bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma
Authors: Dhakal Binod , Hari Parameswaran , Chhabra Saurabh , Szabo Aniko , Lum Lawrence G , Glass Deborah D , Park Jee Hyun , Donato Michele , Siegel David S , Felizardo Tania C , Fowler Daniel H
Published: January 2025

Background

Polyclonal autologous T cells that are epigenetically reprogrammed through mTOR inhibition and IFN-α polarization (RAPA-201) represent a novel approach to the adoptive T cell therapy of cancer. Ex vivo inhibition of mTOR results causes a shift towards T central memory (TCM) whereas ex vivo IFN-α promotes type I cytokines, with each of these functions known to enhance the adoptive T cell therapy of cancer. Rapamycin-resistant T cells polarized for a type II cytokine phenotype were previously evaluated in the allogeneic transplantation context.

Methods

The clinical trial (NCT04176380) evaluated RAPA-201 therapy in combination with fludarabine-sparing low-dose host conditioning for the treatment of patients with relapsed, refractory multiple myeloma (RRMM).

Results

From December 2020 to December 2022, 14 patients with RRMM received a median of three RAPA-201 infusions (median dose, 80×106cells). RAPA-201 drug products (DPs) were: polyclonal; enriched for TCMcells; reduced for immune checkpoint expression, including PD1, CD73, and LAIR1; and preferentially secreted Th1 cytokines. The median chemotherapy dose administered per cycle was 1,817 mg total for cyclophosphamide (range, 1,100–2,200) and 2.35 mg/M2for pentostatin (range, 0–16). Nine of 14 patients (64%) achieved disease remission, with eight partial responses and one stringent complete response. Median progression-free survival was 6.0 months (range, 2.1 to>16.8 months). There were no toxicities of any grade attributable to RAPA-201, including no cytokine release syndrome and no immune effector cell-associated neurotoxicity syndrome. Only 4 of 14 patients (29%) had a serious adverse event (≥ grade 3) of any attribution.

Conclusions

Consistent with our hypothesis, ex vivo manufacturing using mTOR inhibition and IFN-α polarization consistently yielded a novel RAPA-201 DP that possessed a desirable phenotype relative to cytokine phenotype, memory status, and checkpoint expression. RAPA-201 recipients had preservation of T cell counts and Th1 cytokine secretion yet had increased T cell receptor clonality that associates with antitumor responses in the setting of monoclonal antibody checkpoint therapy. RAPA-201 therapy overcomes previous barriers to effective autologous polyclonal T-cell therapy, as it is feasible to manufacture, exquisitely safe to administer, and mediates remission in patients with RRMM.

Trial registration number

ClinicalTrials.gov:NCT04176380.
Ischaemia-reperfusion time differences in ST-elevation myocardial infarction in very young patients: a cohort study
Authors: Juan-Salvadores Pablo , De La Torre Fonseca Luis Mariano , Calderon-Cruz Beatriz , Veiga Cesar , Pintos-Rodríguez Samuel , Fernandez Barbeira Saleta , Jimenez Diaz Victor Alfonso , Iñiguez Romo Andres
Published: January 2025

Introduction

ST-elevation myocardial infarction (STEMI) is one of the most prevalent presentations in young patients. It is essential to emphasise that each minute of delay in providing medical care is negatively correlated to the patient’s prognosis. The present study was carried out to evaluate the ischaemia-reperfusion times in patients ≤40 years of age versus individuals >40 years of age and their association with mortality and major adverse cardiac event (MACE) over the long term.

Methods

A retrospective, multicentre cohort study was carried out in 6799 patients diagnosed with STEMI. Two groups were established: patients diagnosed with STEMI and aged >40 years, and patients diagnosed with STEMI and aged ≤40 years.

Results

The patients in the young group had a significantly sooner electrocardiographic diagnosis than the patients >40 years of age. A delay was observed in females, with a relative risk (RR) of 1.21 (95% CI 1.13 to 1.30) (p<0.001). Presenting dyspnoea (RR 1.76, 95% CI 1.5 to 2.06) (p<0.001) or going to a hospital without haemodynamics (RR 1.55, 95% CI 1.45 to 1.67) (p<0.001) was related to increased delay. The occurrence of MACE in the first year of follow-up was related to different risk factors, along with a delay in healthcare (HR 1.25, 95% CI 1.10 to 1.54) (p<0.042).

Conclusion

This study shows that young patients with STEMI tend to receive a sooner diagnosis than older individuals. Delays in healthcare represent one of the main factors related to the occurrence of MACE and non-event-free survival.
Co-producing knowledge about the Pacific walrus and climate change
Authors: Metcalf Vera , Apassingok Daniel , Campbell Iver , Gologergen Arnold , Gologergen Bivers , Noongwook Edwin , Huntington Henry P. , Garlich-Miller Joel L. , Johnson Devin L.
Published: January 2025

