A retrospective study on the efficacy of pegfilgrastim-filgrastim combination regimen in the mobilization for autologous stem cell transplantation in lymphoma patients.

BACKGROUND: The high mobilization failure rate with the mobilization strategy of combining chemotherapy and filgrastim (rhG-CSF) in autologous hematopoietic stem cell transplantation (auto-HSCT) in lymphomas is one of the unresolved issues. Whether the combination of polyethylene glycol filgrastim [pegfilgrastim (PEG-FIL), PEG-rhG-CSF] and filgrastim (FIL) improves the mobilization success rate and the timing of combination therapy has not been studied. METHODS: 107 lymphoma patients who received auto-HSCT were retrospectively enrolled and divided into groups of PEG+FIL and FIL. The group of PEG+FIL received pegfilgrastim (9 mg) on the third day of the chemotherapy, followed by filgrastim (10 µg/kg/day) based on the counts of peripheral blood stem cells (PBSC). The group of FIL received filgrastim 10 µg /kg/day depending on the number of PBSCs. RESULTS: The incidence of neutropenic fever in the group of PEG+FIL was significantly lower than in the group of FIL. The mean recovery time of leukocytes at autologous stem cell transplantation was significantly shorter in the group of PEG+FIL than in the group of FIL. Compared to the groups of FIL, the group of PEG+FIL had lower hospitalization costs. We found that the combination therapy is more recommended for patients with a bone marrow hematopoietic area of less than 30%. Filgrastim is best administered 5-6 days after pegfilgrastim administration. CONCLUSIONS: Compared to conventional filgrastim mobilization, the combination of pegfilgrastim and filgrastim schedule has high efficacy, non-inferior safety, and superior health economic benefits during auto-HSCT.

Correlation between tumor budding and the long-term follow-up outcomes after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND: The effect of tumor budding (TB) on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after endoscopic submucosal dissection (ESD) remains unclear. We evaluated the long-term outcomes of patients with superficial ESCC after ESD and the risk factors of TB for the long-term prognosis. METHODS: We conducted a retrospective study in a Chinese hospital. All patients with ESCC treated by ESD and reported TB were included consecutively. Comparative analyses were conducted in three parts: specimen analysis, follow-up analyses of unmatched patients, and propensity score-matched (PSM) patients. Cox proportional hazard regression models were constructed to identify risk factors for overall survival and recurrence-free survival (RFS). RESULTS: A total of 437 patients were enrolled [154 TB and 283 no tumor budding (NTB)], and 258 patients (52 TB and 206 NTB) were included in the follow-up analysis. Results showed that the invasion depth, differentiation type, and positive vascular invasion (all p < 0.001) of the TB group were significantly different from the NTB group. The all-cause mortality and the median RFS time between the two groups were comparable. RFS rate at 5 years were 84.6% and 80.6%, respectively (p = 0.43). Cox analyses identified that having other cancers but not TB, as a risk factor independently associated with overall survival and RFS after ESD. CONCLUSION: TB tends to be associated with invasion depth, differentiation type, and positive vascular invasion. However, it might not affect the long-term outcomes of patients with superficial ESCC after ESD when other high-risk factors are negative.

A simple predictor for donor-specific anti-HLA antibody desensitisation in haploidentical haematopoietic stem cell transplantation.

