bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of different population-level summary measures for randomised trials with time-to-event outcomes, with a focus on non-inferiority trials
Authors: Quartagno Matteo , Morris Tim P , Gilbert Duncan C , Langley Ruth E , Nankivell Matthew G , Parmar Mahesh KB , White Ian R 
Published: June 2023

Background The population-level summary measure is a key component of the estimand for clinical trials with time-to-event outcomes. This is particularly the case for non-inferiority trials, because different summary measures imply different null hypotheses. Most trials are designed using the hazard ratio as summary measure, but recent studies suggested that the difference in restricted mean survival time might be more powerful, at least in certain situations. In a recent letter, we conjectured that differences between summary measures can be explained using the concept of the non-inferiority frontier and that for a fair simulation comparison of summary measures, the same analysis methods, making the same assumptions, should be used to estimate different summary measures. The aim of this article is to make such a comparison between three commonly used summary measures: hazard ratio, difference in restricted mean survival time and difference in survival at a fixed time point. In addition, we aim to investigate the impact of using an analysis method that assumes proportional hazards on the operating characteristics of a trial designed with any of the three summary measures. Methods We conduct a simulation study in the proportional hazards setting. We estimate difference in restricted mean survival time and difference in survival non-parametrically, without assuming proportional hazards. We also estimate all three measures parametrically, using flexible survival regression, under the proportional hazards assumption. Results Comparing the hazard ratio assuming proportional hazards with the other summary measures not assuming proportional hazards, relative performance varies substantially depending on the specific scenario. Fixing the summary measure, assuming proportional hazards always leads to substantial power gains compared to using non-parametric methods. Fixing the modelling approach to flexible parametric regression assuming proportional hazards, difference in restricted mean survival time is most often the most powerful summary measure among those considered. Conclusion When the hazards are likely to be approximately proportional, reflecting this in the analysis can lead to large gains in power for difference in restricted mean survival time and difference in survival. The choice of summary measure for a non-inferiority trial with time-to-event outcomes should be made on clinical grounds; when any of the three summary measures discussed here is equally justifiable, difference in restricted mean survival time is most often associated with the most powerful test, on the condition that it is estimated under proportional hazards.
Association between blood pressure and different antihypertensive drugs with outcome after ischemic stroke: A Mendelian randomization study
Authors: Liu Hanchen , Zhang Xiaoxi , Zhou Yu , Nguyen Thanh N , Zhang Lei , Xing Pengfei , Li Zifu , Shen Hongjian , Zhang Yongxin , Hua Weilong , Xu Hongye , Zhu Xuan , Chen Lei , Zuo Qiao , Zhao Rui , Li Qiang , Dai Dongwei , Zhang Yongwei , Xu Yi , Huang Qinghai , Liu Jianmin , Yang Pengfei 
Published: June 2023

Background: Observational studies suggest an association between blood pressure (BP) and functional outcomes in ischemic stroke patients but whether this is causal or due to confounding is uncertain. We used Mendelian randomization (MR) to assess causality, and also explore whether particular classes of anti-hypertensives were associated with a better outcome after ischemic stroke. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drugs from genome-wide association studies (GWAS) on 757,601 individuals. The primary outcome was 3-month dependence or death defined as a modified Rankin Scale (mRS) of 3–6. The secondary outcome was disability or death after 90 days defined as mRS 2–6. Cochran’s Q statistic in the inverse variance weighted (IVW) model, the weighted median, MR-Egger regression, leave-one-single-nucleotide polymorphism (SNP)-out analysis, MR-Pleiotropy Residual Sum and Outlier methods were adopted as sensitivity analyses. To validate our primary results, we performed independent repeat analyses and Bi-directional MR analyses. Results: Genetic predisposition to higher systolic and diastolic BP was associated with disability or death after ischemic stroke in univariable IVW MR analysis (odds ratio (OR) 1.29, 95% confidence interval (CI): 1.05–1.59, p = 0.014; OR 1.27, 95% CI: 1.07–1.51, p = 0.006, respectively). Pulse pressure was associated with both dependence or death and disability or death after ischemic stroke (OR = 1.05, 95% CI: 1.02–1.08, p = 0.002; OR = 1.04, 95% CI = 1.01–1.07, p = 0.009, respectively). Angiotensin-converting enzyme inhibitor (ACEI) and calcium channel blocker (CCB) were significantly associated with improved functional outcomes (dependence or death, OR 0.76, 95% CI: 0.62–0.94, p = 0.009; OR 0.89, 95% CI: 0.83–0.97, p = 0.005). Proxies for β-blockers, angiotensin receptor blockers (ARB), and thiazides failed to show associations with functional outcomes ( p > 0.05). Conclusion: We provide evidence for an association of genetic predisposition to higher BP with a higher risk of 3-month functional dependence after ischemic stroke. Our findings support ACEI and CCB as promising antihypertensive drugs for improving functional outcomes in ischemic stroke.
Examining a Diabetes Self-Management Education and Support Telemedicine Model With High-Risk Patients in a Rural Community
Authors: Siminerio Linda , Krall Jodi , Johnson Patricia , Ruppert Kristine , Hammoudeh Rawan , Bandi Archana , Ng Jason M. 
Published: June 2023

