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We present an erratum to our Letter [Opt. Lett.48, 6344 (2023)10.1364/OL.510237]. This erratum corrects the error of Figs. 3(b) and 4(b) made via incorrect scaling in the horizontal axes. The corrections have no influence on the main text and conclusions of the original Letter.
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Green tea (GT) catechins exhibit antiviral effects in experimental studies. However, we lack clinical evidence on the preventive effects of catechin concentrations in gargling against acute upper respiratory tract infections (URTIs). Therefore, we aimed to investigate the concentration-dependence of GT catechins in gargling on the incidence of URTIs. We conducted an open-label randomized study. The target population consisted of 209 students from the University of Shizuoka and Meiji University, who were randomly assigned to high-catechin (approximate catechin concentration: 76.4 mg/dL), low-catechin (approximate catechin concentration: 30.8 mg/dL), and a control water gargling (catechin concentration: 0 mg/dL) group. All participants gargled water or GT daily for 12 weeks. The symptoms of URTIs were recorded on a daily survey form by participants. The incidences of URTIs occurred in 6 (9.1%), 7 (10.8%), and 11 (15.7%) participants in the high-catechin, low-catechin, and water groups, respectively. Cox proportional hazards analysis, using background factors and prevention status as covariates, revealed a hazard ratio of 0.57 (95% Confidence Interval (CI): 0.21-1.55, p = 0.261) for the high-catechin vs. water group and 0.54 (95% CI: 0.20-1.50, p = 0.341) for the low-catechin vs. water group. Our findings showed the incidence of URTIs in a concentration-dependent GT gargling was not significantly different, partly owing to the low event rates caused by intense precautions against the coronavirus disease 2019 pandemic. Our study would serve as a foundation for the development of an advanced protocol with optimal concentrations and a larger number of participants.
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Catequina , Infecções Respiratórias , Chá , Catequina/farmacologia , Catequina/uso terapêutico , Catequina/administração & dosagem , Humanos , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/epidemiologia , Masculino , Feminino , Chá/química , Adulto Jovem , Adulto , Relação Dose-Resposta a Droga , Doença Aguda , Incidência , Antivirais/uso terapêuticoRESUMO
The purpose of this study is to determine whether adding intravenous methylprednisolone pulse (IVMP) to primary adjunctive prednisolone with intravenous immunoglobulin (IVIG) improves treatment resistance and coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) with a high risk of treatment resistance. This multicenter, prospective, observational study was conducted at 28 hospitals in Japan from October 2016 to June 2020. For patients predicted to be resistant to treatment based on a Kobayashi score ≥ 5 and total bilirubin ≥ 1.0 mg/dL, each hospital independently decided to add IVMP followed by prednisolone, prednisolone alone, or nothing to the primary IVIG therapy. In total, 2856 consecutive KD patients were enrolled; of these, 399 (14.0%) were predicted to be treatment resistant. Patients who were resistant to the primary treatment and required additional treatment comprised 59%, 20%, and 26% of the IVIG-alone group, IVIG-plus-prednisolone group, and IVIG-plus-IVMP group, respectively (P < .0001). The CAA incidence (Z score ≥ 2.5) at month 1 was similar among the treatment groups (6.7%, 4.8%, and 7.3%, respectively; P = .66). CAA occurred more frequently in patients who needed third- or later-line therapy.Conclusions: Primary adjunctive corticosteroid therapy improved the treatment response and suppressed inflammation. However, the study found no benefit of adding IVMP to prednisolone therapy. Patients receiving IVIG alone achieved coronary outcomes comparable to those of patients receiving primary adjunctive corticosteroid therapy although they were more likely to require additional rescue treatment. KD inflammation should be resolved no later than the third line of additional treatment to reduce the risk of CAA.Trial registration: University Hospital Medical Information Network Clinical Trials Registry in Japan ( https://www.umin.ac.jp/ctr/index.htm ) under code UMIN000024937.
