Aim
Dapagliflozin is a selective sodium‐glucose co‐transporter 2 (SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of ...dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control.
Methods
Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and proportion of patients achieving HbA1c <7.0% at week 12.
Results
Significant reductions in HbA1c were seen with all dapagliflozin doses (−0.11 to −0.44%) versus placebo (+0.37%). Reductions were also observed in FPG with dapagliflozin (−0.87 to −1.77 mmol/l −15.61 to −31.94 mg/dl) versus placebo (+0.62 mmol/l +11.17 mg/dl). No significant difference in the proportion of patients achieving HbA1c levels <7.0% was noted with dapagliflozin versus placebo. Adverse events (AEs) were more frequent with dapagliflozin (40.7–53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5 mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 0–3.8 and 0–1.8% respectively with dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed.
Conclusions
Compared with placebo, dapagliflozin significantly reduced hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control.
To comprehensively evaluate diagnostic algorithms for myocardial infarction using a high-sensitivity cardiac troponin I (hs-cTnI) assay.
We prospectively enrolled patients with suspected myocardial ...infarction without ST-segment elevation from nine emergency departments in Japan. The diagnostic algorithms evaluated: (i) based on hs-cTnI alone, such as the European Society of Cardiology (ESC) 0/1-h or 0/2-h and High-STEACS pathways; or (ii) used medical history and physical findings, such as the ADAPT, EDACS, HEART, and GRACE pathways. We evaluated the negative predictive value (NPV), sensitivity as safety measures, and proportion of patients classified as low or high-risk as an efficiency measure for a primary outcome of type 1 myocardial infarction or cardiac death within 30 days.
We included 437 patients, and the hs-cTnI was collected at 0 and 1 hours in 407 patients and at 0 and 2 hours in 394. The primary outcome occurred in 8.1% (33/407) and 6.9% (27/394) of patients, respectively. All the algorithms classified low-risk patients without missing those with the primary outcome, except for the GRACE pathway. The hs-cTnI-based algorithms classified more patients as low-risk: the ESC 0/1-h 45.7%; the ESC 0/2-h 50.5%; the High-STEACS pathway 68.5%, than those using history and physical findings (15-30%). The High-STEACS pathway ruled out more patients (20.5%) by hs-cTnI measurement at 0 hours than the ESC 0/1-h and 0/2-h algorithms (7.4%).
The hs-cTnI algorithms, especially the High-STEACS pathway, had excellent safety performance for the early diagnosis of myocardial infarction and offered the greatest improvement in efficiency.
A novel direct core heating fusion process is introduced, in which a preimploded core is predominantly heated by energetic ions driven by LFEX, an extremely energetic ultrashort pulse laser. ...Consequently, we have observed the D(d,n)^{3}He-reacted neutrons (DD beam-fusion neutrons) with the yield of 5×10^{8} n/4π sr. Examination of the beam-fusion neutrons verified that the ions directly collide with the core plasma. While the hot electrons heat the whole core volume, the energetic ions deposit their energies locally in the core, forming hot spots for fuel ignition. As evidenced in the spectrum, the process simultaneously excited thermal neutrons with the yield of 6×10^{7} n/4π sr, raising the local core temperature from 0.8 to 1.8 keV. A one-dimensional hydrocode STAR 1D explains the shell implosion dynamics including the beam fusion and thermal fusion initiated by fast deuterons and carbon ions. A two-dimensional collisional particle-in-cell code predicts the core heating due to resistive processes driven by hot electrons, and also the generation of fast ions, which could be an additional heating source when they reach the core. Since the core density is limited to 2 g/cm^{3} in the current experiment, neither hot electrons nor fast ions can efficiently deposit their energy and the neutron yield remains low. In future work, we will achieve the higher core density (>10 g/cm^{3}); then hot electrons could contribute more to the core heating via drag heating. Together with hot electrons, the ion contribution to fast ignition is indispensable for realizing high-gain fusion. By virtue of its core heating and ignition, the proposed scheme can potentially achieve high gain fusion.
Recently, more and more generic drugs have been used for immunosuppressive drugs in the field of organ transplantation. Some reports have indicated that blood concentration of most generic drugs is ...difficult to maintain stability, and it may cause the difference in graft survival of transplanted organs between original drugs and generic drugs. In this article, we report the cases could not maintain blood concentration of generic drugs of mycophenolate mofetil (MMF).
