bluuebunny/crossref_metadata_2025 huggingface dataset:
Unforced Millennial-Scale Oscillations in a Coupled Climate–Carbon System
Authors: Zhu Fangze , Rose Brian E. J.
Published: January 2025

We identify and investigate spontaneous unforced millennial-scale oscillations in an idealized global coupled climate–carbon model under nearly ice-free conditions. The oscillations first appear due to gradual loss of deep polar ocean stratification in a global warming scenario, which triggers the onset of a subpolar deep circulation, with important implications for ocean carbon storage. The analysis focuses on the residual mean meridional overturning circulation (MOC) due to the significant eddy-driven component. The subpolar deep MOC further invigorates the subtropical deep MOC, increasing global air–sea CO2 fluxes and atmospheric CO2 through upwelling of deep dissolved inorganic carbon (DIC). The increasing atmospheric CO2 leads to global surface warming that further warms and stratifies the subsurface polar ocean, shutting down the subpolar deep MOC and completing a delayed negative feedback which reverses the oscillation phase. Mechanism-denial experiments reveal that the CO2 radiative feedback and time-varying MOC and polar stratification are all essential components of the oscillator mechanism, while winter sea ice and time-varying biological nutrients are not. The millennial time scale is determined by the delayed response of atmospheric CO2 to variations in polar stratification and subpolar deep MOC. This study sheds light on the coupled climate–carbon dynamics behind the internal millennial-scale variability of an ice-free warm climate. We discuss the relevance to understanding observed millennial-scale climate variability during the last glacial period.
Possible Mechanisms behind Dominant Modes of Seasonal Cycle of Rainfall over India
Authors: Bhattacharyya Sujatra , Chakraborty Arindam
Published: January 2025

The South Asian summer monsoon that occurs over 4 months from near summer solstice (June) to near autumnal equinox (September) evolves within the season due to interactions with other climate components. Since most climate patterns are seasonally phase-locked, their interaction and feedback with monsoon should also be season-dependent. Here, using rain gauge–based precipitation over India for 74 years, we show that the onset phase of the monsoon (June) is uncorrelated with the rest of the season (July–September). The propagation of the Madden–Julian oscillation (MJO) over the Indian Ocean triggers northward propagation of precipitable water that plays a key role during the onset phase. The MJO appears over the western equatorial Indian Ocean during both the early and late central Indian onset years. Normal and slow MJO phase propagation during early and late onset years, respectively, gives rise to interannual variations in June rainfall. After onset, till the end of the monsoon season, the interannual variability of the dominant seasonal mode of precipitation is regulated by the phase of El Niño–Southern Oscillation (ENSO) through anomalous moisture convergence. We show that, in June, ENSO does not play a key role because of the opposing impact on wind and moisture. However, from July to September, ENSO perturbs wind and moisture in a way that gives rise to positive feedback between monsoon, ENSO, and large-scale circulation. Such feedback of monsoon with ENSO results in a coherent impact of ENSO on monsoon precipitation in July–September. Our results suggest that the dominant mechanisms for interannual variations in Indian monsoon rainfall in June and the rest of the season are different.

Significance Statement

The variations in rainfall within the monsoon season in India are extremely important for agriculture and water resource management. For such purposes, prediction of the variations in rainfall within the season is more important than the prediction of the seasonal mean. However, very little study has been done to understand the generalized physical processes that govern the monthly variations in rainfall every year without assuming a particular intraseasonal feature. Here, we try to find the existence of the physical modes that are responsible for monthly variations in rainfall every year. We show that the dominant mechanisms behind the interannual variabilities of June and post-June rainfall are different. While June rainfall is governed by equatorial waves, post-June rainfall is a function of feedback between monsoon and ENSO. If the climate models capture these physical modes accurately, the prediction of the seasonal cycle of rainfall will improve substantially.
Premature Coronary Artery Disease Presenting as STEMI in a Teenager
Authors: Modi Morni , Ndunda Paul , Modi Kalgi
Published: January 2025

An 18-year-old teenager with significant atherosclerotic cardiovascular disease (ASCVD) risk factors developed acute chest pain. His electrocardiogram showed inferior ST-segment elevations. Emergent coronary angiogram revealed complete thrombotic occlusion of the right coronary artery. He underwent stenting of the culprit lesion with complete clinical recovery and resolution of his electrocardiographic abnormalities secondary to myocardial infarction.
Secondary Subtalar Arthrodesis: Surgical Outcome and Predictors of Functional Outcome and Quality of Life After Bone Block Distraction vs In Situ Technique
Authors: Eelsing Robin , Al-Sheikh Sally , Halm Jens A. , Schepers Tim
Published: January 2025

Background:

The outcome of a secondary subtalar arthrodesis after prior calcaneal fracture has been widely described. However, the surgical treatment has evolved significantly over the past decade, paralleling the shifts observed in primary repair strategies. Therefore, we describe the outcome following a secondary arthrodesis after an intra-articular calcaneal fracture, comparing the in situ (ISA) and bone block distraction arthrodesis (BBDA) techniques.

Methods:

In total, 339 patients who underwent a subtalar arthrodesis between January 1998 and November 2022 were screened for eligibility. Inclusion criteria were age ≥16 years, having undergone a subtalar arthrodesis following a calcaneal fracture, and a minimal follow-up of 1 year. Exclusion criteria were subtalar arthrodesis before January 2010 and a subtalar arthrodesis within 6 weeks of injury. A total of 259 patients did not meet the inclusion criteria, resulting in the inclusion of 80 patients with 82 fractured calcanei.