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Letermovir is a newly developed antiviral agent used for the prophylaxis of human cytomegalovirus infections in patients undergoing allogeneic hematopoietic cell transplantation. This novel anti-cytomegalovirus drug, used for the prophylaxis of cytomegalovirus reactivation until approximately 200 days after transplantation, effectively reduces the risk of clinically significant cytomegalovirus infection. No human counterpart exists for the terminase complex; letermovir is virus specific and lacks some toxicities previously observed with other anti-cytomegalovirus drugs, such as cytopenia and nephrotoxicity. The absolute bioavailability of letermovir in healthy individuals is estimated to be 94% based on a population-pharmacokinetic analysis. In contrast, oral administration of letermovir to patients undergoing hematopoietic cell transplantation results in lower exposure than that in healthy individuals. Renal or hepatic impairment does not influence the intrinsic clearance of letermovir. Co-administration of letermovir may alter the plasma concentrations of other drugs, including itself, as it acts as a substrate and inhibitor/inducer of several drug-metabolizing enzymes and transporters. In particular, attention should be paid to the drug-drug interactions between letermovir and calcineurin inhibitors or azole antifungal agents, which are commonly used in patients undergoing hematopoietic cell transplantation. This article reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of letermovir, focusing on patients undergoing hematopoietic cell transplantation, healthy individuals, and specific patient subsets.
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Acetatos , Antivirais , Infecções por Citomegalovirus , Interações Medicamentosas , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Antivirais/farmacocinética , Antivirais/administração & dosagem , Quinazolinas/farmacocinética , Quinazolinas/administração & dosagem , Acetatos/farmacocinética , Infecções por Citomegalovirus/prevenção & controle , Transplante HomólogoRESUMO
INTRODUCTION: There is considerable concern about whether endoscopic resection (ER) before additional surgery (AS) for T1 colorectal cancer (CRC) has oncologically potential adverse effects. Therefore, the aim of this study was to compare the long-term outcomes, including overall survival (OS), of patients treated with AS after ER vs primary surgery (PS) for T1 CRC using a propensity score-matched analysis from a large observational study. METHODS: This study investigated 6,105 patients with T1 CRC treated with either ER or surgical resection between 2009 and 2016 at 27 high-volume Japanese institutions, with those undergoing surgery alone included in the PS group and those undergoing AS after ER included in the AS group. Propensity score matching was used for long-term outcomes of mortality and recurrence analysis. RESULTS: After propensity score matching, 1,219 of 2,438 patients were identified in each group. The 5-year OS rates in the AS and PS groups were 97.1% and 96.0%, respectively (hazard ratio: 0.72, 95% confidence interval: 0.49-1.08), indicating the noninferiority of the AS group. Moreover, 32 patients (2.6%) in the AS group and 24 (2.0%) in the PS group had recurrences, with no significant difference between the 2 groups (odds ratio: 1.34, 95% confidence interval: 0.76-2.40, P = 0.344). DISCUSSION: ER before AS for T1 CRC had no adverse effect on patients' long-term outcomes, including the 5-year OS rate. ER is a viable first-line treatment option for endoscopically resectable T1 CRC.
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Small interfering RNAs (siRNAs) are revolutionizing the treatment of liver-associated indications. Yet, robust delivery to extrahepatic tissues remains a challenge. Conjugating lipids (e.g., docosanoic acid [DCA]) to siRNA supports extrahepatic delivery, but tissue accumulation remains lower than that achieved in liver by approved siRNA therapeutics. Early evidence suggests that functionalizing DCA with a head group (e.g., phosphatidylcholine [PC]) may enhance delivery to certain tissues. Here, we report the first systematic evaluation of the effect of PC head group chemistry on the extrahepatic distribution of DCA-conjugated siRNAs. We show that functionalizing DCA with a PC head group enhances siRNA accumulation in heart, muscle, lung, pancreas, duodenum, urinary bladder, and fat. Varying the size of the linker between the phosphate and choline moiety of the PC head group altered the extrahepatic accumulation of siRNA, with the optimal linker length being different for different tissues. Increasing PC head group valency also improved extrahepatic accumulation in a tissue-specific manner. This study demonstrates the structural impact of the PC moiety on the biodistribution of lipid-conjugated siRNA and introduces multiple novel PC variants for the chemical optimization of DCA-conjugated siRNA. These chemical variants can be used in the context of other lipids to increase the repertoire of conjugates for the extrahepatic distribution of siRNAs.
