bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping patient pathways and understanding clinical decision-making in dengue management to inform the development of digital health tools
Authors: Nguyen Quang Huy , Ming Damien K. , Luu An Phuoc , Chanh Ho Quang , Tam Dong Thi Hoai , Truong Nguyen Thanh , Huy Vo Xuan , Hernandez Bernard , Van Nuil Jennifer Ilo , Paton Chris , Georgiou Pantelis , Nguyen Nguyet Minh , Holmes Alison , Tho Phan Vinh , Yacoub Sophie ,   the Vietnam ICU Translational Applications Laboratory (VITAL) investigators
Published: February 2023

Abstract
Background
Dengue is a common viral illness and severe disease results in life-threatening complications. Healthcare services in low- and middle-income countries treat the majority of dengue cases worldwide. However, the clinical decision-making processes which result in effective treatment are poorly characterised within this setting. In order to improve clinical care through interventions relating to digital clinical decision-support systems (CDSS), we set out to establish a framework for clinical decision-making in dengue management to inform implementation.

Methods
We utilised process mapping and task analysis methods to characterise existing dengue management at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. This is a tertiary referral hospital which manages approximately 30,000 patients with dengue each year, accepting referrals from Ho Chi Minh city and the surrounding catchment area. Initial findings were expanded through semi-structured interviews with clinicians in order to understand clinical reasoning and cognitive factors in detail. A grounded theory was used for coding and emergent themes were developed through iterative discussions with clinician-researchers.

Results
Key clinical decision-making points were identified: (i) at the initial patient evaluation for dengue diagnosis to decide on hospital admission and the provision of fluid/blood product therapy, (ii) in those patients who develop severe disease or other complications, (iii) at the point of recurrent shock in balancing the need for fluid therapy with complications of volume overload. From interviews the following themes were identified: prioritising clinical diagnosis and evaluation over existing diagnostics, the role of dengue guidelines published by the Ministry of Health, the impact of seasonality and caseload on decision-making strategies, and the potential role of digital decision-support and disease scoring tools.

Conclusions
The study highlights the contemporary priorities in delivering clinical care to patients with dengue in an endemic setting. Key decision-making processes and the sources of information that were of the greatest utility were identified. These findings serve as a foundation for future clinical interventions and improvements in healthcare. Understanding the decision-making process in greater detail also allows for development and implementation of CDSS which are suited to the local context.
Rural and urban differences in quality of dementia care of persons with dementia and caregivers across all domains: a systematic review
Authors: Arsenault-Lapierre Geneviève , Bui Tammy X. , Le Berre Mélanie , Bergman Howard , Vedel Isabelle 
Published: January 2023

Abstract
Background
There are challenges in healthcare service delivery in rural areas, and this may be especially true for persons with dementia, who have higher needs to access to the healthcare system, and may have difficulties to commute easily and safely to these services. There is a growing body of literature regarding geographical disparities, but there is no comprehensive systematic review of geographical differences in persons with dementia across all domains of care quality. Therefore, the objective of this study is to conduct a systematic review of the literature on rural and urban differences in quality of dementia care outcomes of persons with dementia across all quality-of-care domains.

Methods
We performed a digital search in Ovid MEDLINE on July 16, 2019, updated on May 3, 2021, for French or English records. We selected studies that reported outcome from at least one domain of quality of dementia care (Access, Integration, Effective Care, Efficient Care, Population Health, Safety, and Patient-Centered) in both rural and urban persons with dementia or caregivers. We used rigorous, systematic methods for screening, selection, data extraction and we analyzed outcomes reported by at least two studies using vote counting and appraised the certainty of evidence. Finally, we explored sources of heterogeneity.

Results
From the 38 included studies, we found differences in many dementia care domains. Rural persons with dementia had higher mortality rates (Population Health), lower visits to any physicians (Access), more hospitalizations but shorter stays (Integration), higher antipsychotic medications (Safety), lower use of home care services and higher use of nursing home (Patient-Centered Care) compared to urban persons with dementia.

