bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug landscape in patients receiving general outpatient palliative care in Germany: results from a retrospective analysis of 10,464 patients
Authors: Loosen Sven H. , Schwartz Jacqueline , Grewe Steven , Krieg Sarah , Krieg Andreas , Luedde Tom , Batzler Yann-Nicolas , Kostev Karel , Neukirchen Martin , Roderburg Christoph 
Published: August 2023

Abstract
Background
According to § 27 and § 87 1b of the German Social Code, Book V, general outpatient palliative care (GOPC) aims to promote, maintain, and improve the quality of life and self-determination of seriously ill people. It should enable them to live in dignity until death in their preferred environment. Instead of a curative approach GOPC treatment focuses on the multiprofessional objective of alleviating symptoms and suffering on a case-by-case basis using medication or other measures, as well as the management of an individual treatment plan. The aim of this study was therefore to investigate to what extent medication differs from 12 months prior GOPC treatment within 12 months following GOPC treatment.

Methods
A retrospective database cross sectional study based on the IQVIA Disease Analyzer (DA) was performed, including adult patients with cancer diagnosis and at least one documentation of palliative support between January 1st, 2018 and December 31st, 2021, in 805 general practices (GP).

Results
The results of this study show, that in the context of general general outpatient palliative care, there is a significant increase in the prescription of opioids (18.3% vs. 37.7%), sedatives (7.8% vs. 16.2%) and antiemetics (5.3% vs. 9.7%), as well as a significant reduction in other medications such as statins (21.4% vs. 11.5%), proton pump inhibitors (PPI) (41.2% vs. 35.3%), or antihypertensives (57.5% vs. 46.6%).

Conclusions
Our results support the role of GOPC as an important element in improving pharmacological symptom control and deprescription to improve quality of life of patients at the end of their life.
Network pharmacology prediction and experimental verification of Rhubarb-Peach Kernel promoting apoptosis in endometriosis
Authors: Liao Zi , Lei Ya , Peng Li , Fu Xianyun , Wang Wei , Yang Dan 
Published: August 2023

AbstractBackground“Rhubarb-Peach Kernel” herb pair (RP) one of the most frequently used drug pairs, has been used in traditional medicine in China to treat inflammation and diseases associated with pain. Although it is widely used clinically and has a remarkable curative effect, the mechanism of RP treatment for endometriosis (EMs) remains unclear due to its complicated components. The aim of this study was to investigate the anti-endometriosis effect of RP, with emphasis on apoptosis via network pharmacology prediction, molecular docking and experimental verification.MethodsThe related ingredients and targets of RP in treating EMs were screened out using Traditional Chinese Medicine Systems Pharmacology (TCMSP), Tool for Molecular mechanism of Traditional Chinese Medicine (BATMAN-TCM), and GeneCards database. The data of the protein–protein interaction (PPI) network was obtained by the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) Database. The Metascape database was adopt for Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. After that, the molecular docking of the main active ingredients and apoptosis targets was performed. Finally, the pro-apoptotic effect of RP was verified in hEM15a cells.ResultsA total of 32 RP compounds were collected. Forty-two matching targets were picked out as the correlative targets of RP in treating EMs. Among these, 18 hub targets including P53, CASP3 were recognized by the PPI network. KEGG enrichment analysis discovered that the regulation of apoptosis was one of the potential mechanisms of RP against EMs. Anthraquinone compounds, flavonoids, and triterpenes in RP were identified as crucial active ingredients, involved in the pro-apoptotic effect, which were confirmed subsequently by molecular docking. Additionally, it was verified that RP treatment promoted apoptosis and inhibited the proliferation of EMs cells (assessed by MTT and Flow cytometry). Moreover, the induction of apoptosis in treated EMs cells may be due to the regulation of apoptosis-related protein expression, including P53, BAX, and CASP3.ConclusionsThe results of our study demonstrated that RP may exert its therapeutic effects on EMs through the potential mechanism of promoting apoptosis. Anthraquinones, flavonoids and triterpenoids are the possible pro-apoptotic components in RP.
Health care and harm reduction provider perspectives on treating older adults who use non-medical opioids: a qualitative study set in Chicago
Authors: Mason Maryann , Post Lori Ann , Aggarwal Rahul 
Published: August 2023

Abstract
Background
Opioid overdose death rates are increasing for adults aged 55 and older, with especially high rates in large urban areas. In parallel, admissions to treatment programs for older adults using illicit substances are increasing as well. Despite these trends, there is a lack of information about older adults who use non-medical opioids (NMO) and even less knowledge about their health and service encounters. Conducted in Chicago, Illinois, this qualitative study explores the perspectives of health care and harm reduction service providers who work with older adults using non-medical opioids.

