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D022-Mn3.5Ga thin films were prepared on MgO (100) single crystalline substrates with different buffer layer (Cr, Fe, Cr/Pt and Cr/Au) using an ultra-high-vacuum electron beam vapor deposition system. From XRD patterns, a fundamental (004) peak has clearly observed for all samples. The relatively low saturation magnetization (Ms) of 178 emu/cm3, high magnetic anisotropy (Ku) of 9.1 Merg/cm3 and low surface roughness (Ra) of 0.30 nm were obtained by D022-Mn3.5Ga film (20 nm) on Cr/Pt buffer layer at Ts = 300 °C, Ta = 400 °C (3h). These findings suggest that MnGa film on Cr/Pt buffer layer is a promising PMA layer for future spin electronics devices.

We investigate many-body properties of equally populated three-component fermions with attractive three-body contact interaction in one dimension. A diagrammatic approach suggests the possible occurrence of Cooper triples at low temperature, which are three-body counterparts of Cooper pairs with a two-body attraction. We develop a minimal framework that bridges the crossover from tightly bound trimers to Cooper triples with increasing chemical potential and show how the formation of Cooper triples occurs in the grand-canonical phase diagram. Moreover, we argue that this nontrivial crossover is similar to the hadron-quark crossover proposed in dense matter. A coexistence of medium-induced triples and the underlying Fermi sea at positive chemical potential is analogous to quarkyonic matter consisting of baryonic excitations and the underlying quark Fermi sea. The comparison with the existing quantum Monte Carlo results implies that the emergence of these kinds of three-body states can be a microscopic origin of the peak of the sound velocity along the crossover.

We investigate a polaronic excitation in a one-dimensional spin-1/2 Fermi gas with contact attractive interactions, using the complex Langevin method, which is a promising approach to evade a possible sign problem in quantum Monte Carlo simulations. We found that the complex Langevin method works correctly in a wide range of temperature, interaction strength, and population imbalance. The Fermi polaron energy extracted from the two-point imaginary Green's function is not sensitive to the temperature and the impurity concentration in the parameter region we considered. Our results show a good agreement with the solution of the thermodynamic Bethe ansatz at zero temperature.

Klebsiella pneumoniae carbapenemase (KPC) actively hydrolyzes carbapenems, antibiotics often used a last-line treatment for multidrug-resistant bacteria. KPC clinical relevance resides in its widespread dissemination. In this work, we report the genomic context of KPC coding genes blaKPC-2, blaKPC-3 and blaKPC-30 in multidrug-resistant Klebsiellapneumoniae isolates from Brazil. Plasmids harboring blaKPC-3 and blaKPC-30 were identified. Fifteen additional carbapenem-resistant K. pneumoniae isolates were selected from the same tertiary hospital, collected over a period of 8 years. Their genomes were sequenced in order to evaluate the prevalence and dissemination of blaKPC–harboring plasmids. We found that blaKPC genes were mostly carried by one of two isoforms of transposon Tn4401 (Tn4401a or Tn4401b) that were predominantly located on plasmids highly similar to the previously described plasmid pKPC_FCF3SP (IncN). The identified pKPC_FCF3SP-like plasmids carried either blaKPC-2 or blaKPC-30. Two K. pneumoniae isolates harbored pKpQIL-like (IncFII) plasmids, only recently identified in Brazil; one of them harbored blaKPC-3 in a Tn4401a transposon. Underlining the risk of horizontal spread of KPC coding genes, this study reports the prevalence of blaKPC-2 and the recent spread of blaKPC-3, and blaKPC-30, in association with different isoforms of Tn4401, together with high synteny of plasmid backbones among isolates studied here and in comparison with previous reports.

The pseudogap is a ubiquitous phenomenon in strongly correlated systems, such as high-T_{c} superconductors, ultracold atoms, and nuclear physics. Whereas pairing fluctuations inducing the pseudogap are known to be enhanced in low-dimensional systems, such effects have not been explored well in one of the most fundamental one-dimensional models, that is, Gaudin-Yang model. In this paper, we show how the pseudogap effect emerges in the single-particle excitation in this system using a diagrammatic approach. Fermionic single-particle spectra exhibit a unique crossover from the double-particle dispersion to the pseudogap state with increasing the attractive interaction and the number density at finite temperature. Surprisingly, our results of thermodynamic quantities in unpolarized and polarized gases show an excellent agreement with the recent quantum Monte Carlo and complex Langevin results, indicating the validity of our approach even in the region where the pseudogap appears.

OBJETIVO: O Segundo Consenso Brasileiro de Fator Antinuclear (FAN) em Células HEp-2 ratificou os algoritmos de decisão para leitura dos padrões do FAN na imunofluorescência indireta vistos na primeira edição do Consenso Brasileiro, adicionando ainda um novo algoritmo relacionado com os padrões mistos. MÉTODOS: Tendo em vista a habilidade do teste em detectar autoantígenos nos distintos compartimentos celulares, e não apenas no núcleo, propõe-se novas denominações para este exame laboratorial. RESULTADOS E CONCLUSÕES: Como novas denominações algumas sugestões foram igualmente aceitas, dentro do tema "pesquisa de auto-anticorpos contra constituintes do núcleo (FAN HEp-2), nucléolo, citoplasma e aparelho mitótico". Foram abordadas as principais relevâncias clínicas com os padrões de FAN descritos, facilitando o melhor uso do ensaio pelo médico.

Se realizó un relevamiento de las aves de la reserva Provincial Parque Luro (La Pampa, Argentina). La lista de especies se elaboró en base a observaciones extensivas sobre recorridos preestablecidos, puntos de observación a orillas de los cuerpos de agua y transectas de faja realizados durante los años 1995 a 2001. Se identificaron 146 especies pertenecientes a 42 familias. Los resultados indican que la ornitocenosis estuvo compuesta principalmente por especies residentes. Las familias mejor representadás desde el punto de vista específico fueron los Tyrannidae, Furnariidae y Emberizidae. Durante el período de estudio nidificaron en el área 66 especies, 77 % fueron residentes y 23% residentes estivales. La familia Tyrannidae fue la que aportó el mayor número de especies nidificantes y nidos, debido esto último a la abundancia de Serpophaga griseiceps, Pyrocephalus rubinus y Elaenia parvirostris. Se registró a Molothrus bonariensis como parásita de Zonotrichia capensis y Mimus saturninus.

