bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy
Authors: Yang Lixuan , Ao Yutian , Li Yannan , Dai Baoan , Li Jingchun , Duan Wenzhe , Gao Wei , Zhao Zhonghui , Han Zhenyun , Guo Rongjuan 
Published: February 2023

Abstract
Objective
Patients with hypertension have a risk of depression. Morinda officinalis oligosaccharides (MOOs) have anti-depressant properties. In this study, we aimed to determine whether MOOs can improve the symptoms of depression in individuals with hypertension.

Methods
Dahl salt-sensitive rats fed with a high-salt diet were stimulated by chronic unpredictable mild stress to mimic hypertension with depression. Primary astrocytes and neurons were isolated from these rats. Astrocytes underwent LPS stimulation to simulate the inflammatory astrocytes during depression. MOOs were administrated at 0.1 mg/g/day in vivo and 1.25, 2.5, and 5 mg/mL in vitro. Mitophagy was inhibited using 5 mM 3-methyladenine (3-MA). Astrocyte-mediated neurotoxicity was detected by co-culturing astrocytes and neurons.

Results
MOOs decreased systolic pressure, diastolic pressure, and mean arterial pressure, thereby improving depression-like behavior, including behavioral despair, lack of enthusiasm, and loss of pleasure during hypertension with depression. Furthermore, MOOs inhibited inflammation, astrocytic dysfunction, and mitochondrial damage in the brain. Then, MOOs promoted autophagosome and lysosome enriched in mitochondria in LPS-stimulated astrocytes. MOOs suppressed mitochondrial damage and the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in astrocytes undergoing LPS stimulation. Importantly, MOOs rescued the impaired neurons co-cultured with astrocytes. The effects of MOOs on LPS-stimulated astrocytes were reversed by 3-MA. Finally, MOOs upregulated LPS-downregulated Mfn2 expression in astrocytes. Mfn2 inhibition partly reversed the effects of MOOs on hypertension with depression. Intriguingly, Mfn2 suppression activated PI3K/Akt/mTOR pathway during MOOs treatment.

Conclusions
Astrocytes develop neuroinflammation in response to mitochondrial damage during hypertension with depression. MOOs upregulated Mfn2 expression to activate the PI3K/Akt/mTOR pathway-mediated mitophagy, thereby removing impaired mitochondria in astrocytes.

Highlights

MOOs have anti-hypertensive and anti-depressive properties.

MOOs inhibit inflammation and injury in astrocytes during hypertension with depression.

MOOs induce mitophagy activation in inflammatory astrocytes with mitochondrial damage.

MOOs upregulate Mfn2 expression in astrocytes.

Mfn2 activates mitophagy to resist mitochondrial damage in astrocytes.
Commentary: locating the restriction point
Authors: Brooks Robert F. 
Published: February 2023

AbstractAttempts to map the Restriction Point in the mammalian cell cycle typically involve stimulating quiescent cells with mitogens for increasing intervals, removing the stimulus and then determining the proportion of cells that reach S phase at some point later. This “fixed point” estimate assumes that further cell cycle commitment ceases as soon as the stimulus is removed. In fact, kinetic analysis shows that the probability of cell cycle commitment does not fall back to its initial low value, immediately after a pulse of mitogens, but may instead remain slightly elevated for some while afterwards, compared to the starting quiescent population. Thus, cells entering S phase after a brief exposure to mitogens are not those that pass the Restriction Point early. Rather, they represent cells that continue on to S phase as a result of this residual, low probability of cell cycle commitment. Instead, the mitogen-regulated process(es) affecting the probability of cell cycle commitment are much closer to the start of S phase itself. Since the acquisition of (apparent) mitogen independence is such a poor indicator of the timing of cell cycle commitment, it is argued that a better measure is the point of insensitivity to CDK4,6 inhibitors such as palbociclib, which indicates when hyperphosphorylation of the Retinoblastoma Protein, RB, ceases to be dependent on mitogen-signalling pathways regulating CDK4,6/cyclin D activity.
De-Implementing Opioids for Dental Extractions (DIODE): a multi-clinic, cluster-randomized trial of clinical decision support strategies in dentistry
Authors: Gryczynski Jan , Mitchell Shannon Gwin , Asche Stephen E. , Truitt Anjali R. , Worley Donald C. , Rindal D. Brad 
Published: February 2023

Abstract
Background
Opioid pain relievers are commonly prescribed following dental extractions, but evidence shows that non-opioid analgesics often provide adequate pain relief with fewer risks. The current study examined clinical decision support (CDS) as a tool for de-implementing opioid prescribing in dentistry.

