Avelumab first-line maintenance plus best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma: JAVELIN Bladder 100 Japanese subgroup analysis.

BACKGROUND: The phase 3 JAVELIN Bladder 100 trial showed significantly prolonged overall survival (OS) with avelumab as first-line (1L) maintenance therapy + best supportive care (BSC) vs BSC alone in patients with advanced urothelial carcinoma (UC) that had not progressed with 1L platinum-containing chemotherapy. Efficacy and safety were assessed in patients enrolled in Japan. METHODS: Patients with locally advanced or metastatic UC that had not progressed with 4-6 cycles of 1L platinum-containing chemotherapy were randomized to avelumab (10 mg/kg intravenously every 2 weeks) + BSC or BSC alone. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and safety. RESULTS: In Japanese patients (n = 73) randomized to avelumab + BSC (n = 36) or BSC alone (n = 37), median OS was 24.7 months (95% CI, 18.2-not estimable) vs 18.7 months (95% CI, 12.8-33.0), respectively (HR, 0.81 [95% CI, 0.41-1.58]), and median PFS was 5.6 months (95% CI, 1.9-9.4) vs 1.9 months (95% CI, 1.9-3.8), respectively (HR, 0.63 [95% CI, 0.36-1.11]). In the avelumab + BSC and BSC-alone arms, grade ≥ 3 treatment-emergent adverse events (AEs) occurred in 50.0% vs 8.1%, including grade ≥ 3 treatment-related AEs in 13.9% vs 0%, respectively. Efficacy and safety results in Japanese patients were generally consistent with findings in the overall trial population. CONCLUSION: Avelumab 1L maintenance treatment showed a favorable benefit-risk balance in Japanese patients, supporting avelumab 1L maintenance as a new standard of care in Japanese patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02603432.

A phase 2b, randomized, double-blind, multicenter, vehicle-controlled study to assess the efficacy and safety of two crisaborole regimens in Japanese patients aged 2 years and older with mild-to-moderate atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, xerosis, and eczematous lesions. In Japan, treatment options, such as topical corticosteroids and tacrolimus, are associated with efficacy and safety concerns. Crisaborole ointment, 2%, is a topical non-steroidal anti-inflammatory agent approved in several countries for the treatment of mild-to-moderate AD. This phase 2b, randomized, double-blind study (NCT03954158) assessed the efficacy and safety of two crisaborole regimens versus vehicle in the treatment of Japanese patients aged ≥2 years with mild-to-moderate AD. Each patient was assigned to one of two age cohorts (≥12 or 2-11 years) and randomized to crisaborole once daily (QD) or twice daily (BID). All patients had two target lesions that were each randomly assigned to crisaborole or vehicle at baseline and treated for 2 weeks. The primary endpoint was change from baseline in total sign score (TSS) in crisaborole- or vehicle-treated target lesions on day 15, and secondary endpoints included change from baseline in Investigator's Static Global Assessment (ISGA) and pruritic assessments (Cohort 1: peak pruritus numeric rating scale [NRS]; Cohort 2: Itch Severity Scale Self-Report and Caregiver-Reported Itch Severity NRS) and incidence of treatment-emergent adverse events (TEAEs). This study comprised 81 patients (Cohort 1: n = 41; Cohort 2: n = 40). Crisaborole-treated lesions showed statistically significant reductions in TSS versus vehicle-treated lesions at day 15 (p < 0.01), and numerically larger decreases in TSS were observed with crisaborole BID versus crisaborole QD in both cohorts. Furthermore, crisaborole-treated lesions generally demonstrated greater decreases in ISGA, peak pruritus NRS, Itch Severity Scale, and Caregiver-Reported Itch Severity NRS versus vehicle-treated lesions irrespective of regimen or cohort. Overall, TEAEs were mild; the most frequently reported TEAEs was application site irritation. In summary, both crisaborole regimens, particularly crisaborole BID, demonstrated efficacy and were well tolerated.