Methods
The study used snowball sampling to locate participants with expertise in working with older adults who use non-medical opioids. In total, we conducted 26 semi-structured interviews from September 2021-August 2022. We explored questions regarding participants’ perceptions of older adult opioid use patterns, comorbidities, and involvement in harm reduction outreach and opioid use disorder treatment.

Results
Many of the providers we interviewed consider older adults who use NMO as a distinct population that employ unique use behaviors with the intent to protect them from opioid overdose. However, these same unique behaviors may potentiate their risk for overdose in today’s climate. Providers report initial encounters that are not care seeking for opioid use and primarily oriented around health conditions. Older adults who use non-medical opioids are seen as complex patients due to the need to diagnostically untangle symptoms of substance use from co-morbidities and conditions associated with aging.
Treatment for this population is also viewed as complicated due to the interactions between aging, comorbidities, and substance use. Providers also noted that older adults who use NMO have use behaviors that make them less visible to outreach and treatment service providers, potentially putting them at increased risk for overdose and health conditions associated with opioid use.

Conclusions
Findings from this study are intended to inform future research on care provision for older adults who use non-medical opioids and may be especially applicable to large urban reas with histories of opioid use dating back to earlier drug epidemics of the 1970s, 1980s, and 1990s.
Examining the absorption of post-internship medical officers into the public sector at county-level in devolved Kenya: a qualitative case study
Authors: Zhao Yingxi , Mbuthia Daniel , Munywoki Joshua , Gathara David , Nicodemo Catia , Nzinga Jacinta , English Mike 
Published: August 2023

Abstract
Background
After Kenya’s decentralization and constitutional changes in 2013, 47 devolved county governments are responsible for workforce planning and recruitment including for doctors/medical officers (MO). Data from the Ministry of Health suggested that less than half of these MOs are being absorbed by the public sector between 2015 and 2018. We aimed to examine how post-internship MOs are absorbed into the public sector at the county-level, as part of a broader project focusing on Kenya’s human resources for health.

Methods
We employed a qualitative case study design informed by a simplified health labour market framework. Data included interviews with 30 MOs who finished their internship after 2018, 10 consultants who have supervised MOs, and 51 county/sub-county-level managers who are involved in MOs’ planning and recruitment. A thematic analysis approach was used to examine recruitment processes, outcomes as well as perceived demand and supply.

Results
We found that Kenya has a large mismatch between supply and demand for MOs. An increasing number of medical schools are offering training in medicine while the demand for MOs in the county-level public sector has not been increasing at the same pace due to fiscal resource constraints and preference for other workforce cadres. The local Department of Health put in requests and participate in interviews but do not lead the recruitment process and respondents suggested that it can be subject to political interference and corruption. The imbalance of supply and demand is leading to unemployment, underemployment and migration of post-internship MOs with further impacts on MOs’ wages and contract conditions, especially in the private sector.

Conclusion
The mismatched supply and demand of MO accompanied by problematic recruitment processes led to many MOs not being absorbed by the public sector and subsequent unemployment and underemployment. Although Kenya has ambitious workforce norms, it may need to take a more pragmatic approach and initiate constructive policy dialogue with stakeholders spanning the education, public and private health sectors to better align MO training, recruitment and management.
Rhinovirus infection induces secretion of endothelin-1 from airway epithelial cells in both in vitro and in vivo models
Authors: Dy Alane Blythe C. , Girkin Jason , Marrocco Antonella , Collison Adam , Mwase Chimwemwe , O’Sullivan Michael J. , Phung Thien-Khoi N. , Mattes Joerg , Koziol-White Cynthia , Gern James E. , Bochkov Yury A. , Bartlett Nathan W. , Park Jin-Ah 
Published: August 2023

