bluuebunny/crossref_metadata_2025 huggingface dataset:
Advancing Explainable Autonomous Vehicle Systems: A Comprehensive Review and Research Roadmap
Authors: Tekkesinoglu Sule , Habibovic Azra , Kunze Lars
Published: January 2025

Given the uncertainty surrounding how existing explainability methods for autonomous vehicles (AVs) meet the diverse needs of stakeholders, a thorough investigation is imperative to determine the contexts requiring explanations and suitable interaction strategies. A comprehensive review becomes crucial to assess the alignment of current approaches with varied interests and expectations within the AV ecosystem. This study presents a review to discuss the complexities associated with explanation generation and presentation to facilitate the development of more effective and inclusive explainable AV systems. Our investigation led to categorising existing literature into three primary topics: explanatory tasks, explanatory information, and explanatory information communication. Drawing upon our insights, we have proposed a comprehensive roadmap for future research centred on (i) knowing the interlocutor, (ii) generating timely explanations, (ii) communicating human-friendly explanations, and (iv) continuous learning. Our roadmap is underpinned by principles of responsible research and innovation, emphasising the significance of diverse explanation requirements. To effectively tackle the challenges associated with implementing explainable AV systems, we have delineated various research directions, including the development of privacy-preserving data integration, ethical frameworks, real-time analytics, human-centric interaction design, and enhanced cross-disciplinary collaborations. By exploring these research directions, the study aims to guide the development and deployment of explainable AVs, informed by a holistic understanding of user needs, technological advancements, regulatory compliance, and ethical considerations, thereby ensuring safer and more trustworthy autonomous driving experiences.
Understanding the Lymphatic System: Tissue-on-Chip Modeling
Authors: Polacheck William J. , Dixon J. Brandon , Aw Wen Yih
Published: January 2025

The lymphatic vasculature plays critical roles in maintaining fluid homeostasis, transporting lipid, and facilitating immune surveillance. A growing body of work has identified lymphatic dysfunction as contributing to the severity of myriad diseases and to systemic inflammation, as well as modulating drug responses. Here, we review efforts to reconstruct lymphatic vessels in vitro toward establishing humanized, functional models to advance understanding of lymphatic biology and pathophysiology. We first review lymphatic endothelial cell biology and the biophysical lymphatic microenvironment, with a focus on features that are unique to the lymphatics and that have been used as design parameters for lymphatic-on-chip devices. We then discuss the state of the art for recapitulating lymphatic function in vitro, and we acknowledge limitations and challenges to current approaches. Finally, we discuss opportunities and the need for further development of microphysiological lymphatic systems to bridge the gap in model systems between lymphatic cell culture and animal physiology.
SNHG17 Reprograms Energy Metabolism of Breast Cancer by Activating Mitochondrial DNAs Transcription
Authors: Gao Lin , Huang Jingyi , Xia Jinquan , Zhao Pan , Dong Shaowei , Jiang Wei , Zhou Qianqian , Xu Zhenglei , Luo Hui , Zhou Wenbin , Sun Jichao , Wang Guangsuo , Geng Qingshan , Wang Jigang , Zou Chang
Published: January 2025

In most solid tumors, cellular energy metabolism is primarily dominated by aerobic glycolysis, which fulfills the high demand for biomacromolecules at the expense of reduced ATP production efficiency. Elucidation of the mechanisms by which rapidly proliferating malignant cells acquire sufficient energy in this state of inefficient ATP production from glycolysis could enable development of metabolism targeted therapeutic strategies. In this study, we observed a significant association between elevated expression levels of the long non-coding RNA (lncRNA) SNHG17 and unfavorable prognosis in breast cancer (BCa). SNHG17 promoted BCa cell proliferation by augmenting mitochondrial ATP production. Mechanistically, SNHG17 directly interacted with the p65 subunit of NF-κB and phosphorylated p65 at the threonine 505 site. SNHG17 bound to p65 at its truncated loop2 site, recruited p65 to mitochondria, and co-regulated the transcriptional activation of mitochondrial DNA to promote ATP production. Accordingly, targeting SNHG17 with an anti-sense oligonucleotide (ASO) significantly reduced BCa tumor growth both in vitro and in vivo. Overall, these results established a role for SNHG17 in promoting BCa progression by increasing ATP production and provided insight into the reprogramming of energy metabolism in solid tumors.
SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer
Authors: Lloyd Eloise G. , Jihad Muntadher , Manansala Judhell S. , Li Wenlong , Cheng Priscilla S. W. , Mucciolo Gianluca , Zaccaria Marta , Pinto Teles Sara , Araos Henríquez Joaquín , Harish Sneha , Brais Rebecca , Ashworth Sally , Luo Weike , Johnson Paul M. , Veghini Lisa , Vallespinos Mireia , Corbo Vincenzo , Biffi Giulia
Published: January 2025

Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC. Here, we used single-cell RNA-sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared to KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.
Table 2 from Molecular Differences in Pancreatic Ductal Adenocarcinomas from Black versus White Patients
Authors: Mandal Saurabh , Teslow Emily A. , Huang Minxuan , Yu Yingying , Sridhar Swathi , Crawford Howard C. , Hockenberry Adam J. , Stoppler Melissa C. , Levin Albert M. , Huang Ling
Published: January 2025