Results:

No significant differences between ISA and BBDA in surgical outcome were seen. Subtalar fusion was achieved in 78 of the patients (95.1%). Additionally, a deep surgical site infection occurred in 6 patients (7.8%). The American Orthopaedic Foot & Ankle Society ankle-hindfoot scale (AOFAS) and Foot Function Index (FFI) scores and the EuroQol–5 dimensions (EQ5D) index were similar between the 2 groups. However, a significantly higher EQ5D-VAS was reported by the subjects who received a BBDA (median [interquartile range], 70.0 [52.0-82.0] vs 81.0 [70.0-90.3], P = .021). Multiple regression revealed that a higher Böhler angle before the initial fracture reconstruction significantly improved the AOFAS score, whereas the FFI significantly improved by an initial conservative treatment and implant removal after arthrodesis. Finally, increasing age significantly improved the EQ5D index.

Conclusion:

Our study presents comparable surgical outcomes between ISA and BBDA for secondary subtalar arthrodesis following calcaneal fractures. Functional outcomes, as measured by the AOFAS and FFI scores, were also similar between the 2 techniques, although patients undergoing BBDA reported higher EQ5D visual analog scale scores.

Level of Evidence:

Level III, retrospective cohort study.
Assessing the Effectiveness of Interfacility Transfers for Pediatric Facial Fractures: A Comprehensive Multi-Level 1 Trauma Center Analysis with Proposed Transfer Guidelines
Authors: Hinson Madison , Wright Avery , Kogan Samuel , Runyan Christopher M.
Published: January 2025

Study Design: Retrospective chart review. Background: Pediatric patients with facial trauma are often transferred to specialized trauma centers for advanced evaluations, but the necessity and impact of these transfers remain uncertain. This study aims to assess the need for interfacility transfers and inform the development of evidence-based transfer guidelines for this population. Methods: This retrospective study analyzed data from pediatric facial trauma patients under 18 years old treated between January 2020 and December 2022 at two major Level 1 Trauma Centers. Data was analyzed using Chi-square and Student’s T-Tests, with a significance value of 5%. Results: Of 2,977 patients evaluated, 604 sustained at least one facial fracture. Transferred patients were more likely to present with mandible fractures, while primary evaluation patients had a higher incidence of midface fractures. Transfers for midface fractures were associated with high-energy trauma, open or comminuted fractures, and specialized conservative evaluations. Patients with midface fractures were often transferred for specialized operative treatments but more often received conservative management with no significant impact on outcomes. Transferred patients experienced longer hospital stays and reported more residual symptoms post-discharge, with lower rates of symptom resolution within 1 year. Conclusion: While midface fractures were a frequent reason for transfer, conservative management was typically performed without significant improvements in outcomes. These findings suggest that many transfers could be avoided by implementing interfacility guidelines that account for trauma type, radiographic findings, and access to outpatient care. Streamlining transfer decisions may reduce unnecessary resource use for cases not requiring urgent surgical intervention.
Protection of β2GPI-Deficient Mice from Thrombosis Reflects a Defect in PAR3-facilitated Platelet Activation
Authors: Kulkarni Paresh P , Alluri Ravi Kumar , Godwin Matthew J , Forbes Gabriel L , Merkulova Alona A , Lambert Sylviane , Vijay Aatira , Palihati Maierdan , Kundu Suman , Shim Young Jun , Kalonji Kevin N , Schmaier Alvin H. , Holinstat Michael , CAMERON SCOTT J , McCrae Keith R
Published: January 2025

Antibodies to β2-glycoprotein I (β2GPI) cause thrombosis in antiphospholipid syndrome, however the role of β2GPI in coagulation in vivo is not understood. To address this issue, we developed β2GPI-deficient mice (Apoh-/-) by deleting exon 2 and 3 of Apoh using CRISPR/Cas9 and compared the development of thrombosis in wild-type (WT) and Apoh-/- mice using rose bengal and FeCl3-induced carotid thrombosis, laser-induced cremaster arteriolar injury, and inferior vena cava (IVC) stasis models. We also compared tail bleeding times and activation of platelets from WT and Apoh-/- mice in the absence and presence of β2GPI. Apoh-/- mice demonstrated prolonged time to occlusion of the carotid after exposure to rose bengal or FeCl3, and reduced platelet and fibrin accumulation in cremasteric arterioles after laser injury. Significantly smaller thrombi formed in the IVC of Apoh-/- mice 48 hours after IVC occlusion. The activated partial thromboplastin time and prothrombin time, as well as aPTT reagent and tissue factor-induced thrombin generation times of Apoh-/- and WT plasma revealed no differences. However, we observed significant prolongation of tail bleeding in Apoh-/- mice, and reduced P-selectin expression and fibrinogen binding to activated α2bβ3 on platelets from these mice after stimulation with thrombin; these changes were reversed by β2GPI. A PAR3 antibody blocked thrombin-induced activation of WT platelets and the ability of β2GPI to restore activation of Apoh-/- platelets by thrombin. These studies demonstrate that β2GPI may promote platelet activation by enhancing the ability of PAR3 to present thrombin to PAR4.
Factor XIII: Driving (Cross-)Links in Hemostasis, Thrombosis, and Disease
Authors: Luyendyk James P , Flick Matthew J. , Wolberg Alisa S.
Published: January 2025

