Background : The safety of newly approved drugs must be assessed using postmarketing surveillance data. One of the difficulties in assessing the hazard rates of adverse events induced by the anti-cancer drug TS-1 was that the time to event was not exactly identified due to the interval censoring. Most patients were outpatients who underwent clinical laboratory tests almost periodically at 1- or 2-week intervals and therefore, the occurrence of an adverse event was confirmed at the time of testing days after the event occurrence.
Objective : The purpose of this study was to propose a new model of hazard functions for each of 4 items of adverse event induced by TS-1 using post-marketing surveillance data considering the interval censoring.
Methods : The data obtained from 3, 294 patients with gastric cancer who received an initial 4-week course of therapy with TS-1 administered orally twice a day, followed by a 4-week second course with a 2-week no-treatment period after the initial course, were used to estimate hazard functions. Four items of adverse event--hemoglobin level (HB), white blood cell (WBC), neutrophil (NEUT) and platelet counts (PLT) --were graded, respectively, using the criteria established by the Japan Society of Clinical Oncology. Slip-mixed log-logistic and slip-mixed Weibull models were proposed as candidate models for estimating hazard functions. The goodness of fit of the two candidate models was evaluated by applying them to the above-mentioned data. The hazard functions for each of 4 items were assessed using the model with the better fit.
Results : The initial occurrence of adverse event was shown to follow the slip-mixed log-logistic model for each of 4 items. Although most events occurred early on in the initial course of therapy, a small peak in HB was also observed in the second course, while no such peak appeared for the other items.

The purpose of the present study was to examine the importance of the agonist muscle activity of the post-impact 30 ms phase during drop jump (DJ) for effective rebound performance by comparing those of sprint runners and swimmers. The eight sprint runners (SPRINT) and twelve swimmers (SWIM) were participated in this study. They performed DJ from a 0.3-m height box with maximal rebound efforts. Electromyograms (EMG) of the lower leg muscles (medial gastrocnemius [MG], soleus [SOL] and tibialis anterior [TA]), and vertical ground reaction force together with kinematic data were measured simultaneously during DJ. In addition, the onsets of fascicle stretching of the MG and SOL muscles were measured by using high-speed ultrasonography (521Hz) during DJ. The onsets of the fascicle stretching of SOL during DJ were not significantly different between SPRINT and SWIM (15 ± 7 ms and 16 ± 6 ms, respectively). During DJ, SPRINT showed onset of the SOL EMG before the ground contact (-26 ± 19 ms). Meanwhile, SWIM showed the onset of the SOL EMG after the ground contact of DJ (16 ± 19 ms). These results suggest that the SOL muscles for SWIM cannot be fully-activated during the braking phase. Consequently, the rate of force development during the braking phase of DJ and subsequently rebound height could be reduced in SWIM.

Objective : The incidence rate is used frequently in drug safety assessment. The incidence rate of adverse events is defined as the number of patients experiencing a certain adverse event divided by the number of patients administered a drug in spite of duration of administration (observation). In post-marketing surveillance, the duration of administration (observation) typically differs by patient and most of the analyses fail to take into account the differences in duration of administration (observation). Therefore, we investigated the usefulness of hazard functions in a drug safety assessment using the interim results from Clinical Experience Investigation of the oral anticancer drug, TS-1.
Methods : About three thousand patients with gastric cancer were enrolled in this Clinical Experience Investigation. TS-1 was administrated orally twice daily. One course consisted of consecutive administration for 28 days and 14 days rest. Administration was repeated in two courses. Hematological measurements, stomatitis, anorexia, nausea/vomiting, diarrhea, malaise were analyzed. Adverse events were evaluated in accordance with the criteria of the Japan Society for Cancer Therapy, which were established based on criteria established by the WHO. Time to occurrence of an adverse event was calculated from the first day of administration until the adverse event was first observed. Hazard functions were estimated by smoothing methods using kernel functions.
Results : The occurrence of adverse events using smoothed hazard functions had one peak around 10 days in the first course and decreased by administration rest. With the resumption of administration, the occurrence increased again. The occurrence in the second course were less than that of the first course.
Conclusion : The occurrence peaks of adverse events were estimated graphically by smoothed hazard functions. We conclude that hazard functions are useful as an analytical tool in drug safety assessment.

Objective: Our previous studies suggested that hot spring aquatic exercise may immediately improve the balance ability. As the long-term effects of such repeated exercise have not yet been examined, this present study aims to analyze them, focusing on the balance-related physical indexes. Methods: A total of 12 patients (the number of cerebrovascular disease patients: 5; the number of orthopedic disease patients: 7; mean age: 71.9±13.1; FIM: 117±7.5; and FBS score: 46.4±6.7), who had been treated with hot spring aquatic exercise therapy in our hospital were studied. Each patient showed decreased balance ability due to paralysis, sensory disturbance, or fracture. The measurement indexes were the ability to bend forward while sitting with their legs straight, Functional Balance Scale (FBS), Functional Reach Test (FRT) and Timed Up and Go (TUG) scores, sensory function was measured by the instrument (Semmes-Weinstein Monofilaments), and skin stiffness. Those were measured immediately, 10, 20, and 30 days after the initiation of the intervention.   Furthermore, indexes of eight patients out of those were measured 60 days after the initiation. Each exercise session consisted of walking forward and backward, hip abduction, flexion, and extension, lunge, and squat, which lasted approximately 15 minutes. The loading level was set at a pulse of 77±11.2 ≧ 84±13.5/minute, with a perceived exertion rate (modified Borg Scale) of 0.7±1.0 ≧ 2.4±2.3. Results: The ability to bend forward while sitting with their legs straight, TUG, FBS and sensory function, scores have improved significantly. Any significant improvements were not observed on FRT and skin stiffness. Discussion: The improvement of the sensory function was observed in patients with cerebrovascular disease. This would be because these therapies have the effect on the improvement of higher neuronal function. It is assumed that training efficiency in itself was improved, as the buoyancy and hydrostatic pressure assisted the patients to keep balance.   This exercise showed more effectiveness on the complicated balance indexes. On evaluation of each balance index, the TUG scores significantly improved significantly, while the FRT scores did not show any effects. As the balance-related indexes started to show improvements 30 days after the initiation, it should be recommended to continue this exercise for 30 days or more. Furthermore, in those who had not reached the maximum FBS score 30 days after the initiation, the improvement in scores was observed after 60 days. Further studies will be necessary to analyze these physical indexes, which showed improvements so that more effective exercises for each patient can be programmed taking the relevant balance-related physical indexes into account.