World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XIII - Oral immunotherapy for CMA - Systematic review.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2-8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%-91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6-30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12-770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%-10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

A Safety and Immunogenicity Study of a Single Dose of a Meningococcal (Groups A, C, W, and Y) Polysaccharide Diphtheria Toxoid Conjugate Vaccine (MEN-ACWY-D) in Healthy Japanese Participants.

Meningococcal disease can cause significant disability and mortality. The quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine (Men-ACWY-D) protects against invasive meningococcal disease caused by serogroups A, C, W, and Y. This phase III, open-label, single-arm, multicenter study evaluated the safety and immunogenicity of a single vaccine dose in healthy Japanese adults. The study enrolled 200 participants between 2 and 55 years of age. Immunogenicity was assessed by quantifying the seroprotection rates (the proportion of participants with antibody titers ≥ 1:128 against the capsular polysaccharide from all 4 serogroups measured 28 days after vaccination). Safety endpoints included occurrence, nature, time to onset, duration, intensity, relationship to vaccination, and outcome of solicited and unsolicited adverse events (AEs) and serious AEs (SAEs). Participants included 194 adults, 2 adolescents, and 4 children. Among adults, the seroprotection rates for serogroups A, C, W, and Y were 91.2%, 80.2%, 89.1%, and 93.8%, respectively. Seroconversion rates (the proportion of participants with pre-vaccination titers of < 1:4 and a ≥ 4-fold rise from baseline) were 87.3%, 83.0%, 94.4%, and 96.4%, respectively. No immediate AEs, adverse reactions, SAEs, or deaths were reported for any age group. Men-ACWY-D is well tolerated and immunogenic, eliciting antibodies against capsular polysaccharides from all 4 serogroups in Japanese adults.

Japanese study of tofogliflozin with type 2 diabetes mellitus patients in an observational study of the elderly (J-STEP/EL): A 12-week interim analysis.

AIMS/INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors are a promising treatment for type 2 diabetes mellitus, but are associated with concerns about specific adverse drug reactions. We carried out a 1-year post-marketing surveillance of tofogliflozin, a novel agent in this class, in Japanese elderly patients with type 2 diabetes mellitus and here report the results of a 12-week interim analysis, focusing on adverse drug reactions of special interest. MATERIALS AND METHODS: The present prospective observational study included all type 2 diabetes mellitus patients aged ≥65 years who started tofogliflozin during the first 3 months after its launch. Data on demographic and baseline characteristics, clinical course and adverse events were collected. RESULTS: Of 1,535 patients registered, 1,506 patients whose electronic case report forms were collected and who had at least one follow-up visit were included in the safety analysis at 12 weeks. A total of 178 of 1,506 patients (11.82%) had at least one adverse drug reaction to tofogliflozin. The incidence of adverse drug reactions of special interest (polyuria/pollakiuria, volume depletion-related events, urinary tract infection, genital infection, skin disorders and hypoglycemia) was 2.19, 2.32, 1.33, 1.13, 1.46 and 0.73%, respectively. No new safety concerns were identified. Among those evaluable for clinical effectiveness, the mean (standard deviation) glycated hemoglobin decreased from 7.65% (1.35%) at baseline to 7.25% (1.16%) at 12 weeks by 0.39% (0.94%; P < 0.0001). CONCLUSIONS: This interim analysis characterized the safety profile of tofogliflozin in Japanese elderly patients with type 2 diabetes mellitus during the early post-marketing period.

Duration of anticoagulation following venous thromboembolism: a meta-analysis.