Background: Ongoing support is critical to diabetes self-management education and support (DSMES) effectiveness, but difficult to realize, particularly in areas with limited resources. The objective of this feasibility study was to assess the impact of a virtual support model on diabetes outcomes and acceptability with high-risk patients with type 2 diabetes in a rural community. Methods: In a 12-month nonrandomized trial in federally qualified health centers (FQHCs), patients with hemoglobin A1c (HbA1c) >9% were referred to the Telemedicine for Reach, Education, Access, Treatment, and Ongoing Support (TREAT-ON) program where a Diabetes Care and Education Specialist provided DSMES through videoconferencing. HbA1c change was compared in 30 patients in the intervention group (IG) to a propensity score-matched retrospective control group (CG) of patients who received in-person DSMES delivered by a DCES. Changes in HbA1c, diabetes distress, empowerment, self-care and acceptability were assessed within the intervention group (IG) between those who did and did not meet self-management goals. Results: The IG experienced similar significant reductions in HbA1c as the CG. Most (64%) IG participants achieved their self-management goal. Goal attainers had a significant HbA1c decrease of 0.21% every 3 months as well as significant reduction in diabetes distress and improvement in general dietary intake. Regardless of goal attainment, IG participants reported high levels of acceptability with TREAT-ON. Conclusions: This feasibility study suggests that TREAT-ON was well-received and as effective as traditional in-person DSMES. While findings augment ample evidence regarding DSMES benefits, the TREAT-ON model offers additional advantages and provides validation for telehealth to inform future practice in reaching and supporting self-management for high-risk patients in underserved areas. Trial Registration: Clinicaltrials.gov, # NCT04107935.
Systemic monotherapy with acitretin for erythrodermic psoriasis: results of a retrospective study of 81 patients
Authors: Yu Chenyang , Wu Chao , Yang Yuyan , Jin Hongzhong 
Published: June 2023

Background: Erythrodermic psoriasis (EP) remains challenging to manage because it is rare and has complex complications. Although acitretin is recommended as an appropriate choice for EP, there is a lack of large-scale evidence. Objectives: This study aims to assess the efficacy and safety of acitretin as systemic monotherapy in EP patients. Design: We retrospectively analyzed data from patients with EP who received at least 3 months of acitretin as systemic monotherapy during hospitalization and out-patient follow-up from January 2005 to May 2021 at the Peking Union Medical College Hospital, China. Methods: The efficacy was clinically evaluated after 1, 2, 4, and 12 weeks of treatment, which was classified as a good response (>75% of lesions cleared), partial response (50%–75% cleared), moderate response (25–50% cleared), or no response (<25% cleared). Safety was assessed on the basis of physical examination results and significant changes in laboratory examination results after 12 weeks of treatment. Results: Overall, 81 patients (79.0% men; mean age, 47.9 years) were included. The acitretin dose ranged from 20 to 60 mg/day (0.3 to 0.8 mg/kg/day). The rates of good, partial, and moderate responses were 0.0%, 2.5%, and 42.0% at 1 week; 3.7%, 34.6%, and 61.7% at 2 weeks; 29.6%, 58.0%, and 12.4% at 4 weeks; and 85.2%, 13.6%, and 1.2% at 12 weeks after treatment initiation, respectively. EP patients transformed from psoriasis vulgaris showed a higher good/partial response rate compared with that of EP patients that developed from pustular or articular psoriasis (44.6% vs. 14.3%, p = 0.035). Patients with concurrent infection showed a lower rate of good/partial response compared with that of those without concurrent infection (16.7% vs. 44.4%, p = 0.049). Adverse effects were seen in 45 (55.6%) patients in 12 weeks, and dyslipidemia ( n = 31; 38.3%), xerosis ( n = 24; 29.6%), and elevated liver enzymes ( n = 6; 7.4%) were most commonly reported. Twenty-three patients were followed up for over 3 years, and six (26.1%) patients had EP recurrence. Conclusions: Acitretin as a systemic monotherapy showed satisfactory effectiveness for EP, especially in patients developed from psoriasis vulgaris and without infection.
Integrated health system to assess and manage frailty in community dwelling: Co-design and usability evaluation
Authors: Moral Cristian , Pérez-Rodríguez Rodrigo , Villalba-Mora Elena , Barrio-Cortes Jaime , Ferre Xavier , Rodríguez-Mañas Leocadio 
Published: June 2023