Blood clots are complex structures composed of blood cells and proteins held together by the structural framework provided by an insoluble fibrin network. Factor (F)XIII is a protransglutaminase essential for stabilizing the fibrin network. Activated FXIII(a) introduces novel covalent crosslinks within and between fibrin and other plasma and cellular proteins, and thereby promotes fibrin biochemical and mechanical integrity. These irreversible modifications are also major determinants of clot composition and functional properties. As such, FXIII has central roles in hemostasis and wound healing, thrombosis, and many proinflammatory diseases associated with coagulation activation. FXIII's biochemical properties are as interesting as its biology is unusual, giving rise to unique and still undefined mechanisms. Here we review features underlying FXIII biology, biochemical function, biophysical impact, and (patho)physiologic implications in hemostasis, thrombosis, and disease.
Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response
Authors: Tumuluru Sravya , Godfrey James K. , Cooper Alan , Yu Jovian , Chen Xiufen , MacNabb Brendan , Venkataraman Girish , Zha Yuanyuan , Pelzer Benedikt , Song Joo Y. , Duns Gerben , Sworder Brian , Raj Sandeep S , Bolen Christopher R , Penuel Elicia , Postovalova Ekaterina , Kotlov Nikita , Bagaev Aleksander , Fowler Nathan H , Shouval Roni , Smith Sonali M , Alizadeh Ash A , Steidl Christian , Kline Justin P.
Published: January 2025

Most diffuse large B-cell lymphoma (DLBCL) patients treated with immunotherapies such as bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was applied to multiple large independent datasets in order to characterize DLBCL immune environments, and to define their association with tumor cell-intrinsic genomic alterations and outcomes to CD19-directed CAR T-cell and CD20 x CD3 BsAb therapies. This approach effectively segregated DLBCLs into four immune quadrants (IQ) defined by cell-of-origin and immune-related gene set expression scores. These quadrants consisted of activated B cell-like (ABC) hot, ABC cold, germinal center B cell-like (GCB) hot, GCB cold DLBCLs. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute significantly to orchestrating unique DLBCL immune environments. For instance, SOCS1 loss-of-function mutations were significantly enriched among GCB hot DLBCLs, identifying a putative subset of inflamed DLBCLs that may be inherently susceptible to immunotherapy. In relapsed/refractory DLBCL patients, DLBCL-IQ assignment correlated significantly with clinical benefit with a CD20 x CD3 BsAb (n = 74), but not with CD19-directed CAR T cells (Stanford, n = 51; MSKCC, n = 69). Thus, DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and suggests the endogenous immune environment has a more significant impact on outcomes to BsAb compared to CAR T cell treatment.
Babesiosis and Sickle Red blood Cells: Loss of Deformability, Heightened Osmotic fragility, and Hypervesiculation
Authors: Beri Divya , Rodriguez Marilis A , Singh Manpreet , McLaughlin Daniel , Liu Yunfeng , Zhong Hui , Mendelson Avital , An Xiuli , Manwani Deepa G , Yazdanbakhsh Karina , Lobo Cheryl A
Published: January 2025

Babesiosis in sickle cell disease (SCD) is marked by severe anemia but the underlying red blood cell (RBC) rheological parameters remain largely undefined. Here, we describe altered RBC deformability from both primary (host RBC sickle hemoglobin mediated) and secondary changes (Babesia parasite infection mediated) to the RBC membrane using wild type AA, sickle trait AS and sickle SS RBCs. Our ektacytometry (LORRCA) analysis demonstrates that the changes in the host RBC bio-mechanical properties, pre- and post- Babesia infection, reside on a spectrum of severity, with wild type infected AA cells, despite showing a significant reduction of deformability under both shear and osmolarity gradients, exhibiting only a mild phenotype; compared to infected AS RBCs which show median changes in deformability and infected SS RBCs which exhibit the most dramatic impact of infection on cellular rheology, including an increase in Point of Sickling values. Further, using Image stream cytometric technology to quantify changes in cellular shape and area along with a tunable resistive pulse sensor to measure release of extra-cellular vesicles (EV) from these host RBCs, before and after infection, we offer a potential mechanistic basis for this extreme SS RBC rheologic profile, which include enhanced sickling rates and osmotic fragility, loss of RBC surface area and hypervesiculation in infected SS host RBCs. These results underly the importance of understanding the impact of intra-erythrocytic parasitic infections of SCD RBCs, especially on their cellular membranes and studying the mechanisms that lead to hyper hemolysis and extreme anemia in the SCD patient population.
Physical, chemical and biological properties of MTA Angelus and novel AGM MTA: an in vitro analysis
Authors: Nashibi Sara , Amdjadi Parisa , Ahmadi SeyedehSana , Hekmatian Sara , Torshabi Maryam
Published: January 2025

Introduction

Mineral trioxide aggregate (MTA) is a calcium silicate-based cement that has changed conventional dental therapeutic approaches. This study aimed to evaluate physical, chemical and biological properties of novel AGM MTA, in comparison with MTA Angelus.

