PMDA, the Japanese regulatory agency, has worked for reinforcing and enhancing its post-marketing safety measures as stated in the second mid-term (FY 2009-2013) plan. MIHARI Project-Medical Information for Risk Assessment Initiative was started in FY 2009 to develop a new safety assessment system for post-marketing drugs using Japanese electronic healthcare data in PMDA. In the second mid-term, we examined characteristics of some electronic healthcare data available in Japan including, claims data, hospital information system data and Diagnosis Procedure Combination (DPC) data in order to make efficient use of those databases for the purpose of drug safety assessment. In addition, some pilot pharmacoepidemiological studies for risk assessment and drug utilization were conducted by use of these electronic healthcare data. Based on the accumulated findings, knowledge, and experiences from the pilot studies, we established the framework by FY 2013 to implement pharmacoepidemiology-based safety assessment in PMDA. In the third mid-term (FY 2014-2018), one of the important mission is to apply this framework into the current risk management process of drug safety. For that purpose, cooperation with other divisions of PMDA such as Office of Safety and Office of New Drug is a key. Simultaneously, we will work to establish an access to another database and novel pharmacoepidemiological methods using electronic healthcare data. A large-scale electronic health record database (MID-NET) as well as national claims database are expected to be an important database in the future activities of MIHARI Project. Furthermore, in April 2015, PMDA established new office focusing on Medical Informatics and Epidemiology for further promotion of electronic healthcare data utilization in Japan. In this article, we describe history and past activities of MIHARI Project followed by future challenges.

Between 1987 and 2002, 22 internal iliac artery aneurysms in 14 patients were repaired. In 13 we performed aneurysm excision or reconstruction. There were 3 cases in which simple proximal ligation of the internal iliac artery was performed; in 2 of these CT scans confirmed that the reduction of the internal iliac artery aneurysms was not recognized, but blood flow was not shown in the aneurysm. However, 6 years postoperatively 1 patient was confirmed with an expansion of the aneurysm, and blood flow was seen on a CT scan. In the 2 latest patients, the blood pressure of the internal iliac artery was measured before and after proximal clamping of the internal iliac artery, but the blood pressure of aneurysms could not be fully lowered by proximal ligation of the internal iliac artery. Therefore, endoaneurysmorrhaphy seemed to be the operative method of choice for treatment of the internal iliac artery aneurysms.

We evaluated motor unit (MU) fatigue in the first dorsal interosseous muscle (FDI) using the collision principle. Eight healthy men exerted 70% (short-duration fatigue task: SDF task) and 30% (long-duration fatigue task: LDF task) maximum voluntary contraction of isometric abductions in the left FDI until exhausted. Before and after voluntary contractions, the ulnar nerve was stimulated at the wrist and elbow with supramaximal intensity, and a pair of M-waves was obtained. Fatiguerelated changes were studied in mean power frequency (MPF), averaged rectified value (ARV) calculated from surface EMG, and motor nerve conduction velocity (MCV) and distribution of motor nerve conduction velocity (DMCV) calculated from M-waves. The MPF of voluntary EMG decreased, whereas ARV increased significantly during SDF and LDF tasks, indicating fatigue had developed in the FDI. Endurance was significantly shorter in the SDF task than in the LDF task (p<0.01), whereas differences between tasks were not seen in MPF and ARV changes. Tasks did not affect MCV, but lower components in DMCV increased for both tasks. Increased lower components were larger in the LDF task than in the SDF task. The shift in DMCV indicated that fatigued MUs stopped activity and enduring MUs, which had lower axon conduction velocity, were activated selectively. These results suggest that the collision principle is applicable in evaluating motor unit fatigability.

A 63-year-old woman underwent coronary artery bypass grafting and mitral annuloplasty 4 years previously. She was readmitted owing to heart failure. Cardiac catheterization revealed worsened mitral regurgitation, although the internal thoracic artery (ITA) graft had good patency. Reoperation was performed by median resternotomy and continuous retrograde cardioplegia without clamping the ITA graft. The mitral valve had a perforation in the anterior leaflet, and was replaced by a 29mm Carbo-Medicus valve. The patient was discharged with transient myocardial ischemia. Although median resternotomy and continuous retrograde cardioplegia at reoperation provided on excellent view and myocardial protection, myocardial ischemia in the region perfused by the ITA graft may occur when the ITA graft cannot be clamped during continuous retrograde cardioplegia.

An 11-year-old boy, who underwent a Rastelli operation using a 14mm artificial graft and left pulmonary artery (PA) plasty with an autologous pericardium patch 7 years previously, had severe recurrent left pulmonary stenosis. Reoperation was performed including right ventricular outflow tract reconstruction and left PA plasty. The PA at the most stenotic site was only 2mm in diameter; it was enlarged to 10mm by good exposure and an incision on the pulmonary intima. A bovine pericardium patch with a handmade ePTFE valve was sutured onto the autologous tissue not onto the pulmonary intima to avoid restenosis and in expectation of the growth of the pulmonary orifice. On postoperative 3-D CT, the left pulmonary artery was patent and 9mm in diameter. Pulmonary scintigraphy showed an improvement in the left pulmonary perfusion. This sutureless technique was useful in this case of severe pulmonary stenosis.

In patients with the visceral fat type obesity, there is a high incidence of glucose and lipid metabolic abnormalities and hypertension. We obtained the following results from a study of the relationship between the degree of visceral fat obesity and metabolic and vascular complications in 98 obese patients with various complications.
1. Viceral fat obesity (V/S ratio ≥ 0.4) was found in 74% of the subjects. The incidence was higher in males than females. The highest incidence was observed in both men and women in thier 40s, and there was no increase with age.
2. The V/S ratio was high in patients with hyperlipidemia, diabetes, and fatty liver in that order. In the V/S ≥ 0.4 group, there was a higher incidence of hyperlipidemia and ischemic heart disease than in the V/S<0.4 group.
3. The V/S ratio was higher in the patients with two or more metabolic and vascular complications than in those with only one complication.
4. A questionnaire survey showed that there were many individuals who did almost no exercise and had a long history of obesity in the V/S ≥ 0.4 group.
5. The V/S ≥ 0.4 group had high triglyceride levels. There was a positive correlation between the V/ S ratio or V value and the trigyceride level, but no correlation between S value and triglyceride level.

A 51-year-old man developed a high fever with congestive heart failure after treatment for his dental caries and was admitted to our hospital. Transesophageal echocardiogram showed severe aortic regurgitation with a bicuspid aortic valve where vegetation and perforation was identified on its leaflets. Infective endocarditis caused by Streptococcus constellatus was diagnosed by blood culture. A computed tomography scan of the chest showed enlargement of his ascending aorta with a maximum diameter of 5.0cm. After treatment with antibiotics and diuretics for 60 days, he underwent surgical treatment for his aortic valve and ascending aorta. After excising the diseased aortic leaflets with vegetation, a mechanical prosthetic valve (Carbomedicus 23mm) was implanted. His ascending aorta was also replaced separately with a woven Dacron tube graft. There was an anomalous origin of the right coronary artery which was detached from the ascending aortic wall as a button and was implanted on the tube graft. Histologically the aortic wall showed disappearance of elastic fibers with myxomatous degeneration in the media. Immunohistochemical staining also revealed that matrix metalloproteinase-2 (MMP-2) was strongly expressed in the aortic media. The postoperative course was uneventful and he was discharged on the 37th postoperative day.