bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep alterations as a function of 88 health indicators
Authors: Ujma Péter Przemyslaw , Bódizs Róbert 
Published: March 2024

AbstractBackgroundAlterations in sleep have been described in multiple health conditions and as a function of several medication effects. However, evidence generally stems from small univariate studies. Here, we apply a large-sample, data-driven approach to investigate patterns between in sleep macrostructure, quantitative sleep EEG, and health.MethodsWe use data from the MrOS Sleep Study, containing polysomnography and health data from a large sample (N = 3086) of elderly American men to establish associations between sleep macrostructure, the spectral composition of the electroencephalogram, 38 medical disorders, 2 health behaviors, and the use of 48 medications.ResultsOf sleep macrostructure variables, increased REM latency and reduced REM duration were the most common findings across health indicators, along with increased sleep latency and reduced sleep efficiency. We found that the majority of health indicators were not associated with objective EEG power spectral density (PSD) alterations. Associations with the rest were highly stereotypical, with two principal components accounting for 85–95% of the PSD-health association. PC1 consists of a decrease of slow and an increase of fast PSD components, mainly in NREM. This pattern was most strongly associated with depression/SSRI medication use and age-related disorders. PC2 consists of changes in mid-frequency activity. Increased mid-frequency activity was associated with benzodiazepine use, while decreases were associated with cardiovascular problems and associated medications, in line with a recently proposed hypothesis of immune-mediated circadian demodulation in these disorders. Specific increases in sleep spindle frequency activity were associated with taking benzodiazepines and zolpidem. Sensitivity analyses supported the presence of both disorder and medication effects.ConclusionsSleep alterations are present in various health conditions.
Carbon quantum dots of ginsenoside Rb1 for application in a mouse model of intracerebral Hemorrhage
Authors: Tang Xiaolong , Yang Xinyu , Yu Yamei , Wu Miaojing , Li Yuanyuan , Zhang Zhe , Jia Guangyu , Wang Qi , Tu Wei , Wang Ye , Zhu Xingen , Li Shiyong 
Published: March 2024

AbstractAfter intracerebral hemorrhage (ICH) occurs, the overproduction of reactive oxygen species (ROS) and iron ion overload are the leading causes of secondary damage. Removing excess iron ions and ROS in the meningeal system can effectively alleviate the secondary damage after ICH. This study synthesized ginsenoside Rb1 carbon quantum dots (RBCQDs) using ginsenoside Rb1 and ethylenediamine via a hydrothermal method. RBCQDs exhibit potent capabilities in scavenging ABTS + free radicals and iron ions in solution. After intrathecal injection, the distribution of RBCQDs is predominantly localized in the subarachnoid space. RBCQDs can eliminate ROS and chelate iron ions within the meningeal system. Treatment with RBCQDs significantly improves blood flow in the meningeal system, effectively protecting dying neurons, improving neurological function, and providing a new therapeutic approach for the clinical treatment of ICH.
Multimorbidity healthcare expenditure in Belgium: a 4-year analysis (COMORB study)
Authors: Tran Phuong Bich , Nikolaidis Georgios F. , Abatih Emmanuel , Bos Philippe , Berete Finaba , Gorasso Vanessa , Van der Heyden Johan , Kazibwe Joseph , Tomeny Ewan Morgan , Van Hal Guido , Beutels Philippe , van Olmen Josefien 
Published: March 2024

Abstract
Background
The complex management of health needs in multimorbid patients, alongside limited cost data, presents challenges in developing cost-effective patient-care pathways. We estimated the costs of managing 171 dyads and 969 triads in Belgium, taking into account the influence of morbidity interactions on costs.