A total of 199 chrysanthemum (Chrysanthemum X morifolium Ramat.) cultivars were used in screening for resistance to chrysanthemum stunt viroid (CSVd). Plants were inoculated with CSVd by attaching leaf primordia-free, shoot apical meristems to CSVd-infected root tips of a CSVd-sensitive cultivar. CSVd titres in the first and third youngest expanded leaves were analysed after 2 months in culture, and a systematic classification into four groups was conducted. Long-term cultivation records provided by a breeding nursery confirmed our findings of those screened cultivars classified in vitro as "non-detected-type" (i.e., those expected to have a high level of resistance). In addition, of the 15 candidate cultivars selected as "non-detected-type", four cultivars were shown to have a high level of CSVd-resistance by ex vitro grafting experiments. From the results of our in vitro and ex vitro experiments, the advantages of our newly-developed in v/rra-screening system are discussed. [ABSTRACT FROM AUTHOR]

Abstract  A number of approaches have been proposed to estimate the exposure of non-human biota to ionizing radiation. This paper reports an inter-comparison of the unweighted absorbed dose rates for the whole organism (compared as dose conversion coefficients, or DCCs) for both internal and external exposure, estimated by 11 of these approaches for selected organisms from the Reference Animals and Plants geometries as proposed by the International Commission on Radiological Protection. Inter-comparison results indicate that DCCs for internal exposure compare well between the different approaches, whereas variation is greater for external exposure DCCs. Where variation among internal DCCs is greatest, it is generally due to different daughter products being included in the DCC of the parent. In the case of external exposures, particularly to low-energy β-emitters, variations are most likely to be due to different media densities being assumed. On a radionuclide-by-radionuclide basis, the different approaches tend to compare least favourably for 3H, 14C and the α-emitters. This is consistent with models with different source/target geometry assumptions showing maximum variability in output for the types of radiation having the lowest range across matter. The intercomparison demonstrated that all participating approaches to biota dose calculation are reasonably comparable, despite a range of different assumptions being made. [ABSTRACT FROM AUTHOR]

Substansi pembaharuan hukum ekonomi nasional harus bersendikan Pancasila dan UUD 1945. Idealnya dalam implementasi, hukum ekonomi nasional harus dapat mengakomodasi kepentingan pasar kapitalistik dan ekonomi pasar sosial secara proporsional. Sistem ekonomi yang demikian, menekankan pentingnya kerja sama di satu pihak dan sekaligus juga persaingan di pihak lainnya. Dalam demokrasi ekonomi berarti tidak ada tempat bagi ciri-ciri negatif liberalisme-kapitalisme yang menciptakan survival of the fittest, maupun sistem ekonomi sosialis-komunis.

We study the relation between quark confinement and chiral symmetry breaking in QCD. Using lattice QCD formalism, we analytically express the various ‘confinement indicators’, such as the Polyakov loop, its fluctuations, the Wilson loop, the inter-quark potential and the string tension, in terms of the Dirac eigenmodes. In the Dirac spectral representation, there appears a power of the Dirac eigenvalue such as , which behaves as a reduction factor for small . Consequently, since this reduction factor cannot be cancelled, the low-lying Dirac eigenmodes give negligibly small contribution to the confinement quantities, while they are essential for chiral symmetry breaking. These relations indicate that there is no direct one-to-one correspondence between confinement and chiral symmetry breaking in QCD. In other words, there is some independence of quark confinement from chiral symmetry breaking, which can generally lead to different transition temperatures/densities for deconfinement and chiral restoration. We also investigate the Polyakov loop in terms of the eigenmodes of the Wilson, the clover and the domain-wall fermion kernels, and find similar results. The independence of quark confinement from chiral symmetry breaking seems to be natural, because confinement is realized independently of quark masses and heavy quarks are also confined even without the chiral symmetry. [ABSTRACT FROM AUTHOR]

Introduction : Congenital nasal pyriform aperture stenosis is rare cause of airway obstruction in the newborn. Immediate recognition and appropriate therapy are required for management of these infants. Case Report : We report a case of a female infant that was referred to us six hours of delivery which was noted to have noisy breathing and subcostal recession. Our initial examination showed obvious stertor only on crying and mild subcostal recession. Cold spatula test indicated a patent nasal airway and we were able to pass the smallest suction tube through both nostril. Initially a conservative treatment with nasal drops was advocated however patient condition deteriorated the next day and required an orotracheal intubation. Our subsequent examinations and assessments post extubation were suggestive stenosis of the pyriform aperture. A CT paranasal sinuses showed overgrowth nasal processes of maxilla causing obstruction of the pyriform apertures with megaincisors. The CT brain also revealed semilobar holoprosencephaly and Dandy-Walker malformation/variant. Therefore the diagnosis congenital pyriform aperture was made based on clinical and radiological findings. Subsequently she underwent dilatation using endotracheal tube up to the size 3.0 mm for both nostril and was stented for 2 weeks. Conclusion : In general a conservative management is recommended, but in severe cases or those in which conservative management fails surgical management should be considered. [ABSTRACT FROM AUTHOR]

El terreno sobre el que se ha construido este núcleo residencial ocupa una extensión de 35 Ha, goza de orieníación axil este-oeste, y sus vistas sobre la ciudad de Nancy se desarrollan en sentido sur-sureste. Las dos unidades que presentamos aquí son los bloques A y B: el A, de 400 m de longitud, 43 m de altura y 15 plantas, contiene 920 viviendas; el B, de 300 m de longitud, 50 m de altura y 17 p lantas, aloja 800 viviendas. En las plantas bajas están: los zaguanes, arranque de comunicaciones verticales y locales para guardar los caches de niños, motos, e tc. Ocupan la primera planta—en cada elemento unitario— dos viviendas, con cuatro y cinco habitaciones, respectivamente; y las restantes plantas, otras dos viviendas con tres y cuatro habitaciones. Como características constructivas señalaremos que la cimentación fue realizada según procedimientos tradicionales, pero la estructura y cerramientos han sido ejecutados a base de un sistema de prefabricación pesada. Paralelamente al programa de viviendas, han sido planeados los servicios del núcleo residencial: dos centros comerciales, un cinematógrafo, un centro cultural, tres grupos escolares, edificios para el culto, campo de deportes, garajes, aparcamientos, etc. Tres edificios-torres en forma de estrella de tres brazos, con un total de 786 viviendas, se construirán en un futuro próximo.

We detected Zika virus in breast milk of a woman in Brazil infected with the virus during the 36th week of pregnancy. Virus was detected 33 days after onset of signs and symptoms and 9 days after delivery. No abnormalities were found during fetal assessment or after birth of the infant.