Pacific walruses ( Odobenus rosmarus divergens, Illiger 1815) have long been vital to Indigenous communities along Alaska’s west coast. Although current harvest rates are sustainable, climate change and increased industrial activity in the range of this species pose threats to the population and to hunting safety and success. To gather information relevant to addressing these concerns, the Eskimo Walrus Commission and the US Fish and Wildlife Service held a workshop in August 2023 in Nome, Alaska, with experienced Yupik walrus hunters from the communities of Gambell and Savoonga on St. Lawrence Island, Alaska, and Federal walrus biologists. The 3-day event documented extensive information about walrus biology and behavior, which was used to improve a walrus population model. Workshop discussions also addressed concepts of sustainability and the future of walrus hunting. The workshop benefitted from prior collaboration between the biologists and some of the hunters on a walrus research cruise in the Chukchi Sea earlier the same summer, creating a foundation of common experience and interpersonal relationships. In the longer term, the workshop helped demonstrate the value of equitable collaboration towards shared goals, in part by allowing for open conversations rather than, for example, an extended question-and-answer session regarding model parameters.
Comparing outbreak regimes of western spruce budworm at low- and high-elevation sites in Idaho using dendrochronology
Authors: Woodruff Ian M. , Hicke Jeffrey A. , Andrus Robert A.
Published: January 2025

The western spruce budworm ( Choristoneura freemani; WSB) is the most damaging defoliating insect in the Pacific Northwest. Despite general knowledge about climate influences on WSB, few studies have evaluated how outbreak dynamics are affected by local variability in climate. We used dendrochronological techniques to reconstruct WSB activity in Douglas-firs ( Pseudotsuga menziesii) at three low- and three high-elevation sites (representing climate variability) in Idaho, USA. We first tested different thresholds used in an established algorithm for determining WSB activity and found substantial variability in outbreak metrics. We then compared the timing of our reconstructed outbreaks with activity reported by aerial surveys, historical reports, and other reconstructions. Some agreement occurred in non-outbreak periods, but significant disagreement existed in the timing of outbreaks. Our assessment of topo-climatic influences on reconstructed WSB activity revealed that defoliation frequency was lower at low-elevation sites, with some inconsistencies depending on metric and threshold choice. Finally, we examined the influence of interannual variability of drought on outbreak initiation, finding no consistent effects. Our results reveal sensitivity to the choice of threshold of the reconstruction algorithm and suggest that more investigation is needed to better understand the role of climate, given future conditions that will likely be warmer and drier.
Detecting higher-order chromosome interactions by polymer modeling
Authors: Conte Mattia , Bianco Simona , Esposito Andrea , Abraham Alex , Guha Sougata , Vercellone Francesca , Fontana Andrea , Di Pierno Florinda
Published: January 2025

Recent experiments have revealed that human chromosomes have an intricate three-dimensional architecture in the cell nucleus, encompassing a hierarchy of interactions across multiple genomic scales. Despite those advances, detecting multiway DNA contacts at the single-molecule level remains challenging. Here, we use polymer physics models to investigate higher-order chromosomal contacts within a key genomic region in human colorectal cancer cells. By running extensive Molecular Dynamics simulations, we test model predictions against available experimental data and show that the model ensemble of single-molecule conformations significantly captures complex multiway chromosomal interactions beyond mere pairwise contacts.
Integrating User Profiles and Collaborative Filtering for Smart Recommendation of Tourism City Cultural and Creative Products
Authors: Zhang Shuping
Published: January 2025

In the domain of tourism and cultural creative product recommendations, the design and implementation of personalized recommendation systems are crucial for enhancing user satisfaction and engagement. Although traditional recommendation systems, such as Collaborative Filtering techniques, have been widely applied, they still face challenges in dealing with sparse data and achieving highly personalized recommendations. To solve this problem, a collaborative filtering recommendation method combining user profiles and multi-task knowledge acquisition is proposed in this study. We first construct consumer profiles with the aid of studying users behavioral facts and demographic statistics, after which layout a multi-task learning framework that improves the accuracy and personalization degree of tips through getting to know common functions of various however associated recommendation duties through shared representations. We evaluated our approach on numerous actual-international datasets, and the experimental outcomes display sizable improvements over conventional collaborative filtering strategies and other existing recommendation systems in key overall performance signs along with accuracy, recall, and F1-score. These results indicate that the collaborative filtering advice approach is more advantageous via the mixing of person profiles and multi-venture learning holds sizable software potential inside the subject of tourism metropolis cultural and innovative product recommendations.
A Study of Knowledge Graph and IoT Integration-Based Anomalous Event Tracking Method for Digital Platforms
Authors: Zhou Digui , Tan Qiwen , Huang Hualin , Huang Qi , Qin Ning
Published: January 2025