Methods
We followed a retrospective longitudinal study design, using the linked Belgian Health Interview Survey 2018 and the administrative claim database 2017–2020 hosted by the Intermutualistic Agency. We included people aged 15 and older, who had complete profiles (N = 9753). Applying a system costing perspective, the average annual direct cost per person per dyad/triad was presented in 2022 Euro and comprised mainly direct medical costs. We developed mixed models to analyse the impact of single chronic conditions, dyads and triads on healthcare costs, considering two-/three-way interactions within dyads/triads, key cost determinants and clustering at the household level.

Results
People with multimorbidity constituted nearly half of the study population and their total healthcare cost constituted around three quarters of the healthcare cost of the study population. The most common dyad, arthropathies + dorsopathies, with a 14% prevalence rate, accounted for 11% of the total national health expenditure. The most frequent triad, arthropathies + dorsopathies + hypertension, with a 5% prevalence rate, contributed 5%. The average annual direct costs per person with dyad and triad were €3515 (95% CI 3093–3937) and €4592 (95% CI 3920–5264), respectively. Dyads and triads associated with cancer, diabetes, chronic fatigue, and genitourinary problems incurred the highest costs. In most cases, the cost associated with multimorbidity was lower or not substantially different from the combined cost of the same conditions observed in separate patients.

Conclusion
Prevalent morbidity combinations, rather than high-cost ones, made a greater contribution to total national health expenditure. Our study contributes to the sparse evidence on this topic globally and in Europe, with the aim of improving cost-effective care for patients with diverse needs.
Intriguing insight into unanswered questions about Mpox: exploring health policy implications and considerations
Authors: Manirambona Emery , Khan Sheharyar Hassan , Siddiq Abdelmonem , Albakri Khaled , Salamah Hazem Mohamed , Hassan Noheir Ashraf Ibrahem Fathy , Musa Shuaibu Saidu , Dhama Kuldeep 
Published: March 2024

AbstractThe 2022 multi-country Monkeypox (Mpox) outbreak has added concerns to scientific research. However, unanswered questions about the disease remain. These unanswered questions lie in different aspects, such as transmission, the affected community, clinical presentations, infection and prevention control and treatment and vaccination. It is imperative to address these issues to stop the spread and transmission of disease. We documented unanswered questions with Mpox and offered suggestions that could help put health policy into practice. One of those questions is why gay, bisexual or other men who have sex with men (gbMSM) are the most affected community, underscoring the importance of prioritizing this community regarding treatment, vaccination and post-exposure prophylaxis. In addition, destigmatizing gbMSM and implementing community-based gbMSM consultation and action alongside ethical surveillance can facilitate other preventive measures such as ring vaccination to curb disease transmission and track vaccine efficacy. Relevant to that, vaccine and drug side effects have implied the questionability of their use and stimulated the importance of health policy development regarding expanded access and off-label use, expressing the need for safe drug and vaccine development manufacturing. The possibility of reverse zoonotic has also been raised, thus indicating the requirement to screen not only humans, but also their related animals to understand the real magnitude of reverse zoonosis and its potential risks. Implementing infection prevention and control measures to stop the virus circulation at the human–animal interface that includes One Health approach is essential.
Inhibition of the MALT1-LPCAT3 axis protects cartilage degeneration and osteoarthritis
Authors: Kondreddy Vijay , Banerjee Rajkumar , Devi B. L. A. Prabhavathi , Muralidharan Kathirvel , Piramanayagam Selvakumar 
Published: March 2024

AbstractThe proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1β and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1β-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1β-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1β-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE2, LTB4, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.
Graphical Abstract
A system dynamics approach to understand Dutch adolescents’ sleep health using a causal loop diagram
Authors: Heemskerk Danique M. , Busch Vincent , Piotrowski Jessica T. , Waterlander Wilma E. , Renders Carry M. , van Stralen Maartje M. 
Published: March 2024

Abstract
Background
Healthy sleep is crucial for the physical and mental wellbeing of adolescents. However, many adolescents suffer from poor sleep health. Little is known about how to effectively improve adolescent sleep health as it is shaped by a complex adaptive system of many interacting factors. This study aims to provide insights into the system dynamics underlying adolescent sleep health and to identify impactful leverage points for sleep health promotion interventions.

