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The size of soft colloids (microgels) is essential; however, control over their size has typically been established empirically. Herein, we report a linear-regression model that can predict microgel size using a machine learning method, sparse modeling for small data, which enables the determination of the synthesis conditions for target-sized microgels.
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Therapeutic drug monitoring (TDM) is a personalized treatment approach that involves optimizing drug dosages based on patient-specific factors, such as drug plasma concentrations, therapeutic efficacy, or adverse reactions. The plasma concentration of drugs is determined using liquid chromatography/tandem mass spectrometry (LC-MS/MS) or various immunoassays. Compared with immunoassays, LC-MS/MS requires more pretreatment time as the number of samples increases. Recently, fully automated pretreatment LC-MS/MS systems have been developed to automatically perform whole-sample pretreatment for LC-MS/MS analysis. In this study, we developed a method for simultaneous concentration determination of five analytes (clozapine, mycophenolic acid, sunitinib, N-desethylsunitinib, and voriconazole) using LC-MS/MS for clinical TDM using a fully automated LC-MS/MS pretreatment system. In the developed method, the intra- and inter-assay relative error (RE) values ranged between -14.8% and 11.3%; the intra- and inter-assay coefficient of variation (CV) values were <8.8% and <10.5%, respectively. The analytes showed good stability, with RE values ranging between -13.6% and 10.9% and CV values <8.9%. Furthermore, the plasma concentrations in clinical samples using this method and the conventional manual pretreatment method showed similar results. Therefore, the method developed in this study could be considered a useful pretreatment method for routine TDM in patients.
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Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6ß-hydroxycortisol, deoxycholic acid, and 1ß-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.
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Biomarcadores , Citocromo P-450 CYP3A , Monitoreo de Drogas , Compuestos de Fenilurea , Quinolinas , Humanos , Compuestos de Fenilurea/orina , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/sangre , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Femenino , Quinolinas/orina , Quinolinas/uso terapéutico , Quinolinas/sangre , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Anciano , Persona de Mediana Edad , Masculino , Biomarcadores/orina , Biomarcadores/sangre , Monitoreo de Drogas/métodos , Adulto , Anciano de 80 o más Años , Antineoplásicos/orina , Antineoplásicos/uso terapéutico , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Inhibidores de Proteínas Quinasas/orina , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias/sangre , Neoplasias/orina , Espectrometría de Masas en Tándem/métodos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/orina , Neoplasias Endometriales/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/orina , Cromatografía Liquida/métodos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/orina , Neoplasias de la Tiroides/sangre , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/orina , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/orina , Carcinoma de Células Renales/sangreRESUMEN
BACKGROUND: The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan. METHODS: Between 2002 and 2004, 632 IgAN patients with ≥ 0.5 g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99 g/day; n = 264), moderate (1.00-1.99 g/day, n = 216), or severe (≥ 2.00 g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3 years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy. RESULTS: The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively). CONCLUSION: TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.
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Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Monitoreo de Drogas , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Sulfonamidas/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Masculino , Adulto Joven , Persona de Mediana Edad , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Femenino , Citocromo P-450 CYP3A/metabolismo , Ciclosporina/administración & dosificación , Triazoles/administración & dosificación , Antineoplásicos/administración & dosificaciónRESUMEN
The increased risk of adverse drug reactions due to the concomitant use of antipsychotics is problematic in the treatment of schizophrenia. Therefore, the simultaneous analysis of their plasma concentrations is required. In this study, we developed a simultaneous liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for analyzing plasma antipsychotics approved in Japan for therapeutic drug monitoring (TDM) applications. First, we counted the prescriptions for 16 antipsychotics and concomitant drugs used at the Tohoku University Hospital. LC-MS/MS was used for the simultaneous analysis of 16 antipsychotics and four drug metabolites. This analysis was conducted using a combination of selected reaction monitoring mode and reversed-phase chromatography. Following the examination of the MS/MS and LC conditions, an analytical method validation test was conducted. The developed method was used to analyze plasma antipsychotic levels in patients with schizophrenia. One-third of the patients received treatment with multiple antipsychotics. Under LC-MS/MS conditions, LC separation was performed using a combination of a C18 column and ammonium formate-based mobile phases with a gradient flow. The calibration curves were optimized by adjusting the ion abundance, and 11 compounds met the criteria for intra- and inter-day reproducibility tests. Some stability test results did not meet these criteria; therefore, further investigation is required. The developed method permitted the measurement of all the plasma parameters, including concentrations above the therapeutic range. Therefore, this method may be useful in the daily TDM practice of antipsychotics.