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BACKGROUND: Bone assessment using the MRI DEAL-IQ sequence may have the potential to serve as a substitute for evaluating bone strength by quantifying the bone marrow hematopoietic region (R2*) and marrow adiposity (proton density fat fraction: PDFF). Higher body mass index (BMI) is associated with increased bone mineral density (BMD) in the proximal femur; however, the relationship between BMI and R2* or PDFF remains unclear. Herein, we investigated the correlation between BMI and MRI IDEAL-IQ based R2* or PDFF of the proximal femur. METHODS: A retrospective single-cohort study was conducted on 217 patients diagnosed with non-metastatic prostate cancer between September 2019 and December 2022 who underwent MRI. The correlation between BMI and R2* or PDFF of the proximal femur was analyzed using Spearman's rank correlation test. RESULTS: Among 217 patients (median age, 74 years; median BMI, 23.8 kg/m2), there was a significant positive correlation between BMI and R2* at the right and left proximal femur (r = 0.2686, p < 0.0001; r = 0.2755, p < 0.0001, respectively). Furthermore, BMI and PDFF showed a significant negative correlation (r = -0.239, p = 0.0004; r = -0.2212, p = 0.001, respectively). CONCLUSION: In elderly men, the increased loading on the proximal femur due to elevated BMI was observed to promote a decrease in bone marrow adiposity in the proximal femur, causing a tendency for a transition from fatty marrow to red marrow with hematopoietic activity. These results indicate that the MRI IDEAL-IQ sequence may be valuable for assessing bone quality deterioration in the proximal femur.
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Índice de Massa Corporal , Densidade Óssea , Fêmur , Imageamento por Ressonância Magnética , Humanos , Masculino , Idoso , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Fêmur/diagnóstico por imagem , Fêmur/patologia , Densidade Óssea/fisiologia , Idoso de 80 Anos ou mais , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Adiposidade , Pessoa de Meia-IdadeRESUMO
In situ 3D computed tomography imaging with statistical analysis successfully revealed the water accumulation and drainage characteristics in the stacked gas diffusion layers (GDLs) and membrane electrode assembly (MEA) of a polymer electrolyte fuel cell. Efficient water drainage at the interface between the cathode GDL and MEA was confirmed upon supplying oxygen to the cathode.
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We demonstrate a hybrid integrated laser by transfer printing an InAs/GaAs quantum dot (QD) amplifier on a Si waveguide with distributed Bragg reflectors (DBRs). The QD waveguide amplifier of 1.6 mm long was patterned in the form of an airbridge with the help of a spin-on-glass sacrificial layer and precisely integrated on the silicon-on-insulator (SOI) waveguide by pick-and-place assembly using an elastomer stamp. Laser oscillation was observed around the wavelength of 1250â nm with a threshold current of 47â mA at room temperature and stable operation up to 80°C. Transfer printing of the long QD amplifiers will enable the development of various hybrid integrated laser devices that leverage superior properties of QDs as laser gain medium.
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Programmable protein scaffolds are invaluable in the development of genome engineering tools. The pentatricopeptide repeat (PPR) protein is an attractive platform for RNA manipulation because of its programmable RNA-binding selectivity, which is determined by the combination of amino acid species at three specific sites in the PPR motif. Translation is a key RNA regulatory step that determines the final gene expression level and is involved in various human diseases. In this study, designer PPR protein was used to develop a translational enhancement technique by fusion with the translation initiation factor eIF4G. The results showed that the PPR-eIF4G fusion protein could activate the translation of endogenous c-Myc and p53 mRNAs and control cell fate, indicating that PPR-based translational enhancement is a versatile technique applicable to various endogenous mRNAs in mammalian cells. In addition, the translational enhancement was dependent on both the target position and presence of eIF4G, suggesting the presence of an unknown translation activation mechanism.
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Fator de Iniciação Eucariótico 4G , Proteínas de Ligação a RNA , Animais , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Iniciação Eucariótico 4G/genética , Fator de Iniciação Eucariótico 4G/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA , Mamíferos/genética , Mamíferos/metabolismoRESUMO
The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6â h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30â min for 6â h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.
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Ritmo Circadiano , Núcleo Supraquiasmático , Masculino , Animais , Feminino , Humanos , Ritmo Circadiano/fisiologia , Núcleo Supraquiasmático/fisiologia , Roedores , Mamíferos , NeurôniosRESUMO
We generated gain-switched pulses via electrical pulse excitations in a 1270â nm distributed feedback (DFB) laser diode (LD) with a direct-modulation bandwidth of 30â GHz. The measurements revealed short-pulse widths of 5.3 and 8.8â ps with and without chirp compensation, via a single-mode optical fiber. The 5.3â ps pulses exhibited a spectral width of 0.40â nm (spectral bandwidth of 71â GHz), yielding a time-bandwidth product of 0.38. Although the gain-switched pulses in DFB LDs inherently contain linear and nonlinear chirp, optimized pumping conditions enable generation of nearly transform-limited ps pulses after linear chirp compensation.