Methods

The samples were prepared according to the manufacturer’s instructions. The initial and final setting times were measured via a Gillmore needle following the ISO 6876:2012 standard. The radiopacity of the materials was evaluated against an aluminium step wedge on the basis of the ISO 6876 and 13,116 standards. The pH changes were measured at intervals of 3, 6, 24, 72, 96 and 144 h postimmersion in Hank’s solution and calcium ion release was analysed after 168 h of immersion via inductively coupled plasma optical emission spectroscopy (ICP‒OES). Moreover, the cytotoxicity was assessed through the MTT assay on human dental pulp stem cells (hDPSCs) after 24 and 72 h of exposure to the set/fresh status of various dilutions of MTA extracts, following the ISO 10993-12 standard.

Results

No significant difference was found between the initial setting times of the two materials (Angelus: 11.0 ± 1.0 min, AGM: 10.3 ± 1.5 min); however, MTA Angelus demonstrated a significantly shorter final setting time. Both materials met the minimum radiopacity requirements according to the ISO 6876 standard, with MTA Angelus exhibiting greater radiopacity than AGM MTA. Both materials created an alkaline environment without presenting any differences in each time point and AGM MTA released significantly greater amounts of calcium ions. In the cytotoxicity assessment, while the diluted extracts of both materials did not elicit any cytotoxic effects, the nondiluted samples, after 72 h of exposure, as well as the 30-min set AGM MTA after 24 h of exposure, were shown to be cytotoxic.

Conclusions

In conclusion, MTA Angelus presented a faster setting time and lower cytotoxicity, while AGM MTA demonstrated greater calcium ion release. However, both materials presented clinically acceptable properties and AGM MTA could be a potential alternative to MTA Angelus. However, further clinical studies are required to confirm its application.
Shared decision-making between patients and healthcare providers at rural health facilities in Eastern Uganda: an exploratory qualitative study
Authors: Owino Ranga Solomon , Kituuka Olivia , Kutyabami Paul , Sewankambo Nelson K.
Published: January 2025

Background

Shared decision-making in healthcare is a collaborative process where patients are supported to make informed decisions according to their preferences. Healthcare decisions affect patients' lives which necessitates patients to participate in decisions concerning their health. This study explored experiences and ethical issues related to shared decision-making in a rural healthcare setting.

Methods

An exploratory qualitative study was conducted at Budumba Health Centre III and Butaleja Health Centre III in rural Eastern Uganda. In this study, 23 in-depth interviews were conducted among 12 healthcare providers and 11 patients. Data was analyzed thematically using NVivo-12 plus software.

Results

Four themes emerged which included: Paternalistic cultures of care, challenges, strategies for improvement, and ethical issues. Patients at both facilities expressed the need to be involved in decision-making processes. However, many stressed that they are not engaged in decision-making about their health. Many healthcare providers noted that shared decision-making could improve patient prognosis but are faced with challenges related to low male involvement and the influence of cultural and religious practices, including myths and patriarchal attitudes which impact effective patient engagement.

Ethical issues identified include concerns about informed consent, privacy and confidentiality, deception, and harm.

Conclusions

This study highlighted the need for better sensitization of patients and comprehensive training for healthcare providers to minimize and resolve ethical issues that emerge during shared decision-making processes. Therefore, targeted interventions are needed to enhance decision-making processes in rural healthcare including but not limited to developing shared decision-making manual and continuous training of healthcare providers to ethically engage patients. Further research is needed to explore larger facilities with a bigger scope including patients under 18 years of age and and their surrogates.
Why should we strive to let them thrive? Exploring the links between homecare professionals thriving at work, employee ambidexterity, and innovative behavior
Authors: Slåtten Terje , Mutonyi Barbara Rebecca , Lien Gudbrand
Published: January 2025

Background

The concept of thriving at work (TAW) has received increased interest within health services research in recent years. TAW embraces employees’ experience of being energized and feeling alive when employed in an organization. However, previous research has been limited mainly to the investigation of factors that promote TAW. Consequently, there is a lack of research linking TAW to potential outcomes. Based on this knowledge gap, this study aimed to examine links between TAW and two potential outcomes: employees’ individual innovative behavior (IIB) and employee ambidexterity (EA). Thus, the study contributes to a relatively neglected area, homecare, within the domain of health services research.

Methods

In this cross-sectional study, N = 258 Norwegian homecare professionals in nine municipalities were selected through convenience sampling. The conceptual model's results were analyzed using partial least-squares structural equation modeling with SmartPLS 3 software. The study tested both direct and indirect relationships. Indirect relationships were achieved through bootstrap.

Results

The main results from the empirical study can be summarized as follows: (i) TAW was found to be positively linked to both EA (b = 0.46) and IIB (b = 0.22); (ii) TAW and EA explained about 30% (R2 = 0.29) the variance in IIB; (iii) The relationship between TAW and IIB was found to be mediated by the EA; (iv) TAW was positively linked to each of the two dimensions that constitute EA. However, when comparing the individual strength of linkages, TAW was found to be most strongly linked to the exploitation dimension of EA (b = 0.50) and less strongly linked to the exploration dimension of EA (b = 0.35).