Objective We aimed to co-create and evaluate an integrated system to follow-up frailty in a community dwelling environment and provide a multi-modal tailored intervention. Frailty and dependency among the older population are a major challenge to the sustainability of healthcare systems. Special attention must be paid to the needs and particularities of frail older persons as a vulnerable group. Methods To ensure the solution fits all the stakeholders’ needs, we performed several participatory design activities with them, such as pluralistic usability walkthroughs, design workshops, usability tests and a pre-pilot. The participants in the activities were older people; their informal carers; and specialized and community care professionals. In total, 48 stakeholders participated. Results We created and evaluated an integrated system consisting of four mobile applications and a cloud server, which has been evaluated through a 6-months clinical trial, where secondary endpoints were both usability and user experience evaluation. In total, 10 older adults and 12 healthcare professionals participated in the intervention group using the technological system. Both patients and professionals have positively evaluated their applications. Conclusion Both older adults and healthcare professionals have considered the resulted system easy to use and learn, consistent and secure. In general terms, they also would like to keep using it in the future.
Return to Sport After Multiligament Knee Injury in Young Athletes
Authors: Fine River , Curtis William , Stevens Kaleb , Imada Allicia O. , Stein Elena R. , Treme Gehron , Schenck Robert C. , Richter Dustin L. 
Published: June 2023

Background: While return to sport (RTS) in young athletes after anterior cruciate ligament (ACL) reconstruction has been well studied, little is known regarding their rate of RTS after multiligament knee injury (MLKI). Purpose: To assess the level of and factors associated with RTS after MLKI in young athletes. Study Design: Case series; Level of evidence, 4. Methods: We retrospectively identified 116 patients aged ≤23 years who had sustained an injury to ≥2 knee ligaments and undergone operative reconstruction or repair of ≥1 ligament. Our primary outcome was self-reported RTS at the preinjury level or higher. We estimated the likelihood of RTS using binomial logistic regression. Secondary variables included the 2000 International Knee Documentation Committee Subjective Knee Form (IKDC-SF), ACL–Return to Sport after Injury (ACL-RSI), and 12-Item Short Form Health Survey (SF-12) physical and mental health summaries. Results: A total of 30 (25.9%) patients (24 men, 6 women; mean age, 18.1 ± 2.5 years) completed patient-reported outcome surveys at a mean follow-up of 7.8 years (median, 6.6 years [range, 1.1-19.5 years]). A total of 28 patients underwent surgical treatment of ≥2 ligaments. RTS was achieved by 90% of patients, and 43.3% returned to their preinjury level or higher. Patients who had played sports at a higher level before injury were more likely to RTS at their preinjury level or higher (odds ratio [OR], 3.516 [95% CI, 1.034-11.955]; P = .044), while those who played cutting sports were less likely to do so (OR, 0.013 [95% CI, 0.000-0.461; P = .017). Patients who achieved RTS at their preinjury level or higher had significantly higher IKDC-SF and ACL-RSI scores versus patients who did not ( P = .001 and P = .002, respectively). The number of ligaments injured, age, mental health diagnosis, and SF-12 scores were not associated with the ability to RTS at the preinjury or higher levels. Conclusion: Most young athletes who sustained MLKI were able to return to play at some level, but a minority returned to their preinjury level. Patients who did return at preinjury or higher levels had higher IKDC-SF and ACL-RSI scores than those who did not. Performance in cutting and/or pivoting sports was negatively associated with RTS.
Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells
Authors: Carter Bing Z. , Mak Po Yee , Muftuoglu Muharrem , Tao Wenjing , Ke Baozhen , Pei Jingqi , Bedoy Andrea D. , Ostermann Lauren B. , Nishida Yuki , Isgandarova Sevinj , Sobieski Mary , Nguyen Nghi , Powell Reid T. , Martinez-Moczygemba Margarita , Stephan Clifford , Basyal Mahesh , Pemmaraju Naveen , Boettcher Steffen , Ebert Benjamin L. , Shpall Elizabeth J. , Wallner Barbara , Morgan Robert A. , Karras Georgios I. , Moll Ute M. , Andreeff Michael 
Published: June 2023

Abstract
TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53–wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.
Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma
Authors: Song Zhihui , Wu Wenjun , Wei Wei , Xiao Wenming , Lei Michelle , Cai Kathy Q. , Huang Da Wei , Jeong Subin , Zhang Jing-Ping , Wang Hongbo , Kadin Marshall E. , Waldmann Thomas A. , Staudt Louis M. , Nakagawa Masao , Yang Yibin 
Published: June 2023

Abstract
Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK− ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK− ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK− ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.
Generating porous metal surfaces as a mean to incorporate thymol-loaded nanoparticles
Authors: Zemmour Chalom , Zakharova Sofya , Benny Ofra 
Published: June 2023

