This study reported 5-year data on the safety and effectiveness of prolonged-release tacrolimus (PR-T) in de novo kidney transplant recipients (KTRs) in Japanese routine clinical practice.
This was ...an open-label, prospective, noncomparative, observational, postmarketing surveillance study of de novo KTRs who initiated PR-T as part of routine clinical practice in 43 sites in Japan between March 2009 and March 2011. Follow-up period was March 2010 to March 2016. Effectiveness outcomes included Kaplan-Meier estimated patient survival, graft survival, graft rejection, estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease-4), and creatinine clearance. Adverse drug reactions (ADRs) were recorded.
The safety analysis set comprised 250 de novo KTRs (mean age 45.9 SD, 14.2 years); 249 patients formed the efficacy analysis set. Mean PR-T daily dose decreased during the study (0.14 SD, 0.05, 0.09 SD, 0.05, and 0.05 SD, 0.03 mg/kg at day 0 transplant, week 24, and year 5, respectively), as did tacrolimus trough levels (15.9 SD, 13.4 to 4.0 SD, 1.4 ng/mL between day 1 and year 5). Year 5 Kaplan-Meier estimated patient survival, graft survival, and rejection rates were 96.7%, 93.4%, and 26.9%, respectively. Mean eGFR and serum creatinine levels remained stable from week 4 to year 5 post transplant (eGFR, 48.3 SD, 16.9 vs 48.7 SD, 13.8 mL/min/1.73 m2, respectively; serum creatinine, 1.39 SD, 0.89 vs 1.25 SD, 0.50 mg/dL). Overall, 230 ADRs were reported in 129 (51.6%) patients. Eight patients died during follow-up.
PR-T–based immunosuppression was effective, and renal function remained stable up to 5 years post transplant in routine clinical practice in Japan. Incidence of ADRs was low, and no new safety signals were identified.
•Patient and graft 5-year survival rates were 96.7% and 93.4%, respectively, with prolonged-release tacrolimus.•Five-year kidney transplant rejection rate was 26.9%.•Prolonged-release tacrolimus supported renal function over 5 years.•The incidence of adverse drug reactions was 51.6% over 5 years.•Most adverse drug reactions (71.7%) occurred within 24 weeks post transplant.
Radiation-enhanced diffusion (RED) of copper (Cu) in iron (Fe) is essential for understanding solute/impurity diffusion in nuclear materials, especially reactor pressure vessel steel, but has been ...rarely reported experimentally. In this study, we performed a high-precision investigation of RED using well-controlled electron irradiation and three-dimensional atom probe (3D-AP). Cu-Fe diffusion pairs were created using high-purity Fe and Cu as base materials, and irradiated by 2 MeV electron at a temperature of 773 – 893 K controlled to within ±3 K. Cu diffusion into the Fe matrix was observed at the atomic level using 3D-AP, and the diffusion coefficient was obtained directly using Fick's law. RED was clearly observed, and the ratio of diffusion under irradiation to thermal diffusion was increased as the irradiation temperature decreased. RED was quantitatively evaluated using the reaction kinetics model, and the model which consider only vacancies gave a good agreement. This gave experimental clarification that RED was dominated by irradiation-induced vacancies. In addition, the direct experimental results on the effect of irradiation on the solubility limits of Cu in Fe was obtained; solubility limits under irradiation were found to be lower than those under thermal aging.
Background:
Baricitinib (BAR) and TNF antagonist are the important therapeutic agent for the treatment of rheumatoid arthritis.However there is still few studies of improvement of ultrasonographic ...findings in RA treated comparison with BAR and TNF.
Objectives:
To evaluate the clinical efficacy of BAR and TNF therapy patients with rheumatoid arthritis (RA) using ultrasonography (US).
