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Emicizumab is a humanized bispecific antibody that mimics the cofactor function of factor VIII. In a dose-escalation study in Japanese persons with hemophilia A, including those with factor VIII inhibitors, emicizumab markedly reduced the number of bleeding episodes. Hemophilia A is a serious bleeding disorder caused by a deficiency of clotting factor VIII. Approximately 50% of patients have severe hemophilia A, 1 defined as less than 1% residual factor VIII activity (<1 IU per deciliter). 2 Such patients have severe bleeding from early childhood, and without appropriate treatment, recurrent bleeding into joints can lead to irreversible hemoarthropathy. 3 , 4 Standard treatment for hemophilia A includes regular prophylaxis and episodic treatment with recombinant or plasma-derived factor VIII. The goals of prophylaxis with factor VIII are to increase factor VIII activity to at least a moderate level (1 to 5 IU per deciliter) . . .

Background Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Methods Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. Results The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. Conclusions A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

We assessed the effects of endometrial injection of embryo culture supernatants on assisted reproductive technology (ART) outcomes in frozen-thawed embryo transfer (FET) cycles. Hormone replacement therapy cycles with blastocyst transfer on day 5 after fertilization were included, excluding cycles potentially affecting implantation. The stimulation of endometrial embryo transfer (SEET) group (118 cycles) received endometrial injections of the embryo culture supernatant, while the blastocyst transfer (BT) group (878 cycles) did not. Maternal age was significantly higher in the SEET than in the BT group ( p  < 0.05). The implantation, ongoing pregnancy, and live birth rates were significantly lower (all p  < 0.05) in the SEET than in the BT group. Clinical pregnancy and miscarriage rates were not significantly different between the groups. Age-adjusted odds ratios (ORs) (95% confidence interval [CI]) for implantation and miscarriage were 1.02(0.69–1.52) and 1.97 (1.04–3.72), respectively, in the SEET group. Multivariate analysis was performed, including female age, BMI, AMH, and other potential factors influencing ART outcomes. The adjusted odds ratios (95% CI) for clinical pregnancy and miscarriage in the SEET group were 1.00 (0.63–1.58) and 2.08 (1.02–4.24), respectively. Additionally, the adjusted odds ratio for miscarriage was 0.732 (0.22–2.47) in patients aged < 37 years and 4.63 (1.61–13.3) in those aged ≥ 37 years. In conclusion, endometrial injection of the embryo culture supernatant may adversely affect ART outcomes in FET cycles, especially in maternal age ≥ 37 years.

Full-endoscopic lumbar discectomy (FED) is one of the least invasive procedures for lumbar disc herniation. Patients who receive FED for lumbar disc herniation may develop recurrent herniation at a frequency similar to conventional procedures. Reoperation and risk factors of recurrent lumbar disc herniation were investigated among 909 patients who received FED using an interlaminar approach (FED-IL). Sixty-five of the 909 patients received reoperation for recurrent herniation. Disc height, smoking, diabetes mellitus (DM), subligamentous extrusion (SE) type, and Modic change were identified as the risk factors for recurrence. Other indicators such as LL, Cobb angle, disc migration, age, sex, and body mass index (BMI) did not reach significance. Among 65 patients, reoperation was performed within 14 days following FED-IL (very early) in 7 patients, from 15 days to 3 months (early) in 14 patients, from 3 months to 1 year (midterm) in 17 patients, and after more than 1 year (late) in 27 patients. The very early group included a greater number of males, and the mean age was significantly lower in comparison to other groups. All patients in the very early group received FED-IL for reoperation. Reoperation within 2 weeks allows FED-IL to be performed without adhesion. Fusion surgery was performed on three cases in the early and midterm groups and on 10 cases in the late group, which increased over time as degenerative change and adhesion progressed. The procedure selected to treat recurrent herniation mostly depends on the surgeon’s preference. Revision FED-IL is the first choice for recurrent herniation in terms of minimizing surgical burden, whereas fusion surgery offers the advantage that discectomy can be performed through unscarred tissues. FED-IL is recommended for recurrent herniation within 2 weeks before adhesion progresses.

