale MALDI imaging of outer-layer lipids in intact egg chambers from Drosophila melanogaster.

Fruit fly (Drosophila melanogaster) is a standard model organism used in genetics and molecular biology. Phospholipids are building blocks of cellular membranes, and components of a complex signaling network. Here, we present a facile method, based on matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS), for molecular imaging of phospholipid distributions in submillimeter-sized components of the fruit fly reproductive system. Individual egg chambers were deposited on a specially prepared MALDI target comprising an aluminum slide with a rough surface created by ablation with a microsecond-laser: this helped to immobilize biological specimens, remove excess of saline solution by adhesive forces, carry out microscopic observations, and facilitated distribution of the MALDI matrix. A continuous-flow ultrasound-assisted spray was used for the deposition of MALDI matrix (9-aminoacridine) onto the sample. The upper surface of the specimen was then scanned with a 355-nm solid-state laser with a preset beam focus of 10 µm to obtain negative-ion mode MALDI-MS images. Overall, this provided sufficient spatial resolution to reveal micrometer-scale gradient-like patterns of phospholipids along the anterior/posterior axis of egg chambers. Several phosphatidylinositols are seen to be segregated according to the number of unsaturated bonds, with an elevated abundance of polyunsaturated phosphatidylinositols within the oocyte compartment.

Capillary action-supported contactless atmospheric pressure ionization for the combined sampling and mass spectrometric analysis of biomolecules.

It is proposed that a short tapered capillary can be utilized as a nanoliter-volume sampling tool and sample emitter for generation of gas-phase ions in front of the mass spectrometer, without the need for using an additional electric power supply, a gas supply, or a syringe pump. A wide range of molecules can be analyzed in pure solutions and complex matrixes (cell extract, urine, and plant tissue) with no or minimum sample preparation. Singly and multiply charged ions can be detected in either positive or negative-ion mode. Because of the nanoliter-volume sampling and low spectral background, the mass detection limit for bradykinin is in the low attomole range. Other advantages include simplicity, disposability, and low cost. The putative mechanism of the ion formation in this capillary-action supported contactless spray emitter is discussed.

Incidence and causes of mildly to moderately elevated aminotransferase in Japanese patients with type 2 diabetes.

OBJECTIVES: To identify the association of type 2 diabetes (T2DM) and liver disease with elevated ALT and factors associated with increased ALT in patients with and without T2DM. DESIGN AND SETTING: We performed a retrospective study in adults with ≥ 2 claims for blood tests recorded in the Medical Data Vision claims database between 2010 and 2016. PARTICIPANTS: Patients were entered into T2DM and non-DM groups based on diagnosis and medication claim codes. PRIMARY OUTCOME MEASURE: The primary endpoint was the first follow-up ALT elevation over three times the normal value, and etiologies were categorized by subsequent diagnoses. We estimated the ALT elevation incidence and association with T2DM using Poisson regression and Cox proportional hazard models. RESULTS: We identified 3161 cases of elevated ALT in 104,903 patients (follow-up, 280,659 patient-years). The age- and sex-adjusted incidence of elevated ALT in the T2DM group (13.47 per 1000 patient-years; 95% confidence interval (CI) 12.53-14.48) was significantly higher than that in the non-DM group (8.43 per 1000 patient-years; 95% CI 7.72-9.20, p < 0.0001). Compared to the non-DM group, the T2DM group had an approximately 3.5 times higher risk of fatty liver-related ALT elevation (adjusted hazard ratio (HR), 3.54; 95% CI 1.90-6.58). T2DM was not associated with an increased incidence of jointly elevated ALT and total bilirubin (adjusted HR, 0.94; 95% CI 0.77-1.15). CONCLUSION: T2DM is strongly associated with increased liver enzymes secondary to fatty liver. The causes of liver enzyme abnormalities were not fully characterized due to a high proportion of unexplained ALT elevation.

Anatomic reduction of old displaced lateral condylar fractures of the humerus in children via a posterior approach with olecranon osteotomy.