Methods:
Participants comprised 16 and 45 Japanese RA patients who had recently received BAR and TNF. All patients with a diagnosis of RA according to the 2010 ACR/EULAR criteria. Patients underwent clinical and laboratory assessments every 4 weeks from baseline to 24 weeks, and US assessments at baseline, 4, 12 and 24 weeks. Gray scale (GS) and power doppler (PD) signals were scored using a semi-quantitative scale from 0 to 3 at 26 (0-78) synovial sites (22 joints) in the following joints: bilateral first to fifth metacarpopharangeal (MCP) joints (dorsal recess); first interphalangeal (IP) and second to fifth proximal interphalangeal (PIP) (dorsal recess) joints; and the wrists (dorsal radial, median and ulnar). We evaluated the improvement of GS and PD score from baseline to week 24.
Results:
In the patients receiving BAR (n=16) and TNF (n=45), the mean age was 55.9 vs 54.6 years old (p=0.682), disease duration was 10.2 vs 6.1 years (p=0.094), the rate of MTX use was 75% vs 89% (p=346), the mean MTX dose was 9.3 vs 10.2 mg/w (p=0.443), the rate of ACPA positive was 94% vs 82% (p=0.476), DAS28-ESR was 4.25 vs 4.61 (p=0.289), CDAI was 15.8 vs 18.5 (p=0.210), GS score was 21.6 vs 16.3 (p=0.436) and PD score was 15.0 vs 9.5 (p=0.260). The degree of improvement respective changes in GS and PD score after 4, 12 and 24 weeks were as follows: GS: -7.2 vs -3.7 (p=0.268) and PD: -7.6 vs -2.3 (p=0.158) after 4 weeks, GS: -10.9 vs -5.0 (p=0.161) and PD: -9.2 vs -3.8 (p=0.049) after 12 weeks, GS: -12.9 vs -6.1 (p=0.485) and PD: -11.3 vs -5.7 (p=0.062) after 24 weeks between BAR and TNF (Fig.1, 2). Next, The improvement rate of respective changes in GS and PD score after 4, 12 and 24 weeks were as follows: GS: -23.8% vs -11.6% (p=0.580) and PD: -30.3% vs -16.5% (p=0.343) after 4 weeks, GS: -39.6% vs -15.6% (p=0.129) and PD: -47.1% vs -30.8% (p=0.210) after 12 weeks, GS: -52.2% vs -22.2% (p=0.248) and PD: -77.1% vs -50.1% (p=0.048) after 24 weeks between BAR and TNF.
Conclusion:
The present study provides evidence supporting both the BAR and TNF therapy showed improvement effect over time, but in a comparison between BAR and TNF, the PD score of BAR showed a siginificant improvement effect compared to TNF at 12 and 24 weeks. It was suggeted that BAR may improve inflammatory synovitis earlier compared to TNF.
Disclosure of Interests:
None declared
Long-term placement of prophylactic drains may result in retrograde infections.
To investigate the association between the timing of drain removal and clinical outcomes.
This retrospective, ...single-centre cohort study evaluated 110 patients who underwent elective gastrointestinal or hepatopancreatobiliary surgery and developed subsequent organ/space surgical site infection (SSI) between 2016 and 2020. The difference between the culture-positive species of prophylactic drains and direct aspiration was evaluated; whether the prophylactic drains functioned effectively at the time of SSI diagnosis; and whether the empirical antibiotics administered before drainage were effective against all the detected bacteria. Finally, clinical outcomes were compared between early (i.e. cases wherein the prophylactic drain had already been removed or replaced at the time of SSI diagnosis) and late (removal after diagnosis) drain removal.
The prophylactic drains functioned effectively in only 27 (25%) patients at the time of SSI diagnosis. Due to the results of direct aspiration cultures, 43% of patients required antibiotic escalation. The median time to drain removal or first replacement was seven postoperative days. The early removal group included 43 patients (39%). Compared with early removal, late removal resulted in a higher frequency of vancomycin use (7.0% vs 22.4%; P = 0.037).
Prolonged prophylactic drain placement is associated with complicated infections requiring vancomycin; therefore, the drains should be removed as soon as possible. Additionally, obtaining the cultures of direct aspiration should be actively considered, as escalation of antimicrobial therapy is often performed based on culture results.
Context:
A decrease in pancreatic β-cell mass is involved in the development of type 2 diabetes.