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The 14th Japan Bioanalysis Forum Symposium was held at Tower Hall Funabori, Japan from 1-3 March 2023. The conference theme, 'Bringing Together - the Expertise of Bioanalysis', aimed to enable people from various fields to gather, learn and collaborate together for the common goal of delivering medicines to patients faster. Approximately 360 participants from various fields, including pharmaceutical industries, contractors, academia and regulatory authorities, gathered at an in-person symposium which had an online participation option, for the first time in 4 years. The symposium offered a wide range of topics including ICH M10, new modalities, biomarkers, immunogenicity, electronization and patient-centric sampling. The latest research results were provided from domestic and overseas scientists. This report summarizes the major topics.
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Relatório de Pesquisa , Humanos , Japão , BiomarcadoresRESUMO
BACKGROUND: The effect of the timing of additional doses and the long-term persistence of lyophilized inactivated tissue culture hepatitis A (HA) vaccine (Aimmugen®) on antibodies is unknown. METHODS: A single-center, cross-sectional, observational study was conducted in collaboration with the Japan Air Self-Defense Force, whose personnel were immunized with Aimmugen® when deployed to endemic areas. Patients who consented to this study after a medical examination with blood sampling between June 2022 and February 2023 were included; HA-IgG level in the residual serum was measured using the chemiluminescent immunoassay method. The exact vaccination history was investigated based on immunization records maintained by the Ministry of Defense, and a questionnaire was used to collect confounding factors. RESULTS: Of the 181 participants observed, 49 were in the unvaccinated group, and 132 were in the vaccinated group. Out of the vaccinated group, 6.8 % received either one or two doses, 40.9 % received three doses, and 52.3 % received more than four doses. IgG antibody titers (S/CO value) in each group (0, 1 or 2, 3, and over 4) increased in a frequency-dependent manner, with those vaccinated over four times showing significantly higher IgG antibody titers than all other groups (0.19 ± 0.10 vs 3.66 ± 3.00 vs 7.63 ± 3.57 vs 10.57 ± 1.86, respectively). When the number of months elapsed from the last vaccination to the date of blood collection in each group was plotted against IgG antibody titer, the slope of the regression line flattened out from a decreasing trend in the order 1 or 2, 3, over 4. CONCLUSIONS: Three doses of Aimmugen® are efficacious, but four or more doses induce more robust and sustained antibody production. Additionally, four or more doses may be effective when there is a need to ensure long-term immunity or risk of prolonged exposure.
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População do Leste Asiático , Vacinas contra Hepatite A , Humanos , Estudos Transversais , Vacinação , Vacinas de Produtos Inativados , Imunoglobulina G , Anticorpos AntiviraisRESUMO
Nucleic acid (NA) biomarkers play critical roles in drug development. However, the global regulatory guidelines for assessing quantification methods specific to NA biomarkers are limited. The validation of analytical methods is crucial for the use of biomarkers in clinical and post-marketing evaluations of drug efficacy and adverse reactions. Given that quantitative polymerase chain reaction (qPCR) and reverse transcription qPCR (RT-qPCR) methods are the gold standards for the quantification of NA biomarkers, the Biomarker Analytical Method Validation Study Group in Japan has discussed considerations and made recommendations for the development and validation of qPCR- and RT-qPCR-based analytical methods for endogenous NA biomarkers as drug development tools. This white paper aims to contribute to the global harmonization of NA biomarker assay validation.
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Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase em Tempo Real/métodos , Biomarcadores , JapãoRESUMO
The central circadian clock of the suprachiasmatic nucleus (SCN) is a network consisting of various types of neurons and glial cells. Individual cells have the autonomous molecular machinery of a cellular clock, but their intrinsic periods vary considerably. Here, we show that arginine vasopressin (AVP) neurons set the ensemble period of the SCN network in vivo to control the circadian behavior rhythm. Artificial lengthening of cellular periods by deleting casein kinase 1 delta (CK1δ) in the whole SCN lengthened the free-running period of behavior rhythm to an extent similar to CK1δ deletion specific to AVP neurons. However, in SCN slices, PER2::LUC reporter rhythms of these mice only partially and transiently recapitulated the period lengthening, showing a dissociation between the SCN shell and core with a period instability in the shell. In contrast, in vivo calcium rhythms of both AVP and vasoactive intestinal peptide (VIP) neurons in the SCN of freely moving mice demonstrated stably lengthened periods similar to the behavioral rhythm upon AVP neuron-specific CK1δ deletion, without changing the phase relationships between each other. Furthermore, optogenetic activation of AVP neurons acutely induced calcium increase in VIP neurons in vivo. These results indicate that AVP neurons regulate other SCN neurons, such as VIP neurons, in vivo and thus act as a primary determinant of the SCN ensemble period.