In 4 cases out of 5 cases that we had to change original MMF to generic MMF, there were cases that blood concentration level was not stabilized. There were possibility that the lowered blood concentration level of MMF caused a rejection, in two cases. Mean MMF trough level was decreased from 3.6 ± 1.9 μg/mL to 0.6 ± 0.4 μg/mL. Due to the early detection, it did not become severe or failure of graft function, however, we cannot deny the possibilities that side effects were increased and rejection rose. In these cases, we discontinued to use the generic drugs thereafter due to unstable plasma concentration of MMF.
Some reports have indicated that failure to maintain plasma concentration of MMF leads to rejection. Therefore, maintenance of effective plasma concentration and prevention of rejection are essential to long-term graft survival in kidney transplant.
Generic drug formulations may exhibit differences in effects and absorption compared to the brand-name drug. If the generic drug should be used, patients should be closely monitored.
•We report 4 cases in which patients treated with generic MMF did not maintain sufficient MMF blood concentration levels.•Conversion to the generic drug may cause differences in effects and absorption.•If the generic drug should be used, patients should be closely monitored.
Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age‐specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model ...and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon‐γ cytokine production and promote interleukin‐10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin‐2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC‐treated murine and human CD4+ T cells demonstrated an age‐specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC‐treated mice, suggesting that TAC age‐specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age‐specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age‐specific effects when using TAC.
Tacrolimus shows age‐specific immunosuppressive characteristics linked to effects on calcineurin signaling in both old murine and human T cells, providing a novel insight into age‐adapted immunosuppression.
A tailored-pulse-imploded core with a diameter of 70 μm is flashed by counterirradiating 110 fs, 7 TW laser pulses. Photon emission (>40 eV) from the core exceeds the emission from the imploded ...core by 6 times, even though the heating pulse energies are only one seventh of the implosion energy. The coupling efficiency from the heating laser to the core using counterirradiation is 14% from the enhancement of photon emission. Neutrons are also produced by counterpropagating fast deuterons accelerated by the photon pressure of the heating pulses. A collisional two-dimensional particle-in-cell simulation reveals that the collisionless two counterpropagating fast-electron currents induce mega-Gauss magnetic filaments in the center of the core due to the Weibel instability. The counterpropagating fast-electron currents are absolutely unstable and independent of the core density and resistivity. Fast electrons with energy below a few MeV are trapped by these filaments in the core region, inducing an additional coupling. This might lead to the observed bright photon emissions.
Oxygenation is necessary for aerobic metabolism, which maintains adenosine triphosphate within the graft organ. In recent years, some studies have demonstrated that subnormothermic machine perfusion ...(SNMP) with hemoglobin-based oxygen carriers has the potential to improve oxygen metabolism.
The aim of this study was to evaluate the effectiveness of perfusate with human-derived hemoglobin vesicles (HbV) under SNMP in a pig model of donation after cardiac death.
In this study, pig livers were procured with a warm ischemic time of 60 minutes and were preserved in 3 groups for 240 minutes. The preservation conditions were as follows: 4°C cold storage (Group 1); SNMP with University of Wisconsin perfusate alone (Group 2); and SNMP (21°C) with University of Wisconsin solution and HbV (hemoglobin, 0.6 mg/dL) perfusate (Group 3). All livers were perfused for 120 minutes using pig autologous blood machine perfusion (reperfusion phase). We investigated the aspartate transaminase level and hemodynamics (portal vein resistance and oxygen consumption) in the preservation and reperfusion phases. A histologic study (hematoxylin-eosin staining) was performed after 240 minutes of preservation.
The portal vein resistance of Group 3 was not increased in comparison with Group 2. During preservation, the oxygen consumption of Group 3 was higher than that of Group 2. However, the level of aspartate transaminase did not differ between Groups 2 and 3.
The present study revealed that perfusate with HbV increased the oxygen consumption of the donor liver during SNMP.
•Hemoglobin vesicles (HbV) is a human-derived oxygen carrier.•We evaluated the effectiveness of perfusate with HbV.•Pig liver after cardiac arrest was preserved under subnormothermic machine perfusion.•The perfusate with HbV increased the oxygen consumption during machine perfusion.
