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Whether empirical therapy with carbapenems positively affects the outcomes of critically ill patients with bacterial infections remains unclear. This study aimed to investigate whether the use of carbapenems as the initial antimicrobial administration reduces mortality and whether the duration of carbapenem use affects the detection of multidrug-resistant (MDR) pathogens. This was a post hoc analysis of data acquired from Japanese participating sites from a multicenter, prospective observational study [Determinants of Antimicrobial Use and De-escalation in Critical Care (DIANA study)]. A total of 268 adult patients with clinically suspected or confirmed bacterial infections from 31 Japanese intensive care units (ICUs) were analyzed. The patients were divided into two groups: patients who were administered carbapenems as initial antimicrobials (initial carbapenem group, n = 99) and those who were not administered carbapenems (initial non-carbapenem group, n = 169). The primary outcomes were mortality at day 28 and detection of MDR pathogens. Multivariate logistic regression analysis revealed that mortality at day 28 did not differ between the two groups [18 (18%) vs 27 (16%), respectively; odds ratio: 1.25 (95% confidence interval (CI): 0.59-2.65), P = 0.564]. The subdistribution hazard ratio for detecting MDR pathogens on day 28 per additional day of carbapenem use is 1.08 (95% CI: 1.05-1.13, P < 0.001 using the Fine-Gray model with death regarded as a competing event). In conclusion, in-hospital mortality was similar between the groups, and a longer duration of carbapenem use as the initial antimicrobial therapy resulted in a higher risk of detection of new MDR pathogens.IMPORTANCEWe found no statistical difference in mortality with the empirical use of carbapenems as initial antimicrobial therapy among critically ill patients with bacterial infections. Our study revealed a lower proportion of inappropriate initial antimicrobial administrations than those reported in previous studies. This result suggests the importance of appropriate risk assessment for the involvement of multidrug-resistant (MDR) pathogens and the selection of suitable antibiotics based on risk. To the best of our knowledge, this study is the first to demonstrate that a longer duration of carbapenem use as initial therapy is associated with a higher risk of subsequent detection of MDR pathogens. This finding underscores the importance of efforts to minimize the duration of carbapenem use as initial antimicrobial therapy when it is necessary., Competing Interests: The authors declare no conflict of interest.

Background: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC 24 /MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC 24 /MIC ratio associated with treatment outcomes of infections treated with vancomycin., Methods: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC 24 /MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC 24 /MIC and outcomes., Results: This study included 82 patients. ROC identified a target AUC 24 /MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC 24 /MIC cutoff (34.1%) than for above AUC 24 /MIC cutoff group (9.8%). Multivariate analysis confirmed AUC 24 /MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups., Conclusions: In treating severe/complicated MRSA infections, vancomycin AUC 24 /MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC 24 /MIC ratios., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: There is currently no consensus on clinically effective interventions for polypharmacy among older inpatients., Objective: To evaluate the effect of multidisciplinary team-based medication optimization on survival, unscheduled hospital visits, and rehospitalization in older inpatients with polypharmacy., Design, Setting, and Participants: This open-label randomized clinical trial was conducted at 8 internal medicine inpatient wards within a community hospital in Japan. Participants included medical inpatients 65 years or older who were receiving 5 or more regular medications. Enrollment took place between May 21, 2019, and March 14, 2022. Statistical analysis was performed from September 2023 to May 2024., Intervention: The participants were randomly assigned to receive either an intervention for medication optimization or usual care including medication reconciliation. The intervention consisted of a medication review using the STOPP (Screening Tool of Older Persons' Prescriptions)/START (Screening Tool to Alert to Right Treatment) criteria, followed by a medication optimization proposal for participants and their attending physicians developed by a multidisciplinary team. On discharge, the medication optimization summary was sent to patients' primary care physicians and community pharmacists., Main Outcomes and Measures: The primary outcome was a composite of death, unscheduled hospital visits, and rehospitalization within 12 months. Secondary outcomes included the number of prescribed medications, falls, and adverse events., Results: Between May 21, 2019, and March 14, 2022, 442 participants (mean [SD] age, 81.8 [7.1] years; 223 [50.5%] women) were randomly assigned to the intervention (n = 215) and usual care (n = 227). The intervention group had a significantly lower percentage of patients with 1 or more potentially inappropriate medications than the usual care group at discharge (26.2% vs 33.0%; adjusted odds ratio [OR], 0.56 [95% CI, 0.33-0.94]; P = .03), at 6 months (27.7% vs 37.5%; adjusted OR, 0.50 [95% CI, 0.29-0.86]; P = .01), and at 12 months (26.7% vs 37.4%; adjusted OR, 0.45 [95% CI, 0.25-0.80]; P = .007). The primary composite outcome occurred in 106 participants (49.3%) in the intervention group and 117 (51.5%) in the usual care group (stratified hazard ratio, 0.98 [95% CI, 0.75-1.27]). Adverse events were similar between each group (123 [57.2%] in the intervention group and 135 [59.5%] in the usual care group)., Conclusions and Relevance: In this randomized clinical trial of older inpatients with polypharmacy, the multidisciplinary deprescribing intervention did not reduce death, unscheduled hospital visits, or rehospitalization within 12 months. The intervention was effective in reducing the number of medications with no significant adverse effects on clinical outcomes, even among older inpatients with polypharmacy., Trial Registration: UMIN Clinical Trials Registry: UMIN000035265.