Changes in oral and cognitive functions among older Japanese dental outpatients: A 2-year follow-up study.

BACKGROUND: The relationship between oral and cognitive functions among older people is highly debated. OBJECTIVE: To examine whether oral functions are related to changes in the levels of mild cognitive impairment (MCI) biomarkers in older Japanese outpatients. METHODS: This observational study included 52 outpatients aged ≥65 years who underwent dental examinations at the Fukuoka Dental College Hospital. The Mini-Mental State Examination (MMSE) was performed, and MCI blood biomarker levels were assessed at baseline and after 2 years. The present dental and periodontal conditions and the oral functions (tongue pressure and masticatory performance) were evaluated. Changes in parameters from baseline to follow-up were compared using the Wilcoxon signed-rank test, McNemar test or chi-squared test. Associations among changes in the parameters were analysed using Spearman's rank correlation coefficient. RESULTS: The follow-up rate in this study was 67%. The masticatory performance was improved (p < 0.001), whereas gingival inflammation was decreased (p < 0.001) over the 2-year period. A significant increase in the MMSE score (p < 0.001) and a decrease in MCI risk (p < 0.001) were noted. The decrease in MCI risk was correlated with the increase in both masticatory performance (ρ = -0.34; p < 0.05) and MMSE score (ρ = -0.56; p < 0.01). CONCLUSION: A decrease in MCI risk, as demonstrated by the levels of the blood biomarkers, was correlated with an increase in the masticatory performance in Japanese outpatients.

Expression of aquaporins in response to distinct dehydration stresses that confer stress tolerance in the Antarctic midge Belgica antarctica.

Larvae of the Antarctic midge Belgica antarctica Jacobs (Diptera: Chironomidae) are highly tolerant of diverse environmental stresses, including freezing, severe desiccation, and osmotic extremes. Furthermore, dehydration confers subsequent desiccation and freeze tolerance. While a role for aquaporins-channels for water and other solutes-has been proposed in these dehydration processes, the types of aquaporins involved in dehydration-driven stress tolerance remain unknown. In the present study, we investigated expression of six aquaporins (Drip, Prip, Eglp1, Eglp2, Aqp12L, and Bib) in larvae of B. antarctica subjected to three different dehydration conditions: desiccation, cryoprotective dehydration, and osmotic dehydration. The expression of Drip and Prip was up-regulated under desiccation and cryoprotective dehydration, suggesting a role for these aquaporins in efficient water loss under these dehydration conditions. Conversely, expression of Drip and Prip was down-regulated under osmotic dehydration, suggesting that their expression is suppressed in larvae to combat dehydration. Larval water content was similarly decreased under all three dehydration conditions. Differences in responses of the aquaporins to the three forms of dehydration suggests distinct water management strategies associated with different forms of dehydration stress.

Relationship between cerebral atrophy and number of present teeth in elderly individuals with cognitive decline.

BACKGROUND AND AIM: Recent shifts in the distribution of Japan's population towards older ages, have meant that the chance of encountering patients with dementia in dental clinics is increasing. Many studies have shown that the brain volume decreases along with the progression of dementia. Although previous studies have reported a relationship between tooth loss or periodontitis and the onset of dementia, the pathological mechanisms underlying this association have not been elucidated. In this study, we aimed to examine the relationship between the oral condition and brain atrophy and to discuss how to adequately deal with patients with dementia. PARTICIPANTS AND METHODS: This cross-sectional study included 15 participants who underwent brain magnetic resonance imaging (MRI). The participants were 60 years or older and presented with cognitive decline, including Alzheimer's disease (AD) and mild cognitive impairment (MCI), diagnosed by a neurologist. We obtained information on the oral condition, lifestyle, cognitive function, and brain atrophy. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). MR images of each patient were analyzed using the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) to provide a quantitative measure of the degree of brain atrophy. RESULTS: The study population included 4 male and 11 female patients. The mean age and mean number of present teeth were 75.9 years (SD 6.7) and 15.0 (SD 11.1), respectively. The median MMSE score was 25.6 (SD 3.7). The degree of atrophy of the whole brain was significantly correlated with the number of present teeth (ρ = -0.72, p < 0.05) and the presence of a daily exercise habit (ρ = -0.66, p < 0.05). CONCLUSION: This study demonstrated that the number of present teeth could be an indicator of the progress of dementia. Preserving the teeth as well as the acquisition of a regular exercise habit might be important for preventing progression of dementia. Further research examining a larger study population and analyzing a greater number of factors is warranted.