In digital platforms, abnormal events involve multiple data sources and complex information types, and the difficulty of tracking them increases due to the similarity and interaction between components, operations, and user behavior. Therefore, in order to achieve precise tracking and efficient processing of abnormal events, and thereby improve the stability and security of the platform, a digital platform abnormal event tracking method based on a knowledge graph is proposed. First, using data mining and association rule techniques, abnormal event data in the digital platform are effectively collected and integrated. Subsequently, the data are input into a model that integrates residual atrous convolutional neural networks and conditional random fields to achieve precise identification of key entities. On the basis of entity recognition, the correlation between entities is extracted and a knowledge graph architecture for abnormal events is constructed, providing a solid foundation for subsequent deep analysis. Through a visual interface, the knowledge graph of abnormal events can be intuitively displayed, making it easy for users to quickly understand the full picture of the event. At the same time, the knowledge graph subgraph matching algorithm is adopted, combined with flow graph indexing and optimal matching sequence, to achieve accurate tracking and recognition of abnormal events. The experimental results show that this method can effectively track abnormal events in the digital platform. The first detection time is relatively short, with a mishandling time of 8.3[Formula: see text]s and data duplication of 7.9[Formula: see text]s. The continuous tracking time is long, with a security vulnerability of 50[Formula: see text]min. The false alarm rate is low, with the highest being 2.1% for data duplication, and the false miss rate is also low, with the highest being 0.8% for mishandling. This method can identify the number of abnormal events, which helps to understand the stability and health status of the platform. By timely and effectively preventing abnormal events, the frequency of their occurrence can be reduced, and the overall security and stability of the platform can be improved.
Based on the New Dynamic Network DEA and Malmquist Index of High-Quality Innovation in the New Energy Vehicle Economy Development Research of the Internet of Things
Authors: Deng Lingfeng , Fu Wenzhi , Hu Mengting , Hu Shanmei , Liu Tao
Published: January 2025

This paper takes the enterprise economic data of new energy vehicles (NEVs) in 2018–2023 as the research background, combined with the performance evaluation theory of the NEV industry, and systematically discusses how to make the high-quality innovative development of NEVs as the research purpose. We use the new dynamic network data envelope analysis (DEA) model, Marmquist Index and other and the Internet of Things internationally recognized, scientific and effective data models as research methods to make an in-depth analysis of the business performance of five representative enterprises on multi-quantitative input-output issues. The research results show that the NEV industry has a good development prospect and economic foundation on the whole, but it still faces challenges such as limited space for core technology progress, insufficient carbon emission reduction and environmental protection planning. At the end, this paper puts forward innovation suggestions such as accelerating technological innovation, optimizing production process and responding to preferential policies and exploring international market.
Dynamics of Pinned Pulses in a Class of Nonlinear Reaction–Diffusion Equations with Strong Localized Impurities
Authors: Li Ji , Shen Jianhe , Zhang Qian
Published: January 2025

For linear reaction–diffusion equations, a general geometric singular perturbation framework was developed, to study the impact of strong, spatially localized, smooth nonlinear impurities on the existence, stability, and bifurcation of localized structure, in the paper [ Doelman et al. ,  2018 ]. The multiscale nature enables deriving algebraic conditions determining the existence of pinned single- and multi-pulses. Moreover, linearity enables treating the spectral stability issue for pinned pulses similarly to the problem of existence. In this paper, we move one step further to treat a special type of nonlinear reaction–diffusion equation with the same type of impurity. The additional nonlinear term generates richer and more complex dynamics. We derive algebraic conditions for determining the existence and stability of pinned pulses in terms of Legendre functions.
Dynamics of a Harvested Leslie–Gower Predator–Prey Model with Simplified Holling Type IV Functional Response
Authors: Huangfu Chenyang , Li Zhong , Chen Fengde , Chen Lijuan , He Mengxin
Published: January 2025

This paper investigates a Leslie–Gower predator–prey model with simplified Holling type IV functional response and constant-yield prey harvesting. We analyze conditions for the existence of positive equilibria and prove that the system has at most four positive equilibria. The results show that the double positive equilibrium is a cusp of codimension at most 4, the triple positive equilibrium is a degenerate saddle or nilpotent focus of codimension-3, and the quadruple positive equilibrium is a nilpotent cusp of codimension-5. In addition, as the parameters vary, the system can undergo a cusp-type (or focus-type) degenerate Bogdanov–Takens bifurcation of codimension-4 (or codimension-3). Furthermore, the positive equilibrium is a weak focus of order at most 4, and the model can undergo a degenerate Hopf bifurcation of codimension-4. Finally, our main results are verified by some numerical simulations, which also reveal that there exist three limit cycles containing one positive equilibrium, or one (or two) limit cycles containing three positive equilibria, or a limit cycle as well as a homoclinic loop.
Zero Forcing Number of Cubic and Quartic Cayley Graphs on Abelian Groups
Authors: Li Huixian , Ji Shengjin , Li Guang
Published: January 2025

Let [Formula: see text] be the Cayley graph on the abelian group [Formula: see text]. The zero forcing number [Formula: see text] of graph [Formula: see text] is the minimum of [Formula: see text] over all zero forcing sets [Formula: see text]. In this paper, for cubic connected Cayley graphs [Formula: see text] on abelian groups [Formula: see text], we show that [Formula: see text] or [Formula: see text]. Moreover, we prove that for quartic connected Cayley graphs [Formula: see text] on abelian groups [Formula: see text] with [Formula: see text], either [Formula: see text] or [Formula: see text] is determined by the order of the elements of [Formula: see text].
The geotechnical behavior and microstructural characteristics of the alkaline residue/cement stabilized expansive soil under wetting-drying cycles
Authors: Zhu Fanghua , Wu Zhigang , Zhang Zhifeng , Yang Dahai , Wen Guangjun
Published: January 2025