Summary of race representation in clinical trials evaluating immunotherapies for pancreatic cancer. Numbers in the brackets represent percentages of patients in designated groups
Table 1 from Molecular Differences in Pancreatic Ductal Adenocarcinomas from Black versus White Patients
Authors: Mandal Saurabh , Teslow Emily A. , Huang Minxuan , Yu Yingying , Sridhar Swathi , Crawford Howard C. , Hockenberry Adam J. , Stoppler Melissa C. , Levin Albert M. , Huang Ling
Published: January 2025

Characteristics of patients included in this study. Numbers in the brackets represent percentages of patients in designated groups
Supplementary Table S3 from Molecular Differences in Pancreatic Ductal Adenocarcinomas from Black versus White Patients
Authors: Mandal Saurabh , Teslow Emily A. , Huang Minxuan , Yu Yingying , Sridhar Swathi , Crawford Howard C. , Hockenberry Adam J. , Stoppler Melissa C. , Levin Albert M. , Huang Ling
Published: January 2025

Somatic mutational frequencies in PDAC patients without chemotherapies at the time of biopsy.
Supplementary Table S2 from Molecular Differences in Pancreatic Ductal Adenocarcinomas from Black versus White Patients
Authors: Mandal Saurabh , Teslow Emily A. , Huang Minxuan , Yu Yingying , Sridhar Swathi , Crawford Howard C. , Hockenberry Adam J. , Stoppler Melissa C. , Levin Albert M. , Huang Ling
Published: January 2025

Somatic mutational prevalences in PDAC patients stratified by their sex and race.
Data from Molecular Differences in Pancreatic Ductal Adenocarcinomas from Black versus White Patients
Authors: Mandal Saurabh , Teslow Emily A. , Huang Minxuan , Yu Yingying , Sridhar Swathi , Crawford Howard C. , Hockenberry Adam J. , Stoppler Melissa C. , Levin Albert M. , Huang Ling
Published: January 2025

Abstract
Pancreatic cancer is the third leading cause of cancer-related death in the United States. Black or African American patients have a higher incidence of pancreatic cancer compared with other racial groups. It is unclear whether distinct molecular mechanisms are involved in the development of pancreatic cancer in different racial groups. To identify tumor molecular features that are distinctly associated with race in Black or African American and White patients with pancreatic ductal adenocarcinoma (the main subtype of pancreatic cancer), we analyzed deidentified patient records, including tumor sequencing data and expression of PD-L1, from the Tempus multimodal database. Patients with a primary diagnosis of pancreatic ductal adenocarcinoma and who received molecular testing between November 2017 and March 2023 were included in analyses. Among 4,249 patients analyzed in this study, 452 (10.6%) were Black or African American, and 3,797 (89.4%) were White. Black patients had a higher prevalence of TP53 mutations compared with White patients (P < 0.001). KRASG12R mutations occurred more frequently in female patients in the Black versus White group (P = 0.007). Compared with White patients, Black patients had a higher tumor mutational burden (P < 0.001) and PD-L1 overexpression (P = 0.047). In a separate analysis of recent clinical trials testing immunotherapies for pancreatic cancer, we found that Black patients and other minorities were underrepresented in most trials. These findings suggest race-associated molecular differences in tumors that may impact patient responses to immunotherapies. Our study also supports the importance of improving patient diversity in clinical trials on pancreatic cancer treatments.
Significance:
By analyzing the records of patients with pancreatic cancer in the Tempus multimodal database, we identified genomic mutations and PD-L1 overexpression occurred more frequently in Black patients compared with their White counterparts. These molecular features may contribute to racial disparities in pancreatic cancer.
Association Between Psychiatric Disorders and Amyotrophic Lateral Sclerosis: A Prospective Cohort Study from the UK
Authors: Tan Yushan , Yang Tianmi , Cheng Yangfan , Zhang Sirui , Xiao Yi , Liu Jiyong , Shang Huifang
Published: January 2025

Introduction: Psychiatric disorders have been reported to be associated with amyotrophic lateral sclerosis (ALS). However, evidence for the association remains inconsistent, and it is unclear whether specific categories of psychiatric disorders constitute risk factors for ALS. The study aimed to investigate the association between different categories of psychiatric disorders and the risk of ALS.
Methods: We utilized data from the UK Biobank to conduct a population-based prospective cohort study. Cox proportional hazards models were employed to evaluate the association between a history of various psychiatric disorders including schizophrenia, bipolar disorder, depression, anxiety, stress-related disorders and the risk of ALS. Analyses were adjusted for covariates including sociodemographic factors, lifestyle factors and medical history.
Results: Among the 484,065 participants initially included, 558 participants were diagnosed with ALS during a median follow-up of 13.63 years. With complete adjustment, previous schizophrenia (hazard ratio [HR] 6.32; 95% confidence interval [CI] 2.60-15.36; p<0.001) and depression (HR 1.37; 95% CI 1.03-1.81; p=0.03) were found to be significantly associated with ALS.
Conclusion: This large prospective cohort study indicated the association between schizophrenia, depression and a higher risk of subsequent ALS. These findings suggest potential implications for early process of global neurodegeneration in ALS, underlining the need for further research to explore the underlying mechanisms.
Non-invasive Kupffer-CEUS Enhances the Accuracy of FLLs Diagnosis in Patients with Liver Cirrhosis or Fibrosis: A prospective multicenter study from China
Authors: Li Yunlin , Yu Xiao-Ling , Jing Xiang , Yang Hong , Li Kaiyan , Wu Wei , Lu Shichun , Ding Hong , Liu Guangjian , Cheng Wen , He Guangzhi , Li Kai , Luo Yan , Liu Liping , Jiang Tianan , Zhou Guiming , Xie Xiaoyan , Song Zhigang , Liu Fang-Yi , Yu Jie , Han Zhi-Yu , Cheng Zhi-Gang , Tan Shuilian , Xi Junqing , Dong Xuejuan , Qi Erpeng , Yao Jundong , Dong Xiaocong , Liang Ping
Published: January 2025