Background The failure of frozen-thawed blastocysts to re-expand adequately within a few hours after warming has been reported to have a negative impact on assisted reproductive technology (ART) outcomes. However, the extent to which this failure truly affects ART outcomes has not yet been presented in a manner that is easily understandable to medical practitioners and patients. This study aimed to assess the effects of blastocyst shrinkage on ART outcomes and determine a more effective morphological evaluation approach for use in clinical settings. Methods This retrospective observational cohort study of frozen-thawed blastocyst transfer cycles was conducted from April 2017 to March 2022. Overall, 1,331 cycles were eligible for inclusion, of which 999 were good-quality blastocysts (GQB) and 332 were non-good-quality blastocysts (non-GQB). All frozen-thawed blastocyst transfer cycles performed during the specified study period were included in the study. Exclusion criteria were established to mitigate potential sources of bias as these cycles could impact implantations. We calculated rates and age-adjusted odds ratios of implantation, clinical pregnancy, ongoing pregnancy, and live birth of the re-expansion group, which showed sufficient expansion, and shrinkage group, which showed insufficient expansion. We also calculated the implantation, clinical pregnancy, ongoing pregnancy, and live birth rates of the re-expansion and shrinkage groups for each morphological scoring system parameter. Results A reduced ART outcome was observed with use of blastocysts with shrinkage after vitrification/warming. The age-adjusted odds ratios for implantation, clinical pregnancy, ongoing pregnancy, and live birth were lower in the shrinkage group than in the re-expansion group. Conclusions This study examined the adverse effect of blastocyst shrinkage after warming and recovery culturing on reproductive outcomes in a clinically useful manner by retrospectively examining a substantial number of frozen-thawed embryo transfer cycles. The study findings can possibly reduce concerns regarding over- or under-estimation of blastocyst implantation by allowing providers and patients to refer to the data.

Strigolactones (SLs), a group of plant hormones, induce germination of root-parasitic plants and inhibit shoot branching in many plants. Shoot branching is an important trait that affects the number and quality of flowers and fruits. Root-parasitic plants, such as Phelipanche spp., infect tomato roots and cause economic damage in Europe and North Africa—hence why resistant tomato cultivars are needed. In this study, we found carotenoid cleavage dioxygenase 8-defective mutants of Micro-Tom tomato (slccd8) by the “targeting induced local lesions in genomes” (TILLING) method. The mutants showed excess branching, which was suppressed by exogenously applied SL. Grafting shoot scions of the slccd8 mutants onto wild-type (WT) rootstocks restored normal branching in the scions. The levels of endogenous orobanchol and solanacol in WT were enough detectable, whereas that in the slccd8 mutants were below the detection limit of quantification analysis. Accordingly, root exudates of the slccd8 mutants hardly stimulated seed germination of root parasitic plants. In addition, SL deficiency did not critically affect the fruit traits of Micro-Tom. Using a rhizotron system, we also found that Phelipanche aegyptiaca infection was lower in the slccd8 mutants than in wild-type Micro-Tom because of the low germination. We propose that the slccd8 mutants might be useful as new tomato lines resistant to P. aegyptiaca.