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Antipsicóticos , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Antipsicóticos/sangre , Japón , Humanos , Cromatografía Liquida/métodos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/sangre , Monitoreo de Drogas/métodos , Análisis Químico de la Sangre/métodos , Cromatografía Líquida con Espectrometría de MasasRESUMEN
The development of targeted cancer therapies based on monoclonal antibodies against tumor-associated antigens has progressed markedly over recent decades. This approach is dependent on the identification of tumor-specific, normal tissue-sparing antigenic targets. The transmembrane protein claudin-18 splice variant 2 (CLDN18.2) is frequently and preferentially displayed on the surface of primary gastric adenocarcinomas, making it a promising monoclonal antibody target. Phase 3 studies of zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody targeting CLDN18.2, combined with 5-fluorouracil/leucovorin plus oxaliplatin (modified FOLFOX6) or capecitabine plus oxaliplatin (CAPOX) in advanced or metastatic first-line gastric or gastroesophageal junction (G/GEJ) adenocarcinoma have demonstrated favorable clinical results with zolbetuximab. In studies using xenograft or syngeneic models with gastric cancer cell lines, zolbetuximab mediated death of CLDN18.2-positive human cancer cell lines via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro and demonstrated anti-tumor efficacy as monotherapy and combined with chemotherapy in vivo. Mice treated with zolbetuximab plus chemotherapy displayed a significantly higher frequency of tumor-infiltrating CD8+ T cells versus vehicle/isotype control-treated mice. Furthermore, zolbetuximab combined with an anti-mouse programmed cell death-1 antibody more potently inhibited tumor growth compared with either agent alone. These results support the potential of zolbetuximab as a novel treatment option for G/GEJ adenocarcinoma.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Claudinas , Neoplasias Gástricas , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/inmunología , Animales , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ratones , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Modelos Animales de Enfermedad , Ensayos Antitumor por Modelo de Xenoinjerto , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacosRESUMEN
The need to manufacture components out of copper is significantly increasing, particularly in the solar technology, semiconductor, and electric vehicle sectors. In the past few decades, infrared laser (IR) and green laser (GL) have been the primary technologies used to address this demand, especially for small or thin components. However, with the increased demand for energy saving, alternative joint techniques such as blue diode laser (BDL) are being actively explored. In this paper, bead-on-plate welding experiments on 0.2 mm thick pure copper samples employing a BDL are presented. Two sets of parameters were carefully selected in this investigation, namely Cu-1: Power (P) = 200 W; Speed (s) = 1 mm/s; and angle = 0°, and Cu-2: P = 200 W; s = 5 mm/s; and angle = 10°. The results from both sets of parameters produced defect-free full penetration welds. Hardness test results indicated relatively softer weld zones compared with the base metal. Tensile test samples fractured in the weld zones. Overall, the samples welded with Cu-1 parameters showed better mechanical properties, such as strength and elongation, than those welded with the Cu-2 parameters. The tensile strength and elongation obtained from Cu-1 were marginally lower than those of the unwelded pure copper. The outcomes from this research provide an alternative welding technique that is able to produce reliable, strong, and precise joints, particularly for small and thin components, which can be very challenging to produce.
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The fastening mechanics of prosthetic screws under various conditions is crucial to the maintenance of dental implants. This study comprehensively explores the prosthetic screw rupture in titanium (Ti) and zirconia (ZrO2) superstructures under wet and dry conditions. Superstructures were fabricated using digital technology and subjected to tightening torque trials. Experimental results suggested that the implications of the conventionally recommended torque of 15 Nâ¢cm differ significantly between dry and wet environments. Both Ti and ZrO2 exhibited preloads of >30 Nâ¢cm under dry conditions; however, differences emerged under wet conditions. In addition, screw rupture posed a prominent clinical challenge -particularly during long-term cyclic loading. Notably, the ZrO2 superstructures exhibited a greater resistance to breaking torque than that of Ti. This study underscores the importance of reevaluating torque recommendations with consideration to the distinct characteristics of Ti and ZrO2 in diverse environments.