Methods
Three rounds of single-actor workshops, applying Group Model Building techniques, were held with adolescents (n = 23, 12–15 years), parents (n = 14) and relevant professionals (n = 26). The workshops resulted in a multi-actor Causal Loop Diagram (CLD) visualizing the system dynamics underlying adolescent sleep health. This CLD was supplemented with evidence from the literature. Subsystems, feedback loops and underlying causal mechanisms were identified to understand overarching system dynamics. Potential leverage points for action were identified applying the Action Scales Model (ASM).

Results
The resulting CLD comprised six subsystems around the following themes: (1) School environment; (2) Mental wellbeing; (3) Digital environment; (4) Family & Home environment; (5) Health behaviors & Leisure activities; (6) Personal system. Within and between these subsystems, 16 reinforcing and 7 balancing feedback loops were identified. Approximately 60 potential leverage points on different levels of the system were identified as well.

Conclusions
The multi-actor CLD and identified system dynamics illustrate the complexity of adolescent sleep health and supports the need for developing a coherent package of activities targeting different leverage points at all system levels to induce system change.
HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy
Authors: Shi Hongjie , Yuan Ming , Cai Jie , Lan Lan , Wang Yumou , Wang Wei , Zhou Jianliang , Wang Bin , Yu Wenjun , Dong Zhe , Deng Dawei , Qian Qiaofeng , Li Yang , Zhou Xianwu , Liu Jinping 
Published: March 2024

Abstract
Background
The aberrant secretion and excessive deposition of type I collagen (Col1) are important factors in the pathogenesis of myocardial fibrosis in dilated cardiomyopathy (DCM). However, the precise molecular mechanisms underlying the synthesis and secretion of Col1 remain unclear.

Methods and results
RNA-sequencing analysis revealed an increased HtrA serine peptidase 1 (HTRA1) expression in patients with DCM, which is strongly correlated with myocardial fibrosis. Consistent findings were observed in both human and mouse tissues by immunoblotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence analyses. Pearson’s analysis showed a markedly positive correlation between HTRA1 level and myocardial fibrosis indicators, including extracellular volume fraction (ECV), native T1, and late gadolinium enhancement (LGE), in patients with DCM. In vitro experiments showed that the suppression of HTRA1 inhibited the conversion of cardiac fibroblasts into myofibroblasts and decreased Col1 secretion. Further investigations identified the role of HTRA1 in promoting the formation of endoplasmic reticulum (ER) exit sites, which facilitated the transportation of Col1 from the ER to the Golgi apparatus, thereby increasing its secretion. Conversely, HTRA1 knockdown impeded the retention of Col1 in the ER, triggering ER stress and subsequent induction of ER autophagy to degrade misfolded Col1 and maintain ER homeostasis. In vivo experiments using adeno-associated virus-serotype 9-shHTRA1-green fluorescent protein (AAV9-shHTRA1-GFP) showed that HTRA1 knockdown effectively suppressed myocardial fibrosis and improved left ventricular function in mice with DCM.

Conclusions
The findings of this study provide valuable insights regarding the treatment of DCM-associated myocardial fibrosis and highlight the therapeutic potential of targeting HTRA1-mediated collagen secretion.
Targeting inflammation as cancer therapy
Authors: Wang Manni , Chen Siyuan , He Xuemei , Yuan Yong , Wei Xiawei 
Published: March 2024

AbstractInflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.
Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition
Authors: Deben Christophe , Boullosa Laurie Freire , Fortes Felicia Rodrigues , De La Hoz Edgar Cardenas , Le Compte Maxim , Seghers Sofie , Peeters Marc , Vanlanduit Steve , Lin Abraham , Dijkstra Krijn K. , Van Schil Paul , Hendriks Jeroen M. H. , Prenen Hans , Roeyen Geert , Lardon Filip , Smits Evelien 
Published: March 2024

Abstract
Background
This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF.