Introduction: We aimed to clarify whether the coagulation-fibrinolytic system is activated in a hyper-coiled umbilical cord (HCC)., Methods: This prospective cohort study was conducted at a single perinatal center in Japan, including singleton pregnant women who delivered after 37 weeks of gestation between January and July 2024. Umbilical venous blood was collected immediately after birth and before placental delivery. The coagulation and fibrinolytic systems were measured, and variables were compared between patients with and without HCC., Results: As a variable of cell blood count and hemostatic function, platelet concentration was significantly lower in the HCC group [median (range): 25.5 (17.3-32.1) vs 30.4 (18.5-39.55) x100000/μl, p = 0.020]. For coagulation variables, fibrinogen concentration [105 (63-116) vs 137.5 (56-229) mg/dl, p < 0.001] and antithrombin III [35 (27-51) vs 47.5 (31-62) %, p = 0.022] were significantly lower in the HCC group. Regarding fibrinolytic variables, plasmin inhibitor complex concentration was significantly higher in HCC group [1.3 (1.0-6.9) vs 0.7 (0.3-5.2) μg/ml, p = 0.036]; however, plasminogen concentration was significantly lower in HCC group [40 (32-46) vs 50 (25-64), p < 0.001]., Discussion: This is the first report where the coagulation-fibrinolytic system in the umbilical venous blood in cases with HCC was demonstrated. Findings reveal an activated coagulation-fibrinolytic system even in cases without severe fetal growth restriction due to HCC after 37 weeks of gestation., Competing Interests: Declaration of competing interest The author declares the following financial interests/personal relationships which may be considered as potential competing interests: JUNICHI HASEGAWA reports a relationship with Japan Society for the Promotion of Science, Japan that includes: funding grants. JUNICHI HASEGAWA reports a relationship with Japan Association of Obstetricians and Gynecologists that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Fermented katsuobushi, a traditional Japanese seasoning, is produced from skipjack tuna through smoking, drying and fermentation by xerophilic Aspergillus molds, primarily Aspergillus chevalieri and Aspergillus pseudoglaucus. In this study, we characterized lipolytic enzymes (cLip&#95;1 to cLip&#95;5 and pLip&#95;1 to pLip&#95;3) to clarify their roles in lipid hydrolysis during katsuobushi production under low water activity., Results: The enzymes showed significant diversity in their activity, stability and substrate specificity, and in the hydrolysis profiles of their reactions with fish oil. Phylogenetic analyses revealed that cLip&#95;5 showed a high identity with pLip&#95;2 (94%) and these enzymes formed a phylogenetic cluster with filamentous fungal lipases. Purified recombinant enzymes (rcLip&#95;1, rcLip&#95;2, rcLip&#95;4 and rcLip&#95;5) and wild-type enzymes (cLip&#95;3 and pLip&#95;3) showed varying substrate preferences toward p-nitrophenyl esters. The addition of glycerol to reduce the water activity in the reaction mixture led to increased activities of rcLip&#95;1 and rcLip&#95;4, but it did not affect the activity of the other three enzymes. Among the tested six enzymes, cLip&#95;5 showed the highest hydrolytic activity toward fish oil. The cLip&#95;5 and pLip&#95;2 gene transcript levels were moderately high in strains MK86 and MK88, respectively., Conclusion: cLip&#95;5 and its homolog pLip&#95;2 were identified as the most promising enzymes for katsuobushi fermentation, because of their high hydrolytic activities toward fish oil and adaptability to low water activity conditions. These findings support the selection of optimal Aspergillus strains as starter cultures to potentially shorten the fermentation time and improve the quality and shelf life of katsuobushi. © 2025 Society of Chemical Industry., (© 2025 Society of Chemical Industry.)

We report the development of a redox-responsive system that induces reversible conformational changes in peptides through the design of a seven-membered cyclic α,α-disubstituted α-amino acid with a disulfide bond, 5-amino-1,2-dithiepane-5-carboxylic acid (Dtp). Upon reduction, the disulfide bond in Dtp was cleaved to form thiols, converting Dtp into (2-mercaptoethyl)homocysteine (Mhc), and this process was reversed by oxidation. Dtp-containing peptides predominantly adopted 3 10 -helical conformation in solution, whereas Mhc-containing peptides exhibited a mixture of helical and other conformations. This redox-responsive mechanism allows for precise control over peptide secondary structures, making it a promising approach for designing functional helical peptides capable of acting molecular switches in response to intracellular reductive environments., (© 2025 Wiley-VCH GmbH.)

One major adverse effect of prostate radiotherapy is associated with the rectum. The SpaceOAR system has been developed to address this problem, as it enables treatment planning with a reduced dose to the rectum. This study aimed to evaluate and compare the treatment plans between three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) for prostate cancer using the SpaceOAR system. Thirty-five patients treated with prostate cancer radiation using the SpaceOAR system received a total radiation dose of 60 Gy/20 fractions. The dose constraints and robustness of the plan for VMAT and 3D-CRT were compared. For 3D-CRT, 6-field conformal method and 2-arc conformal method were created and compared in 3 treatment plans together with VMAT. The dose-constraint evaluation was performed using the planning target volume (PTV), rectum (mean dose), bladder (mean dose), and femoral head (mean dose). One issue associated with prostate radiotherapy is the physiological movement of the target prostate gland, which reduces the accuracy of irradiation. The prostate moves several millimeters during irradiation due to physiological movements, and there are reports of a decrease in the PTV index due to this effect. This has a significant impact on the cure rate of prostate cancer. A comparative study of the 3 irradiation methods was conducted to investigate this issue. Each study item was analyzed using the Friedman test to determine the significance of the 3 irradiation methods. Our analysis showed that the dose constraint was statistically significant for VMAT, but 3D-CRT was also sufficient in achieving dose constraints. The hydrogel spacer reduced the rectal dose and improved the dose-constrained fulfillment rate in VMAT and 3D-CRT. In a study of prostate motion during irradiation, 3D-CRT, a robust plan, was superior in the PTV mean evaluation over VMAT, where the multileaf collimator moved in fine increments. VMAT is currently the standard treatment for prostate cancer; however, with the introduction of the SpaceOAR system using hydrogel spacers, 3D-CRT may also be a viable option for prostate cancer treatment., Competing Interests: Conflict of Interest None., (Copyright © 2025 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to evaluate the influence of easing COVID-19 preventive measures following its downgrading to a common infectious disease on COVID-19 occurrence among hospitalized patients., Methods: Nosocomial occurrence of COVID-19 was compared between periods with national infectious disease category 5 versus the preceding category 2 equivalent. Changes in the revised manual included a shorter duration of work restrictions for infected health care practitioners (HCPs); no work restriction for HCPs exposed to SARS-CoV-2 with a negative test on days 1, 3 and 5; discontinuation of universal pre-admission screening; and pre-emptive isolation of patients without screening. Wearing an N95 mask and face shield was required in procedure/care with moderate-to high-risk contact., Results: Although the mean monthly number of infected HCPs increased from 8.1 to 12.7 in the category 5 period (p = 0.034) and that of pre-admission screening decreased to one-fourth, the COVID-19 incidence in hospitalized patients remained similar between the two study periods (1.60 ± 5.59/month versus 1.40 ± 2.63/month, p = 0.358). Clusters, defined as ≥3 COVID-19 patients on the ward, were experienced twice in the preceding period and only once in the category 5 period. The index cases causing nosocomial SARS-CoV-2 transmission mostly involved rehabilitation therapists in the preceding period; five of six index cases were patients in the category 5 period. Following the expanded indication for N95 masks, neither SARS-CoV-2 transmission to patients nor transmission from infected patients was observed in HCPs for 1 year., Conclusion: With sustained, enhanced standard precautions, easing prevention strategies could limit nosocomial SARS-CoV-2 infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure All authors disclosed no financial relationships. Commentary Malignant esophageal strictures can mostly be diagnosed successfully by examination of mucosal biopsy specimens. In some cases, that procedure remains nondiagnostic because of significant overlying necrosis. Malignant strictures with normal or fibrotic overlying mucosa, mostly seen after previous mucosal ablative therapies, are uncommon. and mucosal biopsy specimens alone can be misleading. Further evaluation with EUS and analysis of core needle biopsy specimens can be helpful. This report describes the potential role of submucosal tunneling biopsy in selected cases. Submucosal tunneling is a minimally invasive technique that was initially described to perform POEM in patients with achalasia. When it is performed by an experienced operator, there is a low incidence of intraprocedural and postprocedural adverse events. In the past decade, numerous studies have proved the safety and efficacy of this technique in performing myotomies and even resections of subepithelial lesions. Further studies will be required to evaluate the diagnostic utility of submucosal tunneling in obtaining biopsy specimens from luminal strictures and subepithelial lesions. Muhammad Arslan Baig, MD, Interventional Gastroenterologist, Clinical Assistant Professor of Medicine, University of Texas Health Sciences Center at Tyler, Tyler, Texas, USA Amy Tyberg, MD, FASGE, FACG, Associate Editor for Focal Points