BACKGROUND/PURPOSE: We questioned the principle of treatment of late lateral condylar fracture of a pediatric elbow. We report the results of treating this condition using a different approach. METHODS: We treated six children with type 3 late lateral condylar fractures. The average age was 4.5 years old. The time delay from injury to surgery averaged at 3.8 months. All the displaced lateral condyles were Milch type 2 with significant rotation away from the trochlea. The articular anatomic reduction of the lateral condyles was achieved via ulnar osteotomy in all six cases. We fixed both the fracture and the osteotomy with Kirschner wires buried under the skin. No strenuous passive physical therapy was needed. RESULTS: All lateral condylar fractures and ulnar osteotomies were united within 3 months. Five out of six children had regained full range of motion and symmetric carrying angles at the latest follow-up 2 to 11 years later. Complications included transient physeal change and lateral bump. CONCLUSION: Based on our results, we recommend olecranon osteotomy via a posterior approach as one of the options in treating late cases of type 3 lateral condylar fracture of the elbow with significant displacement in children.

The incidence of medically-attended norovirus gastro-enteritis in Japan: Modelling using a medical care insurance claims database.

BACKGROUND: The burden of medically-attended acute gastro-enteritis (MA-AGE) that can be attributed to norovirus is not well established in Japan. Using a nationwide database of medical care insurance claims, we estimated the incidence of medically-attended norovirus-attributable gastroenteritis (MA-NGE) in Japan. METHODS: The incidences of MA-NGE outpatient consultations or hospitalization in Japan were modelled on seasonal patterns of MA-AGE for unspecified causes derived from the Japan Medical Data Center (JMDC) database for the period July 2007 to June 2015. RESULTS: Mean age-adjusted annual incidence rates (per 10,000 person-years) of MA-NGE associated with outpatient care or hospitalization were 389 (95% CI 269-558) and 13 (95% CI 9-20), respectively. Highest rates were in children under 5 years of age: 1,569 (95% CI 1,325-1,792) for outpatient consultations and 48 (95% CI 39-56) for hospitalizations. Of all gastroenteritis episodes associated with outpatient care or hospitalization, 29% and 31% were attributed to norovirus, respectively. Norovirus was estimated to be responsible for 4,964,000 outpatient visits (95% CI 3,435,000-7,123,000) and 171,000 hospitalizations (95% CI 110,000-251,000) per year across Japan. CONCLUSIONS: Incidence rates of MA-AGE are high in Japan, and norovirus-attributable disease is at least as high as in some other developed countries.

Association between therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors and risk of ileus: a cohort study.

BACKGROUND: Three cases of ileus have been published among dipeptidyl peptidase-4 (DPP-4) inhibitor users in Japan. The purpose of this study was to estimate and compare incidence rates of ileus among alogliptin users and users of other DPP-4 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and voglibose. METHODS: We used the Medical Data Vision database in Japan to conduct a retrospective cohort study among type 2 diabetes mellitus (T2DM) patients who were new users of alogliptin, other DPP-4 inhibitors, GLP-1 receptor agonists, or voglibose between 1 April 2010 and 30 April 2014. The primary outcome was an incident diagnosis of ileus. Kaplan-Meier survival curves were used to estimate ileus events over time. Adjusted Poisson regression models were used to estimate incidence rate ratios (IRR) for ileus and 95 % confidence intervals (CI) by comparing alogliptin users to users of the other study drugs. RESULTS: We identified 82,386 patients with T2DM. In the adjusted model, there was no difference in risk of ileus among patients exposed to alogliptin compared with patients exposed to other DPP-4 inhibitors (IRR 1.15, 95 % CI 0.75-1.75) or GLP-1 receptor agonists (IRR 0.42, 95 % CI 0.14-1.20). The risk of ileus was significantly lower among patients exposed to alogliptin compared with patients exposed to voglibose (IRR 0.55, 95 % CI 0.35-0.88). CONCLUSIONS: The independent risk of ileus among new users of alogliptin did not significantly differ compared with new users of other DPP-4 inhibitors or GLP-1 receptor agonists but was significantly lower than new users of voglibose.