AbstractPorous metals have gained interest in many fields such as biomedicine, electronics, and energy. Despite the many benefits that these structures may offer, one of the major challenges in utilizing porous metals is to incorporate active compounds, either small molecules or macromolecules, on these surfaces. Coatings that contain active molecules have previously been used for biomedical applications to enable the slow release of drugs, e.g., with drug-eluting cardiovascular stents. However, direct deposition of organic materials on metals by coatings is very difficult due to the challenge of obtaining uniform coatings, as well as issues related to layer adherence and mechanical stability. Our study describes an optimization of a production process of different porous metals, aluminum, gold, and titanium, using wet-etching. Pertinent physicochemical measurements were carried out to characterize the porous surfaces. Following the production of porous metal surface, a new methodology for incorporating active materials onto the metals by using mechanical entrapment of polymeric nanoparticles in metal pores was developed. To demonstrate our concept of active material incorporation, we produced an odor-releasing metal object with embedded particles loaded with thymol, an odoriferous molecule. Polymer particles were placed inside nanopores in a 3D-printed titanium ring. Chemical analysis, followed by smell tests, indicated that the smell intensity lasts significantly longer in the porous material containing the nanoparticles, compared with the free thymol.
Co-delivery of curcumin and si-STAT3 with a bioinspired tumor homing for polydopamine nanoparticles for synergistic osteosarcoma therapy
Authors: Wu Kunzhe , Zhou Zhongsheng , Liu Te , Liu Chunkang , Mu Xupeng , Jiang Jinlan 
Published: June 2023

Abstract
Purpose
Owing to the complexity of cancer, a synergistic combination of chemotherapy and gene therapy can be a promising therapeutic strategy. This study aimed to use stem cell membrane (SCM)-camouflaged polydopamine nanoparticles for simultaneous delivery of curcumin (CUR) and siRNA-targeting STAT3 (CPDA/siSTAT3@SCM NPs) for osteosarcoma (OS).

Methods
Transmission electron microscopy, UV–Vis absorbance spectra, zeta potential, cell co-localization, and Coomassie bright blue staining were used to characterize CPDA/siSTAT3@SCM NPs constructed by the self-assembly method. Drug release, cellular uptake, cell proliferation, apoptosis, wound healing, and transwell assays were evaluated in vitro. The expression levels of epithelial–mesenchymal transition (EMT)- and apoptosis-related proteins were measured by western blotting. Furthermore, the biodistribution, antitumor efficacy, and biosafety of CPDA/siSTAT3@SCM NPs in an MG63 xenograft mouse model were evaluated.

Results
CPDA/siSTAT3@SCM NPs were successfully synthesized to deliver CUR and siRNA simultaneously, and they showed osteosarcoma-targeting ability. Furthermore, it showed high cellular uptake and excellent synergistic antitumor effects in vitro. CPDA/siSTAT3@SCM NPs suppressed OS cell proliferation, migration, invasion, and EMT progression, and promoted the apoptotic process. In tumor-bearing mice, the treatment with CPDA/siSTAT3@SCM NPs showed an excellent antitumor effect with no side effects in major organs.

Conclusion
This study revealed that CPDA/siSTAT3@SCM NPs can target drug delivery by biomimetic multifunctional nanoparticles to treat OS through chemo-gene combined therapy.
PacBio single-molecule long-read sequencing provides new insights into the complexity of full-length transcripts in oriental river prawn, macrobrachium nipponense
Authors: Mou Cheng-Yan , Li Qiang , Huang Zhi-Peng , Ke Hong-Yu , Zhao Han , Zhao Zhong-Meng , Duan Yuan-Liang , Li Hua-Dong , Xiao Yu , Qian Zhou-Ming , Du Jun , Zhou Jian , Zhang Lu 
Published: June 2023

Abstract
Background
Oriental river prawn (Macrobrachium nipponense) is one of the most dominant species in shrimp farming in China, which is a rich source of protein and contributes to a significant impact on the quality of human life. Thus, more complete and accurate annotation of gene models are important for the breeding research of oriental river prawn.

Results
A full-length transcriptome of oriental river prawn muscle was obtained using the PacBio Sequel platform. Then, 37.99 Gb of subreads were sequenced, including 584,498 circular consensus sequences, among which 512,216 were full length non-chimeric sequences. After Illumina-based correction of long PacBio reads, 6,599 error-corrected isoforms were identified. Transcriptome structural analysis revealed 2,263 and 2,555 alternative splicing (AS) events and alternative polyadenylation (APA) sites, respectively. In total, 620 novel genes (NGs), 197 putative transcription factors (TFs), and 291 novel long non-coding RNAs (lncRNAs) were identified.

Conclusions
In summary, this study offers novel insights into the transcriptome complexity and diversity of this prawn species, and provides valuable information for understanding the genomic structure and improving the draft genome annotation of oriental river prawn.