Donor-specific HLA antibody (DSA) has been recognised as an independent risk factor for graft failure in patients undergoing haploidentical haematopoietic stem cell transplantation (HID HSCT). Therapeutic plasma exchange (TPE), as a first-line strategy for DSA desensitisation, can promptly reduce serum DSA levels. This study aimed to investigate DSA characteristics and identify a biomarker predicting the efficacy of DSA desensitisation in patients proceeding to HID HSCT. We retrospectively enrolled 32 patients with DSA from April 2021 to January 2024, and analysed the mean fluorescence intensity (MFI) value of DSA at the different time points of desensitisation treatment. Compared with baseline DSA level before TPE, the median MFI of HLA class I DSA was reduced from 8178.6 to 795.3 (p < 0.001), and HLA class II DSA decreased from 6210.9 to 808.8 (p < 0.001) after TPE. The DSA level in 1:16 diluted pre-TPE serum correlated well with DSA value in post-TPE serum (class I, r = 0.85, p < 0.0001; class II, r = 0.94, p < 0.0001), predicting TPE efficacy in 84.4% of patients. Based on the degree of DSA reduction after TPE, patients were divided into complete responders (decreased by >70%), partial responders (decreased by 30 to 70%) and non-responders (decreased by <30%) and the percentages were 43.8%, 25% and 31.2%, respectively. Non-responders receiving aggressive immunotherapy had longer overall survival compared to those receiving standard strategies (p < 0.05). The 1:16 diluted pre-TPE serum may predict the efficacy of TPE and allow for more rational immunotherapy strategy for patients with DSA proceeding to HID HSCT.

Multiple impacts of the COVID-19 pandemic and antimicrobial stewardship on antimicrobial resistance in nosocomial infections: an interrupted time series analysis.

Objectives: The emergency response to the COVID-19 pandemic may disrupt hospital management activities of antimicrobial resistance (AMR). This study aimed to determine the changing AMR trend over the period in China when stringent COVID-19 response measures were implemented. Methods: This retrospective study was conducted in a designated hospital for COVID-19 patients in Guangzhou, China from April 2018 to September 2021. The prevalence of 13 antimicrobial-resistant bacteria was compared before and after the COVID-19 responses through Chi-square tests. Interrupted time series (ITS) models on the weekly prevalence of AMR were established to determine the changing trend. Controlled ITS models were performed to compare the differences between subgroups. Results: A total of 10,134 isolates over 1,265 days were collected. And antimicrobial-resistant strains presented in 38.6% of the testing isolates. The weekly AMR prevalence decreased by 0.29 percentage point (95% CI [0.05-0.80]) after antimicrobial stewardship (AMS) policy, despite an increase in the prevalence of penicillin-resistant Streptococcus pneumoniae (from 0/43 to 15/43, p < 0.001), carbapenem-resistant Escherichia coli (from 20/1254 to 41/1184, p = 0.005), and carbapenem-resistant Klebsiella pneumoniae (from 93/889 to 114/828, p = 0.042). And the changing trend did not vary by gender (male vs. female), age (<65 vs. ≥65 years), service setting (outpatient vs. inpatient), care unit (ICU vs. non-ICU), the primary site of infection (Lung vs. others), and Gram type of bacteria (positive vs. negative). Conclusion: The response to COVID-19 did not lead to an increase in overall AMR; however, it appears that management strategy on the prudent use of antimicrobials likely contributed to a sizable long-term drop. The frequency of several multidrug-resistant bacteria continues to increase after the COVID-19 epidemic. It is crucial to continue to monitor AMR when COVID-19 cases have surged in China after the relaxation of restriction measures.

Superior survival with allogeneic hematopoietic stem cell transplantation versus chemotherapy for high-risk adult acute lymphoblastic leukemia in a PDT-ALL-2016 pediatric-inspired cohort.

Not available.

Clinical Characteristics, Prognosis Factors and Metagenomic Next-Generation Sequencing Diagnosis of Mucormycosis in patients With Hematologic Diseases.