In order to explore the geotechnical behavior of expansive soil stabilized by alkaline residue/cement (ARC) under wetting-drying (W-D) cycles, the shrink-swell characteristics, unconfined compressive strength (UCS), compressibility and microstructural characteristics are experimentally investigated in this study. The findings indicate that the incorporation of ARC, particularly with an alkaline residue (AR) content of less than 5%, significantly mitigates the shrink-swell behavior, reduces soil compressibility, and enhances the UCS of the soil. Beyond this threshold, the soil's strength decreases and compressibility increases with increasing W-D cycles. Microstructural analysis reveals the formation of beneficial cementitious products such as C-A-H, C-S-H, and AFt, which contribute to improve engineering performance in the early stages of W-D cycles. Nevertheless, as the W-D cycles continue, these beneficial products diminish, leading to an increase in soil cracks and pores, which indicates a degradation in soil performance. The research posits that ARC can effectively serve as a partial substitute for cement in the stabilization of expansive soils, with the amount of AR within 5%. Despite ARC's environmental advantages as an alternative binder, it may encompass harmful elements. Therefore, a comprehensive environmental risk assessment is essential. Further studies are needed to discern the enduring effects of environmental variables on soils stabilized with ARC.
Automated Monitoring of Web User Interfaces
Authors: Visconti Ennio , Tsigkanos Christos , Nenzi Laura
Published: January 2025

Application development for the modern Web involves sophisticated engineering workflows – including user interface (UI) aspects. Such user interfaces comprise Web elements that are typically created with HTML/CSS markup and JavaScript-like languages, yielding Web documents. Their testing entails performing checks to examine visual and structural parts of the resulting UI software against requirements such as usability, accessibility, performance, or, increasingly, compliance with standards. However, current techniques are largely ad-hoc and tailor-made to specific classes of requirements or Web technologies and extensively require human-in-the-loop qualitative evaluations. Web UI evaluation so far has lacked formal foundations, which would provide assurances of compliance with requirements in an automatic manner.

To this end,

we devise a methodology and accompanying technical framework for web UIs. In our approach, requirements are formally specified in a spatio-temporal logic able to capture both the layout of visual components as well as how they change over time, as a user interacts with them. The technique we advocate is independent of the underlying technologies a Web application may be developed with, as well as the browser and operating system used.

To concretely support the specification and evaluation of UI requirements, our framework is grounded on open-source tools for instrumenting, analyzing, and reporting spatio-temporal behaviors in webpages. We demonstrate our approach in practice over

Web accessibility standards posing challenges for automated verification.
The Author’s Journey - Understanding and improving the authoring process of theory-driven socially intelligent agents
Authors: Guimarães Manuel , Campos Joana , Santos Pedro A. , Dias João , Prada Rui
Published: January 2025

State of the art agent-modelling tools support the creation of powerful Socially Intelligent Agents (SIAs) capable of engaging in social interactions with participants in various roles and environments. However, their deployment demands a laborious authoring task as it is necessary to manually define behaviour rules and create content for different interaction scenarios.

While Socially Intelligent Agents (SIAs) research has centered on the user experience, we shift focus to the authors. To understand the challenges faced by authors who create these agents, we performed an innovative analysis of the authoring experience in modern agent modelling tools. One key finding is that, while SIA concepts are generally understandable, emotional-based concepts are not as easily comprehended or used by authors. We propose a hybrid solution approach that culminated in the development of Authoring Assisted FAtiMA-Toolkit. The augmented agent modeling tool incorporates a data-driven authoring assistant to boost author productivity while promoting transparency and authorial control. To evaluate the impact of this framework on the authoring experience, we conducted a user study. Results showed that authors using the Authoring-Assisted FAtiMA-Toolkit were on average able to create more SIA-related content in less time.

Our findings suggest that data-augmented, theory-grounded agent modeling tools can support the development of affective social agents by reducing the authoring burden without sacrificing the framework’s clarity or the authors’ control over the content
TAEFuzz
: Automatic Fuzzing for Image-based Deep Learning Systems via Transferable Adversarial Examples
Authors: Ji Shunhui , Huang Changrong , Ren Bin , Dong Hai , Grunske Lars , Xiao Yan , Zhang Pengcheng
Published: January 2025

Deep learning (DL) components have been broadly applied in diverse applications. Similar to traditional software engineering, effective test case generation methods are needed by industry to enhance the quality and robustness of these deep learning components. To this end, we propose a novel automatic software testing technique,
TAEFuzz
(Automatic
Fuzz
-Testing via
T
ransferable
A
dversarial
E
xamples), which aims to automatically assess and enhance the robustness of image-based deep learning (DL) systems based on test cases generated by transferable adversarial examples.
TAEFuzz
alleviates the over-fitting problem during optimized test case generation and prevents test cases from prematurely falling into local optima. In addition,
TAEFuzz
enhances the visual quality of test cases through constraining perturbations inserted into sensitive areas of the images. For a system with low robustness,
TAEFuzz
trains a low-cost denoising module to reduce the impact of perturbations in transferable adversarial examples on the system. Experimental results demonstrate that the test cases generated by
TAEFuzz
can discover up to 46.1% more errors in the targeted systems, and ensure the visual quality of test cases. Compared to existing techniques,
TAEFuzz
also enhances the robustness of the target systems against transferable adversarial examples with the perturbation denoising module.
Preparation of Personalized Medicines through Collaborative Robots: A Hybrid Approach to the End-User Development of Robot Programs
Authors: Gargioni Luigi , Fogli Daniela , Baroni Pietro
Published: January 2025

