Mio Sakuma

High Incidence of NLRP3 Somatic Mosaicism in Patients With Chronic Infantile Neurologic, Cutaneous, Articular Syndrome: Results of an International Multicenter Collaborative Study

OBJECTIVE Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. METHODS An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. RESULTS Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. CONCLUSION Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

Effect of low-protein diet on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials.

Objective To evaluate the effect of low-protein diet on kidney function in patients with diabetic nephropathy. Design A systematic review and a meta-analysis of randomised controlled trials. Data sources MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number (ISRCTN) Register and University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) from inception to 10 December 2012. Internet searches were also carried out with general search engines (Google and Google Scholar). Study selection Randomised controlled trials that compared low-protein diet versus control diet and assessed the effects on kidney function, proteinuria, glycaemic control or nutritional status. Primary and secondary outcome measures and data synthesis The primary outcome was a change in the glomerular filtration rate (GFR). The secondary outcomes were changes in proteinuria, post-treatment value of glycated haemoglobin A1C (HbA1c) and post-treatment value of serum albumin. The results were summarised as the mean difference for continuous outcomes and pooled by the random effects model. Subgroup analyses and sensitivity analyses were conducted regarding patient characteristics, intervention period, methodological quality and assessment of diet compliance. The assessment of diet compliance was performed based on the actual protein intake ratio (APIR) of the low-protein diet group to the control group. Results We identified 13 randomised controlled trials enrolling 779 patients. A low-protein diet was associated with a significant improvement in GFR (5.82 ml/min/1.73 m2, 95% CI 2.30 to 9.33, I2=92%; n=624). This effect was consistent across the subgroups of type of diabetes, stages of nephropathy and intervention period. However, GFR was improved only when diet compliance was fair (8.92, 95% CI 2.75 to 15.09, I2=92% for APIR <0.9 and 0.03, 95% CI −1.49 to 1.56, I2=90% for APIR ≥0.9). Proteinuria and serum albumin were not differed between the groups. HbA1c was slightly but significantly decreased in the low-protein diet group (−0.26%, 95% CI −0.35 to −0.18, I2=0%; n=536). Conclusions Low-protein diet was significantly associated with improvement of diabetic nephropathy. The adverse effects of low-protein diet were not apparent such as worsening of glycaemic control and malnutrition.

Epidemiology of potentially inappropriate medication use in elderly patients in Japanese acute care hospitals

The elderly receive many medications which may have adverse effects. Little evidence is available about the epidemiology of potentially inappropriate medications being prescribed to the elderly in Japan as defined by the Beers criteria, or whether or not these medications result in harm when used in this population.

Birth order effect on childhood food allergy

To cite this article: Kusunoki T, Mukaida K, Morimoto T, Sakuma M, Yasumi T, Nishikomori R, Heike T. Birth order effect on childhood food allergy. Pediatric Allergy Immunology 2012: 23: 250–254.

Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes MellitusClinical Perspective: 10-Year Follow-Up of a Randomized Controlled Trial

Background: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. Methods: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care–controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity. Results: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P>0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82–1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group (P=0.03), and the incidence of hemorrhagic stroke was not different between groups. Conclusions: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00110448.

Incidence and risk factors of hospital falls on long‐term care wards in Japan

RATIONALE, AIMS AND OBJECTIVE Falls among hospitalized patients are an important patient safety issue. In particular, the incidence of falls and risk of related injuries among the elderly are particularly high. Because the epidemiology of falls is not well scrutinized in Japanese long-term care wards, we evaluated the incidence and risk factors of falls in this setting. METHODS A prospective cohort study was conducted on long-term care wards with 160 beds in a general hospital in Japan. All patients admitted to the wards over 25 months were enrolled and followed until discharge. The baseline characteristics and incidences of falls were measured. RESULTS We enrolled 2973 patients with a mean age of 74 years, and median length of stay was 36 days. During the study period, 657 falls occurred in 411 (14%) patients. The incidence of falls was 3.8 per 1000 patient-days, and by 15 and 30 days after admission to the ward, 7.3% and 11.4% of patients, respectively, had fallen. Independent risk factors related to falls during hospitalization were advanced age [≥70 years, hazard ratio (HR) 1.5, 95% confidence interval (CI) 1.2-2.0], history of falls (HR 1.2, 95% CI 1.0-1.5), frequent urination (HR 1.4, 95% CI 1.0-1.8) and requirement for toileting assistance (HR 1.4, 95% CI 1.1-1.8). Among patients who fell during the study period, 23% sustained an injury. CONCLUSIONS Many patients on long-term care wards in Japan were elderly and experienced falls during their hospital stay, with consequent injuries. Taking into account the risk factors identified, we need to devise effective strategies to prevent falls and related injuries.