We investigated the efficacy of cord blood transplantation (CBT) for adult acute lymphoblastic leukemia (ALL) by reviewing medical records of 256 patients reported to the Japan Cord Blood Bank ...Network between June 1997 and August 2006. Cumulative incidence of neutrophil engraftment at day 100 was 78%. Infused CD34-positive cell dose (>1 × 10(5) cells/kg) was associated with successful neutrophil engraftment. Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 37%. A 2-year disease-free and overall survival (OS) rates were 36% and 42%, respectively. Multivariate analysis showed that age (51 or older vs younger than 50) (hazard ratio 1.9, 95% confidence interval (CI), 1.3-2.8, P=0.001), disease status (non-remission vs remission) (hazard ratio 2.2, 95% CI, 1.5-3.2, P<0.0001), grade III-IV acute GVHD (hazard ratio 2.0, 95% CI, 1.2-3.2, P=0.006) and absence of chronic GVHD (hazard ratio 2.4, 95% CI, 1.1-5.1, P=0.02) were negatively associated with OS. CBT is effective for some patients with advanced ALL. It is worth considering for further evaluation.
Much controversy exists over the performance of elderly living donor kidney transplantation. We report the safety of 2 cases of elderly living kidney donations in our hospital.
An 82-year-old man was ...a living kidney donor for his 56-year-old son. The donor suffered from hypertension, but has successfully managed his blood pressure with only one medication. His serum creatinine was 0.7 mg/dL and inulin clearance was 122.5 mL/min, which met the usual criteria for living kidney donors. This was his son's secondary kidney transplantation, and no other donors existed.
An 80-year-old woman was a living kidney donor for her 45-year-old son. Her serum creatinine was 0.61 mg/dL and inulin clearance was 71.7 mL/min, which met the marginal kidney donor criteria.
In both cases, we determined that the donor kidney function was acceptable. Though we explained the risks of the transplantation thoroughly, the patients' strong will to offer a kidney to their family member did not change. We decided to carry out the transplantation. At the time of publication, nearly 2 years have passed since the transplantation, but both donors and recipients are doing well.
In the future, it seems more likely that the number of elderly living donor kidney transplantation will rise. On one hand, there is no absolute contraindication for elderly donors, while on the other hand, the criteria for a living kidney donor must be strictly examined. Furthermore, careful observation of both donors and recipients after transplantation is required.
•We report on the safety of elderly living kidney donors in 2 cases.•Both donors and recipients were doing well approximately 2 years postoperation.•Our case series can contribute to expansion of the donor criteria.
Fast heating is a method of heating an assembled high-density plasma into a hot state by irradiating it with short-duration (sub-picosecond), high-intensity (>1018 W cm−2) laser pulses before the ...plasma expands and dissolves hydrodynamically. In this paper, we present detailed experimental results of fast heating fuel assembled in a spherical deuterated polystyrene shell target of 500 μm diameter and 7 μm thickness with counterbeam illumination by using a HAMA 1 Hz, 5.9 J inertial confinement fusion laser driver with pulse tailoring. These tailored pulses contain three pulses in sequence: a 'foot' pulse of 2.4 J/25 ns, a 'spike' pulse of 0.5 J/300 ps and a 'heater' pulse of 0.4 J/110 fs; these pulses are designed to assemble the fuel and heat it. By varying the energy of the foot pulse, we find that fast heating the fuel is achieved only if the fuel is weakly ablated by the foot pulse and then shock-assembled by the spike pulse into the target centre so that the heater pulse can access the fuel with a focal intensity greater than 1018 W cm−2. Without a foot pulse, the heater pulse contributes to assembling the fuel. For higher foot-pulse energies, the heater pulse drives a hydrodynamic motion with speeds of the order 107 cm s−1 with intensities of the order 1017 W cm−2, resulting in re-assembling and additional heating of the pre-assembled fuel. Once a shock-assembled core is achieved at the target centre, we succeed qualitatively in fast heating the core for shots in sequence with variations of laser energy within 18%. The coupling efficiency from the heating laser to the core is inferred to be (10±2)% in total: (8±1.6)% for the ionized bulk electrons and (2±0.4)% for the bulk ions. The fusion neutron spectrum detected on the laser axis exhibits peaks at 1.0 MeV, 1.7 MeV and 3.8 MeV. These peaks are attributed to the C(d,n)13N and d(d,n)3He reactions induced by counterpropagating fast deuterons accelerated by the photon pressure of the heating pulses.
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