Examination of pain relief effect of Goreisan for glossodynia.

BACKGROUND: Pain in glossodynia may be severe; it may prevent patients from working, interfere with daily life activities, and necessitate a patient's visit to a medical institution for consultation and treatment. The pain may be described as persistent and burning (tingling, tingling) or stinging. Patients may complain of dry mouth (dryness), which is thought to cause inflammation of the tongue and gingival mucous membranes and increased pain. Medications are prescribed based on the symptoms of glossodynia, and the therapeutic effect is confirmed. However, each drug has side effects, for example, pain may reduce, but drowsiness and dizziness may occur; further, there is always a tendency of drowsiness.On the other hand, Goreisan, a Chinese herbal medicine, has already been used by physicians to treat pain in the oral and maxillofacial regions resulting from rapid changes in air pressure. However, the lack of high-quality clinical research has been of concern, and a randomized clinical trial to investigate the efficacy and safety of Goreisan for treatment of pain in glossodynia is warranted. METHODS/DESIGN: This multicenter, randomized, controlled study will involve patients treated for glossodynia-related pain. In the experimental group, Goreisan will be taken for 12 weeks in combination with conventional treatment. Participants in the control group will not take any Kampo medicine; only the standard treatment will be taken. Subsequently, the degree of pain will be assessed, and saliva tests of all the patients on their first visit will be performed. Goreisan will be taken at a dose of 7.5 g/d (minute 3) for 12 consecutive weeks. Twelve weeks later, the degree of pain of each patient will be assessed. DISCUSSION: The purpose of this study is to investigate the efficacy of Goreisan for pain reduction in patients undergoing treatment for glossodynia-related pain. If pain in glossodynia patients can be reduced by the administration of Goreisan, its candidacy as an alternative treatment for pain in glossodynia can be further supported by more reliable research. TRIAL REGISTRATION: The study was registered in the jRCTs071200017. URL https://jrct.niph.go.jp/latest-detail/jRCTs071200017.

A Retrospective, Cross-Sectional Study on the Prevalence of Hyperuricemia Using a Japanese Healthcare Database.

OBJECTIVES: This study aims to evaluate the prevalence of hyperuricemia (HU) considering both serum uric acid (SUA) levels and medication status of urate-lowering drugs (ULDs), and the association between HU and its comorbidities using a Japanese healthcare database. MATERIALS AND METHODS: The study population consisted of 60,828 subjects who had at least one serum uric acid measurement between the fiscal years (FYs) 2010 and 2014 in a Japanese employment-based health insurance database (MinaCare Co., Ltd., Tokyo, Japan), which includes mutually linked medical/pharmaceutical claims data and health check-up data. Hyperuricemia was defined as a SUA level >7.0 mg/dL of the health check-up data and/or a prescription for a ULD. The association between HU and comorbidities were analyzed by comparing the prevalence of HU of each subgroup defined by presence or absence of comorbidity. RESULTS: The prevalence of HU in FY 2014 was 26.8% [95% confidence interval (CI): 26.2 to 27.3%] in male subjects and 0.9% (95% CI: 0.7 to 1.0%) in female subjects. According to the analyses by sex and age, a trend of increasing prevalence with age was observed in both males and females. The prevalence of HU remained stable both in males and females from FYs 2010 to 2014. The positive association between HU and well-known comorbidities were confirmed with the exception of diabetes mellitus and smoking status in male subjects. CONCLUSION: Our results provided a more accurate prevalence of HU in Japanese population. It is important to increase the awareness on HU in the society to reduce the burden of HU-related diseases.