Conclusions

Employees’ level of TAW in homecare services is linked to desirable outcomes, as represented by EA and IIB in this study. Managers should be aware of the development and changes in their employees' TAW levels. Consequently, continuously monitoring and cultivating the TAW of individual employees to determine whether they experience a sense of being energized and feeling alive as members of the organization is an important practical implication. TAW is a key to essential outcomes. Managers should, therefore, strive to let all of their employees thrive.
Noninvasive prenatal diagnosis (NIPD) of non-syndromic hearing loss (NSHL) for singleton and twin pregnancies in the first trimester
Authors: Li Huanyun , Li Shaojun , Zhao Zhenhua , Kong Lingrong , Fu Xinyu , Zhu Jingqi , Feng Jun , Tang Weiqin , Wu Di , Kong Xiangdong
Published: January 2025

Background

Noninvasive prenatal diagnosis (NIPD) has been proven feasible for non-syndromic hearing loss (NSHL) in singleton pregnancies. However, previous research is limited to the second trimester and the application in twin pregnancies is blank. Here we provide a novel algorithmic approach to assess singleton and twin pregnancies in the first trimester.

Methods

A 324.614 kb capture panel was designed to selectively enrich target regions. Parental haplotypes were constructed by target sequencing of blood samples from the parents and the proband. Then single nucleotide polymorphisms (SNP) within target regions were classified into four and six categories in singleton and twin pregnancy, respectively. Combining relative haplotype dosage change (RHDO) and the Bayes factor (BF), fetal fraction (FF) and fetal genotype were deduced in singleton and twin pregnancies. The pregnant women’s NIPD results were validated by invasive prenatal diagnosis and Sanger sequencing.

Results

Sixteen women with singleton pregnancies and one woman with a twin pregnancy were recruited. Among the 16 singleton pregnancies, NIPD was successfully applied in 15 families and the coincidence rate with invasive prenatal diagnosis was 100% (15/15). Only one family NIPD result is “no call” because the imbalance distribution of SNP sites makes it difficult to estimate recombination events. Most (13/15) of pregnant women were diagnosed in the first trimester and the earliest gestation week was the 7th week. The twin pregnancy was a dichorionic diamniotic twin (DCDA). NIPD confirmed one fetus is affected, and another is a carrier with c.299_300delAT of GJB2 gene.

Conclusion

This study represents the pioneering evidence in the field, demonstrating the feasibility of NIPD for NSHL in twin pregnancies. Moreover, it provides a novel and advanced diagnostic approach for families at high risk of NSHL during pregnancy, offering earlier detection, enhanced safety, and improved accuracy.
First evidence of the effectiveness of a field application of RNAi technology in reducing infestation of the mite Varroa destructor in the western honey bee (Apis mellifera)
Authors: Bortolin Francesca , Rigato Emanuele , Perandin Sergio , Granato Anna , Zulian Laura , Millino Caterina , Pacchioni Beniamina , Mutinelli Franco , Fusco Giuseppe
Published: January 2025

Background

The mite Varroa destructor is the most serious pest of the western honey bee (Apis mellifera) and a major factor in the global decline of colonies. Traditional control methods, such as chemical pesticides, although quick and temporarily effective, leave residues in hive products, harming bees and operators’ health, while promoting pathogen resistance and spread. As a sustainable alternative, RNA interference (RNAi) technology has shown great potential for honey bee pest control in laboratory assays, but evidence of effectiveness in the field has been lacking.

Methods

We investigated the efficacy and feasibility of a RNAi treatment to improve bee health under natural beekeeping conditions by integrating a honey bee diet with a mixture of dsRNA targeting V. destructor acetyl-CoA carboxylase, Na+/K+ ATPase and endochitinase genes.

Results

In treated hives, we observed that the average infestation rate of phoretic Varroa mite was reduced by 33% and 42% relative to control bees fed with sucrose and GFP-dsRNA, respectively. The dsRNA treatment did not affect bee survival, and the beekeepers involved in the project found the method manageable in the apiary and non-intrusive to production activities.

Conclusions

Our findings demonstrate the feasibility and effectiveness of RNAi technology in reducing Varroa mite infestations under natural rearing conditions. This study supports the potential of RNAi as a promising alternative to chemical pesticides, offering a targeted, efficient and sustainable solution for managing V. destructor in honey bee populations.

Graphical Abstract
RADAR-AD: assessment of multiple remote monitoring technologies for early detection of Alzheimer’s disease
Authors: Lentzen Manuel , Vairavan Srinivasan , Muurling Marijn , Alepopoulos Vasilis , Atreya Alankar , Boada Merce , de Boer Casper , Conde Pauline , Curcic Jelena , Frisoni Giovanni , Galluzzi Samantha , Gjestsen Martha Therese , Gkioka Mara , Grammatikopoulou Margarita , Hausner Lucrezia , Hinds Chris , Lazarou Ioulietta , de Mendonça Alexandre , Nikolopoulos Spiros , Religa Dorota , Scebba Gaetano , Jelle Visser Pieter , Wittenberg Gayle , Narayan Vaibhav A. , Coello Neva , Brem Anna-Katharine , Aarsland Dag , Fröhlich Holger ,   on behalf of RADAR-AD
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, leading to cognitive and functional decline. Early detection and intervention are crucial for enhancing the quality of life of patients and their families. Remote Monitoring Technologies (RMTs) offer a promising solution for early detection by tracking changes in behavioral and cognitive functions, such as memory, language, and problem-solving skills. Timely detection of these symptoms can facilitate early intervention, potentially slowing disease progression and enabling appropriate treatment and care.