Introduction: It is challenging to diagnose liver masses in the context of a rough liver background using CT and MRI. Perfluorobutane (PFB) CEUS microbubble, an ultrasound contrast agent, has a unique phase called the Kupffer phase. This study aimed to explore whether the diagnostic ability of Kupffer-CEUS is affected by the rough liver background.
Methods: A prospective analysis was conducted on patients with access to histological pathology of FLLs and liver parenchyma from 23 centers between August 2020 and March 2021. Kupffer-CEUS was performed on 552 patients, who were divided into two groups (normal and abnormal) based on the pathological results of liver parenchyma, and the abnormal group was further divided into four groups (Sight liver fibrosis, Serious liver fibrosis, Fatty liver, Mixed). Kupffer-CEUS was divided into vascular phase and vascular & Kupffer phase.
Results: In Kupffer-CEUS, differences in diagnostic efficiency of FLLs between normal and abnormal liver backgrounds were not statistically significant. However, in patients with abnormal liver backgrounds, the specificity (57.45% vs. 74.47%, P=0.008) and accuracy (89.81% vs. 96.92%, P<0.001) of the vascular phase in distinguishing malignant from benign lesions were statistically lower than those of the vascular & Kupffer phase. Subgroup analysis revealed that the sensitivity, specificity, and accuracy of vascular & Kupffer phase in screening FLLs were all higher than those of vascular phase, except for the accuracy in patients with serious liver fibrosis (98.51% vs. 94.06, P<0.001).
Conclusion: This study indicated that although there is no obvious restriction on the choice of Kupffer-CEUS methods when diagnosing liver masses in patients with normal or abnormal liver backgrounds, Kupffer phase CEUS can effectively reduce the misdiagnosis of FLLs. Particularly for patients with serious liver fibrosis, contrast-enhanced ultrasound combined with the Kupffer phase can provide a more accurate diagnosis than conventional contrast-enhanced ultrasonography.
Significant Dry Weight Reduction After Transition from Peritoneal Dialysis to Hemodialysis
Authors: Lin Yen-Ting , Tsai Ming-Tsun , Chen Tzen-Wen , Lin Chih-Ching , Li Szu-Yuan
Published: January 2025

Background
Dry weight management in dialysis patients is crucial but often subjective, primarily based on symptoms. Due to continuous fluid removal in peritoneal dialysis (PD) and intermittent ultrafiltration in hemodialysis (HD), symptom-based assessments may be biased, leading to varying results. Surprisingly, no direct comparison of dry weight changes between PD and HD has been conducted. This study aims to evaluate the impact of transitioning from PD to HD on body weight and related clinical parameters.
Methods
This retrospective cohort study included 127 stable PD patients who transitioned to HD. Changes in body weight, echocardiographic parameters, albumin, and hemoglobin levels were analyzed over a one-year period post-transition.
Results
The mean patient age was 57.1 ± 15.5 years, with an average PD vintage of 5.8 ± 4.9 years. Most patients had hypertension. After transitioning to HD, body weight decreased significantly, with a reduction of -2.8 kg at one month, -5.3 kg at three months, and -7.5 kg one year post-transition. Echocardiographic parameters showed no significant changes. However, serum albumin and hemoglobin levels increased slightly but significantly after the transition, and the number of antihypertensive medications was also reduced.
Conclusion
The transition from PD to HD results in significant reductions in body weight. These findings underscore the often-overlooked issue of fluid overload in PD patients and its potential impact on patient outcomes.
Progressive Increase in Renal Sympathetic Nerve Activity Induced by Cold Exposure
Authors: Yoshimoto Misa , Yagi Kana , Ikegame Shizuka , Miki Kenju
Published: January 2025

BACKGROUND:

Exposure to cold environments is linked to cold-induced hypertension due to activated sympathetic nerve activity (SNA) and arterial baroreceptor reflex dysfunction. However, direct measurement of SNA during cold-induced hypertension and changes in baroreflex control of SNA remain unexplored.

METHODS:

Chronically instrumented rats were exposed to cold temperatures (10 °C) over 4 days after a control period (24 °C), and renal and lumbar sympathetic nerve activities were simultaneously measured during cold-induced hypertension. Baroreflex curves for renal SNA (RSNA) and lumbar SNA and heart rate were generated by altering arterial pressure via a bolus intravenous infusion of vasoactive drugs.

RESULTS:

RSNA increased immediately after cold exposure, increased progressively throughout the 4-day period, and remained high after the cold exposure ended. Cold exposure shifted the RSNA baroreflex curve to the right and upward, gradually increasing the upper plateau (maximum capacity of sympathetic drive). The upper plateau remained elevated even after the cold exposure ended. Conversely, cold exposure increased lumbar SNA, heart rate, and arterial pressure, which subsequently returned to control levels after the cold exposure ended. These data indicate that cold exposure increases the maximum capacity to drive renal SNA in a regionally different and time-dependent manner through cumulative effects.