INTRODUCTION: New diagnostic methods and antifungal strategies may improve prognosis of mucormycosis. We describe the diagnostic value of metagenomic next⁃generation sequencing (mNGS) and identify the prognostic factors of mucormycosis. METHODS: We conducted a retrospective study of hematologic patients suffered from mucormycosis and treated with monotherapy [amphotericin B (AmB) or posaconazole] or combination therapy (AmB and posaconazole). The primary outcome was 84-day all-cause mortality after diagnosis. RESULTS: Ninety-five patients were included, with "proven" (n = 27), "probable" (n = 16) mucormycosis confirmed by traditional diagnostic methods, and "possible" (n = 52) mucormycosis with positive mNGS results. The mortality rate at 84 days was 44.2%. Possible + mNGS patients and probable patients had similar diagnosis processes, overall survival rates (44.2% vs 50.0%, p = 0.685) and overall response rates to effective drugs (44.0% vs 37.5%, p = 0.647). Furthermore, the median diagnostic time was shorter in possible + mNGS patients than proven and probable patients (14 vs 26 days, p < 0.001). Combination therapy was associated with better survival compared to monotherapy at six weeks after treatment (78.8% vs 53.1%, p = 0.0075). Multivariate analysis showed that combination therapy was the protective factor (HR = 0.338, 95% CI: 0.162-0.703, p = 0.004), though diabetes (HR = 3.864, 95% CI: 1.897-7.874, p < 0.001) and hypoxemia (HR = 3.536, 95% CI: 1.874-6.673, p < 0.001) were risk factors for mortality. CONCLUSIONS: Mucormycosis is a life-threatening infection. Early management of diabetes and hypoxemia may improve the prognosis. Exploring effective diagnostic and treatment methods is important, and combination antifungal therapy seems to hold potential benefits.

Exploring user acceptance of online virtual reality exhibition technologies: A case study of Liangzhu Museum.

Museums increasingly rely on cutting-edge digital technologies to attract visitors. Understanding the intricate factors influencing user acceptance of these technologies is, however, crucial for their effective use. This study therefore proposes a model, grounded in the technology acceptance model, to investigate user acceptance of online virtual reality (VR) museum exhibitions. Leveraging the online VR exhibition at Liangzhu Museum as a case study, data were collected from 313 participants and analyzed using partial least squares structural equation modeling (PLS-SEM) with Smart PLS. Semi-structured interviews with 15 individuals were conducted to complement the quantitative findings. The results reveal that factors such as interactivity, immersion, and presence positively influenced users' intrinsic technological beliefs (perceived ease of use, perceived enjoyment, and perceived usefulness), ultimately affecting their willingness to use and intention to visit on-site. Notably, immersion had a direct positive effect on perceived usefulness. There is a pressing need to leverage digital and web technologies to cater to the increasingly complex and diverse needs of online visitors, and emphasizing navigational performance in online VR exhibitions is also paramount for enhancing the overall user experience.

The protective effects of aqueous extract of Schisandra sphenanthera against alcoholic liver disease partly through the PI3K-AKT-IKK signaling pathway.

Purpose: This study aimed to investigated the key chemical components and the effect of the aqueous extract of Schisandra sphenanthera (SSAE) on alcoholic liver disease (ALD) and the related molecular mechanism. Methods: This study employed UPLC-Q-TOF-MS/MS to identify the chemical compositions in SSAE. ALD rat model was established through oral administration of white spirit. Transcriptome sequencing, weighted gene co-expression network construction analysis (WGCNA), and network pharmacology were used to predict key compositions and pathways targeted by SSAE for the treatment of ALD. Enzyme-linked immunosorbent assay (ELISA), biochemical kits, hematoxylin-eosin (HE) staining, Western blotting (WB) analysis, and immunohistochemical analysis were used to validate the mechanism of action of SSAE in treating ALD. Results: Active ingredients such as schisandrin A, schisandrol A, and schisandrol B were found to regulate the PI3K/AKT/IKK signaling pathway. Compared to the model group, the SSAE group demonstrated significant improvements in cellular solidification and tissue inflammation in the liver tissues of ALD model rats. Additionally, SSAE regulated the levels of a spartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol dehydrogenase (ADH), and aldehyde Dehydrogenase (ALDH) in serum (P < 0.05); Western blotting and immunohistochemical analyses showed that the expression levels of phosphorylated PI3K, AKT, IKK, NFκB, and FOXO1 proteins were significantly reduced in liver tissues (P < 0.05), whereas the expression level of Bcl-2 proteins was significantly increased (P < 0.05). Conclusion: The active components of SSAE were schisandrin A, schisandrol A, and schisandrol B, which regulated the phosphorylation levels of PI3K, AKT, IKK, and NFκB and the expression of FOXO1 protein and upregulated the expression of Bcl-2 protein in the liver tissues of ALD rats. These findings indicate that SSAE acts against ALD partly through the PI3K-AKT-IKK signaling pathway. This study provided a reference for future research and treatment of ALD and the development of novel natural hepatoprotective drugs.