Conclusions
This comprehensive portrait of rural–urban differences in dementia care highlights possible geographically based inequities and can be used by researchers and decision makers to guide development of more equitable dementia care policies.
BRD4 is involved in viral exacerbation of chronic obstructive pulmonary disease
Authors: Duan Yifei , Zhou Siyi , Wang Jianmiao 
Published: January 2023

AbstractBackgroundOur previous studies have suggested that bromodomain protein 4 (BRD4) is increased in the lung of stable chronic obstructive pulmonary disease (COPD) patients, which has been shown to be involved in inflammatory responses. We investigated its role in the viral exacerbation of COPD.MethodsBRD4, interleukin (IL)-6 and IL-8 were measured in the blood and sputum of stable COPD patients and patients with viral exacerbation. Mice were exposed to cigarette smoke (CS) and/or infected with influenza virus as an in vivo model. BRD4, IL-6 and keratinocyte-derived chemokine (KC) were measured in the lung. BEAS-2B cells were treated with CS extract and/or influenza virus as an in vitro model. BRD4, IL-6 and IL-8 were measured in the cells and/or culture supernatant.ResultsBRD4 was increased in COPD patients with viral exacerbation compared with those in stable condition and its expression was correlated with IL-6 and IL-8 expression. Inflammatory cells, IL-6, KC and BRD4 were synergistically induced in the lung of mice by viral infection and CS exposure, and the former three were decreased by JQ1 (BRD4 inhibitor) treatment. IL-6, IL-8 and BRD4 were significantly induced by CS extract and influenza virus in bronchial epithelial cells, and this upregulation was suppressed by knockdown of BRD4 expression.ConclusionsOur findings indicate that CS and viruses may synergistically induce IL-6 and IL-8 expression through their synergistic induction of BRD4 expression, which might contribute to the enhanced inflammatory response in the viral exacerbation of COPD.
Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis
Authors: Liu Ruijiao , Duan Tengfei , Yu Li , Tang Yongzhong , Liu Shikun , Wang Chunjiang , Fang Wei-Jin 
Published: February 2023

Abstract
Background
Increased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis.

Methods and results
We used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg−1 d−1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L−1) + palmitic acid (PA, 100 μmol L−1) or C16 ceramide (CER, 20 μmol L−1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated.

Conclusions
These results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.
In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer
Authors: Ge Chun , Huang Xintong , Zhang Sujie , Yuan Man , Tan Zhaoyi , Xu Chen , Jie Qiong , Zhang Jingjing , Zou Jianjun , Zhu Yubing , Feng Dong , Zhang Yue , Aa Jiye 
Published: January 2023

Abstract
Background
As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs.

Methods
Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for cellular PK in co-culture models.

Results
CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP.

Conclusion
The simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.
Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network
Authors: Yang Zihan , Zhou Li , Si Tongxu , Chen Siyuan , Liu Chengxi , Ng Kelvin Kaki , Wang Zesheng , Chen Zhiji , Qiu Chan , Liu Guopan , Wang Qingliang , Zhou Xiaoyu , Zhang Liang , Yao Zhongping , He Song , Yang Mengsu , Zhou Zhihang 
Published: January 2023

AbstractBackgroundExcessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear.MethodsLC–MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC–MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype.ResultsLysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis.ConclusionsLH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.
Plasma derived extracellular vesicle biomarkers of microglia activation in an experimental stroke model
Authors: Roseborough A. D. , Myers S. J. , Khazaee R. , Zhu Y. , Zhao L. , Iorio E. , Elahi F. M. , Pasternak S. H. , Whitehead S. N. 
Published: January 2023