Background: The Anticholinergic Risk Scale and Total Anticholinergic Load were developed to assess the risks associated with anticholinergic drugs. Recently, the Japan Anticholinergic Risk Scale was introduced; however, the total anticholinergic load for adverse events has not been clarified, and the criteria for risk assessment in clinical practice have not been established. In this study, we used data from the Japanese Adverse Drug Event Report (JADER) database provided by the Pharmaceuticals and Medical Devices Agency to determine the total anticholinergic load associated with reported adverse events related to anticholinergic syndrome., Methods: Using JADER data from April 2004 to September 2023, we investigated the association between drugs included in the J-ARS and adverse events related to anticholinergic syndrome. In addition, we calculated the total anticholinergic load for each case involving a drug recorded in the JADER database and compared it with other adverse events associated with anticholinergic effects., Results: Based on the JADER data, we observed an association between anticholinergic syndrome-related adverse events and the drugs listed in the J-ARS, confirming the feasibility of calculating the total anticholinergic drug burden for each case. In the group reporting anticholinergic syndrome-related adverse events, the mean ± standard deviation of the total anticholinergic load was 4.20 ± 3.09., Conclusions: The mean total anticholinergic load of anticholinergic syndrome-related adverse events obtained from the JADER database in this study supports the development of a comprehensive risk assessment of anticholinergic drugs in clinical practice., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Intracrinology-wherein hormones are synthesized in the organ where they exert their effect without release into circulation-has been described. However, molecular mechanisms of hormone deactivation within intracrine tissue are still largely unknown. The meibomian glands in the eyelids produce oil (meibum) to the ocular surface to prevent dehydration (dry eye). Androgens are generated inside this gland and are crucial for its tissue-homeostasis. However, there is no data showing the presence of androgens in meibum, implying local conversion/deactivation into unknown metabolites. Here, we performed radioactive tracer studies in combination with pharmacological enzyme inhibition, followed by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and found three androgen metabolites-androstanedione, androsterone, and epiandrosterone-in mouse and human meibomian glands. Accounting for the enzymatic conversion, we show tissue-endogenous 3α/3β-ketosteroid reductase expression. We therefore reinforce the idea that androgens are metabolically inactivated within the glands. These metabolite markers may help to assess meibomian local androgen activity using meibum., Competing Interests: M.D., T.S., and S.K. received a research grant from Senju Pharmaceutical Co., Ltd. M.M. and T.N. are employed by Senju Pharmaceutical Co., Ltd., (© 2025 The Author(s).)

Background/aims: Rare disease drug development faces unique challenges, such as genotypic and phenotypic heterogeneity within small patient populations and a lack of established outcome measures for conditions without previously successful drug development programs. These challenges complicate the process of selecting the appropriate trial endpoints and conducting clinical trials in rare diseases. In this descriptive study, we examined novel drug approvals for non-oncologic rare diseases by the U.S. Food and Drug Administration's Center for Drug Evaluation and Research over the past decade and characterized key regulatory and trial design elements with a focus on the primary efficacy endpoint utilized as the basis of approval., Methods: Using the Food and Drug Administration's Data Analysis Search Host database, we identified novel new drug applications and biologics license applications with orphan drug designation that were approved between 2013 and 2022 for non-oncologic indications. From Food and Drug Administration review documents and other external databases, we examined characteristics of pivotal trials for the included drugs, such as therapeutic area, trial design, and type of primary efficacy endpoints. Differences in trial design elements associated with primary efficacy endpoint type were assessed such as randomization and blinding. Then, we summarized the primary efficacy endpoint types utilized in pivotal trials by therapeutic area, approval pathway, and whether the disease etiology is well defined., Results: One hundred and seven drugs that met our inclusion criteria were approved between 2013 and 2022. Assessment of the 107 drug development programs identified 150 pivotal trials that were subsequently analyzed. The pivotal trials were mostly randomized (80%) and blinded (69.3%). Biomarkers (41.1%) and clinical outcomes (42.1%) were commonly utilized as primary efficacy endpoints. Analysis of the use of clinical trial design elements across trials that utilized biomarkers, clinical outcomes, or composite endpoints did not reveal statistically significant differences. The choice of primary efficacy endpoint varied by the drug's therapeutic area, approval pathway, and whether the indicated disease etiology was well defined. For example, biomarkers were commonly selected as primary efficacy endpoints in hematology drug approvals (70.6%), whereas clinical outcomes were commonly selected in neurology drug approvals (69.6%). Further, if the disease etiology was well defined, biomarkers were more commonly used as primary efficacy endpoints in pivotal trials (44.7%) than if the disease etiology was not well defined (27.3%)., Discussion: In the past 10 years, numerous novel drugs have been approved to treat non-oncologic rare diseases in various therapeutic areas. To demonstrate their efficacy for regulatory approval, biomarkers and clinical outcomes were commonly utilized as primary efficacy endpoints. Biomarkers were not only frequently used as surrogate efficacy endpoints in accelerated approvals, but also in traditionally approved rare disease drugs. The choice of primary efficacy endpoints varied by therapeutic area, approval pathway, and understanding of disease etiology., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Intensive lipid-lowering therapy (ILLT) is crucial for preventing secondary acute coronary syndrome (ACS). However, achieving target low-density lipoprotein cholesterol (LDL-C) levels remains challenging in clinical practice., Methods and Results: This retrospective study included 534 patients with ACS who underwent primary percutaneous coronary intervention (PCI) between September 2016 and August 2022. The ILLT protocol, wherein ezetimibe and statins are prescribed, was introduced in September 2019. We compared the rate of achievement of the LDL-C target of <70 mg/dL at the first outpatient visit and the incidence of cardiovascular events during the 3-year observation period after PCI between the conventional therapy (n=226) and ILLT (n=308) groups. The ILLT group had a higher achievement rate than the conventional therapy group (71.8% vs. 48.7%; P=0.001). In the ILLT group, 17% of statin-naïve patients did not achieve the LDL-C target, and the cutoff value of LDL-C on admission for predicting non-achievement of this target was 146 mg/dL. Patients in the ILLT group showed a significantly lower incidence of cardiovascular events than those in the conventional therapy group (hazard ratio 0.57; 95% confidence interval 0.34-0.97)., Conclusions: Implementing the ILLT protocol using statins and ezetimibe helped achieve the target LDL-C level early in patients with ACS and may consequently improve prognosis. However, patients with LDL-C levels ≥146 mg/dL on admission may need more intensive treatment., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2025, THE JAPANESE CIRCULATION SOCIETY.)