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Tornillos Óseos , Ensayo de Materiales , Titanio , Torque , Circonio , Circonio/química , Titanio/química , Análisis del Estrés Dental , Implantes Dentales , Propiedades de Superficie , Fracaso de la Restauración Dental , Materiales Dentales/químicaRESUMEN
We conducted a randomized phase 3 study to investigate the efficacy and safety of GH treatment in prepubertal Japanese patients with short stature due to SHOX deficiency. The patients were randomly allocated to the GH-GH group (n = 10), in which the patients were treated with GH (0.35 mg/kg/wk) subcutaneously once daily for 24 mo, or the no-treatment (NT)-GH group (n = 9), in which the patients were untreated for the first 12 mo and then administered the same dosage of GH for the next 12 mo. At month 12, the ∆height standard deviation score (SDS) for chronological age (CA) and serum IGF-1 level were significantly higher in the GH-GH group than those in the NT-GH group. In contrast, bone age (BA) and ΔBA/ΔCA were numerically higher in the GH-GH group but were not statistically significant. At month 24, these parameters were comparable between the two groups. The height velocity was significantly larger in the GH-GH group during the first year and in the NT-GH group during the second year. No serious adverse drug reactions were observed; however, one patient in the GH-GH group exhibited increased insulin resistance at month 24. These results indicated that GH is a promising treatment option for short stature in patients with SHOX deficiency.
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Assistive medical image classifiers can greatly reduce the workload of medical personnel. However, traditional machine learning methods require large amounts of well-labeled data and long learning times to solve medical image classification problems, which can lead to high training costs and poor applicability. To address this problem, a novel unsupervised breast cancer image classification model based on multiscale texture analysis and a dynamic learning strategy for mammograms is proposed in this paper. First, a gray-level cooccurrence matrix and Tamura coarseness are used to transfer images to multiscale texture feature vectors. Then, an unsupervised dynamic learning mechanism is used to classify these vectors. In the simulation experiments with a resolution of 40 pixels, the accuracy, precision, F1-score and AUC of the proposed method reach 91.500%, 92.780%, 91.370%, and 91.500%, respectively. The experimental results show that the proposed method can provide an effective reference for breast cancer diagnosis.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Aprendizaje Automático , Mamografía , Simulación por ComputadorRESUMEN
BACKGROUND: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers' experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews. METHODS: Semi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience. RESULTS: Seven caregivers from 16 trial sites participated, representing seven children aged 8-18 years who had received pabinafusp alfa for 3.3-3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa. CONCLUSION: Caregivers' perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa's potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.
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Iduronato Sulfatasa , Mucopolisacaridosis II , Masculino , Niño , Humanos , Mucopolisacaridosis II/tratamiento farmacológico , Cuidadores/psicología , Calidad de Vida , Japón , Iduronato Sulfatasa/uso terapéutico , Terapia de Reemplazo Enzimático/métodos , Enfermedades Raras/tratamiento farmacológicoRESUMEN
OBJECTIVES: There is concern that hydroxyzine exacerbates delirium, but a recent preliminary study suggested that the combination of haloperidol and hydroxyzine was effective against delirium. This study examined whether the concomitant use of hydroxyzine and haloperidol worsened delirium in patients with cancer. METHODS: This retrospective, observational study was conducted at 2 general hospitals in Japan. The medical records of patients with cancer who received haloperidol for delirium from July to December 2020 were reviewed. The treatments for delirium included haloperidol alone or haloperidol combined with hydroxyzine. The primary outcome was the duration from the first day of haloperidol administration to the resolution of delirium, defined as its absence for 2 consecutive days. The time to delirium resolution was analyzed to compare the haloperidol group and hydroxyzine combination group using the log-rank test with the Kaplan-Meier method. Secondary outcomes were (1) the total dose of antipsychotic medications, including those other than haloperidol (measured in chlorpromazine-equivalent doses), and (2) the frequencies of detrimental incidents during delirium, specifically falls and self-removal of drip infusion lines. The unpaired t-test and Fisher's exact test were used to analyze secondary outcomes. RESULTS: Of 497 patients who received haloperidol, 118 (23.7%) also received hydroxyzine. No significant difference in time to delirium resolution was found between the haloperidol group and the hydroxyzine combination group (log-rank test, P = 0.631). No significant difference between groups was found in either chlorpromazine-equivalent doses or the frequency of detrimental incidents. SIGNIFICANCE OF RESULTS: This study showed that the concomitant use of hydroxyzine and haloperidol did not worsen delirium in patients with cancer.