Safety and efficacy of first-line dacomitinib in Japanese patients with advanced non-small cell lung cancer.

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first-line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28-d cycles, in patients with EGFR-activating mutation-positive (EGFR-positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non-small cell lung cancer (NSCLC). The primary endpoint was progression-free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307-0.961]; 2-sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0-31.3] mo, 9.3 [95% CI, 7.4-14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first-line dacomitinib in Japanese patients with EGFR-positive advanced NSCLC.

Phase 1 study of crisaborole in Japanese healthy volunteers and patients with atopic dermatitis.

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0-400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.

Expression Profiles of NOS Isoforms in Dental Pulp and Odontoblasts in nNOS Knockout Mice.

Active oxygen and free radicals are involved in metabolism in cells and tissues. Immunohistological studies of related enzymes are few, and the morphological dynamics of these enzymes in dental pulp and odontoblasts remain to be elucidated. Nitric oxide synthase (NOS) has 3 isoforms: nNOS, iNOS, and eNOS. The aim of this study was to investigate the profiles of NOS isoforms in the absence of nNOS in dental pulp and odontoblasts. Five-week-old male C57BL/6 and nNOS knockout (KO) mice were sacrificed and expression of nNOS, iNOS, and eNOS determined immunohistochemically. Expression of nNOS was positive, whereas that of iNOS was negative and eNOS weakly positive in the dental pulp and odontoblasts of the control mice. In nNOS KO mice, expression of iNOS was positive in dental pulp and strongly positive in odontoblasts, whereas that of eNOS was stronger in fibroblasts, endothelial cells in the vicinity of blood vessels in the dental pulp, and odontoblasts. Expression of nNOS was negative in the nNOS KO mice. This suggests that iNOS and eNOS compensate for nNOS deficiency in vascular endothelial cells and fibroblasts in the dental pulp and odontoblasts.

The effect of midazolam administration for the prevention of emergence agitation in pediatric patients with extreme fear and non-cooperation undergoing dental treatment under sevoflurane anesthesia, a double-blind, randomized study.

Background: Sevoflurane is generally the preferred anesthetic agent for general anesthesia in pediatric patients, due to its rapid induction and recovery characteristics. However, it has been recognized that a major complication is emergence agitation when awakening from general anesthesia. The aim of this study was to evaluate the occurrence rate of emergence agitation in the operating room and postoperative recovery area following intraoperative administration of midazolam to pediatric patients under general anesthesia. Patients and methods: One hundred and twenty pediatric patients undergoing dental treatment under sevoflurane anesthesia were enrolled in this study. The patients were divided into three groups (n=40 each in the 0.1 mg/kg midazolam, 0.05 mg/kg midazolam, and control with saline groups). Midazolam or saline was injected intravenously approximately 30 minutes before the end of the dental treatment. We used the Richmond Agitation and Sedation Scale (RASS) to assess the level of sedation and drowsiness at emergence phase in the operating room. We also used the Pediatric Anesthesia Emergence Delirium Scale (PAED) to assess the level of agitation and delirium at the full recovery phase from anesthesia in the recovery area. Results: At the emergence phase, the incidence of emergence agitation in the 0.1 mg/kg midazolam group was significantly lower than in the other groups (p=0.0010). At the recovery phase, there was no significant difference among the three groups. The odds ratio between PAED score and RASS score was 4.0 using logistic regression analysis. The odds ratio between PAED score and Disability was 2.5. Conclusion: Administration of a single dose of 0.1 mg/kg midazolam dose significantly decreases the incidence of severe emergence agitation at the emergence after sevoflurane anesthesia, but not at the recovery phase. Furthermore, the evaluation of sedative and agitation condition using RASS score at emergence from anesthesia is useful to predict occurrence of agitation in the recovery phase.