Objective:
The purpose of this study was to evaluate the β-cell mass and the incidence of β-cell ...neogenesis, replication, and apoptosis at both the prediabetic and diabetic stages.
Methods:
We conducted a cross-sectional study of pancreatic tissues obtained from 42 patients undergoing a pancreatectomy who were classified into 4 groups: normal glucose tolerance (n = 11), impaired glucose tolerance (n = 11), newly diagnosed diabetes (n = 10), and long-standing type 2 diabetes (n = 10).
Results:
The relative β-cell area decreased and the β-cell apoptosis increased during the development of diabetes. The number of single and clustered β-cells, some of which coexpressed nestin, increased in the patients with impaired glucose tolerance and newly diagnosed diabetes. The prevalence of cells positive for both insulin and glucagon or somatostatin also increased in these patients compared with those with normal glucose tolerance. These double-positive cells were mainly localized in single and clustered β-cells, rather than large islets, and were also positive for Pdx1 or Ngn3. The percentage of insulin-positive cells embedded within ducts increased in the impaired glucose tolerance group. There were no significant differences in the incidence of cells positive for both insulin and Ki67 among the groups.
Conclusions:
These results suggest that β-cell neogenesis, rather than replication, predominates during impaired glucose tolerance and newly diagnosed diabetes in humans and may serve as a compensatory mechanism for the decreased β-cell mass.
Coronavirus disease 2019 (COVID-19) caused by human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide problem. From the standpoint of hospital infection control, determining ...the source of infection is critical. We conducted the present study to evaluate the efficacy of using whole genome sequencing to determine the source of infection in hospitalized patients who do not have a clear infectious contact history. Recently, we encountered two seemingly separate COVID-19 clusters in a tertiary hospital. Whole viral genome sequencing distinguished the two clusters according to the viral haplotype. However, the source of infection was unclear in 14 patients with COVID-19 who were clinically unlinked to clusters 1 or 2. These patients, who had no clear history of infectious contact within the hospital (‘undetermined source of infection’), had haplotypes similar to those in cluster 2 but did not have two of the mutations used to characterize cluster 2, suggesting that these 14 cases of ‘undetermined source of infection’ were not derived from cluster 2. Whole viral genome sequencing can be useful for confirming that sporadic COVID-19 cases with an undetermined source of infection are indeed not part of clusters at the institutional level.
This study investigated the safety and effectiveness of conversion from cyclosporine- to prolonged-release tacrolimus (PR-T)-based immunosuppression in kidney transplant recipients (KTRs) in Japanese ...routine clinical practice.
This was a prospective observational study of stable KTRs who were converted from cyclosporine to PR-T according to local clinical practice. Clinical data were collected up to 12 months postconversion. Study outcomes included conversion dosing ratios, PR-T dose and trough levels, change in estimated glomerular filtration rate between conversion and month 12, graft/patient survival, and rejection rate (Kaplan–Meier). Outcomes of ongoing preconversion hypertrichosis, gingival hypertrophy, and cyclosporine-related renal toxicity were detailed. Data for adverse drug reactions were collected.
Overall, 266 patients (mean ± SD age 51.9 ± 13.5 years) were included. The mean ± SD conversion ratio (PR-T:cyclosporine, mg:mg) was 0.029 ± 0.017. After an initial decrease between conversion and month 3, mean ± SD PR-T daily dose remained stable up to month 12 (2.4 ± 1.5 mg at months 3 and 12), as did tacrolimus trough blood levels (3.5 ± 1.8 vs 3.6 ± 1.7 ng/mL, respectively). Estimated glomerular filtration rate was stable over 12 months (mean ± SD change from conversion to month 12 was 0.3 ± 7.8 mL/min/1.73m2). Month 12 Kaplan–Meier patient and graft survival rates were 99.6% and 95.5%, respectively. Eight patients reported 9 rejection episodes. PR-T demonstrated potential to improve cyclosporine-related renal toxicity, hypertrichosis, and gingival hypertrophy. Postconversion, 46 adverse drug reactions were reported in 39 patients (14.7%); there was 1 death.
Conversion from cyclosporine to PR-T in Japanese stable KTRs was effective and tolerable over 12 months, with low rates of rejection reported.