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A critical degree of podocyte depletion causes glomerulosclerosis, and persistent podocyte loss in glomerular diseases drives the progression to end-stage kidney disease. The extent of podocyte injury at a point in time can be histologically assessed by measuring podocyte number, size, and density ("Biopsy podometrics"). However, repeated invasive renal biopsies are associated with increased risk and cost. A noninvasive method for assessing podocyte injury and depletion is required. Albuminuria and proteinuria do not always correlate with disease activity. Podocytes are located on the urinary space side of the glomerular basement membrane, and as they undergo stress or detach, their products can be identified in urine. This raises the possibility that urinary podocyte products can serve as clinically useful markers for monitoring glomerular disease activity and progression ("Urinary podometrics"). We previously reported that urinary sediment podocyte mRNA reflects disease activity in both animal models and human glomerular diseases. This includes diabetes and hypertension which together account for 60% of new-onset dialysis induction patients. Improving approaches to preventing progression is an urgent priority for the renal community. Sufficient evidence now exists to indicate that monitoring urinary podocyte markers could serve as a useful adjunctive strategy for determining the level of current disease activity and response to therapy in progressive glomerular diseases.
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Biomarcadores , Podocitos , Podocitos/patología , Humanos , Biomarcadores/orina , Animales , Insuficiencia Renal Crónica/orina , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/diagnóstico , Progresión de la Enfermedad , Proteinuria/orina , Proteinuria/etiología , Lesión Renal Aguda/orina , Lesión Renal Aguda/patología , Lesión Renal Aguda/terapia , Lesión Renal Aguda/etiologíaRESUMEN
Unreasonable medical fees can cause problems such as increased medical costs, greater medical disparities, decreased medical standards, and physician shortages. To prevent such problems, it is important to set appropriate medical fees, ensure their proper use, and improve the efficiency of medical care. The treatment of patients with maxillofacial defects is generally more expensive compared with general prosthodontic treatment because it involves more materials and requires more frequently follow-ups for longer period. However, the actual time required for maxillofacial prosthetic treatment is unclear. Therefore, in this study, we aimed to clarify the amount of time spent treating maxillofacial prosthetic patients. We analyzed clinical data from patients undergoing routine maxillofacial prosthetic treatment, irrespective of difficulty level, at 8 university hospitals and 2 dental clinics. We also collected data from maxillofacial prosthodontists on the treatment time required for various Japanese health insurance items, including the fabrication of maxillofacial prostheses. The results revealed that some aspects of maxillofacial prosthetic treatment may take longer to perform and are more costly to perform than previously thought, suggesting the need for some adjustments to the health insurance reimbursement system. Maintaining an appropriate balance between expenditures and fees will greatly benefit patients and physicians, ensuring positive health outcomes and a healthy society.
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Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.
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Mucopolisacaridosis I , Humanos , Mucopolisacaridosis I/terapia , Mucopolisacaridosis I/tratamiento farmacológico , Iduronidasa/efectos adversos , Iduronidasa/genética , Iduronidasa/metabolismo , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Receptores de Transferrina/genética , Heparitina Sulfato/metabolismoRESUMEN
Iron deficiency/excess may be associated with worse prognosis in patients undergoing hemodialysis. This study ascertained the association of the estimated total body iron (TBI) with mortality in patients receiving hemodialysis. Multicenter clinical data collected in the Miyazaki Dialysis Cohort Study from 943 patients receiving hemodialysis were analyzed after stratification into tertile categories by baseline TBI-estimated as the heme iron plus iron storage from ferritin levels. The primary outcome was a 5-year all-cause mortality; hazard ratios of the TBI-all-cause mortality association were estimated using Cox models adjusted for potential confounders, including clinical characteristics, laboratory, and drug data, wherein patients with high TBI were the reference category. The receiver operating characteristic (ROC) curve analyses of TBI, serum ferritin levels, and transferrin saturation were performed to predict all-cause mortality; a total of 232 patients died during the follow-up. The low TBI group (<1.6 g) had significantly higher hazard ratios of mortality than the high TBI group (≥2.0 g). As ROC curve analyses showed, TBI predicted mortality more accurately than either levels of serum ferritin or transferrin saturation. Lower TBI increases the mortality risk of Japanese hemodialysis patients, and further studies should examine whether iron supplementation therapy that avoids low TBI improves prognosis.