In this study, we investigated the mechanisms underlying carrageenan-induced chronic pain and the therapeutic effect of the anti-inflammatory drug meloxicam. Rats were injected with 3 % carrageenan into the masseter muscle. These rats exhibited acute and chronic hypersensitivity to mechanical stimuli for 6 weeks after injection. Pre-treatment with meloxicam prevented carrageenan-induced chronic hypersensitivity. Furthermore, minocycline and dexamethasone, but not acetaminophen, suppressed carrageenan-induced hypersensitivity in the chronic phase. Microglial reactivity in the trigeminal spinal subnucleus caudalis (Vc) was assessed by immunohistochemistry 3 days after treatment. The reactivity of microglial cells in the Vc was increased in carrageenan-treated rats compared with vehicle-injected rats. Meloxicam and dexamethasone, but not acetaminophen, prevented carrageenan-induced microglial hyperreactivity in the Vc. These results suggest that early prevention of peripheral/spinal inflammation suppresses microglial reactivity in the Vc and inhibits the development of orofacial chronic pain., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 The Authors.)

Malnutrition is observed in approximately 20-50% of hospitals and long-term care facilities. We examined the effects of malted rice amazake beverage on the nutritional status and gut microbiome of older patients and residents in an integrated long-term care facility; 13 older patients and residents (84.6 ± 9.3 years) were prescribed 35 g of malted rice amazake daily for six weeks. Gut microbiome analysis, body composition and blood biochemistry test results, defecation surveys, dietary intake, and medications were recorded before and after the intervention. After the intervention, the Geriatric Nutritional Risk Index (GNRI) increased from 83.6 ± 9.1 points to 86.0 ± 9.8 points, and serum albumin increased from 3.3 ± 0.5 g/dL to 3.4 ± 0.5 g/dL. The α-diversity of gut bacteria increased from 390.1 ± 89.4 before to 447.2 ± 108.1, and the abundance of Desulfovibrio decreased from 0.76 ± 0.47% to 0.56 ± 0.60%. ΔGNRI showed a positive correlation with Δ Bifidobacterium and Δ Barnesiella , but a negative correlation with Δ Klebsiella . Consumption of malted rice amazake for six weeks improved the GNRI and altered the gut microbiome of older patients and residents at moderate risk of nutritional disorders. Malted rice amazake may be a new way to improve nutrition because it has a high nutritional value, mainly in terms of carbohydrates, and improves the gut microbiome.

Aim: This study aimed to clarify factors that affect turnover intention of nurses in Japanese nursing homes (NHs)., Methods: Cross-sectional nationwide self-administered anonymous questionnaire survey was conducted among 2000 nurses and 1000 directors from 1000 NHs. Data were collected between December 2019 and January 2020. The questionnaire contained NH nurses' turnover intention，organizational factors such as work conditions, and so on; individual factors such as self-evaluation of nursing practice and so on. Responses were obtained from 267 nurses and 163 directors (response rates: 13.4% and 16.3%, respectively). This analysis included 196 responses from both nurses and directors from NHs. Univariate analysis and logistic regression analyses were performed to examine factors affecting nurses' turnover intentions., Results: Regarding the NH nurses' turnover intention, 49.5% responded "no intention to leave," 50.5% responded "intention to leave." Of these "intention to leave," 41.4% responded "I wanted to work in a medical facility." A stronger burden of on-call shift (OR [odds ratio] = 1.54, 95% CI [confidence interval]: 1.10-2.16) and a lower affective organizational commitment (OR = 0.71, 95% CI: 0.62-0.80) indicated a higher turnover intention of NH nurses., Conclusions: Retention of NH nurses may be increased by reducing the burden of on-call shifts and enhancing affective organizational commitment., (© 2024 Japan Academy of Nursing Science.)

In this study, we examined the effect of a bundled approach to blood collection for blood culture on decreasing contamination. Commensal organisms were considered contaminants on the basis of the clinical course if they were recovered from only a single blood draw (set) and if a positive result for two sets was not obtained within 72 hours. The main elements of the bundle were blood collection by venipuncture, skin preparation with a chlorhexidine alcohol swab, disinfection of culture bottles, and use of a sterile blood transfer device instead of the two-needle technique for inoculation. In the bundle intervention, chlorhexidine alcohol was first introduced in the hospital, and use of the blood transfer device was increased during the intervention. Both items were used in most patients requiring blood cultures. Blood collection through a line caused contamination in only one case. The contamination rate decreased significantly from 2.0% to 1.0% after introduction of the bundle approach (3-year control period vs. 2-year bundle period, p<0.001), and a significant decrease in the contamination rate was observed for coagulase-negative Staphylococcus (p<0.001). A high contamination rate was found in August and September during the control period. The contamination rate of Bacillus species was significantly higher in those 2 months than in other months. A seasonal increase was not observed during the bundle period. A low contamination rate of 1.0% was achieved using our bundled collection approach for blood culture., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Doi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: The authors declare that they have no conflict of interest.

Objective: Both periodontal disease and obesity are risk factors for dementia, but their links to 1brain function remain unclear. In this study, we examined the effects of oral infection with a periodontal pathogen on cognitive function in a mouse model of obesity, focusing on the roles of microglia., Methods: To create a mouse model of diet-induced obesity and periodontitis, male C57BL/6 J mice were first fed a high-fat diet containing 60% lipid calories for 18 weeks, beginning at 12 weeks of age, to achieve diet-induced obesity. Then, Porphyromonas gingivalis administration in the oral cavity twice weekly for 6 weeks was performed to induce periodontitis in obese mice., Results: Obese mice orally exposed to P. gingivalis showed cognitive impairment in the novel object recognition test. Increased expression levels of inflammatory cytokines (e.g. interleukin-1β and tumor necrosis factor-α) were observed in the hippocampus of P. gingivalis -treated obese mice. Immunohistochemical analysis revealed that microglia cell body size was increased in the hippocampus and prefrontal cortex of P. gingivalis -treated obese mice, indicating microglial activation. Furthermore, depletion of microglia by PLX3397, a colony-stimulating factor 1 receptor inhibitor, ameliorated cognitive dysfunction., Conclusion: These results suggest that microglia mediate periodontal infection-induced cognitive dysfunction in obesity., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Pericoronary adipose tissue attenuation (PCATA) is a novel imaging biomarker of pericoronary inflammation associated with coronary artery disease. Several studies have reported the usefulness of PCATA among people of European ethnicity; however, data are lacking concerning those of Asian ethnicity., Objectives: This multicenter study aimed to evaluate the effect of PCATA on prognosis in East Asian patients., Methods: Between August 2011 and December 2016, 2,172 patients underwent clinically indicated coronary computed tomography angiography (CTA) at 4 hospitals in Japan. Among them, 1,270 patients were analyzed. PCATA was evaluated using coronary CTA to measure pericoronary adipose tissue density surrounding the 3 major coronary arteries. The outcomes were composite cardiovascular events, including cardiovascular death and acute coronary syndrome; 33 cardiovascular events observed during a median follow-up of 6.0 years (Q1-Q3: 3.6-8.2 years)., Results: Right coronary artery (RCA)-PCATA was significantly higher in patients with cardiovascular events than in those without (-63.7 ± 8.9 HU vs -67.4 ± 9.1 HU, respectively; P = 0.021). High RCA-PCATA was significantly associated with cardiovascular events in a model that included the Hisayama risk score and adverse coronary CTA findings (HR: 1.55; 95% CI: 1.07-2.24; P = 0.019)., Conclusions: High RCA-PCATA showed significant association with future cardiovascular events after adjusting conventional risk factors and adverse coronary CTA findings in East Asian patients who underwent clinically indicated coronary CTA., Competing Interests: This work was supported by JSPS KAKENHI (Grant No. 21K08052). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2025 The Authors.)