Differential Effect of Low-Dose Aspirin for Primary Prevention of Atherosclerotic Events in Diabetes Management: A subanalysis of the JPAD trial

OBJECTIVE Recent reports showed that low-dose aspirin was ineffective in the primary prevention of cardiovascular events in diabetic patients overall. We hypothesized that low-dose aspirin would be beneficial in patients receiving insulin therapy, as a high-risk group. RESEARCH DESIGN AND METHODS This study is a subanalysis of the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial—a randomized, controlled, open-label trial. We randomly assigned 2,539 patients with type 2 diabetes and no previous cardiovascular disease to the low-dose aspirin group (81 or 100 mg daily) or to the no-aspirin group. The median follow-up period was 4.4 years. We investigated the effect of low-dose aspirin on preventing atherosclerotic events in groups receiving different diabetes management. RESULTS At baseline, 326 patients were treated with insulin, 1,750 with oral hypoglycemic agents (OHAs), and 463 with diet alone. The insulin group had the longest history of diabetes, the worst glycemic control, and the highest prevalence of diabetic microangiopathies. The diet-alone group had the opposite characteristics. The incidence of atherosclerotic events was 26.6, 14.6, and 10.4 cases per 1,000 person-years in the insulin, OHA, and diet-alone groups, respectively. In the insulin and OHA groups, low-dose aspirin did not affect atherosclerotic events (insulin: hazard ratio [HR] 1.19 [95% CI 0.60−2.40]; OHA: HR 0.84 [0.57−1.24]). In the diet-alone group, low-dose aspirin significantly reduced atherosclerotic events, despite the lowest event rates (HR 0.21 [0.05−0.64]). CONCLUSIONS Low-dose aspirin reduced atherosclerotic events predominantly in the diet-alone group and not in the insulin or OHA groups.

Effect of eczema on the association between season of birth and food allergy in Japanese children

Food allergy (FA) in childhood has been shown to be more prevalent in those born in autumn and winter. The mechanisms of this season‐of‐birth effect remain unclear, although shortage of vitamin D during infancy has been considered one possible mechanism. The purpose of this study was to investigate the effect of eczema on the season‐of‐birth effect on FA in infancy.

Total and low-density lipoprotein cholesterol levels are associated with atopy in schoolchildren.

Analysis of general childhood population data showed that there was a significant positive association between total and low-density lipoprotein cholesterol levels and atopy, independent of obesity or sex, which suggest a relationship between hyperlipidemia and greater allergic sensitization among schoolchildren.

Adverse drug events and medication errors in Japanese paediatric inpatients: a retrospective cohort study

Objectives Knowledge about the epidemiology of adverse drug events (ADEs) and medication errors in paediatric inpatients is limited outside Western countries. To improve paediatric patient safety worldwide, assessing local epidemiology is essential. Design The Japan Adverse Drug Events (JADE) Study was a cohort study. Setting Paediatric inpatients at two tertiary care teaching hospitals in Japan. Main outcome measures ADEs and medication errors identified by onsite review of all medical charts, incident reports and prescription queries by pharmacists. Two independent physicians reviewed all incidents and classified ADEs and medication errors, as well as their severity and preventability. Results We enrolled 1189 admissions which included 12 691 patient-days during the study period, and identified 480 ADEs and 826 medication errors. The incidence of ADEs was 37.8 (95% CI 34.4 to 41.2) per 1000 patient-days and that of medication errors was 65.1 (95% CI 60.6 to 69.5) per 1000 patient-days. Among ADEs, 4%, 23% and 73% were fatal or life-threatening, serious and significant, respectively. Among the 480 ADEs, 36 (8%) were considered to be preventable which accounted for 4% of all medication errors, while 668 (81%) of all medication errors were judged to have the potential to cause harm to patients. The most common error stage for preventable ADEs was monitoring (78%) whereas 95% of potential ADEs occurred at the ordering stage. Conclusions ADEs and medication errors were common in paediatric inpatients in Japan, though the proportion of ADEs that were preventable was low. The ordering and monitoring stages appeared most important for improving safety.