Methods
This prospective, cluster-randomized trial examined CDS for dental pain management at 22 HealthPartners Dental Group clinics in Minnesota. Dental providers (n = 49) were randomized to deliver care using CDS, CDS with patient education materials (CDS-E), or standard practice (SP). Randomization was stratified by provider type (dentist vs. oral surgeon) and baseline opioid prescribing volume. Patient records of dental extractions were examined for January 2019 through May 2021, representing a 12-month baseline and 15-month intervention period (N = 12,924). Opioid prescription at the visit (no vs. yes) was the primary outcome. Data were analyzed using generalized linear mixed models, adjusting for patient sex and age, extraction complexity, and baseline prescribing strata (volume and provider type).

Results
Patients were 56.2% female, with a mean age of 46.7 (SD = 20.0) years. Providers were 8% oral surgeons, 57% female, and with a mean age of 43.7 (SD = 11.2) years. There were significant decreases in opioid prescribing during the study (P < 0.001), representing a continuation of pre-existing trends to reduce opioid prescribing in these dental practices. There were no significant differences in opioid prescribing between CDS and SP (OR = 1.29; 97.5% CI = 0.93, 1.79; P = 0.08), or CDS-E and SP arms (OR = 1.27; 97.5% CI = 0.86, 1.79; P = 0.18). The direction of the association favored greater reductions in opioid prescribing in the SP arm. Despite training and implementation support, utilization of the CDS was low, particularly among oral surgeons, who were significantly more likely than other dentists to prescribe opioids. Among non-oral surgeon providers with the opportunity to access it, CDS utilization was not significantly associated with opioid prescribing.

Conclusions
Equipping dentists with CDS resources, whether alone or accompanied by patient education materials, did not accelerate reductions in opioid prescribing beyond those observed in standard practice. Strategies are needed to enhance CDS utilization for patient care and safety surrounding analgesia following dental extractions.

Trial registration
Clinicaltrials.gov, NCT03584789.
Estimating the prevalence of Epstein–Barr virus in primary gastric lymphoma: a systematic review and meta-analysis
Authors: Hirabayashi Mayo , Traverse-Glehen Alexandra , Combes Jean-Damien , Clifford Gary M. , de Martel Catherine 
Published: February 2023

AbstractThe stomach is a common site for extranodal non-Hodgkin’s lymphoma. While Helicobacter pylori (H. pylori) is the main established risk factor for primary gastric lymphoma, a fraction could be aetiologically associated with Epstein–Barr virus (EBV), a known haematolymphoid carcinogen. We systematically searched five databases from 1 January 1990 until 31 May 2022 for studies reporting EBV prevalence in gastric lymphoma tumour tissue by in-situ hybridisation (ISH) for EBV-encoded small RNA (PROSPERO CRD42020164473). We included representative series of more than five gastric lymphoma cases. Pooled prevalence and corresponding 95% confidence intervals (CI) of EBV in gastric tumour cells were calculated for two major gastric B-cell lymphoma types, mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). When available, we also extracted data on H. pylori prevalence and survival by EBV status. We found ten studies including 194 cases of gastric MALT lymphoma and 11 studies including 643 cases of gastric DLBCL. EBV prevalence was 2.2% (95% CI: 0.5–13.3) in gastric MALT lymphoma and 11.0% (95% CI: 5.2–20.0) in gastric DLBCL. In a subset of studies, the prevalence of H. pylori was higher in gastric MALT lymphoma (51/69) compared to gastric DLBCL (62/102). Overall, our findings suggest that EBV is rarely seen in MALT lymphoma but is associated with around 10% of gastric DLBCL, similar to the proportion observed at other primary sites. EBV-related lymphoma adds a small number of cases to the burden of cancer that could be prevented by the future development of a vaccine against EBV.
Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup
Authors: Ghannoum Marc , Gosselin Sophie , Hoffman Robert S. , Lavergne Valery , Mégarbane Bruno , Hassanian-Moghaddam Hossein , Rif Maria , Kallab Siba , Bird Steven , Wood David M. , Roberts Darren M. ,   for the EXTRIP Workgroup, Alhatali Badria , Anseeuw Kurt , Berling Ingrid , Bouchard Josée , Bunchman Timothy E. , Calello Diane P. , Chin Paul K. , Doi Kent , Galvao Tais , Goldfarb David S. , Hoegberg Lotte C. G. , Kebede Sofia , Kielstein Jan T. , Lewington Andrew , Li Yi , Macedo Etienne M. , MacLaren Rob , Mowry James B. , Nolin Thomas D. , Ostermann Marlies , Peng Ai , Roy Jean-Philippe , Shepherd Greene , Vijayan Anitha , Walsh Steven J. , Wong Anselm , Yates Christopher 
Published: February 2023

AbstractEthylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid–base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong (“we recommend”) or weak/conditional (“we suggest”), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8–12 mmol/L or anion gap 23–27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is < 18 mmol/L or suggested if EG concentration is < 4 mmol/L. The dosage of antidotes (fomepizole or ethanol) needs to be adjusted during ECTR.
Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis
Authors: Campagna Maria Pia , Xavier Alexandre , Stankovich Jim , Maltby Vicki E. , Slee Mark , Yeh Wei Z. , Kilpatrick Trevor , Scott Rodney J. , Butzkueven Helmut , Lechner-Scott Jeannette , Lea Rodney A. , Jokubaitis Vilija G. 
Published: February 2023

Abstract
Background
Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS.

Results
We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5–44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women.

Conclusion
Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential ‘CNS signature’ of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
Evaluation of optimal monoenergetic images acquired by dual-energy CT in the diagnosis of T staging of thoracic esophageal cancer
Authors: Cheng Fanrong , Liu Yan , Du Lihong , Wang Lei , Li Lan , Shi Jinfang , Wang Xiaoxia , Zhang Jiuquan 
Published: February 2023

Abstract
Objectives
The purpose of our study was to objectively and subjectively assess optimal monoenergetic image (MEI (+)) characteristics from dual-energy CT (DECT) and the diagnostic performance for the T staging in patients with thoracic esophageal cancer (EC).

Methods
In this retrospective study, patients with histopathologically confirmed EC who underwent DECT from September 2019 to December 2020 were enrolled. One standard polyenergetic image (PEI) and five MEI (+) were reconstructed. Two readers independently assessed the lesion conspicuity subjectively and calculated the contrast-to-noise ratio (CNR) and the signal-to-noise ratio (SNR) of EC. Two readers independently assessed the T stage on the optimal MEI (+) and PEI subjectively. Multiple quantitative parameters were measured to assess the diagnostic performance to identify T1-2 from T3-4 in EC patients.

Results
The study included 68 patients. Subjectively, primary tumor delineation received the highest ratings in MEI (+) 40 keV of the venous phase. Objectively, MEI (+) images showed significantly higher SNR compared with PEI (p < 0.05), peaking at MEI (+) 40 keV in the venous phase. CNR of tumor (MEI (+) 40 keV -80 keV) was all significantly higher than PEI in arterial and venous phases (p < 0.05), peaking at MEI (+) 40 keV in venous phases. The agreement between MEI (+) 40 keV and pathologic T categories was 81.63% (40/49). Rho values in venous phases had excellent diagnostic efficiency for identifying T1-2 from T3-4 (AUC = 0.84).

Conclusions
MEI (+) reconstructions at low keV in the venous phase improved the assessment of lesion conspicuity and also have great potential for preoperative assessment of T staging in patients with EC.
Integrated analysis of RNA methylation regulators crosstalk and immune infiltration for predictive and personalized therapy of diabetic nephropathy
Authors: Li Jia , Liu Dongwei , Ren Jingjing , Li Guangpu , Zhao Zihao , Zhao Huanhuan , Yan Qianqian , Duan Jiayu , Liu Zhangsuo 
Published: February 2023

Abstract
Background
RNA methylation is a widely known post-transcriptional regulation which exists in many cancer and immune system diseases. However, the potential role and crosstalk of five types RNA methylation regulators in diabetic nephropathy (DN) and immune microenvironment remain unclear.

Methods
The mRNA expression of 37 RNA modification regulators and RNA modification regulators related genes were identified in 112 samples from 5 Gene Expression Omnibus datasets. Nonnegative Matrix Factorization clustering method was performed to determine RNA modification patterns. The ssGSEA algorithms and the expression of human leukocyte antigen were employed to assess the immune microenvironment characteristics. Risk model based on differentially expression genes responsible for the modification regulators was constructed to evaluate its predictive capability in DN patients. Furthermore, the results were validated by using immunofluorescence co-localizations and protein experiments in vitro.