Microfluidic Chip Coupled with Thermal Desorption Atmospheric Pressure Ionization Mass Spectrometry.

Microfluidic chips have been used as platforms for a diversity of research purposes such as for separation and micro-reaction. One of the suitable detectors for microfluidic chip is mass spectrometry. Because microfluidic chips are generally operated in an open air condition, mass spectrometry coupled with atmospheric pressure ion sources can suit the requirement with minimum compromise. In this study, we develop a new interface to couple a microfluidic chip with mass spectrometry. A capillary tip coated with a layer of graphite, capable of absorbing energy of near-infrared (NIR) light is used to interface microfluidic chip with mass spectrometry. An NIR laser diode (λ=808 nm) is used to irradiate the capillary tip for assisting the generation of spray from the eluent of the microfluidic chip. An electrospray is provided to fuse with the spray generated from the microfluidic chip for post-ionization. Transesterification is used as the example to demonstrate the feasibility of using this interface to couple microfluidic chip with mass spectrometry.

Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation in Taiwan.

BACKGROUND: Economic evaluation of dabigatran, a new anti-antithrombotic agent, is done mostly in Western countries. It remains to be seen whether dabigatran will be cost effective in a practice environment where warfarin is significantly underused and the costs of both warfarin and international normalized ration INR monitoring are cheap. METHODS: We performed a cost-effectiveness analysis with a Markov model to evaluate the value of dabigatran to prevent stroke and systemic embolism in patients with atrial fibrillation (AF) in Taiwan. Dabigatran was given through sequential dosing, where patients<80 years old received 150 mg of dabigatran twice a day and the dosage was reduced to 110 mgs for patients ≥ 80 years old. Dabigatran was compared with warfarin under two scenarios: the "real-world adjusted-dose warfarin" assuming all AF patients eligible for warfarin were given the medication and maintained at the INR observed in routine clinical practice in Taiwan, and the "real-world prescribing behaviour" similar to the treatment with antithrombotics in real-world practice in Taiwan, where eligible patients could receive warfarin, aspirin, or no treatment. RESULTS: The percentage of AF patients who received warfarin, aspirin or no treatment in Taiwan was 16%, 62% and 22%, respectively. The event rates of ischemic stroke per 100 patient-years were 4.5, 8.0, and 6.0 for sequential dabigatran, real-world prescribing behaviour and real-world warfarin use, respectively. The incremental cost-effectiveness ratio was $280 US per quality-adjusted-year (QALY) in the real-world prescribing scenario and $10,551 US/QALY in real-word warfarin use. CONCLUSIONS: Dabigatran was highly cost-effective in a clinical practice setting where warfarin has been significantly underused.

Assessment of statin-associated muscle toxicity in Japan: a cohort study conducted using claims database and laboratory information.

OBJECTIVE: To estimate the incidence of muscle toxicity in patients receiving statin therapy by examining study populations, drug exposure status and outcome definitions. DESIGN: A retrospective cohort study. SETTING: 16 medical facilities in Japan providing information on laboratory tests performed in and claims received by their facilities between 1 April 2004 and 31 December 2010. PARTICIPANTS: A database representing a cohort of 35 903 adult statin (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin) users was studied. Use of interacting drugs (fibrates, triazoles, macrolides, amiodarone and ciclosporin) by these patients was determined. MAIN OUTCOME MEASURE: Statin-associated muscle toxicity (the 'event') was identified based on a diagnosis of muscle-related disorders (myopathy or rhabdomyolysis) and/or abnormal elevation of creatine kinase (CK) concentrations. Events were excluded if the patients had CK elevation-related conditions other than muscle toxicity. Incidence rates for muscle toxicity were determined per 1000 person-years, with 95% CI determined by Poisson regression. RESULTS: A total of 18 036 patients accounted for 42 193 person-years of statin therapy, and 43 events were identified. The incidence of muscle toxicity in the patients treated with statins was 1.02 (95% CI 0.76 to 1.37)/1000 person-years. The estimates varied when outcome definitions were modified from 0.09/1000 person-years, which met both diagnosis and CK 10× greater than the upper limit of normal range (ULN) criteria, to 2.06/1000 person-years, which met diagnosis or CK 5× ULN criterion. The incidence of muscle toxicity was also influenced by the statin therapies selected, but no significant differences were observed. Among 2430 patients (13.5%) received interacting drugs with statins, only three muscle toxicity cases were observed (incidence: 1.69/1000 person-years). CONCLUSIONS: This database study suggested that statin use is generally well tolerated and safe; however, the risk of muscle toxicity related to the use of interacting drugs requires further exploration.