Abstract
Background
Rhinovirus (RV) infection of airway epithelial cells triggers asthma exacerbations, during which airway smooth muscle (ASM) excessively contracts. Due to ASM contraction, airway epithelial cells become mechanically compressed. We previously reported that compressed human bronchial epithelial (HBE) cells are a source of endothelin-1 (ET-1) that causes ASM contraction. Here, we hypothesized that epithelial sensing of RV by TLR3 and epithelial compression induce ET-1 secretion through a TGF-β receptor (TGFβR)-dependent mechanism.

Methods
To test this, we used primary HBE cells well-differentiated in air–liquid interface culture and two mouse models (ovalbumin and house dust mite) of allergic airway disease (AAD). HBE cells were infected with RV-A16, treated with a TLR3 agonist (poly(I:C)), or exposed to compression. Thereafter, EDN1 (ET-1 protein-encoding gene) mRNA expression and secreted ET-1 protein were measured. We examined the role of TGFβR in ET-1 secretion using either a pharmacologic inhibitor of TGFβR or recombinant TGF-β1 protein. In the AAD mouse models, allergen-sensitized and allergen-challenged mice were subsequently infected with RV. We then measured ET-1 in bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR) following methacholine challenge.

Results
Our data reveal that RV infection induced EDN1 expression and ET-1 secretion in HBE cells, potentially mediated by TLR3. TGFβR activation was partially required for ET-1 secretion, which was induced by RV, poly(I:C), or compression. TGFβR activation alone was sufficient to increase ET-1 secretion. In AAD mouse models, RV induced ET-1 secretion in BALF, which positively correlated with AHR.

Conclusions
Our data provide evidence that RV infection increased epithelial-cell ET-1 secretion through a TGFβR-dependent mechanism, which contributes to bronchoconstriction during RV-induced asthma exacerbations.
Expanding the genetic toolbox of Rhodotorula toruloides by identification and validation of six novel promoters induced or repressed under nitrogen starvation
Authors: Brink Daniel P. , Mierke Friederike , Norbeck Joakim , Siewers Verena , Andlid Thomas 
Published: August 2023

Abstract
Background
The non-conventional yeast Rhodotorula toruloides is an emerging host organism in biotechnology by merit of its natural capacity to accumulate high levels of carotenoids and intracellular storage lipids from a variety of carbon sources. While the number of genetic engineering strategies that employ R. toruloides is increasing, the lack of genetic tools available for modification of this yeast is still limiting strain development. For instance, several strong, constitutive R. toruloides promoters have been characterized, but to date, only five inducible promoters have been identified. Although nitrogen-limited cultivation conditions are commonly used to induce lipid accumulation in this yeast, no promoters regulated by nitrogen starvation have been described for R. toruloides.

Results
In this study, we used a combination of genomics and transcriptomics methods to identify novel R. toruloides promoter sequences that are either inducible or repressible by nitrogen starvation. RNA sequencing was used to assess gene expression in the recently isolated strain R. toruloides BOT-A2 during exponential growth and during nitrogen starvation, when cultivated with either glucose or xylose as the carbon source. The genome of BOT-A2 was sequenced using a combination of long- and short-read sequencing and annotated with support of the RNAseq data. Differential expression analysis was used to identify genes with a |log2 fold change|≥ 2 when comparing their expression during nitrogen depletion to that during exponential growth. The promoter regions from 16 of these genes were evaluated for their ability to drive the expression of a fluorescent reporter gene. Three promoters that were clearly upregulated under nitrogen starvation and three that were downregulated were selected and further characterized. One promoter, derived from gene RTBOTA2_003877, was found to function like an on–off switch, as it was only upregulated under full nitrogen depletion and downregulated in the presence of the nitrogen source.