Parental Satisfaction with Ambulatory Anesthesia during Dental Treatment for Disabled Individuals and Their Preference for Same in Future.

The purpose of this study was to survey parental satisfaction with ambulatory anesthesia during dental treatment in disabled patients. Factors associated with parental preference for general anesthesia during future dental treatment in such patients were also investigated. A questionnaire was mailed to the parents of 181 disabled individuals who underwent dental treatment under ambulatory anesthesia at Tokyo Dental College Suidobashi Hospital between 2012 and 2016. A total of 71 responses were received (39.2%). The mean patient age was 18 years, and disabilities included autism spectrum disorder, intellectual disability, cerebral palsy, and epilepsy. The items surveyed included dental treatment details, number of times patients received general anesthesia, type of anesthetic used, anesthesia induction method, durations of treatment and anesthesia, and the presence or absence of intraoperative or postoperative complications. Questionnaire items queried problems related to dental care, anesthesia history, preoperative anxiety, length of fasting period, induction of general anesthesia, nursing and hospital room environment, postoperative anxiety, overall evaluation, and whether the parent would prefer general anesthesia during future dental treatment. The patients were divided into 2 groups: those whose parents preferred general anesthesia during future dental treatment and those whose parents did not. The results revealed that, where disabled individuals had previously received general anesthesia during dental treatment, the parents were more likely to prefer general anesthesia during future dental treatment.

Effects of general anesthesia on postoperative sleep cycles in dentally disabled patients.

AIMS: Although it has been reported that general anesthesia affect the perioperative sleep cycle, no studies have yet evaluated how general anesthesia affects dentally disabled patients. In this study, we investigated the alteration of perioperative sleep cycles in dentally disabled patients receiving dental treatment under general anesthesia. SUBJECTS AND METHODS: The study included 16 patients receiving dental procedures under general anesthesia. Using a sleep monitoring mat, the patients' sleep cycles were measured at home from 5 days before the scheduled surgery date until 5 days after discharge following general anesthesia. The change in all the variables of sleep cycles were analyzed in comparison to the value in preoperative period. Daily differences in these variables were assessed for statistical analysis. RESULTS: The percentage of deep sleep (Stages 3 and 4) decreased significantly on postoperative day 1, and the percentage of light sleep increased. Furthermore, sleep cycles were significantly extended on postoperative day 1. CONCLUSION: The percentage of deep sleep decreased significantly on postoperative day 1 while the percentage of light sleep increased. Sleep cycles were also significantly extended on postoperative day 1. These results reveal that the sleep cycle is somehow affected on the first day following general anesthesia.

Interim analysis based on the weighted log-rank test for delayed treatment effects under staggered patient entry.

Fleming and Harrington's G(ρ,γ) class of weighted log-rank tests is appropriate for detecting delayed treatment effects such as those seen in cancer vaccines. A conditional power (CP) and an alpha spending function (ASF) approach are useful for interim analyses that are conducted with the aim of early termination due to futility and efficacy, respectively. However, calculation of the CP and the total Type I error probability are often not considered for delayed effects under the staggered patient entry. In this article, we first propose methods for calculating the CP analytically based on the weighted log-rank test. We compared the performances of the proposed methods with two other methods (i.e., usual log-rank test and optimal one) under the delayed alternatives. Our simulations demonstrated that the CP based on the weighted log-rank test was more powerful than that of the usual log-rank test and was comparable to the CP based on the optimal log-rank test. Second, we quantitatively evaluated the degree to which the Type I error probability was inflated when an ASF approach with forced independent increments assumption was applied to the weighted log-rank test. The proposed method will provide valuable tools in the decision-making stage of the interim analysis.

Immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine compared to the 23-valent pneumococcal polysaccharide vaccine in elderly Japanese adults.