The Prevalence and Associated Factors of Post-COVID-19 Fatigue: A Systematic Review and Meta-Analysis.

After the coronavirus disease 2019 (COVID-19) pandemic, numerous individuals experienced the enduring consequences of infection. One of the psychological symptoms that patients report most frequently is persistent fatigue, which is also called post-COVID-19 fatigue. This persistent fatigue can prolong recovery time for hospitalized patients and reduce exercise motivation for residents, affecting their health and working conditions. To determine the prevalence and associated factors, we conducted searches in PubMed, Embase, Web of Science, and Cochrane Library, from inception to 27 March 2023, and a total of 38 studies and 17,738 patients were included in this analysis. We analyzed data and estimated publication bias by Egger's test and funnel plot by STATA 14. We summarized the prevalence of post-COVID-19 fatigue and calculated the pooled OR to determine associated factors. This study revealed that the prevalence of fatigue in post-COVID-19 syndrome was 46.6% (95% CI: 38.5%-54.7%). Being female (OR: 0.40, 95% CI: 0.24-0.56), older age (OR: 0.04, 95% CI: 0.01-0.07), clinical severity (OR: 0.66, 95% CI: 0.24-1.09), the number of acute COVID symptoms (OR: 3.23, 95% CI: 1.83-5.69), preexisting hypertension (OR: 1.24, 95% CI: 1.08-1.42), lung disease (OR: 2.71, 95% CI: 1.07-6.89), and depression (OR: 1.55, 95% CI: 1.01-2.39) were risk factors for post-COVID-19 fatigue. By revealing the association of these factors with fatigue, it can help us to identify and treat post-COVID-19 fatigue early.

aKNNO: single-cell and spatial transcriptomics clustering with an optimized adaptive k-nearest neighbor graph.

Typical clustering methods for single-cell and spatial transcriptomics struggle to identify rare cell types, while approaches tailored to detect rare cell types gain this ability at the cost of poorer performance for grouping abundant ones. Here, we develop aKNNO to simultaneously identify abundant and rare cell types based on an adaptive k-nearest neighbor graph with optimization. Benchmarking on 38 simulated and 20 single-cell and spatial transcriptomics datasets demonstrates that aKNNO identifies both abundant and rare cell types more accurately than general and specialized methods. Using only gene expression aKNNO maps abundant and rare cells more precisely compared to integrative approaches.

Polystyrene nanoplastics induce apoptosis, autophagy, and steroidogenesis disruption in granulosa cells to reduce oocyte quality and fertility by inhibiting the PI3K/AKT pathway in female mice.

BACKGROUND: Nanoplastics (NPs) are emerging pollutants that pose risks to living organisms. Recent findings have unveiled the reproductive harm caused by polystyrene nanoparticles (PS-NPs) in female animals, yet the intricate mechanism remains incompletely understood. Under this research, we investigated whether sustained exposure to PS-NPs at certain concentrations in vivo can enter oocytes through the zona pellucida or through other routes that affect female reproduction. RESULTS: We show that PS-NPs disrupted ovarian functions and decreased oocyte quality, which may be a contributing factor to lower female fertility in mice. RNA sequencing of mouse ovaries illustrated that the PI3K-AKT signaling pathway emerged as the predominant environmental information processing pathway responding to PS-NPs. Western blotting results of ovaries in vivo and cells in vitro showed that PS-NPs deactivated PI3K-AKT signaling pathway by down-regulating the expression of PI3K and reducing AKT phosphorylation at the protein level, PI3K-AKT signaling pathway which was accompanied by the activation of autophagy and apoptosis and the disruption of steroidogenesis in granulosa cells. Since PS-NPs penetrate granulosa cells but not oocytes, we examined whether PS-NPs indirectly affect oocyte quality through granulosa cells using a granulosa cell-oocyte coculture system. Preincubation of granulosa cells with PS-NPs causes granulosa cell dysfunction, resulting in a decrease in the quality of the cocultured oocytes that can be reversed by the addition of 17ß-estradiol. CONCLUSIONS: This study provides findings on how PS-NPs impact ovarian function and include transcriptome sequencing analysis of ovarian tissue. The study demonstrates that PS-NPs impair oocyte quality by altering the functioning of ovarian granulosa cells. Therefore, it is necessary to focus on the research on the effects of PS-NPs on female reproduction and the related methods that may mitigate their toxicity.