Methods
Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy.

Results
The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids.

Conclusion
Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.
txci-ATAC-seq: a massive-scale single-cell technique to profile chromatin accessibility
Authors: Zhang Hao , Mulqueen Ryan M. , Iannuzo Natalie , Farrera Dominique O. , Polverino Francesca , Galligan James J. , Ledford Julie G. , Adey Andrew C. , Cusanovich Darren A. 
Published: March 2024

AbstractWe develop a large-scale single-cell ATAC-seq method by combining Tn5-based pre-indexing with 10× Genomics barcoding, enabling the indexing of up to 200,000 nuclei across multiple samples in a single reaction. We profile 449,953 nuclei across diverse tissues, including the human cortex, mouse brain, human lung, mouse lung, mouse liver, and lung tissue from a club cell secretory protein knockout (CC16−/−) model. Our study of CC16−/−nuclei uncovers previously underappreciated technical artifacts derived from remnant 129 mouse strain genetic material, which cause profound cell-type-specific changes in regulatory elements near many genes, thereby confounding the interpretation of this commonly referenced mouse model.
Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized controlled open-label multi-center trial (INTERCEPT study)
Authors: Streichart Lillian , Felldin Marie , Ekberg Jana , Mjörnstedt Lars , Lindnér Per , Lennerling Annette , Bröcker Verena , Mölne Johan , Holgersson Jan , Daenen Kristien , Wennberg Lars , Lorant Tomas , Baid-Agrawal Seema 
Published: March 2024

Abstract
Background
Chronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.

Methods
The INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05.
The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.

Discussion
No effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.

Trial registration
ClinicalTrials.gov NCT04561986. Registered on September 24, 2020
Infantile atopic dermatitis – increasing severity predicts negative impacts on maternal and infant sleep: a mixed methods study
Authors: Harbottle Zoe , Nötzel Amanda , Golding Michael A. , Bhamra Manvir , Kopsch Isac , Wilking Erik , Jonsson Marina , Abrams Elissa M. , Halbrich Michelle A. , Simons Elinor , Roos Leslie E. , Keddy-Grant Jill A. , Gerstner Thomas V. , St-Vincent Jo-Anne , Ekström Sandra , Protudjer Jennifer L. P. 
Published: March 2024

Abstract
Background
While the impacts of atopic dermatitis (AD) on maternal and child sleep outcomes have been previously explored, less is known about the associations between infantile AD and sleep quality and quantity.

Objective
To describe the perceived causes of AD-associated maternal sleep disturbances and the association between AD severity and infant sleep outcomes.

Methods
Mothers with infants aged < 19 months old with a diagnosis of AD were recruited from social media and medical clinics in Winnipeg, Canada between October 2021 and May 2022. Infant AD severity was classified using maternal-reported data on the Patient-Oriented Scoring Atopic Dermatitis tool (PO-SCORAD). Quantitative data were collected via a series of questionnaires with a subset of mothers subsequently completing semi-structured interviews. Quantitative and qualitative data were integrated in the discussion.

Results
Mothers of infants with moderate/severe AD (6/12) were more likely to report their infant suffering from a higher degree of sleeplessness (i.e., ≥ 5 on a scale of 0–10) over the past 48 h compared to mothers of infants with mild AD (0/18). This was supported by qualitative findings where mothers described how their infant’s sleep quality and quantity worsened with AD severity. Additionally, 7/32 mothers reported that their child’s AD, regardless of severity, disturbed their sleep. Maternal sleep loss was most commonly attributed to infant itching (6/7), followed by worry (4/7).

Conclusion
Infantile AD severity was associated with worse sleep outcomes for both mothers and infants. We propose that maternal and infantile sleep quality and quantity can be improved by reducing AD severity through adherence to topical treatments.