Streptococcus pneumoniae is a major cause of severe disease worldwide, particularly in the elderly population. Due to increasing life expectancy in Japan and elsewhere, an effective vaccine which offers the possibility of prolonged protection is required. Protein conjugated pneumococcal vaccines, which have the ability to boost immunity (immunologic memory) on natural exposure or revaccination, may meet these requirements. An unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been available for decades; however data on protection against pneumonia are inconsistent. For the first time, a randomized, modified double-blind trial comparing the 13-valent pneumococcal conjugate vaccine (PCV13) with PPSV23 was conducted in PPSV23-naive adults ≥65 years of age in Japan. This study showed that statistically significantly greater functional antibody responses as measured by opsonophagocytic assays 1 month after vaccination were elicited in the PCV13 group (n = 366) compared with the PPSV23 group (n = 367) for 9 of the 12 serotypes in common with both vaccines and for serotype 6A, unique to PCV13. Local reactions collected within 14 days of vaccination were more frequent in the PCV13 (57.5%, 211/367) than PPSV23 (44.9%, 166/370) group, although severity was generally mild to moderate; systemic and adverse events were similar across groups. There were no treatment-related serious adverse events. Consistent with global studies comparing PCV13 with PPSV23, PCV13 use in Japanese subjects was safe and well-tolerated and elicited greater functional immune responses than PPSV23 for the majority of PCV13-serotypes. PCV13 has the potential to protect against pneumococcal disease in Japanese elderly adults.

Estimation of treatment effect adjusting for dependent censoring using the IPCW method: an application to a large primary prevention study for coronary events (MEGA study).

BACKGROUND: The MEGA study is a randomized controlled trial conducted in Japan to evaluate the primary preventive effect of pravastatin against coronary heart disease (CHD), in which 8214 subjects are randomized to diet or diet plus pravastatin. Pravastatin reduces the incidence of CHD (hazard ratio=0.67; 95%CI: 0.49-0.91). In the MEGA study, in addition to the usual loss to follow-up cases, there is another problem of drop-outs due to the refusal of further follow-up at 5 years. PURPOSE: To estimate the treatment effect adjusting for some types of dependent censorings observed in the MEGA study and to assess the sensitivity of standard analysis results for these censoring cases. METHODS: The proposed method is a straightforward extension of the inverse probability of censoring weighted (IPCW) method for settings with more than one reason for censoring, where the propensities for drop-outs are modeled separately for each reason. Simulation studies are also conducted to compare the properties of the IPCW estimate with the standard analysis assuming independent censorings. RESULTS: Simulation studies show that the IPCW estimate can correct for selection bias due to dependent censoring that can be explained by measured factors, while the standard analysis is biased. Applying the proposed method to the MEGA study data, several prognostic factors are associated with the censoring processes, and after adjusting for these dependent censorings, slightly larger treatment effects for pravastatin are observed for both CHD (primary endpoint) and stroke (secondary endpoint) events. LIMITATIONS: The method developed is based on the fundamental assumption of sequentially ignorable censoring. CONCLUSIONS: Our proposed method provides a valuable approach for estimating treatment effect adjusting for several types of dependent censorings. Dependent censorings observed in the MEGA study did not cause a severe selection bias attributable to the covariates and the results from the standard analysis were robust in relation to the censorings.

Aminoglycoside-induced hearing loss in a patient with the 961 mutation in mitochondrial DNA.

The A1555G mutation in the mitochondrial 12S ribosomal RNA gene is often found in patients with hearing loss after aminoglycoside exposure. A second pathogenic mutation in this gene, deletion of thymidine at position 961 with varying numbers of cytosines inserted (delT961Cn), has recently been found to predispose patients to aminoglycoside-induced deafness. We report on a Japanese patient bearing the delT961Cn who had streptomycin-induced deafness. Our report suggests that the delT961Cn plays an important secondary role in the pathogenesis of deafness caused by aminoglycosides. The combination of taking family histories and molecular screening at the 1555 and 961 positions is thought to reduce the frequency of tragic irreversible deafness due to aminoglycosides.