Conclusions
Six new R. toruloides promoters that were either upregulated or downregulated under nitrogen-starvation were identified. These substantially contribute to the available promoters when engineering this organism and are foreseen to be particularly useful for future engineering strategies requiring specific regulation of target genes in accordance with nitrogen availability.
Next-generation nanomaterials: advancing ocular anti-inflammatory drug therapy
Authors: Wei Jing , Mu Jinyu , Tang Yong , Qin Dalian , Duan Junguo , Wu Anguo 
Published: August 2023

AbstractOphthalmic inflammatory diseases, including conjunctivitis, keratitis, uveitis, scleritis, and related conditions, pose considerable challenges to effective management and treatment. This review article investigates the potential of advanced nanomaterials in revolutionizing ocular anti-inflammatory drug interventions. By conducting an exhaustive analysis of recent advancements and assessing the potential benefits and limitations, this review aims to identify promising avenues for future research and clinical applications. The review commences with a detailed exploration of various nanomaterial categories, such as liposomes, dendrimers, nanoparticles (NPs), and hydrogels, emphasizing their unique properties and capabilities for accurate drug delivery. Subsequently, we explore the etiology and pathophysiology of ophthalmic inflammatory disorders, highlighting the urgent necessity for innovative therapeutic strategies and examining recent preclinical and clinical investigations employing nanomaterial-based drug delivery systems. We discuss the advantages of these cutting-edge systems, such as biocompatibility, bioavailability, controlled release, and targeted delivery, alongside potential challenges, which encompass immunogenicity, toxicity, and regulatory hurdles. Furthermore, we emphasize the significance of interdisciplinary collaborations among material scientists, pharmacologists, and clinicians in expediting the translation of these breakthroughs from laboratory environments to clinical practice. In summary, this review accentuates the remarkable potential of advanced nanomaterials in redefining ocular anti-inflammatory drug therapy. We fervently support continued research and development in this rapidly evolving field to overcome existing barriers and improve patient outcomes for ophthalmic inflammatory disorders.Graphical Abstract
Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade
Authors: Li Jinteng , Ye Feng , Xu Xiaojun , Xu Peitao , Wang Peng , Zheng Guan , Ye Guiwen , Yu Wenhui , Su Zepeng , Lin Jiajie , Che Yunshu , Liu Zhidong , Feng Pei , Cao Qian , Li Dateng , Xie Zhongyu , Wu Yanfeng , Shen Huiyong 
Published: August 2023

AbstractSustained inflammatory invasion leads to joint damage and progressive disability in several autoimmune rheumatic diseases. In recent decades, targeting M1 macrophage polarization has been suggested as a promising therapeutic strategy for autoimmune arthritis. P300/CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) that exhibits a strong positive relationship with the proinflammatory microenvironment. However, whether PCAF mediates M1 macrophage polarization remains poorly studied, and whether targeting PCAF can protect against autoimmune arthritis in vivo remains unclear. Commonly used drugs can cause serious side effects in patients because of their extensive and nonspecific distribution in the human body. One strategy for overcoming this challenge is to develop drug nanocarriers that target the drug to desirable regions and reduce the fraction of drug that reaches undesirable targets. In this study, we demonstrated that PCAF inhibition could effectively inhibit M1 polarization and alleviate arthritis in mice with collagen-induced arthritis (CIA) via synergistic NF-κB and H3K9Ac blockade. We further designed dextran sulfate (DS)-based nanoparticles (DSNPs) carrying garcinol (a PCAF inhibitor) to specifically target M1 macrophages in inflamed joints of the CIA mouse model via SR-A–SR-A ligand interactions. Compared to free garcinol, garcinol-loaded DSNPs selectively targeted M1 macrophages in inflamed joints and significantly improved therapeutic efficacy in vivo. In summary, our study indicates that targeted PCAF inhibition with nanoparticles might be a promising strategy for treating autoimmune arthritis via M1 macrophage polarization inhibition.
Silk fibroin-based embolic agent for transhepatic artery embolization with multiple therapeutic potentials
Authors: Shi Linlin , Li Danni , Tong Qianqian , Jia Guorong , Li Xiaohong , Zhang Lan , Han Qingqing , Li Rou , Zuo Changjing , Zhang Wei , Li Xiao 
Published: August 2023