•Kidney recipients were converted from cyclosporine to prolonged-release tacrolimus.•Tacrolimus trough blood levels were stable after Month 3 postconversion.•Renal function, lipid levels, and blood pressure were maintained post conversion.•Cyclosporine-related adverse events were generally improved by conversion.
STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodiumglucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus ...(T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m
2
) into four subgroups (≥90, 60 to <90, 45 to <60, and <45) and two subgroups (≥60 and <60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA
1c
), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to <90 or ≥90 mL/min/1.73 m
2
. Bodyweight and HbA1c decreased in all subgroups, the latter by − 0.91% to − 0.40% (P <0.05 vs. baseline). eGFR increased in the 45 to <60 mL/min/1.73 m
2
subgroup (+ 1.42 ± 8.77 mL/min/1.73 m
2
; P = 0.006). It decreased in the ≥90 and 60 to <90 mL/min/1.73 m
2
subgroups (− 8.27 ± 13.73 and − 1.22 ± 10.34 mL/min/1.73 m
2
; P <0.001), but not to <60 mL/min/1.73 m
2
. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA
1c
and bodyweight were observed regardless of the presence of renal impairment.
Contents
Mycotoxins may affect animal health, including reproduction. Little is known about the clinical relevance of exposure of horses to contaminated feed. This study aimed at (i) monitoring the ...levels of the mycotoxins zearalenone (ZEN), with its metabolites α‐ and β‐zearalenol (α‐ and β‐ZOL), and sterigmatocystin (STC) in urine samples from thoroughbred mares in Japan and (ii) relating these findings to the potential effects on reproductive efficacy of breeding mares. Sixty‐three urine samples of breeding mares from 59 breeding farms were used. Urine samples and reproductive records were collected from each mare when it was presented to the stallion station. Urinary concentrations of ZEN, α‐ and β‐ZOL, and STC were measured using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). ZEN, α‐ and β‐ZOL were measurable in the urine of all examined mares, indicating the prevalence of ZEN in equine feeds. In seven of the 63 samples, STC was also detected at levels ranging from 1.3 to 18.0 pg/mg creatinine. No significant correlation between the concentrations of mycotoxins and pregnancy status was observed. In conclusion, measurement of mycotoxins in urine samples is a useful non‐invasive method for monitoring the systemic exposure of mares to multiple mycotoxins.
Objectives: The purpose of this study was to evaluate the relationship between the micro-tensile bond strength to dentin and mechanical properties of the cured adhesive resins.
Methods: Coronal ...dentin surfaces of extracted human teeth were treated with four commercial self-etching priming systems (Clearfil SE Bond; UniFil Bond; Tokuso Mac-Bond II; and Imperva Fluoro Bond) and bonded with a resin composite. After 24
h storage in water at 37°C, the bonded specimens were trimmed and subjected to micro-tensile bond strength testing at a cross-head speed of 1
mm/min. Debonded surfaces were observed under a FE-SEM. For testing mechanical properties, 0.7-mm thick slabs of each adhesive resin were prepared, light-cured, and stored dry at the room temperature for 24
h. After trimming, ultimate micro-tensile strength was measured. The nano-hardness and Young's modulus were also evaluated using cured adhesives that were prepared in the same manner as described above.
Results: The micro-tensile bond strengths to dentin and ultimate micro-tensile strengths of the resins were not significantly different among all systems (
P>0.05). However, the nano-hardness and Young's modulus of Clearfil SE Bond and Imperva Fluoro Bond adhesive resins were significantly higher than those of UniFil Bond and Tokuso Mac-Bond II resins (
P<0.05). The micro-tensile bond strength significantly correlated with the ultimate micro-tensile strength of the resins (
r
2=0.77;
P<0.05), but was not correlated with the nano-hardness or Young's modulus (
P>0.05). SEM observation of the debonded surfaces revealed a mixed type of fracture with a combination of interfacial and cohesive failure within the adhesive resin.
Significance: The four self-etching priming systems exhibited similar dentin bond strengths, which also correlates with the ultimate strength of the adhesive resins.
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