Results
We found 24 RNA methylation regulators were significant differently expressed in glomeruli in DN group compared with control group. Four methylation-related genes and six RNA regulators were introduced into riskScore model using univariate Logistic regression and integrated LASSO regression, which could precisely distinguish the DN and healthy individuals. Group with high-risk score was associated with high immune infiltration. Three distinct RNA modification patterns were identified, which has significant differences in immune microenvironment, biological pathway and eGFR. Validation analyses showed the METTL3, ADAR1, DNMT1 were upregulated whereas YTHDC1 was downregulated in DN podocyte cell lines comparing with cells cultured by the normal glucose.

Conclusion
Our study reveals that RNA methylation regulators and immune infiltration regulation play critical roles in the pathogenesis of DN. The bioinformatic analyses combine with verification in vitro could provide robust evidence for identification of predictive RNA methylation regulators in DN.
Interleukin 6 and interferon gamma haplotypes are related to cytokine serum levels in dogs in an endemic Leishmania infantum region
Authors: Álvarez Luis , Marín-García Pablo-Jesús , Rentero-Garrido Pilar , Martinez-Jimenez Celia Pilar , Llobat Lola 
Published: February 2023

Abstract
Background
The Ibizan Hound is a canine breed native to the Mediterranean region, where leishmaniasis is an endemic zoonosis. Several studies indicate a low prevalence of this disease in Ibizan Hound dogs, whereas other canine breeds present a high prevalence. However, the underlying molecular mechanisms still remain unknown. The aim of this work is to analyse the relationship between serum levels of cytokines and the genomic profiles in two canine breeds, Ibizan Hound (resistant canine breed model) and Boxer (susceptible canine breed model).

Methods
In this study, we analyse the haplotypes of genes encoding cytokines related to immune response of Leishmania infantum infection in twenty-four Boxers and twenty-eight Ibizan Hounds apparently healthy using CanineHD DNA Analysis BeadChip including 165,480 mapped positions. The haplo.glm extension of haplo.score was used to perform a General Linear Model (GLM) regression to estimate the magnitude of individual haplotype effects within each cytokine.

Results
Mean levels of interferon gamma (IFN-γ), interleukin 2 (IL-2) and IL-18 in Boxer dogs were 0.19 ± 0.05 ng/ml, 46.70 ± 4.54 ng/ml, and 36.37 ± 30.59 pg/ml, whereas Ibizan Hound dogs present 0.49 ± 0.05 ng/ml, 64.55 ± 4.54 ng/ml, and 492.10 ± 31.18 pg/ml, respectively. The GLM regression shows fifteen haplotypes with statistically significant effect on the cytokine serum levels (P < 0.05). The more relevant are IL6-CGAAG and IFNG-GCA haplotypes, which increase and decrease the IL-2, IL-8 and IFN-γ serum levels, respectively.

Conclusions
Haplotypes in the IFNG and IL6 genes have been correlated to serum levels of IFN-γ, IL-2 and IL-18, and a moderate effect has been found on IL8 haplotype correlated to IL-8 and IL-18 serum levels. The results indicate that the resistance to L. infantum infection could be a consequence of certain haplotypes with a high frequency in the Ibizan Hound dog breed, while susceptibility to the disease would be related to other specific haplotypes, with high frequency in Boxer. Future studies are needed to elucidate whether these differences and haplotypes are related to different phenotypes in immune response and expression gene regulation to L. infantum infections in dogs and their possible application in new treatments and vaccines.

Graphical Abstract
Possible future scenarios of the general health social security system in Colombia for the year 2033
Authors: Aguilar Pedro Leon Cruz , Vásquez Javier Enrique Medina 
Published: February 2023

AbstractThis article formulates possible future scenarios for the Colombian General Health and Social Security System (GHSSS) in 2033 when it reaches its 40th anniversary. The research draws on intuitive logic from the School of Human and Social Foresight (Masini, Penser le futur, 2000). The approach considers that in contexts of high instability and high conflict of interests, a combination of methods is required for the analysis of relevant transformations. It entails applying methods based on evidence, expertise, interaction, and creativity as discussed by Keenan and Popper (Foresight 10:16–36, 2008). Three scenarios are devised with the participation of real actors representing a plurality of visions from the public, private, academic, and social sectors. Finally, two future scenarios are featured, the one chosen by the experts before the triumph of the current government and the one that the Ministry of Health will present to the Colombian Congress for approval in 2023.