CONCLUSIONS:

Four days of cold exposure resulted in reversible effects increasing arterial pressure via lumbar SNA and heart rate, alongside time-dependent cumulative effects on RSNA. This study provides direct evidence of a self-activating pathway for RSNA that is activated by cold exposure, thus initiating cold-induced hypertension.
Aprocitentan for Blood Pressure Reduction in Black Patients
Authors: Flack John M. , Schlaich Markus P. , Weber Michael A. , Sassi-Sayadi Mouna , Narkiewicz Krzysztof , Clozel Martine , Dreier Roland F. , Andrawis Nabil S. , Danaietash Parisa , Gabra Nashwa , Scott David , Wang Ji-Guang , Ferdinand Keith C.
Published: January 2025

BACKGROUND:

Black individuals frequently present with resistant hypertension and disproportionately increased cardiovascular risk. We investigated the blood pressure (BP)-lowering effect of the dual endothelin receptor antagonist aprocitentan in Black individuals enrolled in the PRECISION study (Parallel-Group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension).

METHODS:

Patients with confirmed resistant hypertension were randomized to aprocitentan 12.5 mg, 25 mg, or placebo for 4 weeks (part 1). They subsequently received aprocitentan 25 mg for 32 weeks (part 2) before re-randomization to aprocitentan 25 mg or placebo (part 3).

RESULTS:

Eighty-two patients randomized in the PRECISION study were Black individuals. At week 4, aprocitentan 12.5 and 25 mg reduced office trough systolic BP (−11.3 and −11.9 mm Hg) to a similar degree as placebo (−12.0 mm Hg). Using 24-hour ambulatory BP monitoring, the placebo effect was minimal (−0.7 mm Hg), and aprocitentan reduced systolic BP by 4.0 and 8.6 mm Hg. During part 2, office BP continued to decrease (−16.4 mm Hg at week 36). In part 3, office and ambulatory systolic BP increased on placebo (+9.9 and +8.1 mm Hg, respectively), whereas the BP-lowering effect was maintained with aprocitentan. Aprocitentan markedly reduced albuminuria during the study. The most frequent adverse event was peripheral edema, occurring in 3 patients (10%) receiving aprocitentan 25 mg versus none receiving aprocitentan 12.5 mg or placebo.

CONCLUSIONS:

Aprocitentan reduced BP and albuminuria in Black individuals with resistant hypertension. The BP-lowering efficacy was similar to that of the overall PRECISION population. Aprocitentan may represent an important addition to the often difficult-to-control hypertension in Black individuals.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03541174.
Aging platelets shift their hemostatic properties to inflammatory functions
Authors: Anjum Afra , Mader Magdalena , Mahameed Shaan , Muraly Abhinaya , Denorme Frederik , Kliem Fabian P. , Rossaro Dario , Akgöl Sezer , Di Fina Lea , Mulkers Maité , Laun Lisa Sophia , Li Lukas , Kupper Nadja , Yue Keyang , Hoffknecht Marie-Louise , Akhalkatsi Anastassia , Loew Quentin , Pircher Joachim , Escaig Raphael , Strasser Erwin F. , Wichmann Christian , Pekayvaz Kami , Nieswandt Bernhard , Schulz Christian , Robles Maria S. , Kaiser Rainer , Massberg Steffen , Campbell Robert A. , Nicolai Leo
Published: January 2025

Platelets are crucial players in hemostasis and thrombosis, but also contribute to immune regulation and host defense, using different receptors, signaling pathways and effector functions, respectively. Whether distinct subsets of platelets specialize in these diverse tasks is insufficiently understood. Here, we employed an in vivo pulse-labelling method in Mus musculus models for tracking in vivo platelet ageing and its functional implications. Using in vitro and in vivo assays, we reveal that young, reticulated platelets show heightened responses in the setting of clot formation, with corresponding, increased responses to agonists, adhesion, and retractile function. Unexpectedly, aged platelets lose their hemostatic proficiency but are more prone to react to inflammatory challenge: compared to reticulated platelets, this cohort was more likely to form platelet-leukocyte aggregates and showed increased adhesion to neutrophils in vitro, as well as enhanced bactericidal function. In vivo, this was reflected in increased pulmonary recruitment of aged platelets in an acute lung injury model. Proteomic analyses confirmed upregulation of immune pathways in this cohort, including enhanced procoagulant function. In mouse models of prolonged platelet half-life, this resulted in increased pulmonary leukocyte infiltration and inflammation upon acute lung injury. Similarly, human platelet concentrates decreased their hemostatic function and elevated their putative immunomodulatory potential in vitro over time, and in a mouse model of platelet transfusion, aged platelet concentrates resulted in augmented inflammation. In summary, we show that platelets exhibit age-dependent phenotypic shifts allowing them to fulfill their diverse tasks in the vasculature. As functional alterations of aging platelets extend to platelet concentrates, this may hold important implications for transfusion medicine.
FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells
Authors: Araújo Joana L , Wagenblast Elvin , Voisin Veronique , McLeod Jessica , Gan Olga I. , Bansal Suraj , Jin Liqing , Mitchell Amanda , Gratton Blaise , Cutting Sarah Kristen , Arruda Andrea , Doedens Monica , Travas Anthea , Kim Dennis Dong Hwan , Capo-Chichi Jose-Mario , Abelson Sagi , Minden Mark D , Wang Jean CY , Sobrinho-Simões Manuel A , Pinto-do-Ó Perpétua , Lechman Eric R , Dick John E.
Published: January 2025