The influence of Type I and III collagen on the proliferation, migration and differentiation of myoblasts.

Myoblast is a kind of activated muscle stem cell. Its biological activities, such as proliferation, migration, differentiation, and fusion, play a crucial role in maintaining the integrity of the skeletal muscle system. These activities of myoblasts can be significantly influenced by the extracellular matrix. Collagen, being a principal constituent of the extracellular matrix, substantially influences these biological activities. In skeletal muscle, collagen I and III are two kinds of primary collagen types. Their influence on myoblasts and the difference between them remain ambiguous. The purpose of this study is to discover the influence of collagen I and III on biological function of myoblasts and compare their differences. We used C2C12 cell line and primary myoblasts to discover the effect of collagen I and III on proliferation, migration and differentiation of myoblasts and then performed the transcriptome sequencing and analysis. The results showed that both collagen I and III enhanced the proliferation of myoblasts, with no statistical difference between them. Similarly, collagen I and III enhanced the migration of myoblasts, with collagen I was more pronounced in Transwell assay. On the contrary, collagen I and III inhibited myoblasts differentiation, with collagen III was more pronounced at gene expression level. The transcriptome sequencing identified DEGs and enrichment analysis elucidated different terms between Type I and III collagen. Collectively, our research preliminarily elucidated the influence of collagen I and III on myoblasts and their difference and provided the preliminary experimental foundation for subsequent research.

Multimodal abnormalities of brain structures in adolescents and young adults with major depressive disorder: An activation likelihood estimation meta-analysis.

BACKGROUND: Major depressive disorder (MDD) in adolescents and young adults contributes significantly to global morbidity, with inconsistent findings on brain structural changes from structural magnetic resonance imaging studies. Activation likelihood estimation (ALE) offers a method to synthesize these diverse findings and identify consistent brain anomalies. AIM: To identify consistent brain structural changes in adolescents and young adults with MDD using ALE meta-analysis. METHODS: We performed a comprehensive literature search in PubMed, Web of Science, Embase, and Chinese National Knowledge Infrastructure databases for neuroimaging studies on MDD among adolescents and young adults published up to November 19, 2023. Two independent researchers performed the study selection, quality assessment, and data extraction. The ALE technique was employed to synthesize findings on localized brain function anomalies in MDD patients, which was supplemented by sensitivity analyses. RESULTS: Twenty-two studies comprising fourteen diffusion tensor imaging (DTI) studies and eight voxel-based morphometry (VBM) studies, and involving 451 MDD patients and 465 healthy controls (HCs) for DTI and 664 MDD patients and 946 HCs for VBM, were included. DTI-based ALE demonstrated significant reductions in fractional anisotropy (FA) values in the right caudate head, right insula, and right lentiform nucleus putamen in adolescents and young adults with MDD compared to HCs, with no regions exhibiting increased FA values. VBM-based ALE did not demonstrate significant alterations in gray matter volume. Sensitivity analyses highlighted consistent findings in the right caudate head (11 of 14 analyses), right insula (10 of 14 analyses), and right lentiform nucleus putamen (11 of 14 analyses). CONCLUSION: Structural alterations in the right caudate head, right insula, and right lentiform nucleus putamen in young MDD patients may contribute to its recurrent nature, offering insights for targeted therapies.