Study Objective: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended-spectrum β-lactamase producing enterobacterales (ESBL-E) and investigate optimal dosing regimens for not undergoing hemodialysis (non-HD) and undergoing hemodialysis (HD) patients., Design: Prospective observational study., Patients: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022., Measurements: Total and Unbound CMZ concentration was measured by high-performance liquid chromatography (HPLC) with solid-phase extraction and ultrafiltration., Setting: Determining the CMZ dosing regimen involved modified creatinine clearance (CL CR ) with measured body weight (BW) using the Cockcroft-Gault equation. For non-HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre-HD), and 1 and 3 h after starting HD and post-HD. All blood samples were collected at steady-state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non-HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule., Main Results: CMZ measurement methods were established. A model analysis of unbound PK in 37 non-HD patients incorporated creatinine clearance (CL CR ) using the Cockcroft-Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non-HD patients with an ESBL-E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CL CR of 60 mL/min required administration of 2 g every 6 h (1- and 3-h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL-E MIC of 4 mg/L., Conclusions: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL-E-infected patients., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Introduction: Cell-free and concentrated ascites reinfusion therapy (CART) is used for the treatment of diuretic-resistant ascites. An increase in circuit pressure and clogging of the filtration membrane often occur in CART for malignant ascites., Methods: To clarify the precise mechanism of filter clogging, we performed an ultrastructural observation study of the filtration membrane after the filtration of malignant ascites., Results: The deposition on the filtration membrane was composed of blood cells, fibrin, or both. Cellular deposition was associated with a greater number of blood cells in the original ascites fluid. In contrast, fibrin deposition was associated with higher levels of interleukin-6, α1-antitrypsin, haptoglobin, and fibrinogen/fibrin degradation products., Conclusion: Our results suggest that the specific pathophysiologies of malignancy (such as inflammation or coagulation/fibrinolysis) and characteristics of malignant ascites (highly concentrated and cell-rich) are associated with clogging of the filtration membrane during CART., (© 2021 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Nanomedicine is seen as a potential central player in the delivery of personalized medicine. Biocompatibility issues of nanoparticles have largely been resolved over the past decade. Despite their tremendous progress, less than 1% of applied nanosystems can hit their intended target location, such as a solid tumor, and this remains an obstacle to their full ability and potential with a high translational value. Therefore, achieving immune-tolerable, blood-compatible, and biofriendly nanoparticles remains an unmet need. The translational success of nanoformulations from bench to bedside involves a thorough assessment of their design, compatibility beyond cytotoxicity such as immune toxicity, blood compatibility, and immune-mediated destruction/rejection/clearance profile. Here, we report a one-pot process-engineered synthesis of ultrasmall gold nanoparticles (uGNPs) suitable for better body and renal clearance delivery of their payloads. We have obtained uGNP sizes of as low as 3 nm and have engineered the synthesis to allow them to be accurately sized (almost nanometer by nanometer). The synthesized uGNPs are biocompatible and can easily be functionalized to carry drugs, peptides, antibodies, and other therapeutic molecules. We have performed in vitro cell viability assays, immunotoxicity assays, inflammatory cytokine analysis, a complement activation study, and blood coagulation studies with the uGNPs to confirm their safety. These can help to set up a long-term safety-benefit framework of experimentation to reveal whether any designed nanoparticles are immune-tolerable and can be used as payload carriers for next-generation vaccines, chemotherapeutic drugs, and theranostic agents with better body clearance ability and deep tissue penetration.