Leukemic stem cells (LSCs) fuel acute myeloid leukemia (AML) growth and relapse, but therapies tailored towards eradicating LSCs without harming normal hematopoietic stem cells (HSCs) are lacking. FLT3 is considered an important therapeutic target due to frequent mutation in AML and association with relapse. However, there has been limited clinical success with FLT3 drug targeting, suggesting either that FLT3 is not a vulnerability in LSC, or that more potent inhibition is required, a scenario where HSC toxicity could become limiting. We tested these possibilities by ablating FLT3 using CRISPR/Cas9-mediated FLT3 knock-out (FLT3-KO) in human LSCs and HSCs followed by functional xenograft assays. FLT3-KO in LSCs from FLT3-ITD mutated, but not FLT3-wild type (WT) AMLs, resulted in short-term leukemic grafts of FLT3-KO edited cells that disappeared by 12 weeks. By contrast, FLT3-KO in HSCs from fetal liver, cord blood and adult bone marrow did not impair multilineage hematopoiesis in primary and secondary xenografts. Our study establishes FLT3 as an ideal therapeutic target where ITD+ LSC are eradicated upon FLT3 deletion, while HSCs are spared. These findings support the development of more potent FLT3-targeting drugs or gene-editing approaches for LSC eradication to improve clinical outcomes.
NETs persisting in vasculature undergo self-renewal with consequences for subsequent infection: a mouse model study
Authors: Santocki Michal , Such Anna , Drab Dominika , Burczyk Gabriela , Kolaczkowska Elzbieta
Published: January 2025

While key for pathogen immobilization, neutrophil extracellular traps (NETs) often cause severe bystander cell/tissue damage. This was hypothesized to depend on their prolonged presence in the vasculature, leading to cytotoxicity. Imaging of NETs (histones, neutrophil elastase, extracellular DNA) with intravital microscopy in blood vessels of mouse livers in a pathogen-replicative-free environment (endotoxemia) led to detection of NET proteins attached to the endothelium for months despite the early disappearance of extracellular DNA. Intravascular liver macrophages (Kupffer cells) and neutrophils, but not monocytes, were involved in NET removal. They utilized scavenger receptors (SR-A) and Toll-like receptors (TLR2/4) to recognize NET components. Despite the absence of further stimuli, 14 days later a second wave of NET formation occurred, initiated by remnants of NETs from the first wave. The second burst of NET production was triggered by histones, which induced an inflammatory milieu (IL-1β) and activated platelets and coagulation-related events, including factor VII-activating protease (FSAP) activity. This in turn recruited and activated neutrophils to release the second wave of NETs. In peptidyl arginine deiminase (PAD4)-deficient mice, not forming NETs, inflammation and liver damage were reduced in comparison to their wild-type counterparts. When mice were challenged with methicillin-resistant Staphylococcus aureus (MRSA) 14 or 165 days post the second NETs, the course of infection/injury was diminished and exacerbated, respectively. Our study demonstrates that the complete removal of NETs in vivo takes much longer than hypothesized, and a vicious cycle of NET formation/disassembly impacts subsequent infection, depending on the time elapsed since its occurrence.
Ferritin Outperforms Other Biomarkers in Predicting Bone Marrow Iron Stores in Hematological Patients
Authors: Lahtiharju Tapio , Savola Paula , Lempiäinen Anna , Helin Tuukka Antero , Joutsi-Korhonen Lotta
Published: January 2025

Although iron deficiency anemia is common, interpreting iron laboratory test results can be challenging in patients with comorbidities. We aimed to study the accuracy of common iron biomarkers compared with bone marrow iron staining in a large retrospective dataset of hematological patients. We collected from 6610 patients (median age 66 years) results of iron staining, with their concurrent ferritin, transferrin saturation, soluble transferrin receptor, transferrin, hemoglobin, and mean red blood cell volume results from Helsinki University Hospital electronic health records. In receiver operating characteristics (ROC) analysis, ferritin had the highest area under curve (AUC) with 88% (95% CI 86-90%) for females and 89% (87-91%) for males in predicting reduced bone marrow iron. Using a ferritin cut-off of 30 µg/L resulted in high specificity rates of 97% in females and 99% in males. However, sensitivity rates were only 54% and 35%, respectively. Other studied biomarkers had inferior AUCs. Multivariate logistic regression models did not significantly perform better in prediction compared to ferritin alone. With 50% pre-probability for reduced iron stores, a ferritin of 30 µg/L (females) and 51 µg/L (males) had 95% positive predictive value for reduced iron stores. A 95% negative predictive value was achieved at 1750 µg/L (females) and 4967 µg/L (males). In our large population study, ferritin was the best single biomarker for iron deficiency in secondary care. Adding other blood tests in a multivariate model did not improve performance. However, in these hematological patients, even a high ferritin did not rule out iron deficiency with 95% certainty.
‘They went for the test together but came back separately’: a constructivist grounded theory perspective on male engagement in antenatal HIV testing in Bamenda, Cameroon
Authors: Foglabenchi Lily Haritu , Nyahkeh Nancy Manigha , Stöckl Heidi , Marchant Tanya
Published: January 2025

Introduction

Male engagement in HIV testing during pregnancy significantly contributes towards the prevention of maternal seroconversion and paediatric HIV acquisition. Despite this, men especially the male partners of pregnant women have been consistently missing in the HIV prevention cascade. The factors accounting for sub-optimal levels in male engagement intersect but reasons for this are poorly understood. Using the combined perspectives of pregnant women and their partners, this study aims to expand the evidence on the forces that influence prenatal HIV testing behaviours among couples in Bamenda, Cameroon.