AbstractChronic microglia activation post-stroke is associated with worse neurological and cognitive outcomes. However, measurement of microglia activation in vivo is currently limited. Plasma derived extracellular vesicles (EVs) are cell-specific indicators that may allow for non-invasive measurement of microglia phenotype. The aim of this study was to identify activation-state specific microglia EVs (MEVs) in vitro followed by validation in an experimental stroke model. Following pro-inflammatory activation, MEVs contain the microglia protein TMEM119 alongside increased expression of the Toll-like receptor 4 co-receptor CD14. Immunoprecipitation followed by fluorescent nanoparticle tracking analysis (ONI Nanoimager) was used to confirm the isolation of TMEM119+/CD14+ EVs from rat plasma. Electron microscopy confirmed that TMEM119 and CD14 localize to the MEV membrane. To model ischemia, plasma was collected from 3-month wildtype Fischer344 rats prior to, 7 and 28 days after endothelin-1 or saline injection into the dorsal right striatum. Fluorescently labelled MEVs were directly measured in the plasma using nanoflow cytometry (Apogee A60 Microplus). We report a significant increase in circulating TMEM119+/CD14+ EVs 28-days post-stroke in comparison to baseline levels and saline-injected rats, which correlated weakly with stroke volume. TMEM119+/MHC-II+ EVs were also increased post-stroke in comparison to baseline and saline-injected animals. This study is the first to describe an EV biomarker of activated microglia detected directly in plasma following stroke and represents a future tool for the measurement of microglia activity in vivo.
What coloration brings: Implications of background adaptation to oxidative stress in anurans
Authors: Radovanović Tijana B. , Petrović Tamara G. , Gavrilović Branka R. , Despotović Svetlana G. , Gavrić Jelena P. , Kijanović Ana , Mirč Marko , Tomašević Kolarov Nataša , Vukov Tanja , Prokić Marko D. 
Published: January 2023

Abstract
Background
Urban development results in habitat destruction, affecting populations of amphibians, the most fragile group of vertebrates. With changes in the environment, these animals become more exposed to light and predators. To enhance their chances of survival, they display plasticity of body coloration. Aside from adaptive benefits, animals exhibiting background matching meet the energetic costs and restrictions of changing body tones. To study the physiological consequences of Hyla arborea tadpole adaptation to background color, we followed oxidative stress parameters after rearing larvae on a constant background (black/white) and after changing the background color.

Results
Larvae cultivated for 20 days on constant substrate color exhibited differences in body coloration but without differences in lipid peroxidation (LPO) concentration between dark and pale individuals, suggesting that coloration investment during this period did not induce higher oxidative damage in darker tadpoles. Prolonged exposure of larvae (37 days) to a dark habitat increased antioxidative system defense and LPO concentrations, compared to animals reared permanently in the white surroundings. The positive correlation of oxidative damage with color intensity of individuals points to the physiological consequences of higher investment in the number of pigment cells necessary for dark pigmentation. In individuals faced with non-matching background and change in body coloration, defense system declined and LPO occurred relative to individuals cultivated in white habitat.

Conclusion
Here, we have pointed to consequences related to background matching and stress that amphibians experienced during chromatic adaptations. Background color change causes a complex physiological response affecting the antioxidative defense parameters. This investigation elucidates the accompanying cost of amphibiansʼ adjustment to an altered environment.
Sleep disorders in the acute phase of coronavirus disease 2019: an overview and risk factor study
Authors: Li Cun , Cai Hong-bin , Zhou Qing , Zhang Hua-qiu , Wang Man , Kang Hui-cong 
Published: January 2023

Abstract
Background
Sleep disorders are common during the outbreak of pandemic diseases, and similar disorders are noted in hospitalized COVID-19 patients. It is valuable to explore the clinical manifestations and risk factors for sleep disorders in COVID-19 patients.

Methods
Inpatients with COVID-19 were enrolled. Detailed clinical information was collected, and sleep quality was assessed by PSQI. Patients were divided into a sleep disorder group and a normal group based on a PSQI ≥ 7, and the clinical features were compared between the groups.

Results
Fifty-three patients were enrolled, and 47.2% presented sleep disorders. Sleep disorders were associated with older age (> 50), anemia and carbon dioxide retention. Furthermore, factors associated with abnormal component scores of the PSQI were: (1) patients with older age were more likely to have decreased sleep quality, prolonged sleep latency, decreased sleep efficiency, sleep disturbances, and daytime dysfunction; (2) decreased sleep quality and prolonged sleep latency were associated with dyspnea, whereas carbon dioxide retention and more lobes involved in chest CT were associated with prolonged sleep latency; (3) decreased sleep efficiency was more prevalent in patients with anemia.