Strigolactones (SLs), a group of plant hormones, induce germination of root-parasitic plants and inhibit shoot branching in many plants. Shoot branching is an important trait that affects the number and quality of flowers and fruits. Root-parasitic plants, such as Phelipanche spp., infect tomato roots and cause economic damage in Europe and North Africa-hence why resistant tomato cultivars are needed. In this study, we found carotenoid cleavage dioxygenase 8-defective mutants of Micro-Tom tomato (slccd8) by the \"targeting induced local lesions in genomes\" (TILLING) method. The mutants showed excess branching, which was suppressed by exogenously applied SL. Grafting shoot scions of the slccd8 mutants onto wild-type (WT) rootstocks restored normal branching in the scions. The levels of endogenous orobanchol and solanacol in WT were enough detectable, whereas that in the slccd8 mutants were below the detection limit of quantification analysis. Accordingly, root exudates of the slccd8 mutants hardly stimulated seed germination of root parasitic plants. In addition, SL deficiency did not critically affect the fruit traits of Micro-Tom. Using a rhizotron system, we also found that Phelipanche aegyptiaca infection was lower in the slccd8 mutants than in wild-type Micro-Tom because of the low germination. We propose that the slccd8 mutants might be useful as new tomato lines resistant to P. aegyptiaca.Strigolactones (SLs), a group of plant hormones, induce germination of root-parasitic plants and inhibit shoot branching in many plants. Shoot branching is an important trait that affects the number and quality of flowers and fruits. Root-parasitic plants, such as Phelipanche spp., infect tomato roots and cause economic damage in Europe and North Africa-hence why resistant tomato cultivars are needed. In this study, we found carotenoid cleavage dioxygenase 8-defective mutants of Micro-Tom tomato (slccd8) by the \"targeting induced local lesions in genomes\" (TILLING) method. The mutants showed excess branching, which was suppressed by exogenously applied SL. Grafting shoot scions of the slccd8 mutants onto wild-type (WT) rootstocks restored normal branching in the scions. The levels of endogenous orobanchol and solanacol in WT were enough detectable, whereas that in the slccd8 mutants were below the detection limit of quantification analysis. Accordingly, root exudates of the slccd8 mutants hardly stimulated seed germination of root parasitic plants. In addition, SL deficiency did not critically affect the fruit traits of Micro-Tom. Using a rhizotron system, we also found that Phelipanche aegyptiaca infection was lower in the slccd8 mutants than in wild-type Micro-Tom because of the low germination. We propose that the slccd8 mutants might be useful as new tomato lines resistant to P. aegyptiaca.

Anemia is common among young women, and iron deficiency is one of the leading causes. In Europe and the US, the iron fortification of flour increased oral iron intake and decreased anemia prevalence from 30% to 10%. The National Nutrition Survey in Japan revealed that anemia prevalence among young Japanese women is increasing; however, no nationwide preventive policy has been aimed at iron deficiency anemia. The endpoint of this study was the estimation of anemia prevalence among healthy Japanese woman, based on a large sample size. We collected data from the consecutive check-up examination records of apparently healthy women (n = 13,147). We defined hemoglobin lower than 12 g/dL as anemia, hemoglobin lower than 10 g/dL as severe anemia, and a mean corpuscular volume lower than 80 fl as microcytic anemia. Of the 13,147 persons, anemia was identified in 2331 (17.3 %), and severe and microcytic anemia in 438 (3.3 %) and 700 (5.2 %), respectively. Among women younger than 50 years, anemia was identified in 22.3 %, and 25.2 % of them had severe anemia. In conclusion, the prevalence of anemia and severe anemia among young women is high in Japan. Some action needs to be considered to improve women's quality of life.

In today's highly globalised world, protecting human security is a core challenge for political leaders who are simultaneously dealing with terrorism, refugee and migration crises, disease epidemics, and climate change. Promoting universal health coverage (UHC) will help prevent another disease outbreak similar to the recent Ebola outbreak in west Africa, and create robust health systems, capable of withstanding future shocks. Robust health systems, in turn, are the prerequisites for achieving UHC. We propose three areas for global health action by the G7 countries at their meeting in Japan in May, 2016, to protect human security around the world: restructuring of the global health architecture so that it enables preparedness and responses to health emergencies; development of platforms to share best practices and harness shared learning about the resilience and sustainability of health systems; and strengthening of coordination and financing for research and development and system innovations for global health security. Rather than creating new funding or organisations, global leaders should reorganise current financing structures and institutions so that they work more effectively and efficiently. By making smart investments, countries will improve their capacity to monitor, track, review, and assess health system performance and accountability, and thereby be better prepared for future global health shocks.