Background: Frailty increases the risk of needing nursing care and significantly affects the life and functional prognosis of older individuals. Early detection and tailored interventions are crucial for maintaining and enhancing their life functions. Recognizing distinct clinical phenotypes is essential for devising appropriate interventions. This study aimed to explore diverse frailty phenotypes, focusing on poor nutrition in older Japanese individuals through observational research., Methods: Twenty-one nursing home residents underwent a comprehensive survey covering physical, blood, dietary, cardiac, cognitive, nutritional, nursing care, frailty, agitated behavior, and gut microbiome assessments (high-throughput 16S rRNA gene sequencing). Using clustering analysis with 239 survey items (excluding gut microbiome), participants were classified into subgroups based on clinical phenotypes, and group characteristics were compared through analysis., Results: Individuals with moderate or severe frailty and suspected dementia formed subgroups with distinct clinical phenotypes based on nutritional, defecation, and nursing care statuses. The gut microbiome significantly varied among these groups ( p = 0.007), indicating its correlation with changes in clinical phenotype. Nutritional status differences suggested poor nutrition as a differentiating factor in the core clinical phenotype., Conclusions: This study proposes that the gut microbiome differs based on the clinical phenotype of Japanese older individuals with frailty, and targeted interventions addressing the gut microbiome may contribute to preventing frailty in this population.

Designer receptors exclusively activated by designer drugs (DREADDs) are engineered G-protein-coupled receptors that afford reversible manipulation of neuronal activity in vivo. Here, we introduce size-reduced DREADD derivatives miniD q and miniD i , which inherit the basic receptor properties from the G q -coupled excitatory receptor hM3D q and the G i -coupled inhibitory receptor hM4D i , respectively, while being approximately 30% smaller in size. Taking advantage of the compact size of the receptors, we generated an adeno-associated virus (AAV) vector carrying both miniD q and the other DREADD family receptor (κ-opioid receptor-based inhibitory DREADD [KORD]) within the maximum AAV capacity (4.7 kb), allowing us to modulate neuronal activity and animal behavior in both excitatory and inhibitory directions using a single viral vector. We confirmed that expressing miniD q , but not miniD i , allowed activation of striatum activity in the cynomolgus monkey (Macaca fascicularis). The compact DREADDs may thus widen the opportunity for multiplexed interrogation and/or intervention in neuronal regulation in mice and non-human primates., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The human gut environment undergoes substantial changes as a host ages. This investigation centered on the gut microbiome diversity among patients with severe motor and intellectual disabilities (SMID), examining the association between the gut microbiome composition and physical characteristics with varying levels of diversity., Methods: Fourteen subjects were investigated, with physical and defecation status, blood biochemical test, gut microbiome profiling, and fecal metabolites used to divide the patients into a high-diversity group (HD, eight patients) and a low-diversity group (LD, six patients)., Results: Findings indicated that the microbiome of the LD group showed delayed maturation reminiscent of neonates and lactating infants. Analysis of the fecal bile acids (BAs) revealed a markedly diminished proportion of deoxycholic acid in the secondary BAs in the LD group, suggestive of inadequate conversion from primary to secondary BAs. Furthermore, the LD group presented with loose stools. The LD group exhibited a higher degree of physical severity, with all patients bedridden and fed via gastrostomy with only enteral formula received., Conclusions: The composition of the gut microbiome and BAs in the LD group was found to differ from those of healthy individuals and the HD group, indicating a potentially immature gut environment for these individuals.