Galenic formulations are personalized medicines prepared by pharmacists in their laboratories. They are produced in small batches considering single patients’ characteristics, such as age, gender, allergies, and the like, thus contributing to responsible health. The production process is performed manually with the support of mechanic machines. This activity is time-consuming, prone to errors, and subject to quality variations. In this paper, we propose the integration of collaborative robots into the galenic formulation process to obtain several advantages, such as increased productivity, reduced variability, improved accuracy, and minimized risks associated with human error. Additionally, the use of robots can alleviate the physical burden on human operators, allowing them to focus on higher-level tasks that require critical thinking and decision-making. To achieve this goal, a software application, called PRAISE (Pharmaceutical Robotic and AI System for End users), has been developed; it is meant to support end users (i.e., pharmacists) in defining robot programs suitable to the case at hand. This application is conceived as an End-User Development (EUD) environment, which implements a hybrid interaction approach based on a natural language interface leveraging Large Language Models and a graphical interface to check and possibly revise the user-created robot programs. A user study carried out with 9 pharmacists demonstrates the validity of the approach.
Cell-Instructive Biomaterials with Native-Like Biochemical Complexity
Authors: Marjan Tuba , Lafuente-Gómez Nuria , Rampal Akaansha , Mooney David J. , Peyton Shelly R. , Qazi Taimoor H.
Published: January 2025

Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases. In this review, we discuss advances in characterizing, mimicking, and harnessing biochemical signals in developing advanced engineered biomaterials. An overview of the diverse forms in which these biochemical signals exist and their effects on intracellular signal transduction is also provided. Finally, we highlight the application of biochemically complex biomaterials in the three broadly defined areas of tissue regeneration, immunoengineering, and organoid morphogenesis.
Single-Session Interventions for Mental Health Problems and Service Engagement: Umbrella Review of Systematic Reviews and Meta-Analyses
Authors: Schleider Jessica L. , Zapata Juan Pablo , Rapoport Andy , Wescott Annie , Ghosh Arka , Kaveladze Benji , Szkody Erica , Ahuvia Isaac L.
Published: January 2025

Most people with mental health needs cannot access treatment; among those who do, many access services only once. Accordingly, single-session interventions (SSIs) may help bridge the treatment gap. We conducted the first umbrella review synthesizing research on SSIs for mental health problems and service engagement in youth and adults. Our search yielded 24 systematic reviews of SSIs, which included 415 unique trials. Twenty reviews (83.33%) reported significant, positive effects of SSIs for one or more outcomes (anxiety, depression, externalizing problems, eating problems, substance use, treatment engagement or uptake). Across 12 reviews that meta-analytically examined SSIs’ effectiveness relative to controls, SSIs showed a positive effect across outcomes and age groups (standardized mean difference = −0.25, I
2 = 43.17%). Per AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews), some methodological concerns emerged across reviews, such as low rates of preregistration. Overall, findings support the clinical utility of SSIs for certain psychological problems and populations. Implementation research is needed to integrate effective SSIs into systems of care.
Sexual dimorphism in the downregulation of extracellular matrix genes contributes to aortic stiffness in female mice
Authors: Kamau Anne N. , Sakamuri Anil , Okoye Delphine O. , Sengottaian Divya , Cannon Jennifer , Guerrero-Millan Josefa , Sullivan Jennifer C. , Miller Kristin S. , Liu Yutao , Ogola Benard O.
Published: January 2025

FCG mice model can segregate vascular phenotypes by sex hormones, sex chromosomes, and their interaction. We show increased aortic stiffening in XX versus XY female mice and decreased ECM genes, suggesting decreased distensibility and impaired mechanotransduction in XXF versus XYF mice aortas. Therefore, the XX versus XY differences imply a unique role for sex chromosomes in regulating aortic integrity and ECM genes in female mice.
Sexual dimorphism in right ventricular adaptation to pressure overload involves differential angiogenic response
Authors: Seelemann Erica R. , Panchakshari Sheethal , Labana Parabhjot Kaur , Wolverton Maxwell M. , Deng Yupu , Abdelwahab Haya , Consmueller Chris , Stewart Duncan J. , Chaudhary Ketul R.
Published: January 2025

Female patients with pulmonary hypertension have better right ventricular adaptation compared with male. These sex differences were modeled in right heart failure susceptible Fischer CDF rat using pulmonary artery banding model. Preservation of right ventricular function in female rats is linked to better right ventricular angiogenic response that involves higher intrinsic angiogenic ability of female right ventricular endothelial cells together with the proangiogenic effects of female sex hormone estradiol through sphingosine kinase-1.
Comprehensive echocardiographic protocol for pigs with emphasis on diastolic function: advantages over MRI assessment
Authors: Martinez Naya Nadia , Sharp Thomas E. , Sgai Manuela G. , Capcha Jose M. C. , Shehadeh Lina A.
Published: January 2025