Methods

The RADAR-AD study was designed to evaluate the accuracy and validity of multiple RMTs in detecting functional decline across various stages of AD in a real-world setting, compared to standard clinical rating scales. Our approach involved a univariate analysis using Analysis of Covariance (ANCOVA) to analyze individual features of six RMTs while adjusting for variables such as age, sex, years of education, clinical site, BMI and season. Additionally, we employed four machine learning classifiers – Logistic Regression, Decision Tree, Random Forest, and XGBoost – using a nested cross-validation approach to assess the discriminatory capabilities of the RMTs.

Results

The ANCOVA results indicated significant differences between healthy and AD subjects regarding reduced physical activity, less REM sleep, altered gait patterns, and decreased cognitive functioning. The machine-learning-based analysis demonstrated that RMT-based models could identify subjects in the prodromal stage with an Area Under the ROC Curve of 73.0 %. In addition, our findings show that the Amsterdam iADL questionnaire has high discriminatory abilities.

Conclusions

RMTs show promise in AD detection already in the prodromal stage. Using them could allow for earlier detection and intervention, thereby improving patients’ quality of life. Furthermore, the Amsterdam iADL questionnaire holds high potential when employed remotely.
Evaluating the Impact Performance of Environmentally Friendly Asphalt Concrete Slabs Containing Different Proportions of Recycled Concrete Aggregate and Corrugated Steel Fibers
Authors: Mansour Walid , Ashraf Diaa , Basha Ali
Published: January 2025

The current research focuses on recycling construction waste by producing asphalt concrete mixtures containing varying proportions of recycled concrete aggregate (RCA), ranging from 0 to 50%. To ensure the improvement of the asphalt mixtures' properties in terms of Marshall stability, flow, bulk density, air void ratio, and splitting tensile strength, steel fibers were added at a volume fraction of 1.0%. The experimental program consisted of 12 asphalt cylinders with a diameter of 102 mm and a height of 64 mm, cast with different asphalt mixtures to study the effects of varying RCA proportions as well as the addition of steel fibers on the mechanical properties of the asphalt concrete mixtures. The stability of the asphalt mixtures decreased by 17.6%, 23.2%, and 28.8% when RCA was used at ratios of 30%, 40%, and 50%, respectively, compared to the reference mixture. The Marshall stability of asphalt mixtures containing steel fibers was higher than that of their counterparts without fibers. Moreover, 12 asphalt slabs were cast with different ratios of RCA in preparation for testing under the impact load resulting from the free fall of a 10-kg steel mass from a height of 2 m. The results revealed that the ratio between the back and front crater diameters for slabs containing 10%, 20%, 30%, 40%, and 50% RCA after incorporating steel fibers was 1.15, 1.17, 1.15, 1.28, and 1.36, respectively. These ratios were smaller than those of the counterpart slabs without steel fibers by 18%, 19%, 19%, 7%, and 18%, respectively. Moreover, due to the low accuracy of existing mathematical models for predicting the penetration depth of asphalt slabs made with RCA, this research presents a developed mathematical model capable of accurately predicting the penetration depth of such slabs. This model considers both the ratio of RCA and the steel fibers within the asphalt mixtures.
The quest for environmental analytical microbiology: absolute quantitative microbiome using cellular internal standards
Authors: Wang Chunxiao , Yang Yu , Xu Xiaoqing , Wang Dou , Shi Xianghui , Liu Lei , Deng Yu , Li Liguan , Zhang Tong
Published: January 2025

Background

High-throughput sequencing has revolutionized environmental microbiome research, providing both quantitative and qualitative insights into nucleic acid targets in the environment. The resulting microbial composition (community structure) data are essential for environmental analytical microbiology, enabling characterization of community dynamics and assessing microbial pollutants for the development of intervention strategies. However, the relative abundances derived from sequencing impede comparisons across samples and studies.

Results

This review systematically summarizes various absolute quantification (AQ) methods and their applications to obtain the absolute abundance of microbial cells and genetic elements. By critically comparing the strengths and limitations of AQ methods, we advocate the use of cellular internal standard-based high-throughput sequencing as an appropriate AQ approach for studying environmental microbiome originated from samples of complex matrices and high heterogeneity. To minimize ambiguity and facilitate cross-study comparisons, we outline essential reporting elements for technical considerations, and provide a checklist as a reference for environmental microbiome research.

Conclusions

In summary, we propose absolute microbiome quantification using cellular internal standards for environmental analytical microbiology, and we anticipate that this approach will greatly benefit future studies.

Graphical Abstract
Effects of hydrate distribution on the anisotropic electrical properties of fractured reservoirs through effective medium modeling
Authors: Han Tongcheng , Liu Shengbiao , Fu Li-Yun
Published: January 2025