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Hierro , Fallo Renal Crónico , Mortalidad , Humanos , Estudios de Cohortes , Pueblos del Este de Asia , Ferritinas , Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Transferrina/análisis , TransferrinasRESUMEN
High-dimensional optimization presents a novel challenge within the realm of intelligent computing, necessitating innovative approaches. When tackling high-dimensional spaces, traditional evolutionary tools often encounter pitfalls, including dimensional catastrophes and a propensity to become trapped in local optima, ultimately compromising result accuracy. To address this issue, we introduce the Pair Barracuda Swarm Optimization (PBSO) algorithm in this paper. PBSO employs a unique strategy for constructing barracuda pairs, effectively mitigating the challenges posed by high dimensionality. Furthermore, we enhance global search capabilities by incorporating a support barracuda alongside the leading barracuda pair. To assess the algorithm's performance, we conduct experiments utilizing the CEC2017 standard function and compare PBSO against five state-of-the-art natural-inspired optimizers in the control group. Across 29 test functions, PBSO consistently secures top rankings with 9 first-place, 13 second-place, 5 third-place, 1 fourth-place, and 1 fifth-place finishes, yielding an average rank of 2.0345. These empirical findings affirm that PBSO stands as the superior choice among all test algorithms, offering a dependable solution for high-dimensional optimization challenges.
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High-dimensional optimization has numerous potential applications in both academia and industry. It is a major challenge for optimization algorithms to generate very accurate solutions in high-dimensional search spaces. However, traditional search tools are prone to dimensional catastrophes and local optima, thus failing to provide high-precision results. To solve these problems, a novel hermit crab optimization algorithm (the HCOA) is introduced in this paper. Inspired by the group behaviour of hermit crabs, the HCOA combines the optimal search and historical path search to balance the depth and breadth searches. In the experimental section of the paper, the HCOA competes with 5 well-known metaheuristic algorithms in the CEC2017 benchmark functions, which contain 29 functions, with 23 of these ranking first. The state of work BPSO-CM is also chosen to compare with the HCOA, and the competition shows that the HCOA has a better performance in the 100-dimensional test of the CEC2017 benchmark functions. All the experimental results demonstrate that the HCOA presents highly accurate and robust results for high-dimensional optimization problems.
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A deep memory bare-bones particle swarm optimization algorithm (DMBBPSO) for single-objective optimization problems is proposed in this paper. The DMBBPSO is able to perform high-precision local search while maintaining a large global search, thus providing a reliable solution to high-dimensional complex optimization problems. Normally, maintaining high accuracy while conducting global searches is an important challenge for single-objective optimizers. Traditional particle swarms optimizers can rapidly lose the diversity during iterations and are unable to perform global searches efficiently, and thus are more likely to be trapped by local optima. To address this problem, the DMBBPSO combines multiple memory storage mechanism (MMSM) and a layer-by-layer activation strategy (LAS). The MMSM catalyzes a set of deep memories to increase the diversity of the particle swarm. For every single particle, both of the personal best position and deep memories will be used in the evaluation process. The LAS enables the particle swarm to avoid premature convergence while enhancing local search capabilities. The collaboration between MMSM and LAS enhances the diversity of the particle swarm, which in turn enhances the robustness of the DMBBPSO. To investigate the optimization ability of the DMBBPSO for single-objective optimization problems, The CEC2017 benchmark functions are used in experiments. Five state-of-the-art evolutionary algorithms are used in the control group. Finally, experimental results demonstrate that the DMBBPSO can provide high precision results for single-objective optimization problems.