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Arginina Vasopressina , Cálcio , Animais , Camundongos , Neurônios , Núcleo Supraquiasmático , Neuroglia , Peptídeo Intestinal VasoativoRESUMO
Many female mammals have recurring cycles of ovulation and sexual behaviors that are regulated by reproductive hormones and confer reproductive success. In addition to sexual behaviors, circadian behavioral rhythms of locomotor activity also fluctuate across the estrous cycle in rodents. Moreover, there is a bidirectional relationship between circadian rhythms and estrous cyclicity since mice with disrupted circadian rhythms also have compromised estrous cycles resulting in fewer pregnancies. In the present study, we assessed whether extending day length, which alters circadian rhythms, normalizes estrous cyclicity in mice. We found that Period (Per) 1/2/3 triple knockout (KO) mice, that have disabled canonical molecular circadian clocks, have markedly disrupted estrous cycles. Surprisingly, extending the day length by only 2 h per day restored regular 4- or 5-day estrous cycles to Per1/2/3 KO mice. Longer days also induced consistent 4-day, rather than 5-day, estrous cycles in wild-type C57BL/6J mice. These data demonstrate that extending daytime light exposure could be used for enhancing reproductive success.
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Background: There are no standardised criteria for the 'regional' pericolic node in colon cancer, which represents a major cause of the international uncertainty regarding the optimal bowel resection margin. This study aimed to determine 'regional' pericolic nodes based on prospective lymph node (LN) mapping. Methods: According to preplanned in vivo measurements of the bowel, the anatomical distributions of the feeding artery and LNs were determined in 2996 stages I-III colon cancer patients who underwent colectomy with resection margin >10 cm at 25 institutions in Japan. Findings: The mean number of retrieved pericolic nodes was 20.9 (standard deviation, 10.8) per patient. In all patients except seven (0.2%), the primary feeding artery was distributed within 10 cm of the primary tumour. The metastatic pericolic node most distant from the primary tumour was within 3 cm in 837 patients, 3-5 cm in 130 patients, 5-7 cm in 39 patients and 7-10 cm in 34 patients. Only four patients (0.1%) had pericolic lymphatic spread beyond 10 cm; all of whom had T3/4 tumours accompanying extensive mesenteric lymphatic spread. The location of metastatic pericolic node did not differ by the feeding artery's distribution. Postoperatively, none of the 2996 patients developed recurrence in the remaining pericolic nodes. Interpretation: The pericolic nodes designated as 'regional' were those located within 10 cm of the primary tumours, which should be fully considered when determining the bowel resection margin, even in the era of complete mesocolic excision. Funding: Japanese Society for Cancer of the Colon and Rectum.
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Introduction: The trigeminal nerve conveys delicate sensations such as warmth, pain, and tactile pressure in the oral and facial regions, and most trigeminal afferent cell bodies are located in the trigeminal ganglion. Our previous study has shown that sensations in trigeminal nerve innervated areas, specifically in the maxillofacial region, exhibit diurnal variation and that sensitivity changes time-dependently. In this study, we aimed to clarify the rhythm of expression of clock gene in the trigeminal ganglion of mice to elucidate the mechanism of circadian regulation in the same area. Methods: Immunohistochemistry examined the expression of the PER2 protein in the suprachiasmatic nucleus and trigeminal ganglion of wild-type mice. To measure gene expression as bioluminescence, PERIOD2::LUCIFERASE knock-in (PER2::LUC) mice were used. Unilateral trigeminal ganglion and brain sections including the suprachiasmatic nucleus were incubated ex vivo. Bioluminescence levels were then measured using a highly sensitive photodetector. The same experiments were then conducted with Cry1 gene-deficient (Cry1-/- ) or Cry2 gene-deficient (Cry2-/- ) mice. Results: In the trigeminal ganglion, immunohistochemistry localized PER2 protein expression within the neuronal cell body. Mouse trigeminal ganglion ex vivo tissues showed distinct circadian oscillations in PER2::LUC levels in all genotypes, wild-type, Cry1-/- , and Cry2-/- . The period was shorter in the trigeminal ganglion than in the suprachiasmatic nucleus; it was shorter in Cry1-/- and longer in Cry2-/- mice than in the wild-type mice. Conclusion: The expression of Per2 in neurons of the trigeminal ganglion in ex vivo culture and the oscillation in a distinct circadian rhythm suggests that the trigeminal ganglion is responsible for the relay of sensory inputs and temporal gating through autonomous circadian oscillations.