Background Estimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had ...limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories. Study Design Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory. Setting & Participants Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study. Reference Test Measured GFR (mGFR) computed from inulin clearance. Index Test Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4). Measurements Performance of equations was assessed by means of bias (eGFR − mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient. Results In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS–MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2 ) = 194 × Serum creatinine−1.094 × Age−0.287 × 0.739 (if female). In the validation data set, bias was −1.3 ± 19.4 versus −5.9 ± 19.0 mL/min/1.73 m2 ( P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% ( P = 0.6) for equation 3 versus equation 1 and −2.1 ± 19.0 versus −7.9 ± 18.7 mL/min/1.73 m2 ( P < 0.001) and 75% versus 73% ( P = 0.06) for equation 4 versus equation 2 ( P = 0.06), respectively. Limitation Most study participants had chronic kidney disease, and some may have had changing GFRs. Conclusion The new Japanese coefficient for the modified IDMS–MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.
Marginal zone lymphoma (MZL) is a low-grade B-cell lymphoma derived from marginal-zone B cells. Because of a lack of specific immunohistochemical markers, MZL is mainly diagnosed based on the ...cytological appearance and growth pattern of the tumor. Marginal-zone B cells were recently shown to selectively express immunoglobulin superfamily receptor translocation-associated 1 (IRTA1), but the antibody used in that study is not commercially available. We therefore investigated the IRTA1 expression in non-neoplastic lymphoid tissues and 261 malignant lymphomas, examining the ability of a commercially available antibody to accurately diagnose MZL. Among 29 MZLs, 23 of 25 extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphomas), 3 of 6 splenic MZLs and 3 of 6 nodal MZLs were positive for IRTA1. Among the 98 diffuse large B-cell lymphomas (DLBCLs), 33 were positive for IRTA1, including 1 of 38 follicular lymphomas (FLs), and all precursor B-lymphoblastic (2 of 2) and T-lymphoblastic (7 of 7) leukemia/lymphomas. Other mature B-cell and T-cell lymphomas, and Hodgkin lymphoma were negative for IRTA1. In MALT lymphoma, positive cells were detected mainly in intraepithelial and subepithelial marginal-zone B cells. In one case of grade 3 FL, IRTA1 was also expressed in the area of large-cell transformation. When tumors were classified as germinal-center B cell–like (GCB) or non-GCB using the algorithm of Hans, positive expression of IRTA1 was correlated significantly with non-GCB DLBCLs (P < .05). These results demonstrated the ability of the commercially available IRTA1 antibody to distinguish MALT lymphoma from other low-grade B-cell lymphomas.
There are an estimated 1·3–4·0 million cases of cholera and 20 000–140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral ...candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans.
We did a double-blind, randomised, placebo-controlled, dose-escalation, phase 1 study at one centre in Tokyo, Japan. Eligible participants were healthy adult men with measurable serum and faecal antibodies against CTB at screening. Participants were excluded if they had allergy to rice; history of cholera or travellers' diarrhoea; poorly controlled constipation; abnormal results on hepatic, renal, or haematological screening tests; use of any over-the-counter drugs within 7 days before first administration; inability to use a medically acceptable means of contraception; or other reasons by medical judgment of the investigator. Three dose cohorts of participants were randomly assigned by block to receive oral MucoRice-CTB (1 g, 3 g, or 6 g) or placebo (1 g, 3 g, or 6 g), once every 2 weeks for 8 weeks (for a total of 4 doses). The dose groups were performed sequentially, and each dose cohort was completed before the higher dose cohort began. All medical staff, participants, and most trial staff were masked to treatment allocation. The primary outcomes were safety and tolerability, measured by 12-lead electrocardiogram; vital signs; haematology, biochemistry, and urinalysis; rice protein-specific serum IgE antibody concentration; and monitoring of adverse events. Participants were assessed at baseline and at 1, 2, 4, 6, 8, and 16 weeks after the first administration of vaccine or placebo. The safety analysis set included all participants enrolled in the trial who received at least one dose of the study drug or placebo and were compliant with good clinical practice. The full analysis population included all participants enrolled in the trial who received at least one dose of the study drug and for whom any data were obtained after the start of study drug administration. Meta-genomic analysis of study participants was performed using bacterial DNA from faecal samples before vaccination. This trial is registered with UMIN.ac.jp, UMIN000018001.
Between June 23, 2015, and May 31, 2016, 226 participants were recruited and assessed for eligibility. 166 participants were excluded based on health condition or schedule. We then randomly selected 60 male volunteers aged 20–40 years who were enrolled and assigned to MucoRice-CTB (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g), or placebo (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g). All participants received at least one dose of study drug or placebo and were included in the safety analyses. Two participants given MucoRice-CTB 3 g and one participant given MucoRice-CTB 6 g were lost to follow-up and excluded from the efficacy analysis. Serum CTB-specific IgG and IgA antibody concentrations in participants who received 6 g MucoRice-CTB increased significantly in both a time-dependent and dose-dependent manner compared with those in the placebo groups (p for interaction=0·002 for IgG, p=0·004 for IgA). Genome analysis of subjects' faeces before vaccination revealed that compared to non-responders, responders had a gut microbiota of higher diversity with the presence of Escherichia coli and Shigella spp. 28 (93%) of 30 participants who received MucoRice-CTB at any dose had at least one adverse event during the study period, compared with 30 (100%) of 30 participants given placebo. Grade 3 or higher adverse events were reported in four participants in the MucoRice-CTB group (5 events) and four participants in the placebo group (10 events). The most common serious adverse event was haemoglobin decreased (2 events in 2 participants in the pooled MucoRice-CTB group, 2 events in 2 participants in the placebo group; all grade 3).
Participants given MucoRice-CTB showed increased CTB-specific serum IgG and IgA antibody concentrations without inducing serious adverse events, indicating that MucoRice-CTB could be a safe and potent vaccine to prevent diarrhoeal disease. MucoRice-CTB induced neutralising antibodies against diarrhoeal toxins in a gut microbiota-dependent manner. A similar phase 1 trial will be done with participants of other ethnicities to substantiate our findings.
Translational Research Acceleration Network Program of Japan Agency for Medical Research and Development; Ministry of Education, Culture, Sports, Science and Technology, Japan; Science and Technology Research Partnership for Sustainable Development; Grant-in-Aid for Scientific Research (S) (18H05280) (to H K) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Young Scientists (B) (16K16144) (to Y K) from JSPS; Grant-in-Aid for Young Scientists (18K18148) (to Y K) from JSPS; Grant from International Joint Usage/Research Center (K3002), the Institute of Medical Science, University of Tokyo
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