CONTEXT: Patients with venous thromboembolism (VTE) are susceptible to recurrent events, but whether prolonging anticoagulation is warranted in patients with VTE remains controversial. OBJECTIVE: To review the available evidence and quantify the risks and benefits of extending the duration of anticoagulation in patients with VTE. DATA SOURCES: PubMed, EMBase Pharmacology, the Cochrane database, clinical trial Web sites, and a hand search of reference lists. STUDY SELECTION: Included studies were randomized controlled trials with results published from 1969 through 2004 and evaluating the duration of anticoagulation in patients with VTE that measured recurrent VTE. Excluded studies were those enrolling only pure populations of high-risk patients. Two independent reviewers assessed each article for inclusion and exclusion criteria, with adjudication by a third reviewer in cases of disagreement. Fifteen of 67 studies were included in the analysis. DATA EXTRACTION: Two independent reviewers performed data extraction using a standardized form, with adjudication by the remainder of the investigators in cases of disagreement. Data regarding recurrent VTE, major bleeding, person-time at risk, and study quality were extracted. DATA SYNTHESIS: If patients in the long-term therapy group remained receiving anticoagulation, the risk of recurrent VTE with long- vs short-term therapy was reduced (weighted incidence rate, 0.020 vs 0.126 events/person-year; rate difference, -0.106 [95% confidence interval {CI}, -0.145 to -0.067]; P<.001; pooled incidence rate ratio [IRR], 0.21 [95% CI, 0.14 to 0.31]; P<.001). If anticoagulation in the long-term therapy group was discontinued, the risk reduction was less pronounced (weighted incidence rate, 0.052 vs 0.072 events/person-year; rate difference, -0.020 [95% CI, -0.039 to -0.001]; P = .04; pooled IRR, 0.69 [95% CI, 0.53 to 0.91]; P = .009). The risk of major bleeding with long- vs short-term therapy was similar (weighted incidence rate, 0.011 vs 0.006 events/person-year; rate difference, 0.005 [95% CI, -0.002 to 0.011]; P = .14; pooled IRR, 1.80 [95% CI, 0.72 to 4.51]; P = .21). CONCLUSIONS: Patients who receive extended anticoagulation are protected from recurrent VTE while receiving long-term therapy. The clinical benefit is maintained after anticoagulation is discontinued, but the magnitude of the benefit is less pronounced.

A Japanese study to assess immunogenicity and safety of a typhoid Vi polysaccharide vaccine.

BACKGROUND: Although typhoid fever is rare in Japan, imported cases have been reported occasionally in travelers returning from endemic areas. To achieve licensing of a typhoid Vi polysaccharide vaccine (Typhim Vi(®)) and make it widely available in Japan, this study was conducted at the request of the Japanese Ministry of Health Labor and Welfare to assess the immunogenicity and safety of this vaccine when given as a single dose (the recommended schedule of administration) in a Japanese population. METHODS: In this multi-center, open-label, non-comparative, intervention study performed in Japan, 200 healthy volunteers (188 adults [≥ 18 years of age], 7 adolescents [12-17 years of age] and 5 children [2-11 years of age]) were administered Typhim Vi(®). Immunogenicity was assessed 28 days after vaccinations using an ELISA method of anti-Vi antibody detection. A 4-fold increase in anti-Vi titer was considered as the threshold for seroconversion for anti-Vi antibodies. Safety was assessed up to 28 days following vaccination. RESULTS: Overall, 92.0% (95% confidence interval [CI]: 87.3-95.4%) of participants achieved seroconversion 28 days after a single dose of typhoid Vi polysaccharide vaccine. GMTs of Vi antibody titers increased from 6.6 (95% CI: 5.8-7.4) prior to vaccination to 157.3 (95% CI: 135.1-183.2) on Day 28 after vaccination. The geometric mean of individual anti-Vi antibody titer ratios (Day 28/Day 0) was 23.9 (95% CI: 20.3-28.3). There were no immediate adverse events and no adverse events led to the discontinuation of participants from the study. Across all age groups, pain and myalgia were the most frequently reported injection site and systemic reactions, respectively. Most of these reactions were mild in intensity and resolved within 7 days. CONCLUSIONS: A single dose of typhoid Vi polysaccharide vaccine, Typhim Vi(®), demonstrated good safety and immunogenicity profile in a Japanese population.