Fracture-filling hydrate reservoirs have been widely discovered, and electrical properties are typically employed for the characterization of fractured reservoirs. However, fractured hydrate reservoirs are usually electrically anisotropic, and the distribution of hydrate in the fractures will significantly affect the anisotropic electrical properties of the reservoirs. Therefore, the accurate quantification of hydrate requires to understand the effects of hydrate distribution on the anisotropic electrical properties of fractured reservoirs. We have developed a two-step effective medium modeling approach for the anisotropic electrical properties of reservoirs with floating and bridging hydrate in the aligned fractures, and applied it to studying the effects of floating and bridging hydrate on the anisotropic electrical properties of fractured reservoirs with varying fracture parameters and background electrical properties. The aspect ratios for the hydrate with distinct distribution, the only unknown parameters in the model, are determined by best fitting the modeling results to a published numerical dataset for the hydrate saturation dependent anisotropic electrical conductivity of a fractured reservoir with floating and bridging hydrate in the aligned fractures. The fracture parameters and the background conductivity are found to both affect the anisotropic electrical properties of the fracture-filling hydrate reservoirs, and the effects are systematically impacted by the hydrate with different distribution in the fractures. The results reveal the effects of hydrate distribution on the anisotropic electrical properties of fractured reservoirs, and provide a modeling basis for the accurate quantification of hydrate in fractured reservoirs through measured anisotropic electrical properties.
Botensilimab (Fc-enhanced anti–cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti–PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas
Authors: Wilky Breelyn A. , Schwartz Gary K. , Gordon Michael S. , El-Khoueiry Anthony B. , Bullock Andrea J. , Henick Brian , Agulnik Mark , Singh Arun , Mahadevan Daruka , Stebbing Justin , Delepine Chloe , Chand Dhan , Avagyan Manushak , Wu Wei , Johnson Benny , Grossman Joseph E. , O'Day Steven , Trent Jonathan C. , Jones Robin L. , Tsimberidou Apostolia M.
Published: January 2025

PURPOSE

Outcomes for patients with advanced sarcomas are poor and there is a high unmet need to develop novel therapies. The purpose of this phase I study was to define the safety and efficacy of botensilimab (BOT), an Fc-enhanced anti–cytotoxic lymphocyte-association protein-4 antibody, plus balstilimab (BAL), an anti–PD-1 antibody, in advanced sarcomas.

METHODS

BOT was administered intravenously (IV) at 1 mg/kg or 2 mg/kg once every 6 weeks in combination with BAL IV at 3 mg/kg once every 2 weeks for up to 2 years. The primary end point was to determine dose-limiting toxicities during the dose-escalation period. Secondary end points include objective response rate (ORR), duration of response (DOR), disease control rate, and progression-free survival (PFS) by RECIST 1.1. Exploratory end points include assessing patient biomarkers including tumor mutational burden, cytokines, and PD-L1 expression.

RESULTS

Overall, 64 patients with sarcoma were treated; all were evaluable for safety and 52 for efficacy. The most common treatment-related adverse event (TRAE) was diarrhea/colitis occurring in 35.9% of patients, with grade 3 in 6.3% of patients. No grade 4 or 5 TRAEs were reported. For all evaluable patients, ORR was 19.2% (95% CI, 9.6 to 32.5), and 27.8% (95% CI, 9.7 to 53.5) for evaluable patients with angiosarcoma (n = 18); 33.3% in visceral and 22.2% in cutaneous subtypes. Median PFS for evaluable patients was 4.4 months (95% CI, 2.8 to 6.1), with a 6-month PFS rate of 36% (95% CI, 22 to 50) and a median DOR of 21.7 months (95% CI, 1.9 to not reached).

CONCLUSION

The combination of BOT/BAL demonstrated promising efficacy and safety in a large cohort of heavily pretreated sarcoma patients. This encouraging activity warrants further investigation (ClinicalTrials.gov identifier:
NCT03860272
).
Retrospective analysis of HAIP therapy in metastatic colorectal cancer: Efficacy, safety, and prognostic factors.
Authors: Sawyer Matthew , Jones Amy Little , Moscowitz Anna , Brown Timothy J. , Kainthla Radhika , Al Matar Salwan , Kazmi Syed Mohammad Ali , Verma Nilesh
Published: January 2025

126

Background:
HAIP (hepatic arterial infusion pump) therapy is a promising intervention for metastatic colorectal cancer (mCRC) with liver metastases, addressing significant challenges in management and prognosis. It offers targeted treatment to maximize efficacy while minimizing systemic toxicity. We present a retrospective analysis of patients with metastatic colorectal adenocarcinoma treated with HAIP therapy at an academic center and safety net hospital.
Methods:
Patients with mCRC and hepatic metastasis who received at least one HAIP floxuridine (FUDR) cycle from 2013 to 2023 were included. Baseline data, including demographics, tumor characteristics, and treatment history, were collected pre-HAIP. The main outcome was overall survival (OS) post-pump placement, with secondary outcomes being real-world progression-free survival (rwPFS) and HAIP-related complications.
Results:
In total, 88 patients were evaluated for inclusion, of whom 63 met inclusion criteria and were included for analysis. The median age of included patients was 46 years (interquartile range (IQR) 41-57) and 54% were male. Prior to HAIP, 38 (60%) of patients received one line of systemic therapy, while 18 (29%) had two. The median OS from HAIP placement was 28.0 months (95% CI 21.9-NR) and median rwPFS was 11.2 months (95% CI 7.1-16.1). Baseline bilirubin, KRAS mutant status, and CEA were associated with OS in the multivariate cox model. The most common complication from HAIP placement was hematoma (n=4, 6.3%), followed by pump infection (n=2, 3.2%). Grade 3 toxicities from FUDR infusion were infrequent, involving alkaline phosphatase (n=6), AST or ALT elevation (n=3), bilirubin increase (n=2), and platelet count decrease (n=1).
Conclusions:
HAIP treatment is associated with durable responses and few complications, making it well-tolerated by patients. For individuals with colorectal cancer and hepatic metastases, HAIP chemotherapy using FUDR presents a viable and effective treatment option, potentially improving overall outcomes and quality of life. Further prospective and randomized work may establish the role for HAIP in mCRC with liver metastases.
Neoadjuvant therapy in T3 and T4 colon cancer: Is there a promising future?
Authors: Pena Paola , Sousa Aryanna , AlMasad Qusai , Kwon Steve ,   Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center
Published: January 2025