Effectiveness of sulpiride in adult patients with schizophrenia.

The objective of this study is to compare the effectiveness among sulpiride, risperidone, olanzapine, and haloperidol by evaluating the persistence of drug use. A retrospective cohort study was conducted by analyzing the National Health Insurance Research Database of Taiwan. Patients with schizophrenia aged 18-65 years and newly prescribed with a single oral antipsychotic medication between years 2003 and 2008 were included. The primary outcome was the persistence of antipsychotic agents by calculating the treatment duration till treatment changed. All defined treatment changes were also analyzed separately, including discontinuation, switching, augmentation, and hospitalization. A total of 1324 eligible patients were included, with an average age of 36 years old and approximately 45% of them were female. The most prevalent antipsychotic use was risperidone (42.1%), followed by sulpiride (36.0%), haloperidol (14.2%), and olanzapine (7.7%). After adjusting for patient demographics, mental illness characteristics, and propensity score, the Cox regression models found that the risk of nonpersistence was significantly higher in patients receiving risperidone (hazard ratio [HR], 1.22; 95% CI, 1.06-1.40), haloperidol (HR, 1.98; 95% CI, 1.63-2.40), and olanzapine (HR, 1.34; 95% CI, 1.07-1.68), as compared with sulpiride, suggesting the effectiveness of sulpiride was better than the other 3 antipsychotics. Therefore, this study would provide strong grounds for a properly conducted randomized controlled trial of the clinical- and cost-effectiveness of sulpiride vs atypical antipsychotics.

Risk of insomnia attributable to ß-blockers in elderly patients with newly diagnosed hypertension.

Use of ß-blockers may cause insomnia and central nervous system and/or psychological side effects, but data are limited on the relative risks of insomnia among ß-blockers. This retrospective cohort study used Taiwan's National Health Insurance claims database from 2003 to 2007, where 4,063 patients aged above 65 years with newly diagnosed hypertension and treated with ß-blockers were followed for 1 year. The primary endpoint was a new insomnia event within 30 days of treatment initiation. Adjusted odds ratios of insomnia were obtained by logistic regressions, controlling for baseline risk factors of insomnia. Using propranolol therapy as the reference, the adjusted odds ratio (95% confidence interval) for the insomnia risk was 0.47 (0.35-0.63) for non-propranolol users, 0.31 (0.19-0.50) for bisoprolol, and 0.46 (0.33-0.66) for atenolol. Compared to the patients using non-selective ß-blockers, the adjusted odds ratio was 0.48 (0.36-0.34) for those using selective ß(1)-blockers. Additionally, the adjusted odds ratio was 0.72 (0.53-0.96) for ß-blockers with low lipophilicity when compared to those with high lipophilicity. The use of bisoprolol and atenolol was associated with the lowest risk of insomnia in elderly patients, as compared to propranolol. ß-Blockers with high selectivity in ß(1)-receptors and/or low lipophilicity were associated with a lower risk of insomnia.

C.I. Pigment red 266.

C.I. Pigment Red 266, or 4-[[4-(aminocarbonyl)phenyl]hydrazono]-N-(2-methoxyphenyl)-3-oxo-3,4-dihydronaphthalene-2-carboxamide, C(25)H(20)N(4)O(4), adopts the keto-hydrazone tautomeric form with significant intramolecular hydrogen bonding. The molecules pack to form layers involving an extensive network of intermolecular hydrogen bonds, in which the primary amide group plays a prominent role. The good technical performance of this pigment in application may be attributed principally to the pattern of intra- and intermolecular hydrogen bonding.