Anatomical positioning: porcine heart is more central and caudal than human heart; apical views are obtained at sixth to seventh intercostal space; right parasternal views are most reliable in pigs. Technical requirements are as follows: standardized sedation protocol is essential; specialized veterinary procedure table; and integrated electrocardiogram (ECG) monitoring for timing. Clinical value: excellent translational model for cardiovascular research; regular protocol adjustment based on animal size.
Figure S4 from Serially Quantifying TERT Rearrangement Breakpoints in ctDNA Enables Minimal Residual Disease Monitoring in Patients with Neuroblastoma
Authors: Hollander Jan F. , Szymansky Annabell , Wünschel Jasmin , Astrahantseff Kathy , Rosswog Carolina , Thorwarth Anne , Thole-Kliesch Theresa M. , Chamorro González Rocío , Hundsdörfer Patrick , Hauptmann Kathrin , Schmelz Karin , Gürgen Dennis , Rogasch Julian M.M. , Henssen Anton G. , Fischer Matthias , Schulte Johannes H. , Eckert Cornelia , Eggert Angelika , Lodrini Marco , Deubzer Hedwig E.
Published: January 2025

Figure S4
Figure S3 from Serially Quantifying TERT Rearrangement Breakpoints in ctDNA Enables Minimal Residual Disease Monitoring in Patients with Neuroblastoma
Authors: Hollander Jan F. , Szymansky Annabell , Wünschel Jasmin , Astrahantseff Kathy , Rosswog Carolina , Thorwarth Anne , Thole-Kliesch Theresa M. , Chamorro González Rocío , Hundsdörfer Patrick , Hauptmann Kathrin , Schmelz Karin , Gürgen Dennis , Rogasch Julian M.M. , Henssen Anton G. , Fischer Matthias , Schulte Johannes H. , Eckert Cornelia , Eggert Angelika , Lodrini Marco , Deubzer Hedwig E.
Published: January 2025

Figure S3
Figure 5 from Serially Quantifying TERT Rearrangement Breakpoints in ctDNA Enables Minimal Residual Disease Monitoring in Patients with Neuroblastoma
Authors: Hollander Jan F. , Szymansky Annabell , Wünschel Jasmin , Astrahantseff Kathy , Rosswog Carolina , Thorwarth Anne , Thole-Kliesch Theresa M. , Chamorro González Rocío , Hundsdörfer Patrick , Hauptmann Kathrin , Schmelz Karin , Gürgen Dennis , Rogasch Julian M.M. , Henssen Anton G. , Fischer Matthias , Schulte Johannes H. , Eckert Cornelia , Eggert Angelika , Lodrini Marco , Deubzer Hedwig E.
Published: January 2025

Bone marrow (BM) plasma is sufficient to detect TERT breakpoint, ALK p.R1275Q mutation, and ALK copy numbers in the novel ddPCR assay. Comparative analysis of TERT breakpoints, ALK p.R1275Q mutation, and ALK copy numbers in cell free DNA in the separated liquid component (BM plasma) and the cellular fraction samples from BM aspirates from patients P2 (days 0, 148, and 310 after diagnosis), P3 (days 423 and 482 after diagnosis), and P4 (day 134 in hospital). Pairs from the same patient sample are connected by lines.
CC Genotype at TCF7L2 Diabetes Risk Locus rs7903146 Directs a Coordinated Fatty Acid Response to a Mediterranean Diet Intervention: A Randomized Controlled Trial
Authors: Parnell Laurence D. , Lai Chao-Qiang , Holzapfel Christina , Christensen Jacob J. , Ordovás José M.
Published: January 2025

Introduction: Previous studies identified genetic links between the TCF7L2 C/T variant rs7903146, type 2 diabetes (T2D), and obesity. We wished to deepen our understanding of how specific diets interact with this variant to affect blood metabolites, an aspect not previously investigated. Hence, we conducted a controlled study where individuals with different genotypes followed a Mediterranean (Med) or low-fat (LF) diet for 1 week. Methods: Participants were recruited from the Boston, MA (USA) area. Anthropometric and clinical measures were taken. Genotypes at rs7903146 were ascertained, with homozygous carriers of the more common and protective CC or risk TT genotype invited to participate. Participants followed both diets (LF or Med) for 1 week with ∼10 days’ washout between diets. Blood samples taken at the beginning and end of each diet period underwent metabolomics analysis using nuclear magnetic resonance spectroscopy. We evaluated how the diet affected different metabolites based on genetic profile. Results: The cohort of 35 persons was 43% female, aged 18–70 y, with BMI between 26.4 and 33.9 kg/m2. Focusing on fatty acids (FAs) and other lipid metabolic factors (n = 23), we observed a greater number and stronger correlations among these factors in the CC genotype-Med diet group than in the other three genotype-diet combinations. An aggregate of 11 factors, each negatively correlating with delta-saturated fatty acids (SFA), showed a significant genotype-Med diet interaction on delta-SFA in CC individuals on the Med diet (p = 0.0046). A similar genotype-Med diet interaction was observed for delta-monounsaturated fatty acids (p = 0.0078). These interactions were not statistically significant at the end of the LF intervention. Conclusion: Our findings suggest that the Med diet has a stronger influence on regulating lipid factors in individuals with the CC genotype at the TCF7L2 variant rs7903146. This diet-genotype interaction may have significant implications for understanding the inter-individual variation of metabolic response on specific dietary regimens.
Understanding the Support Needs of People with Autosomal Dominant Polycystic Kidney Disease: A Qualitative Phenomenological Descriptive Study
Authors: Rasmussen Katrine Schmidt , Khatir Dinah Sherzad , Birn Henrik , Poulsen Selina Emilie , Finderup Jeanette
Published: January 2025