Methods

This qualitative study purposively selected pregnant women receiving prenatal care for semi-structured interviews (n = 38); focus group discussion (n = 6) and their male partners (n = 30 for semi-structured interviews and n = 6 for focus group discussion) in Nkwen Baptist Hospital—an urban hospital in Bamenda, Cameroon. Nvivo was used for data management and subsequently we performed a grounded theory analysis through memoing and constant comparisons.

Results

Maternal HIV risk perception was the prominent theme intersecting with couple communication, perceptions on HIV testing outcome, and engagement of male partners by facility staff to influence couple prenatal HIV testing behaviours. Although participants recognised the need for couple HIV testing, individual, interspousal, structural and socio-cultural factors determined uptake of male partner testing. Perceptions on HIV risk were largely inaccurate and strongly gendered. For example, normative expectations on female fidelity were perceived as a buffer against HIV acquisition but this was not the norm regarding male partner behaviour. Also, couple communication was rare or subtle—mostly initiated by women who suspected spousal infidelity. For some men, HIV testing was a conscious decision to confirm fidelity, for others this was challenged by the fear of sero-discordant results and assumptions that maternal test results were a representation of their sero-status.

Conclusion

Male partner involvement in prenatal HIV testing is largely influenced by gendered perceptions on HIV risk and couple testing outcomes. Given that these perceptions are moderated by spousal communication and the engagement of male partners by health facility staff, we call for gender-transformative interventions and policies that offer education on prenatal HIV risk, support couple communication and spousal disclosure.
Medication patterns and potentially inappropriate medication in patients with metastatic breast cancer: results of the BRE-BY-MED study
Authors: Brandstetter Lilly Sophia , Grau Anna , Heuschmann Peter U. , Müller-Reiter Max , Salmen Jessica , Störk Stefan , Wöckel Achim , Reese Jens-Peter
Published: January 2025

Background

The treatment of metastatic breast cancer (mBC) focuses on prolonging patient survival, providing adequate symptom management, and maintaining quality of life (QoL). This includes supportive therapy to prevent or treat potential side effects and handle comorbidities. The combination of mBC therapy, supportive therapy, and treatment for comorbidities increases the risk for polypharmacy, potential drug-drug interactions (pDDI), potentially inappropriate medication (PIM), and potentially missing drugs (pMD). Therefore, the aim of this study was to assess medication patterns of mBC patients in routine care within a cohort study from South Germany.

Methods

Between July 2022 and February 2024 individuals with advanced or mBC, aged ≥ 18 years, living in Bavaria, and who gave written informed consent, were included in the BRE-BY-MED “Breast Cancer Care in Bavaria for Patients with Metastatic Disease” cohort study (DRKS00026601). BRE-BY-MED was carried out at the University Hospital Würzburg with the primary aim of estimating the prevalence of guideline-concordant treatment. For the present analysis cross-sectional data from the baseline assessment was used. Medication was extracted from routine medical records. PIM, pDDI and pMD were assessed using established criteria. Polypharmacy was defined as ≥ 5 concomitantly prescribed drugs.

Results

Ninety-three patients with a median age of 57 years (IQR = 48–64 years), were consecutively enrolled in the BRE-BY-MED study. One patient was male. At baseline, a total of 668 drugs were documented for all patients, including 131 unique substances, of which 44% were mBC therapy, 18% supportive therapy and 38% treatment for comorbidities or supplements. Patients took a median of 6 (IQR = 5–9) concomitant drugs. Polypharmacy (i.e. ≥ 5 concomitant drugs) was observed in 80.6% (n = 75) of the patients. PIM were documented in 9.7% (n = 9), pDDI in 12.9% (n = 12) and pMD in 64.5% (n = 60) of the patients.

Conclusion

We observed a high drug burden in mBC patients, largely due to treatment for comorbidities. These drugs might not only be associated with additional risk for side effects, pDDI, or PIM use, yet might also contribute to low medication adherence, higher medication costs and impaired QoL. Considering the burden of mBC and the predicted life expectancy, mBC patients might benefit from closer monitoring of their medication.
The risks of adverse events with mirtazapine for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis
Authors: Kamp Caroline Barkholt , Petersen Johanne Juul , Faltermeier Pascal , Juul Sophie , Sillassen Christina Dam Bjerregaard , Siddiqui Faiza , Andersen Rebecca Kjaer , Moncrieff Joanna , Horowitz Mark Abie , Hengartner Michael Pascal , Kirsch Irving , Gluud Christian , Jakobsen Janus Christian
Published: January 2025

Background

Mirtazapine is used to treat depression worldwide, and the effects of mirtazapine on depression rating scales are well-known. Our primary objective was to assess the risks of adverse events with mirtazapine for major depressive disorder.

Methods

We searched relevant sources from inception to 7 March 2024 for randomised clinical trials comparing mirtazapine versus placebo in adults with major depressive disorder. The primary outcomes were suicides or suicide attempts, serious adverse events, and non-serious adverse events. Data were synthesised using meta-analysis and Trial Sequential Analysis.