Pentacoordinated pyramidal structures and bonding properties of WN10-/0: anion photoelectron spectroscopy and theoretical calculations.

Anion photoelectron spectroscopy and theoretical calculations were used to investigate the structural and bonding properties of WN10-/0. The electron affinity of WN10 is measured to be 1.582 ± 0.030 eV. The frequency of the NN stretch in WN10 is measured to be 2170 ± 80 cm-1, which is red-shifted with respect to that of the dinitrogen molecule indicating that the NN bonds are weakened in WN10. The theoretical adiabatic detachment energy (ADE) and vertical detachment energy (VDE) of WN10- obtained by calculations at the CCSD(T)/CBS level agree well with experimental results. The structures of WN10-/0 are C4v symmetric pentacoordinated pyramidal structures with five end-on dinitrogen ligands. Our experiments show that the peak of WN10- is dominant in the mass spectrum of anionic WNn, whereas the mass peak of WN12+ is dominant in the mass spectrum of cationic WNn, implying that the stabilities of WNn clusters are strongly related to their charge states.

Aurantiacibacter hainanensis sp. nov. and Qipengyuania zhejiangensis sp. nov., two novel Erythrobacteraceae species isolated from tidal flat sediments.

Two Gram-stain-negative, rod-shaped, non-motile, aerobic and carotenoid-producing strains, belonging to the family Erythrobacteraceae, designated as H149T and Z2T, were isolated from tidal flat sediment samples collected in Hainan and Zhejiang, PR China, respectively. Growth of strain H149T occurred at 15-42 °C, 0-10.0 % (w/v) NaCl, and pH 6.0-8.5, with the optima at 35-37 °C, 3.0-3.5 % (w/v) NaCl and pH 7.0. Strain Z2T grew at 15-37 °C, 0-6.0 % (w/v) NaCl, and pH 6.0-9.5, with the optima at 25-30 °C, 0.5-1.0 % (w/v) NaCl and pH 6.0-6.5. Ubiquinone-10 was the sole ubiquinone in two strains. The predominant cellular fatty acids of strain H149T were C16 : 0, summed feature 3 and summed feature 8, while those of strain Z2T were C17 : 1 ω6c, summed feature 3 and summed feature 8. Strains H149T and Z2T shared diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and sphingoglycolipid as major polar lipids. The 16S rRNA gene sequence identity analysis indicated that strain H149T had the highest sequence identity of 98.4 % with Aurantiacibacter odishensis KCTC 23981T, and strain Z2T had that of 98.2 % with Qipengyuania pacifica NZ-96T. Phylogenetic trees based on 16S rRNA gene and core-genome sequences revealed that strains H149T and Z2T formed two independent clades in the genera Aurantiacibacter and Qipengyuania, respectively. Strain H149T had average nucleotide identity values of 74.0-81.3 % and in silico DNA-DNA hybridization values of 18.5-23.1 % with Aurantiacibacter type strains, while strain Z2T had values of 73.3-78.7 % and 14.5-33.3 % with Qipengyuania type strains. The genomic DNA G+C contents of strains H149T and Z2T were 64.3 and 61.8 %, respectively. Based on the genetic, genomic, phylogenetic, physiological and chemotaxonomic results, strains H149T (=KCTC 8397T=MCCC 1K08920T) and Z2T (=KCTC 8396T=MCCC 1K08946T) are concluded to represent two novel Erythrobacteraceae species for which the names Aurantiacibacter hainanensis sp. nov. and Qipengyuania zhejiangensis sp. nov. are proposed, respectively.

Applications of intelligent technology in the evaluation of mutagenicity.