Objectives: One possible reason for the long-term patency of no-touch (NT) saphenous vein grafts (SVG) is the preservation of the vasa vasorum in the adventitia/perivascular adipose tissue (PAT). We investigated the vasa vasorum of the NT SVG in vivo using frequency-domain optical coherence tomography (FD-OCT), performed qualitative and quantitative analyses and compared them with the conventional SVG., Methods: An FD-OCT study was performed on 14 SVG at the postoperative coronary angiography 1-2 weeks postoperatively (NT group, n = 9; conventional group, n = 5)., Results: Many signal-poor tubular lumen structures that can be recognized in the cross-sectional and longitudinal profiles, which indicates the vasa vasorum, were observed in the adventitial/PAT layer in the NT SVG. In contrast, the vasa vasorum were less abundant in the conventional SVG. The volume of vasa vasorum per millimetre of graft in the no-touch group was significantly higher than in the conventional group [0.0020 (0.0017, 0.0043) mm3 and 0.0003 (0.0000, 0.0006) mm3, P = 0.023]., Conclusions: FD-OCT showed abundant vasa vasorum in the thick adventitia/PAT layer of NT saphenous veins in vivo. In contrast, few vasa vasorum were observed in the conventional SVG., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Purpose: The effects of daily teriparatide (D-PTH, 20 μg/day), weekly high-dose teriparatide (W-PTH, 56.5 μg/week), or bisphosphonate (BP) on the vertebra and proximal femur were investigated using quantitative computed tomography (QCT)., Methods: A total of 131 postmenopausal women with a history of fragility fractures were randomized to receive D-PTH, W-PTH, or bisphosphonate (oral alendronate or risedronate). QCT were evaluated at baseline and after 18 months of treatment., Results: A total of 86 participants were evaluated by QCT (Spine: D-PTH: 25, W-PTH: 21, BP: 29. Hip: PTH: 22, W-PTH: 21, BP: 32. Dropout rate: 30.5 %). QCT of the vertebra showed that D-PTH, W-PTH, and BP increased total vBMD (+34.8 %, +18.2 %, +11.1 %), trabecular vBMD (+50.8 %, +20.8 %, +12.2 %), and marginal vBMD (+20.0 %, +14.0 %, +11.5 %). The increase in trabecular vBMD was greater in the D-PTH group than in the W-PTH and BP groups. QCT of the proximal femur showed that D-PTH, W-PTH, and BP increased total vBMD (+2.8 %, +3.6 %, +3.2 %) and trabecular vBMD (+7.7 %, +5.1 %, +3.4 %), while only W-PTH and BP significantly increased cortical vBMD (-0.1 %, +1.5 %, +1.6 %). Although there was no significant increase in cortical vBMD in the D-PTH group, cortical bone volume (BV) increased in all three treatment groups (+2.1 %, +3.6 %, +3.1 %)., Conclusions: D-PTH had a strong effect on trabecular bone of vertebra. Although D-PTH did not increase cortical BMD of proximal femur, it increased cortical BV. W-PTH had a moderate effect on trabecular bone of vertebra, while it increased both cortical BMD and BV of proximal femur. Although BP had a limited effect on trabecular bone of vertebra compared to teriparatide, it increased both cortical BMD and BV of proximal femur., Competing Interests: Declaration of competing interest This study was supported by Asahi Kasei Pharma Corporation and Eli Lilly Japan K.K., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function., Methods: To investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF., Results: Differences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively)., Conclusions: Ipragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic function., Competing Interests: Declaration of competing interest TI received lecture fees from JCR Pharmaceuticals and KyowaKirin; and outsourcing fees from Organization for Clinical Medicine Promotion. AT received honoraria from Boehringer Ingelheim Japan and research funding from GlaxoSmithKline, Takeda, Bristol-Myers Squibb, and Novo Nordisk. HT received honoraria from Abbott Medical Japan, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Ono, Mitsubishi Tanabe, and Takeda. MS received grants and personal fees from Mitsubishi Tanabe, Takeda, Daiichi Sankyo, Astellas, Pfizer, Novartis, Boehringer Ingelheim, Bayer, MSD, Kowa, and AstraZeneca. NK has received honoraria from AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim Japan, Daiichi Sankyo, Eli Lilly Japan, Kowa, Mitsubishi Tanabe Pharma, MSD, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Otsuka, Takeda Pharmaceutical; Research grants from Asahi Kasei, Astellas, Boehringer Ingelheim Japan, Fuji Yakuhin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Novartis Pharma, Teijin Pharma; Scholarships from Bayer Yakuhin, Medtronic, Teijin Pharma. All other authors declare no competing interests. AT and KN are Editorial Board members of Cardiovascular Diabetology and were not involved in handling this manuscript during the submission and the review processes., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Immunoglobulin G4 (IgG4)-related diseases are systemic fibroinflammatory disease characterized by extensive infiltration of IgG4-positive plasma cells in the affected tissue(s), with high plasma levels of IgG4. However, coronary involvement is rare., Case Summary: A 70-year-old man was diagnosed with IgG4-related coronary arteritis, pancreatitis, and cholangitis during full-body contrast computed tomography (CT) examination prior to surgery for an iliac artery aneurysm. 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/CT showed increased uptake of 18 F-FDG in the pancreas, extrahepatic bile ducts, and proximal right coronary artery (RCA). Despite the patient being asymptomatic, the RCA showed severe stenosis. The patient was administered a conservative treatment with prednisolone, 30 mg/day, gradually tapered to 5 mg/day, for 6 months. Two years later, contrast CT showed improvement of the pancreatic and bile duct lesions; however, the steroid therapy had not improved the coronary artery lesions, and gradual progression of the lesions was observed. Percutaneous coronary intervention was performed with a cutting balloon in the RCA, and good patency was maintained for 1 year after the procedure., Discussion: Steroid therapy is the first-line treatment for IgG4-related diseases; however, there may be some refractory cases. The stenotic and aneurysmal types of IgG4-related coronary arteritis are life-threatening; therefore, we performed revascularization using balloon angioplasty. Determining the optimal revascularization technique for drug-refractory cases requires further investigation., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Breast metastasis from small cell neuroendocrine carcinoma (SNEC) is very rare. In the present report, we describe a case of a female patient who was initially diagnosed with triple negative primary bilateral breast cancer, but during systemic examination, the diagnosis was bilateral breast metastasis from SNEC., Case Presentation: A 62-year-old woman with no history of smoking presented to the Department of General Medicine with left-sided chest pain, and computed tomography revealed masses in both breasts and left pleural thickening that was further confirmed by mammography and ultrasound of the breasts. A needle biopsy was performed, and triple negative primary bilateral breast cancer was diagnosed. Because progastrin-releasing peptide (ProGRP) 37,300 pg/ml (normal range, 0-81.0 pg/ml) and neuron-specific enolase 35.0 ng/ml (normal range, 0-16.3 ng/ml) levels were elevated, thoracoscopic biopsy was performed, and SNEC was diagnosed. Pathological examinations showed that the bilateral breast masses were also positive for immunohistochemical staining of chromogranin A, synaptophysin, and CD56, leading to a diagnosis of bilateral breast metastasis of neuroendocrine tumor., Conclusion: Although very rare, the possibility of breast metastasis should be considered when malignancy is suspected in other organs., (© 2024. The Author(s).)

Conformational freedom-restricted peptides, such as stapled peptides, play a crucial role in the advancement of functional peptide development. We synthesized stapled octapeptides using α-carbocyclic α,α-disubstituted α-amino acids, particularly 3-allyloxy-1-aminocyclopentane-1-carboxylic acid, as the crosslink motifs. The organocatalytic capabilities of the synthesized stapled peptides were assessed in an asymmetric nucleophilic epoxidation reaction because the catalytic activities are known to be proportional to α-helicity. Despite incorporating side-chain crosslinks, the enantioselectivities of the epoxidation reaction catalyzed by stapled octapeptides were found to be comparable to those obtained using unstapled peptides. Interestingly, the stapled peptides using α-carbocyclic α,α-disubstituted α-amino acids demonstrated higher reactivities and stereoselectivities (up to 99% ee) compared to stapled peptides derived from ( S )-α-(4-pentenyl)alanine, a commonly used motif for stapled peptides. These differences could be attributed to the increased α-helicity of the former stapled peptide in contrast to the latter, as evidenced by the X-ray crystallographic structures of their N - tert -butoxycarbonyl derivatives.

Introduction: Glucagon-like peptide 1 receptor agonists (GLP1Ras) have emerged as pivotal agents in diabetes management and organ protection. However, their use is limited due to the necessity for injectable administration. The advent of the first oral GLP1Ra (oral semaglutide) in Japan since 2021 is expected to expand its usage. The aim of this study is to survey the efficacy and tolerability of oral semaglutide in clinical practice., Materials and Methods: We retrospectively analyzed 120 outpatients diagnosed with type 2 diabetes mellitus who had received oral semaglutide for >6 months. Changes in clinical parameters during oral semaglutide treatment from baseline to 12 months were analyzed. The inverse probability weighting method using the propensity score was used to evaluate the differences in clinical parameters at 6 months after treatment, based on the patients' obesity levels., Results: Body weight (BW), glycated hemoglobin A 1c (HbA 1c ), and alanine aminotransferase (ALT) levels at baseline decreased significantly after treatment compared with those at 12 months (P < 0.001, P < 0.001, and P = 0.03, respectively). The patients were divided into two groups using a cutoff baseline body mass index (BMI) of 30.3 kg/m 2 . Although no significant difference was observed, changes in body weight and HbA 1c indicated a potentially greater decrease in the BMI ≧ 30.3 group than that in the BMI < 30.3 group (P = 0.07 and 0.13, respectively). Among 206 registered patients, 25 (12.1%) discontinued oral-semaglutide treatment owing to adverse effects, including gastrointestinal symptoms., Conclusions: Oral semaglutide treatment demonstrates efficacy and tolerability for managing type 2 diabetes mellitus in Japan. Significant improvements in metabolic factors induced by oral semaglutide are anticipated, particularly in obese patients., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism of protein synthesis. However, the current method has substantial issues: contamination by rRNAs and the lack of appropriate methods to measure ribosome numbers in transcripts. Here, we overcome these hurdles through the development of "Ribo-FilterOut", which is based on the separation of footprints from ribosome subunits by ultrafiltration, and "Ribo-Calibration", which relies on external spike-ins of stoichiometrically defined mRNA-ribosome complexes. A combination of these approaches estimates the number of ribosomes on a transcript, the translation initiation rate, and the overall number of translation events before its decay, all in a genome-wide manner. Moreover, our method reveals the allocation of ribosomes under heat shock stress, during aging, and across cell types. Our strategy of modified ribosome profiling measures kinetic and stoichiometric parameters of cellular translation across the transcriptome., (© 2024. The Author(s).)