Results

We included 17 trials randomising 2,131 participants to mirtazapine versus placebo. All results were at high risk of bias, and the certainty of the evidence was very low. The included trials assessed outcomes at a maximum of 12 weeks after randomisation. Meta-analysis and Trial Sequential Analysis showed insufficient information to determine the effects of mirtazapine on the risks of suicides or suicide attempts and serious adverse events. Meta-analyses showed that mirtazapine increased the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite but decreased the risk of headaches.

Conclusions

There is a lack of evidence on the effects of mirtazapine on suicides and serious adverse events. Mirtazapine increases the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite. Mirtazapine might decrease the risk of headaches. The long-term effects of mirtazapine are unknown.

Prospero id

CRD42022315395.
Prevalence of complications and comorbidities associated with obesity: a health insurance claims analysis
Authors: Bae Jay P. , Nelson David R. , Boye Kristina S. , Mather Kieren J.
Published: January 2025

Background

Despite the substantial burden of obesity in the United States (US), data on the comprehensive range of comorbidities in different age groups is limited. This study assessed the prevalence of various comorbidities among people diagnosed with obesity (as per ICD-10 diagnosis code) across age cohorts and compared how they differ from people without obesity.

Methods

This cross-sectional study analyzed individuals from all four regions (Midwest, Northeast, South, and West) of the US who had continuous insurance coverage from 2018 to 2020, using a large health insurance claims database (Merative™ MarketScan®). Identification of disorders relied on ICD-10 diagnosis code in patient claims and their prevalence was calculated.

Results

Of 6,935,911 individuals, people with a diagnosis of obesity accounted for 22.0%, 33.6%, and 34.4% in the 18–39 years, 40–64 years, and ≥ 65 years age groups, respectively. Within age strata, the mean age of people with obesity was comparable with those without obesity. Comorbidity burden was significantly higher among people with obesity, but increased with age in both obesity and non-obesity groups. Comorbidities with highest prevalence in people with obesity included: (i) hypertension (18–39 years: 29.0%, 40–64 years: 66.2%, ≥ 65 years: 89.4%), (ii) dyslipidemia (18–39 years: 28.1%, 40–64 years: 65.4%, ≥ 65 years: 88.0%), (iii) depression or anxiety (18–39 years: 44.1%, 40–64 years: 39.0%, ≥ 65 years: 38.9%), and (iv) prediabetes (18–39 years: 17.1%, 40–64 years: 32.2%, ≥ 65 years: 35.3%). Notably, increased prevalence of cardiometabolic risk factors such as hypertension and dyslipidemia began at an earlier age in people with obesity as compared with those without obesity. Ratio of prevalence between obesity and non-obesity groups was highest for the 18–39 years age group, as compared to older groups. Disorders such as obstructive sleep apnea, osteoarthritis, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, coronary heart diseases (CHD), and chronic kidney diseases also exhibited substantial burden among those with obesity.

Conclusions

In this claims study, hypertension and dyslipidemia were the leading comorbidities in people with obesity, with an increasing prevalence with age. The burden of cardiometabolic comorbidities among the younger age group suggested potential risk for early onset of CHD in later life. Understanding the range of obesity-related comorbidities seen in this claims data may encourage healthcare professionals and healthcare systems to systematically diagnose and better manage these disorders. Further research using additional data sources can offer a more accurate view of the prevalence of obesity and its impact.
Epidemiologic trends of cleft lip and/or palate in Switzerland
Authors: Beyeler Joël , Lauener Anic , Katsaros Christos , La Scala Giorgio C. , Degen Martin
Published: January 2025

Background

Epidemiologic data on the number of cleft lip and/or palate (orofacial cleft (OFC)) births in Switzerland are currently sparse. However, this knowledge is essential for better understanding the etiologies underlying the various cleft phenotypes and providing expectant parents with the best possible healthcare planning and counseling.

Methods

This is the first descriptive study to report data on the prevalence of the various cleft types, their sex, and regional distributions in Switzerland. Data for the years 1998–2021 were obtained from the Swiss Federal Statistical Office. Due to the notable initial underreporting of cleft cases from 1998 to 2006, this period was omitted from the final analyses.

Results

Between 2007 and 2021, the prevalence of all Swiss OFC cases per 10,000 live births was 12.5, with a stable trend. Cleft lip was the least common anomaly. Except for cleft palate, which was more common in females, males were generally more affected by OFC than females. There was no discernible regional trend for any of the malformations, even though the prevalence differed throughout the seven Swiss regions.

Conclusions

This study presents the first descriptive epidemiologic profiles for OFCs in Switzerland and emphasizes the importance of nationwide OFC registries with an accurate and reliable reporting system for the benefit of current and future patients with clefts, their parents or caregivers, and society as a whole.
The proof is in the pudding: patient engagement in studying cannabidiol in mild cognitive impairment
Authors: Keck Antonia , Scheuermann Julia-Sophia , Scheerbaum Petra , Graessel Elmar , Müller-Vahl Kirsten R.
Published: January 2025

Background

Patient engagement (PE) in clinical trials has gained importance yet remains uncommon, particularly in patients with mild cognitive impairment (MCI), a critical precursor to Alzheimer’s disease (AD). Cannabidiol (CBD) shows potential in slowing MCI progression due to its neuroprotective and anti-inflammatory properties. In CBD research, PE is underutilized too. To design a study on CBD for MCI, we administered an online survey to individuals with MCI to better understand their preferences for trial setup and outcomes.