Abstract
Background
The excellent physicochemical and biomedical properties make silk fibroin (SF) suitable for the development of biomedical materials. In this research, the silk fibroin microspheres (SFMS) were customized in two size ranges, and then carried gold nanoparticles or doxorubicin to evaluate the performance of drug loading and releasing. Embolization efficiency was evaluated in rat caudal artery and rabbit auricular artery, and the in vivo distribution of iodinated SFMS (125I/131I-SFMS) after embolization of rat hepatic artery was dynamically recorded by SPECT. Transhepatic arterial radioembolization (TARE) with 131I-SFMS was performed on rat models with liver cancer. The whole procedure of selective internal radiation was recorded with SPECT/CT, and the therapeutic effects were evaluated with 18 F-FDG PET/CT. Lastly, the enzymatic degradation was recorded and followed with the evaluation of particle size on clearance of sub-micron silk fibroin.

Results
SFMS were of smooth surface and regular shape with pervasive pores on the surface and inside the microspheres, and of suitable size range for TAE. Drug-loading functionalized SFMS with chemotherapy or radio-sensitization, and the enhanced therapeutic effects were proved in treating HUH-7 cells as lasting doxorubicin release or more lethal radiation. For artery embolization, SFMS effectively blocked the blood supply; when 131I-SFMS serving as the embolic agent, the good labeling stability and embolization performance guaranteed the favorable therapeutic effects in treating in situ liver tumor. At the 5th day post TARE with 37 MBq/3 mg 131I-SFMS per mice, tumor activity was quickly inhibited to a comparable glucose metabolism level with surrounding normal liver. More importantly, for the fragments of biodegradable SFMS, smaller sized SF (< 800 nm) metabolized in gastrointestinal tract and excreted by the urinary system, while SF (> 800 nm) entered the liver within 72 h for further metabolism.

Conclusion
The feasibility of SFMS as degradable TARE agent for liver cancer was primarily proved as providing multiple therapeutic potentials.

Graphical abstract
Ideal marker for targeted axillary dissection (IMTAD): a prospective multicentre trial
Authors: Žatecký Jan , Coufal Oldřich , Zapletal Ondřej , Kubala Otakar , Kepičová Markéta , Faridová Adéla , Rauš Karel , Gatěk Jiří , Kosáč Peter , Peteja Matúš 
Published: August 2023

Abstract
Background
Targeted axillary dissection (TAD) is an established method for axillary staging in patients with breast cancer after neoadjuvant chemotherapy (NAC). TAD consists of sentinel lymph node biopsy and initially pathological lymph node excision, which must be marked by a reliable marker before NAC.

Methods
The IMTAD study is a prospective multicentre trial comparing three localisation markers for lymph node localisation (clip + iodine seed, magnetic seed, carbon suspension) facilitating subsequent surgical excision in the form of TAD. The primary outcome was to prospectively compare the reliability, accuracy, and safety according to complication rate during marker implantation and detection and marker dislodgement.

Results
One hundred eighty-nine patients were included in the study—in 135 patients clip + iodine seed was used, in 30 patients magnetic seed and in 24 patients carbon suspension. The complication rate during the marker implantation and detection were not statistically significant between individual markers (p = 0.263; p = 0.117). Marker dislodgement was reported in 4 patients with clip + iodine seed localisation (3.0%), dislodgement did not occur in other localisation methods (p = 0.999). The false-negativity of sentinel lymph node (SLN) was observed in 8 patients, the false-negativity of targeted lymph nodes (TLN) wasn´t observed at all, the false-negativity rate (FNR) from the subcohort of ypN + patients for SLN is 9.6% and for TLN 0.0%.

Conclusion
The IMTAD study indicated, that clip + iodine seed, magnetic seed and carbon suspension are statistically comparable in terms of complications during marker implantation and detection and marker dislodgement proving their safety, accuracy, and reliability in TAD. The study confirmed, that the FNR of the TLN was lower than the FNR of the SLN proving that the TLN is a better marker for axillary lymph node status after NAC.

Trial registration
NCT04580251. Name of registry: Clinicaltrials.gov. Date of registration: 8.10.2020.