The number of patients hospitalized with dementia is increasing, but one symptom, apathy, tends to be overlooked and unaddressed. Thus, this study determines how nurses certified in dementia nursing engage with older patients with dementia who exhibit apathy during hospitalization. A qualitative study using semi-structured interviews with 10 dementia care nurses in Japan was conducted. Through conventional content analysis, 10 categories were generated. They included (1) initiating patient engagement when their physiological or daily-life problems become more pronounced, (2) assessing and identifying the causes of decreased motivation from multiple perspectives, (3) assessing patients from multiple perspectives to determine the best way to start supporting them, (4) providing reassurance through basic dementia care, (5) incorporating pleasant stimuli into the hospital environment, (6) providing care based on patients' circumstances and abilities by collaborating with multiple professionals. Nurses initiate involvement with patients when their daily life problems become more pronounced. They conduct comprehensive assessments from multiple perspectives and collaborate with other professionals to ensure patient care and safety. They also extend their support to patients' families and maintain long-term involvement. Apathetic older patients benefit from basic nursing care practices and a patient-centered approach, which do not require specialization or additional costs and resources.

The sweetpotato whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) is challenging to control using chemical pesticides owing to its resistance to many insecticides. Thus, there has been an increasing demand for alternative control measures. Thus, this study evaluated the efficacy of a newly designed pest suction machine to manage whiteflies on tomato plants (Solanum lycopersicum L.) (Solanales: Solanaceae) in greenhouses over 2 seasons. The suction machine comprised a battery-powered cart with a mounted suction unit, an ultrasonic device, and green lights. Ultrasonic irradiation provided non-contact vibration, facilitating the movement of adult whiteflies away from the plants, and green lights attracted them to the suction device. This combination effectively captured whitefly adults, even with a weak suction force, saving electricity consumption. The efficacy of suction machine was further evaluated by measuring the number of whitefly adults caught by the machine and the number of adults and nymphs remaining on the tomato leaves. The whitefly population was considerably lower in the treated blocks than in the non-treated blocks in the autumn trial. The machine reduced the density of whitefly adults without using chemical pesticides. Although a lot of optimizations would be required, suction control is an additional and alternative strategy that may be incorporated in the integrated pest management of whiteflies on greenhouse tomato plants., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The cyclic peptide cyclo (Val-Leu-Leu-d-Phe-Pro) 2 (peptide 1 ) was specifically designed for structural chemistry investigations, drawing inspiration from Gramicidin S (GS). Previous studies have shown that Pro residues within 1 adopt a down-puckering conformation of the pyrrolidine ring. By incorporating fluoride-Pro with 4- trans / cis -isomers into 1 , an up-puckering conformation was successfully induced. In the current investigation, introducing hy-droxy-prolines with 4- trans / cis -isomer configurations (tHyp/cHyp) into 1 gave cyclo (Val-Leu-Leu-d-Phe-tHyp) 2 methanol disolvate monohydrate, C 62 H 94 N 10 O 12 ·2CH 4 O·H 2 O ( 4 ), and cyclo (Val-Leu-Leu-d-Phe-cHyp) 2 monohydrate, C 62 H 94 N 10 O 12 ·H 2 O ( 5 ), respectively. However, the puckering of 4 and 5 remained in the down conformation, regardless of the geometric position of the hydroxyl group. Although the backbone structure of 4 with trans -substitution was asymmetric, the asymmetric backbone of 5 with cis -substitution was unexpected. It is speculated that the anti-cipated influence of stress from the geometric positioning, which was expected to affect the puckering, may have been mitigated by inter-actions between the hydroxyl groups of hy-droxy-proline, the solvent mol-ecules, and peptides., (© Asano et al. 2024.)

To investigate the correlation between the aggregated state and photoluminescence (PL) mechanism of dual fluorescent (FL) and phosphorescent (PH) polyimides (PIs), the photophysical processes of FL-type BP-PI , PH-type DBrBP-PI , and their corresponding imide model compounds ( BP-MC and DBrBP-MC ) dispersed in poly(methyl methacrylate) (PMMA) films were analyzed at elevated pressures up to 8 GPa using a diamond anvil cell. Dibromo-substituted DBrBP-MC demonstrated a shorter wavelength absorption than BP-MC owing to the larger dihedral angle in the biphenyl moiety. Both MCs exhibited red-shifts in their absorption spectra with increasing pressure, indicating planarization occurred at the biphenyl moieties associated with the compression of the free volume in PMMA. The PL intensity of BP-MC increased with increasing pressure, while its quantum yield (Φ PL ) decreased sharply due to the enhanced energy transfer via the Förster mechanism. In contrast, the PH quantum yield (Φ PH ) of DBrBP-MC monotonically increased at lower pressures, while it showed excitation wavelength-dependent behaviors at higher pressures: Φ PH remained unchanged under excitation at 340 nm but gradually increased under excitation at 365 nm. This fact suggests that, at higher pressures, 365 nm excitation promoted intersystem crossing (ISC) from excited singlet states at higher energy levels. Using this phenomenon, a significant pressure-induced PH enhancement (PIPE) was observed for DBrBP-PI up to 0.9 GPa upon excitation at 365 nm, which is a rare phenomenon for organic polymers. This study indicates that even in colorless and optically transparent amorphous polymers, an enhancement of PH due to restricted molecular motion and intensified ISC outweighs the deactivation due to intermolecular energy transfer under certain pressures, leading to an increase in Φ PH .

Pasteurellosis is a common zoonotic infection that occurs after an animal bite or scratch (B/S). We compared the clinical features of six patients with non-B/S pasteurellosis with those of 14 patients with B/S infections. Pasteurella multocida was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all six non-B/S infections, whereas 13 of the 14 B/S infections were identified with diagnostic kits. The non-B/S infections were pneumonia (n = 3), skin and soft tissue infections (n = 2), and bacteremia (n = 1). Pneumonia occurred in two patients with underlying pulmonary disease, whereas ventilator-associated pneumonia developed in one patient with cerebral infarction. Pasteurella multocida was isolated from a blood specimen and nasal swab from a patient with liver cirrhosis (Child-Pugh class C) and diabetes. Cellulitis developed in one patient with diabetes and normal-pressure hydrocephalus, who had an open wound following a fall, and in one patient with diabetes and a foot ulcer. Three patients with non-B/S infections had no pet and no episode of recent animal contact. The rate of moderate-to-severe comorbidities was significantly higher in patients with non-B/S infections than in those with B/S infections (100% and 14.3%, respectively, p < 0.001). In conclusion, non-B/S infections can develop in patients with chronic pulmonary disease, invasive mechanical ventilation, or open wounds, or who are immunocompromised, irrespective of obvious animal exposure. In contrast to B/S infections, non-B/S pasteurellosis should be considered opportunistic., Competing Interests: Declaration of competing interest All the authors declare that they have no conflicts of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)