Methods

We asked 209 individuals with MCI to complete an online survey assessing (i) willingness to participate in a trial using CBD; (ii) importance of improvements in various domains; (iii) acceptance of adverse events (AEs); (iv) reasons for AE-related dropout; (v) willingness to undergo blood sampling and lumbar puncture to assess AD pathology; and (vi) willingness to participate in a trial with a 50% chance of receiving a placebo. Data were analyzed with descriptive statistics.

Results

N = 118 agreed to participate and N = 88 completed the survey. Participants prioritized improvement in cognitive abilities (87.5%), followed by quality of life (63.6%), daily activities (55.7%), sleep (55.7%), pain (52.3%), mood (52.3%), behavior (48.9%), and anxiety (43.2%). Headache (55.7%) was the least accepted AE followed by nausea (46.6%), fatigue (35.2%), and diarrhea (35.2%). Persistent diarrhea (90.9%) and severe fatigue (84.1%) were the main reasons for potential dropout. While most would undergo blood sampling (67.0%), only a minority (21.6%) would accept lumbar puncture. One-third were ready to participate (34.1%), while 54.5% were interested pending details. Among those in favor of participation, 71.6% would participate even with a 50% chance of placebo.

Conclusions

Our study identified cognitive improvement as highly relevant for patients, indicating cognitive assessment tools as primary endpoints in MCI research. Given concerns about AEs, dose titration should be carefully considered to enhance acceptance and prevent AEs. Blood sampling seems well-accepted for AD biomarker assessment. Despite potential AEs, participation in a trial using CBD for MCI is seen as attractive, even under placebo-controlled conditions. This cross-sectional study emphasizes the importance of patient engagement in designing high-quality trials for using CBD to treat MCI.
Dynamic co-evolution of transposable elements and the piRNA pathway in African cichlid fishes
Authors: Almeida Miguel Vasconcelos , Blumer Moritz , Yuan Chengwei Ulrika , Sierra Pío , Price Jonathan L. , Quah Fu Xiang , Friman Aleksandr , Dallaire Alexandra , Vernaz Grégoire , Putman Audrey L. K. , Smith Alan M. , Joyce Domino A. , Butter Falk , Haase Astrid D. , Durbin Richard , Santos M. Emília , Miska Eric A.
Published: January 2025

Background

East African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. We set out to bridge this gap and to understand the interactions between TEs and their cichlid hosts.

Results

Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed strong conservation of TE silencing factors in cichlids, and an expansion of piwil1 genes in Lake Malawi cichlids, likely driven by PiggyBac TEs. The expanded piwil1 copies have signatures of positive selection and retain amino acid residues essential for catalytic activity. Furthermore, the gonads of African cichlids express a Piwi-interacting RNA (piRNA) pathway that targets TEs. We define the genomic sites of piRNA production in African cichlids and find divergence in closely related species, in line with fast evolution of piRNA-producing loci.

Conclusions

Our findings suggest dynamic co-evolution of TEs and host silencing pathways in the African cichlid radiations. We propose that this co-evolution has contributed to cichlid genomic diversity.
Comparative analysis of NR and NiR gene families reveals nitrite formation mechanisms in two Toona species
Authors: Wei Yi , Dai Jianhua , Fan Yanru , Yin Hengfu , Liu Jun , Han Xiaojiao
Published: January 2025

Background

Toona sinensis and Toona ciliata both belong to the same genus in the Meliaceae family; however, the nitrate and nitrite contents in T. sinensis are significantly higher than those in T. ciliata. Given the growing emphasis on dietary health, it has become imperative to implement breeding strategies to reduce the excessive nitrite levels in T. sinensis. Nitrate reductase (NR) and nitrite reductase (NiR) are crucial enzymes in plant nitrogen metabolism. In this study, we employed a comparative analysis of the NR and NiR gene families in T. sinensis and T. ciliata. By integrating bioinformatics and expression pattern assessments, we aimed to elucidate the underlying factors contributing to the variance in nitrate and nitrite levels between these two species.

Results

T. sinensis exhibited higher nitrate and nitrite contents than T. ciliata. Through comprehensive genome-wide analysis, we identified two TsNRs and two TsNiRs in T. sinensis, compared to one TcNiR and two TcNiRs in T. ciliata, suggesting an expansion of NR members in T. sinensis relative to T. ciliata. The NR and NiR proteins in T. sinensis and T. ciliata share high sequence similarity and exhibit close genetic relationships with their counterparts in Populus trichocarpa and Salix purpurea. The exon–intron structures and conserved motifs of these genes were stringently conserved throughout evolutionary history. All the seven NR and NiR genes in both T. sinensis and T. ciliata harbor various cis-regulatory elements within their promoter sequences, which are associated with development, stress response, and hormonal regulation. Furthermore, the expression of TsNiR and TcNiR genes was also found to be tissue-specific. Among them, TcNR1 and TsNR2 exhibited the highest expression observed in mature leaves. Especially, the expression level of TsNR2 in mature leaves was 400-fold higher than in other tissues. In addition, transient overexpression of TsNiR1 and TsNiR2 in T. sinensis significantly reduced nitrite content.

Conclusions

The higher nitrite accumulation in T. sinensis compared to T. ciliata is attributed to its lower nitrite reductase activity, the expansion of the NR gene family, and the elevated expression of TsNR2 in the leaves.

Graphic Abstract