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary kidney disease and the fourth most common cause of kidney failure. Patients may be aware of their condition from an early age or discover it unexpectedly, with varying levels of familial knowledge about the disease. This chronic condition presents significant challenges for healthcare professionals. The study aimed to investigate how people with ADPKD experience their participation in a dedicated ADPKD clinic and to investigate their support needs in managing their disease in everyday life. Methods: A qualitative phenomenological descriptive study was conducted, involving semi-structured telephone interviews with patients who attended a newly established dedicated ADPKD clinic between March and April 2023. The data were analyzed using Malterud’s principles of systematic text condensation. Results: In total, 18 out of 22 patients agreed to participate in the interviews. Six themes emerged from the interviews. Participants expressed feelings of uncertainty about their future and highlighted the necessity for personalized care tailored to their individual circumstances. They reported challenges in coping with emotions associated with the disease and sought assistance in making difficult decisions. Maintaining control over their health and illness was a significant theme, alongside a desire for increased knowledge about their condition. Conclusion: Our study supports existing knowledge in this area. In this study, the participants experienced satisfaction with the dedicated ADPKD clinic, feeling well informed, listened to, and more at ease after the check-up. Investing in a dedicated ADPKD clinic could help alleviate the uncertainty that many people with ADPKD experience.
Interventions to Prevent and Manage Infections in Pregnancy
Authors: Yasin Rahima , Jiang Li , Das Jai K. , Bhutta Zulfiqar A.
Published: January 2025

Background: Care interventions aimed at preventing and treating maternal infections during the gestational period are of paramount importance. Timely immunizations, screening strategies, and management of maternal infections reduce the risk of complications for the developing fetus and play a pivotal role in improving neonatal outcomes. Summary: We aim to summarize evidence for a total of thirteen interventions, pertaining to the prevention and treatment of maternal infections during the antenatal period, from Every Newborn Series published in The Lancet 2014. We identified the most recent systematic reviews, extracted data from each review, and conducted a sub-group meta-analysis for low-income countries and lower-middle-income countries (LMICs) for outcomes relevant to neonatal health. Findings from our papers indicate limited evidence from LMICs, highlighting the pressing need for coordinated efforts to close this gap and strengthen the body of inclusive evidence on prevention and treatment of maternal infections during pregnancy. Key Messages: Evidence from LMICs suggests that influenza virus vaccination had no effect on stillbirth, preterm birth, small for gestational age, or low birthweight (LBW). Insecticide-treated bed nets in pregnancy reduced the risk of fetal loss and improved the babies’ birthweight. Changing a two-dose intermittent preventive treatment (IPTp) regimen to more frequent IPTp dosing decreased the risk of LBW and significantly improved babies’ birthweight. Addition of antibacterial antibiotic to the IPTp regimen significantly reduced the risk of LBW. Antibiotic treatments for syphilis and chlamydia had a significant effect on LBW. Treatment of documented periodontal disease during pregnancy reduced the risk of LBW.
Tetrastigma fruticosum, a new species of Vitaceae from limestone karst in central Laos
Authors: TAGANE SHUICHIRO , SOULADETH PHETLASY , PHONEPASEUTH PHONGPHAYBOUN , VONGTHAVONE THYRAPHON , KONGXAISAVATH DEUANTA , YAMAMOTO TAKENORI , MURAKAMI NORIAKI
Published: January 2025

A new species of Tetrastigma, T. fruticosum (Vitaceae), from the limestone karst in Khammouane Province, central Laos, is described. The new species can be distinguished from the previously known species in the genus by a combination of its shrubby habit, absence of tendrils, pedately 5-foliolate leaves (rarely 4, 6, or 7-foliolate) with shallowly emarginated leaflet, and 1-seeded oblong-ellipsoid fruits. A description, photographs, vernacular name and preliminary conservation status are provided for it.
Reevaluating the infraspecific taxa of Maesa rugosa C.B. Clarke (Primulaceae): Taxonomic reassessment and typification update
Authors: DHATCHANAMOORTHY NARAYANASAMY , DEVANATHAN KRISHANAMOORTHY
Published: January 2025

Maesa rugosa C.B. Clarke is a tropical shrub belonging to the family Primulaceae. Despite its prevalent distribution and morphological variation, the infraspecific taxonomy of M. rugosa remains unclear. The present study reevaluates the infraspecific classification of M. rugosa based on a comprehensive analysis of the morphological characters. Our study results in reorganizing three infraspecific taxa including one new variety and one new combination. We also provide an update on the typification of two names M. rugosa C.B. Clarke and M. rugosa var. griffithii C.B. Clarke following Articles 9.2 and 9.17 of the ICN code.
Role of the Spring Sea Surface Temperature over the Southeastern Indian Ocean in Bridging the Indian Ocean Dipole and Subsequent ENSO
Authors: Zhong Yue , Lin Wenshi , Zhang Tuantuan , Yuan Dongliang , Yang Song , Lin Shuheng , Yu Wei
Published: January 2025