144

Background:
Neoadjuvant chemotherapy (NAC) is increasingly being considered over standard upfront surgery followed by adjuvant chemotherapy for locally advanced colon cancer. Studies have been underpowered to look at the impact of NAC on overall survival (OS) in individual clinical T stages.
Methods:
A nationwide retrospective analysis using the National Cancer Database to evaluate patients with clinical stage T3 and T4 colon adenocarcinomas from 2010 to 2020. Cox proportional hazards model was used to evaluate the impact of NAC approach compared to upfront surgery on OS. Clinical and pathological T stages were compared among those who underwent upfront surgery to evaluate accuracy of clinical T staging.
Results:
Total of 60,557 patients were identified - 2,313 patients undergoing NAC and 58,245 undergoing upfront surgery. In the past decade, use of NAC increased from 1.73% to 12.13%. In our multivariable survival analysis combining clinical T3 and T4 patients, we observed a worse OS in the NAC group (HR 1.16, 95% CI 1.07-1.26). We found no OS benefit for patients undergoing NAC approach for clinical stage T3 (HR 1.13, 95% CI 0.99-1.28) but found a significant OS benefit for patients undergoing NAC approach for clinical stage T4 (HR 0.85, 95% CI 0.77-0.95). We observed that clinical T4 stage was accurately staged in 90.48% with overstaging in 9.52%; clinical T3 stage was accurately staged in 95.24% with overstaging in 2.18% of patients.
Conclusions:
Our analysis demonstrated OS benefit of the NAC approach in T4 colon adenocarcinoma but not in T3. The study highlights the importance of evaluating survival benefit of NAC separately for T3 and T4 colon adenocarcinoma in future studies, and the challenges of accurate clinical staging of colon cancer for NAC planning.
Encorafenib and cetuximab with/without binimetinib therapies for patients with
BRAF
-mutated metastatic colorectal cancer with prognostic factors: The BEETS trial (JACCRO CC-18).
Authors: Sunakawa Yu , Inoue Eisuke , Kotani Daisuke , Denda Tadamichi , Inagaki Chiaki , Kashiwada Tomomi , Horita Yosuke , Sugaya Akinori , Suwa Yusuke , Ohta Takashi , Kuramochi Hidekazu , Oshima Kotoe , Shiozawa Manabu , Yuki Satoshi , Tsuji Akihito , Muro Kei , Ichikawa Wataru , Fujii Masashi
Published: January 2025

164

Background:
BRAF inhibitor combination therapies, triplet (encorafenib, binimetinib and cetuximab) and doublet (encorafenib and cetuximab), have been approved for
BRAF
-mutated metastatic colorectal cancer (mCRC) in Japan. The treatment with triplet is recommended for patients (pts) with clinical prognostic factors according to the sub-group analysis of the BEACON CRC trial. However, it is unclear whether the treatment strategy is useful. We therefore conducted a study on the use of combination therapy with triplet or doublet based on observational study that accumulated real world data.
Methods:
The BEETS trial was a multicenter observational study to prospectively evaluate the efficacy and safety of BRAF inhibitor combination therapy as a 2nd- or 3rd-line treatment in pts with
BRAF
-mutated mCRC in clinical practice [UMIN000045530]. Two hundred pts were assigned to either triplet or doublet therapy based on the physician’s choice. The primary endpoint was overall survival (OS). The secondary endpoints included overall response rate (ORR), disease control rate, progression-free survival (PFS), and safety. The exploratory analysis was performed to evaluate the efficacy of triplet and doublet therapies in all pts and pts with clinical prognostic factors (PS1, 3 or more metastatic sites, elevated CRP value, or primary tumor present) using inverse probability weighting (IPW) analysis based on propensity scores to account for potential cofounding factors.
Results:
Among 203 pts enrolled from Oct 2021 to Nov 2023, 195 pts were evaluable (median age 67 years old, 52% male, ECOG PS 0/1/2 55%/39%/6%, no. of prior regimens 1/2 85%/15%, right-sided primary 61%, MSI-high 7%, triplet regimen 57%). Median OS was 13.2 months (95%CI 11.4-17.4) with 1y-survival rate of 53%, and median PFS was 4.9 months. Comparing the triplet and doublet using IPW, the median OS and PFS were comparable between the two treatments (triplet vs. doublet; 16.0 months vs. 13.6 months [HR 0.88, 95%CI 0.53-1.48] and 5.7 months vs. 4.8 months [HR 0.87, 95%CI 0.59-1.28]). In 139 pts with any prognostic factors, median OS and 1y-survival rate were 13.2 months vs. 9.6 months [HR 0.80, 95%CI 0.45-1.43] and 54% vs. 42%, median PFS and ORR were 5.3 months vs. 4.2 months [HR 0.75, 95%CI 0.48-1.19] and 34% vs. 42%, in the triplet vs. doublet therapy, respectively.
Conclusions:
Our study demonstrated that BRAF inhibitor doublet therapy is a reasonable treatment for
BRAF
-mutated mCRC. However, triplet therapy may be a clinically useful for pts with clinical prognostic factors.
Clinical trial information: UMIN000045530
.