Bioassays are widely used in assessment of mutagenicity. Alternative methods have also been developed, including "intelligent evaluation", which depends on the quality of data, strategies, and techniques. CISOC-PSMT is an Ames test prediction system. The strategies and techniques for intelligent evaluation and four applications of CISOC-PSMT are presented; roles in pesticide management, environmental protection, drug discovery, and safety management of chemicals are introduced.

Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies.

The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood-brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.

Prevalence of involuntary treatment among community-living older persons with dementia: A systematic review.

OBJECTIVE: This systematic review and meta-analysis aimed to ascertain the prevalence of involuntary treatment among community-living older persons with dementia and explore associated factors. METHODS: We comprehensively searched seven electronic databases (PubMed, Embase, Cochrane Library, Web of Science, CINAHL, PsycINFO, and Scopus) from their inception to October 17, 2023, with an update conducted on April 1, 2024. Meta-analysis synthesized prevalence estimates of involuntary treatment and its three subcategories, with 95% confidence intervals. RESULTS: This study included 11 research papers involving 12,136 community-dwelling individuals with cognitive impairment and dementia from 19 countries. The pooled prevalence of involuntary treatment among community-dwelling older persons with dementia was 45.2% (95% CI: 33.7-60.5%). Subcategories included physical restraints (9.8%, 95% CI: 5.1-18.8%), psychotropic medication (19.1%, 95% CI: 13.6-26.9%), and non-consensual care (34.3%, 27.6-42.7%). Factors influencing involuntary treatment were categorized as caregiver-related and care recipient-related. CONCLUSION: This study underscores the prevalent use of involuntary treatment among community-dwelling older persons with dementia, emphasizing its association with specific caregiver and care recipient factors. Addressing these findings underscores the importance of proactive measures and targeted interventions to improve the quality of care for this vulnerable population.

Calibrated CAR Signaling Enables Low-Dose Therapy in Large B-Cell Lymphoma.

We designed a CD19-targeted CAR comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3z and 4-1BB/CD3z CARs. Here we report the first-in-human, phase 1 clinical trial of 19(T2)28z-1XX CAR T cells in relapsed/refractory large B-cell lymphoma. We hypothesized that 1XX CAR T cells may be effective at low doses and investigated 4 doubling dose levels starting from 25×106 CAR T cells. The overall response rate (ORR) was 82% and complete response (CR) rate 71% in the entire cohort (n=28) and 88% ORR and 75% CR in 16 patients treated at 25×106. With the median follow-up of 24 months, the 1-year EFS was 61% (95% CI: 45-82%). Overall, grade ≥3 CRS and ICANS rates were low at 4% and 7%. The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses and may benefit the treatment of other hematological malignancies, solid tumors and autoimmunity.

Actin-bundling protein fimbrin serves as a new auxin biosynthesis orchestrator in Arabidopsis root tips.

Plants delicately regulate endogenous auxin levels through the coordination of transport, biosynthesis, and inactivation, which is crucial for growth and development. While it is well-established that the actin cytoskeleton can regulate auxin levels by affecting polar transport, its potential role in auxin biosynthesis has remained largely unexplored. Using LC-MS/MS-based methods combined with fluorescent auxin marker detection, we observed a significant increase in root auxin levels upon deletion of the actin bundling proteins AtFIM4 and AtFIM5. Fluorescent observation, immunoblotting analysis, and biochemical approaches revealed that AtFIM4 and AtFIM5 affect the protein abundance of the key auxin synthesis enzyme YUC8 in roots. AtFIM4 and AtFIM5 regulate the auxin synthesis enzyme YUC8 at the protein level, with its degradation mediated by the 26S proteasome. This regulation modulates auxin synthesis and endogenous auxin levels in roots, consequently impacting root development. Based on these findings, we propose a molecular pathway centered on the 'actin cytoskeleton-26S proteasome-YUC8-auxin' axis that controls auxin levels. Our findings shed light on a new pathway through which plants regulate auxin synthesis. Moreover, this study illuminates a newfound role of the actin cytoskeleton in regulating plant growth and development, particularly through its involvement in maintaining protein homeostasis via the 26S proteasome.