A significant relationship exists between the Indian Ocean dipole (IOD) and the following year’s El Niño–Southern Oscillation (ENSO), in spite of the uncertainty in the associated mechanisms. Here, we show that the spring sea surface temperature (SST) anomalies over the southeastern Indian Ocean (SEIO) play a bridging role in the teleconnection of the IOD and subsequent year’s ENSO. A positive IOD could induce a positive tendency of SST in the SEIO region from autumn to winter, primarily through the cloud–radiation–SST feedback, forming an anomalous SEIO warming which persists into the subsequent spring. As the oceanic forcing dominates in spring, the SEIO warming can induce/maintain the anomalous anticyclonic circulation over the western North Pacific according to the Gill model response, accompanied by easterly wind anomalies over the western equatorial Pacific that generate eastward-propagating upwelling Kelvin waves. As a result, anomalous cooling appears in the central-eastern tropical Pacific in the following seasons, manifesting as a La Niña mode. Additionally, the role of the ocean channel (i.e., the Indonesian Throughflow) in connecting the spring SEIO SST and the subsequent eastern Pacific SSTs is also discussed.
Biochemical osteomalacia in adults undergoing vitamin D testing in the North-East of Scotland
Authors: Macleod Angus D , Bolland Mark J , Balfour Andrew , Grey Andrew , Newmark Josh , Avenell Alison
Published: January 2025

Background

International guidelines give greatly varying definitions of 25-hydroxyvitamin D (25OHD) insufficiency and deficiency. Vitamin D testing is increasing despite 2016 UK guidance for adults advising routine vitamin D supplementation October-March and year-round for high risk groups. A service evaluation of vitamin D testing and biochemical osteomalacia in the North-East of Scotland (57–58°N) could inform definitions and testing guidance.

Methods

We identified adult 25OHD requests 8/7/2008–29/2/2020 and albumin-adjusted serum calcium (aCa), parathyroid hormone (PTH) and alkaline phosphatase (ALP) within 6 months of 25OHD testing. After excluding renal impairment and liver disease, we defined biochemical osteomalacia as ALP >130 IU/L and aCa <2.0 mmol/L and elevated PTH >9.2 or >6.8 pmol/L, depending on the assay. Possible biochemical osteomalacia was defined as 2 of these abnormalities in the absence of the third measurement. From these cases anonymised clinical data were then examined to confirm the diagnosis of osteomalacia.

Results

25,379 eligible patients had 25OHD measured: 25% were <25 nmol/L (6,258/25,379) and 18% <20 nmol/L (4,536/25,379). 0.5% (126/25,379) of eligible patients had biochemical or possible biochemical osteomalacia. After reviewing clinical records, only 0.1% (29/25,379) had clinically confirmed osteomalacia, equivalent to 2–3 cases/y for a population of 0.5 million, none of the untreated cases of clinically confirmed osteomalacia had 25OHD >25 nmol/L. For the entire tested population, when 25OHD was <25 nmol/L untreated osteomalacia confirmed by clinical records was rare (0.4%).

Conclusions

Osteomalacia is rare in North-East Scotland. Our data call into question designating 25OHD 25–50 nmol/L ‘insufficiency’. The risk of osteomalacia even when 25OHD is <25 nmol/L is very low.
Adaptive promising zone design for sequential parallel comparison design with continuous outcomes
Authors: Lu Xinlin , Shan Guogen
Published: January 2025

Introduction:

The sequential parallel comparison design has emerged as a valuable tool in clinical trials with high placebo response rates. To further enhance its efficiency and effectiveness, adaptive strategies, such as sample size adjustment and allocation ratio modification can be employed.

Methods:

We compared the performance of Jennison and Turnbull’s method and the Promising Zone approach for sample size adjustment in a two-phase sequential parallel comparison design study. We also evaluated the impact of allocation ratio adjustments using Neyman and Optimal allocation strategies. Various scenarios were simulated to assess the effects of different design parameters, including weight in the test statistic, initial randomization ratio, and interim analysis timing.

Results:

The Promising Zone approach demonstrated superior or comparable power to Jennison and Turnbull’s method at equivalent expected sample sizes while maintaining the intuitive property that more promising interim results lead to smaller required follow-up sample sizes. However, the Promising Zone approach may require a larger maximum possible sample size in some cases. The addition of allocation ratio adjustments offered minimal improvements overall, but showed potential benefits when the variance in the treatment group was larger than that in the placebo group. We also applied our findings to a real-world example from the AVP-923 trial in patients with Alzheimer’s disease-related agitation, demonstrating the practical implications of adaptive sequential parallel comparison designs in clinical research.

Discussion:

Adaptive strategies can significantly enhance the efficiency of sequential parallel comparison designs. The choice between sample size adjustment methods should consider trade-offs between power, expected sample size, and maximum adjusted sample size. Although allocation ratio adjustments showed limited overall impact, they may be beneficial in specific scenarios. Future research should explore the application of these adaptive strategies to binary and survival outcomes in sequential parallel comparison designs.