Conclusions
Sleep disorders were prevalent in patients during the acute phase of COVID-19, and many risk factors (older age, anemia, carbon dioxide retention, the number of lobes involved in chest CT, and dyspnea) were identified. It is important to assess the presence of sleep disorders in patients to provide early intervention.
Can severity of a humanitarian crisis be quantified? Assessment of the INFORM severity index
Authors: Lopez Velma K. , Nika Angeliki , Blanton Curtis , Talley Leisel , Garfield Richard 
Published: January 2023

Abstract
Background
Those responding to humanitarian crises have an ethical imperative to respond most where the need is greatest. Metrics are used to estimate the severity of a given crisis. The INFORM Severity Index, one such metric, has become widely used to guide policy makers in humanitarian response decision making. The index, however, has not undergone critical statistical review. If imprecise or incorrect, the quality of decision making for humanitarian response will be affected. This analysis asks, how precise and how well does this index reflect the severity of conditions for people affected by disaster or war?

Results
The INFORM Severity Index is calculated from 35 publicly available indicators, which conceptually reflect the severity of each crisis. We used 172 unique global crises from the INFORM Severity Index database that occurred January 1 to November 30, 2019 or were ongoing by this date. We applied exploratory factor analysis (EFA) to determine common factors within the dataset. We then applied a second-order confirmatory factor analysis (CFA) to predict crisis severity as a latent construct. Model fit was assessed via chi-square goodness-of-fit statistic, Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), and Root Mean Square Error of Approximation (RMSEA). The EFA models suggested a 3- or 4- factor solution, with 46 and 53% variance explained in each model, respectively. The final CFA was parsimonious, containing three factors comprised of 11 indicators, with reasonable model fit (Chi-squared = 107, with 40 degrees of freedom, CFI = 0.94, TLI = 0.92, RMSEA = 0.10). In the second-order CFA, the magnitude of standardized factor-loading on the ‘societal governance’ latent construct had the strongest association with the latent construct of ‘crisis severity’ (0.73), followed by the ‘humanitarian access/safety’ construct (0.56).

Conclusions
A metric of crisis-severity is a critical step towards improving humanitarian response, but only when it reflects real life conditions. Our work is a first step in refining an existing framework to better quantify crisis severity.
Study on the regulatory effect of Panax notoginseng saponins combined with bone mesenchymal stem cell transplantation on IRAK1/TRAF6-NF-κB pathway in patients with diabetic cutaneous ulcers
Authors: Du Yuqing , Chen Weijian , Li Youshan , Liang Du , Liu Guobin 
Published: January 2023

AbstractPanax notoginseng saponins (PNSs) have been found as the major active ingredient of Panax notoginseng (Burkill) F.H.Chen (PN) leaves, which has the effect of reducing inflammatory response, facilitating fibroblast proliferation, as well as promoting angiogenesis. This study aimed to investigate the molecular basis of PNS combined with bone mesenchymal stem cells (BMSCs) for treating diabetic cutaneous ulcers (DCU) and its mechanism of action. Methods. A total of 75 SD rats were selected to make diabetic cutaneous ulcers model. According random number table method, the rats were randomly divided into a control group, a DCU group, a BMSCs group, a PNS group and BMSCs + PNS group. Five groups of rats were given without treatment. After being treated for 7 days, the rats were anesthetized with pentobarbital, and granulation tissue was collected from the central point of the wound. They were used for pathological analysis, Western blot (WB) and polymerase chain reaction (PCR) assays. Results. The wound healing area was the largest in the BMSCs + PNS group. HE staining results showed that the PNS + BMSCs group could promote the formation of new epidermis and reduce the infiltration of inflammatory cells. Immunohistochemistry (IHC) results showed that the PNS + BMSCs group could up-regulate the expression of Ki67 protein and cell proliferation. In addition, PNS combined with BMSCs up-regulated the expression of miR-146-5p and down-regulated the expression of IL-1β, IL-6 and TNF-α, IRAK1, TRAF6 and p65 in the NF-κB signaling pathway (p < 0.05). Conclusions. PNS combined with bone mesenchymal stem cell transplantation up-regulated miR-146a-5p targeting and binding to IRAK1/TRAF6, inhibiting the activation of NF-κB pathway, which reduced the inflammatory response of DCU and facilitated the skin healing of DCU. Thus, this study provides a theoretical basis and a novel therapeutic option for the treatment of DFU with PNS combined with BMSCs.