Introduction: Whether medication optimisation improves clinical outcomes in elderly individuals remains unclear. The current study aims to evaluate the effect of multidisciplinary team-based medication optimisation on survival, rehospitalisation and unscheduled hospital visits in elderly patients., Methods and Analysis: We report the protocol of a single-centre, open-label, randomised controlled trial. The enrolled subjects will be medical inpatients, aged 65 years or older, admitted to a community hospital and receiving five or more regular medications. The participants will be randomly assigned to receive either an intervention for medication optimisation or the usual care. The intervention will consist of a multidisciplinary team-based medication review, followed by a medication optimisation proposal based on the Screening Tool of Older Persons' potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment criteria and an implicit medication optimisation protocol. Medication optimisation summaries will be sent to primary care physicians and community pharmacists on discharge. The primary outcome will be a composite of death, unscheduled hospital visits and rehospitalisation until 48 weeks after randomisation. Secondary outcomes will include each of the primary endpoints, the number of prescribed medications, quality of life score, level of long-term care required, drug-related adverse events, death during hospitalisation and falls. Participants will be followed up for 48 weeks with bimonthly telephone interviews to assess the primary and secondary outcomes. A log-rank test stratified by randomisation factors will be used to compare the incidence of the composite endpoint. The study was initiated in 2019 and a minimum of 500 patients will be enrolled., Ethics and Dissemination: The study protocol has been approved by the Institutional Ethical Committee of St. Marianna University School of Medicine (No. 4129). The results of the current study will be submitted to a peer-reviewed journal., Trial Registration Number: UMIN000035265., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neurotensin receptor type 1 (NTSR1), a member of the G-protein-coupled receptor (GPCR) family, is naturally activated by binding of a neurotensin peptide, leading to a variety of physiological effects. The budding yeast Saccharomyces cerevisiae is a proven host organism for assaying the agonistic activation of human GPCRs. Previous studies showed that yeast cells can functionally express human NTSR1 receptor, permitting the detection of neurotensin-promoted signaling using a ZsGreen fluorescent reporter gene. However, the fluorescence intensity (sensitivity) of NTSR1-expressing yeast cells is low compared to that of yeast cells expressing other human GPCRs (e.g., human somatostatin receptors). The present study sought to increase the sensitivity of the NTSR1-expressing yeast for use as a fluorescent biosensor, including modification of the expression of human NTSR1 in yeast. Changes in the transcription, translation, and transport of the receptor are attempted by altering the promoter, consensus Kozak-like sequence, and secretion signal sequences of the NTSR1-encoding gene. The resulting yeast cells exhibited increased sensitivity to exogenously added peptide. The cells are further engineered by using cell-surface display technology to ensure that the agonistic peptides are secreted and tethered to the yeast cell wall, yielding cells with enhanced NTSR1 activation. This yeast biosensor holds promise for the identification of agonists to treat NTSR1-related diseases., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Flos Chrysanthemi (Gongju, GJ) is used to prepare a herbal tea that is commonly consumed as a health beverage in Asia and is believed to contain abundant beneficial antioxidants. To rapidly identify the chemical constituents and to obtain the profile related to antioxidant activity, an online analytical method combining high-performance liquid chromatography-diode-array detector-electrospray ionization-ion-trap time-of-flight mass spectrometry (HPLC-DAD-ESI-IT-TOF-MS(n)) and postcolumn derivatization (PCD) has been applied for a precise and thorough identification of the chemical constituents. Meanwhile, the antioxidant profile has also been characterized by directly measuring the scavenging activity of each compound for the free radical produced by DPPH. As a result, 13 compounds have been identified in GJ, 7 of which account for its antioxidant activity. The established LC-MS(n)-PCD system has proved to offer a useful strategy for correlating the chemical profile with the bioactivities of the components without their isolation and purification, and may be used for multicomponent analysis of active substances in other foods and herbs.