Factors affecting performance of hospital infection control in Japan.

BACKGROUND: In Japan, hospital infection control (IC) programs are frequently underresourced, and their improvement is considered a pressing issue. METHODS: In 2005, we conducted a questionnaire survey of 638 teaching hospitals (most with 300 or more beds) and 882 nonteaching hospitals (most with fewer than 300 beds) in Japan. We analyzed associations among resources, infrastructures, activities, and performance related to IC. RESULTS: A total of 423 teaching hospitals (66.3%) and 377 nonteaching hospitals (50.2%) responded to the survey. The teaching hospitals had more IC infrastructure, such as full-time infection control practitioners (ICPs), link nurses, and infection control teams (ICTs), compared with the nonteaching hospitals. Infection surveillance was more likely to be implemented in hospitals with more ICP full-time equivalents (FTEs). IC performance scores were significantly higher in the teaching hospitals than in the nonteaching hospitals. In multivariate analyses, greater IC infrastructure, such as ICP FTEs, full-time IC nurses, and regular ICT rounds were significantly associated with IC performance. Hospital accreditation and hospital size also were significantly associated with higher IC performance scores. CONCLUSION: Given the strong associations found among IC infrastructure and performance, a new framework for evaluating IC infrastructure and for providing financial support may be effective in enhancing IC programs.

Comparisons of risk-adjusted clinical outcomes for patients with aneurysmal subarachnoid haemorrhage across eight teaching hospitals in Japan.

OBJECTIVES: To assess predictive value of patient characteristics and severity of aneurysmal subarachnoid haemorrhage (SAH) patients for clinical outcomes, and thereby estimate risk-adjusted clinical outcomes and compare the outcomes across hospitals. METHODS: We selected 256 aneurysmal SAH patients from eight teaching hospitals in Japan. The clinical outcomes of patients at the time of discharge were assessed by the Glasgow Outcome Scale (GOS). A multiple logistic regression analysis was performed to identify predictors for the GOS status at the time of discharge. The risk-adjusted proportion of patients with a favourable GOS outcome was then estimated for each facility and compared across hospitals. RESULTS: The logistic regression analysis revealed that younger age (P < 0.001), patients with good World Federations of Neurological Surgeons grade at admission (P < 0.001) and absence of chronic renal failure or ischaemic heart disease as a comorbid condition (P < 0.001) were identified as significant predictors for favourable GOS outcome at the time of discharge among aneurysmal SAH patients (C statistic = 0.88). We found that one hospital had significantly better outcomes than the others. CONCLUSION: After comparison of risk-adjusted values across hospitals, the clinical management methods of the hospital that showed the best performance were examined and shared among providers.

Impact of hospital accreditation on infection control programs in teaching hospitals in Japan.

BACKGROUND: In Japan, hospital infection control (IC) programs are frequently under-resourced, whereas their improvement is considered a pressing issue. Hospital accreditation may have a positive impact on IC program performance. The Japan Council for Quality Health Care (JCQHC) is a hospital accreditation organization that now prescribes broad elements of IC as part of its accreditation standards. METHODS: We sent questionnaire surveys to all teaching hospitals in Japan to characterize the current situation of hospital IC activities and identify the impact of accreditation on IC infrastructure and performance. The self-administered questionnaire that we used was developed based on the JCQHC accreditation standards. Surveys were sent to all institutions in 2004 and again in 2005. RESULTS: Of the 638 hospitals surveyed, 335 (52%) answered in both years. Most IC practitioners in Japanese teaching hospitals were working part time and spent limited hours performing IC duties. Surveillance was poorly implemented in Japan, and IC activities without evidence of effectiveness were widely performed. Surveillance was implemented more frequently in hospitals with adequate IC staffing. Improvement in IC infrastructure and performance between the surveys was larger in the newly accredited hospitals than the others. CONCLUSIONS: Hospital accreditation had a significant impact on hospitals' IC infrastructure and performance.