During embryogenesis, the Peyer's patch anlagen are induced by a cell population that produces lymphotoxin (LT) alpha(1)beta(2) following stimulation of IL-7Ralpha. In this study, we show that the LT-producing cell is localized within the IL-7Ralpha(+) and integrin alpha(4)beta(7) (alpha(4)beta(7))(+) population in the embryonic intestine. Lineage commitment to the LT producer phenotype in the fetal liver coincides with expression of alpha(4)beta(7). Before expression of alpha(4)beta(7), the potential of IL-7Ralpha(+) population to generate B cells is lost. However, the progenitors for T cells and LT producer cells reside in the IL-7Ralpha(+)alpha(4)beta(7)(+) cells, but during subsequent differentiation, the potential to give rise to T cells is lost. This IL-7Ralpha(+)alpha(4)beta(7)(+) population migrates to the intestine, where it induces the Peyer's patch anlagen. When stimulated with IL-15 or IL-3 and TNF, the intestinal IL-7Ralpha(+)alpha(4)beta(7)(+) population can differentiate into fully competent NK1.1(+) NK cells or CD11c(+) APCs. Expression of alpha(4)beta(7) is lost during differentiation of both lineages; IL-7Ralpha expression is lost during NK1.1(+) cells differentiation. A newly discovered lineage(-)IL-7Ralpha(+)c-Kit(+)alpha(4)beta(7)(+) population in the fetal liver is committed to T, NK, dendritic, and fetal intestinal LT producer lineage, the latter being an intermediate stage during differentiation of NK and dendritic cells.

We have shown that Peyer's patch (PP) first develops as a simple and even cell aggregation during embryogenesis. To investigate when and how such a simple cell aggregation forms the complex PP architecture, we analyzed the distribution of cells expressing IL-7R alpha (PP inducer cells), VCAM-1 (mesenchymal cells), CD11c (dendritic cells), and mature lymphocytes by whole-mount immunostaining of 17.5 days post coitus to 2 days postpartum mouse gut. Our results show that compartmentalization of PP anlagen commences at day 18.5 of gestation by clustering and subsequent follicle formation of IL-7R alpha(+), VCAM-1(+), and CD11c(+) cells. This process adds the primitive architecture of PP anlage with several follicles in which IL-7R alpha(+) cells localize in the center, while VCAM-1(+) and CD11c(+) cells localize at the fringe. This follicle formation is accompanied by the establishment of PP-specific vascular network expressing mucosal addressin cellular adhesion molecule-1. Mature B and T lymphocytes entering in the PP anlage are distributed promptly to their own target zones; B cells to the follicle and T cells to nonfollicular zones. Our analysis of scid/scid mouse indicate that the initial processes including formation of PP-specific vascular network occur in the absence of lymphocytes. These observations indicate that the basic architecture of PP is formed by a set of cell lineages assembled during the initial phase of induction of PP anlagen before entry of mature lymphocytes.

Phosphorylation of both tyrosine and serine residues of focal adhesion kinase (FAK) was stimulated by the adhesion of BALB/c mouse 3T3 cells to fibronectin, but phosphorylation of threonine was not detectable. Acidic and basic fibroblast growth factors also stimulated the phosphorylation of serine and tyrosine of FAK in cells adhered to poly-L-lysine, but epidermal growth factor and platelet-derived growth factor did not. A fusion protein of fibronectin and basic fibroblast growth factor effectively induced the phosphorylation of FAK. Phosphorylation of FAK in the rat myoblast L-6 cell line, which lacks fibroblast growth factor receptors, was not stimulated by fibroblast growth factors, suggesting that the interaction of fibroblast growth factors with their receptors might cause the phosphorylation of FAK.

We constructed a fusion protein of the cell-binding domain of human fibronectin and human basic fibroblast growth factor, and prepared a polypeptide with both cell-adhesive activity and growth factor activity. A human gene fragment coding for basic fibroblast growth factor was amplified by the polymerase chain reaction, and introduced into the expression vector pTF7520, which encodes the cell-binding domain of human fibronectin. The resulting plasmid encoded a fusion protein in which basic fibroblast growth factor was added covalently to the C-terminal end of the fibronectin fragment. The fusion protein was expressed in Escherichia coli JM109 cells and purified from the extract by heparin affinity chromatography. The purified fusion protein had cell-adhesive activity toward BALB/c 3T3 cells, and stimulated their DNA synthesis in serum-depleted cultures. The fusion protein gave maximum mitogenic activity at the concentration of 10 nM. The fusion protein adsorbed to culture dishes, or added to collagen gels, stimulated the growth of human umbilical-vein endothelial cells. The fusion protein stimulated the angiogenesis in chorioallantoic membranes of developing chick embryos.