bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of an educational intervention to improve medical student cost awareness: a prospective cohort study
Authors: Tait Sarah D , Oshima Sachiko M , Leeras Harold J , Gunn Alexander , Sarver Melissa , Gunes Funda , Greenup Rachel A.
Published: January 2023

Background

In the context of rising healthcare costs, formal education on treatment-related financial hardship is lacking in many medical schools, leaving future physicians undereducated and unprepared to engage in high-value care.

Method

We performed a prospective cohort study to characterize medical student knowledge regarding treatment-related financial hardship from 2019 to 2020 and 2020–2021, with the latter cohort receiving a targeted educational intervention to increase cost awareness. Using Kirkpatrick’s four-level training evaluation model, survey data was analyzed to characterize the acceptability of the intervention and the impact of the intervention on student knowledge, attitudes, and self-reported preparedness to engage in cost-conscious care.

Results

Overall, N = 142 medical students completed the study survey; 61 (47.3%) in the non-intervention arm and 81 (66.4%) in the intervention arm. Of the 81 who completed the baseline survey in the intervention arm, 65 (80.2%) completed the immediate post-intervention survey and 39 (48.1%) completed the two-month post-intervention survey. Following the educational intervention, students reported a significantly increased understanding of common financial terms, access to cost-related resources, and level of comfort and preparedness in engaging in discussions around cost compared to their pre-intervention responses. The majority of participants (97.4%) reported that they would recommend the intervention to future students. A greater proportion of financially stressed students reported considering patient costs when making treatment decisions compared to their non-financially stressed peers.

Conclusions

Targeted educational interventions to increase cost awareness have the potential to improve both medical student knowledge and preparedness to engage in cost-conscious care. Student financial stress may impact high-value care practices. Robust curricula on high-value care, including treatment-related financial hardship, should be formalized and universal within medical school training.
The influence of professional identity on how the receiver receives and responds to a speaking up message: a cross-sectional study
Authors: Barlow Melanie , Watson Bernadette , Jones Elizabeth , Maccallum Fiona , Morse Kate J.
Published: January 2023

Background

Research focused on understanding what enables or hinders health professionals to speak up about a safety concern has been to date predominately atheoretical and speaker focused. However, the role the receiver of the message plays in these often-difficult encounters is highly influential. To date, speaking up programs have created conversational mnemonics that technically should respectfully engage the receiver, yet speaking up remains challenging. This paper utilises Communication Accommodation Theory to explore the impact the communication behaviour and speaker characteristics has on the receiver of a speaking up message, and if these impacts differ between receiver groups (clinical disciplines).

Method

Clinicians (N = 208) from varying disciplines responded to two hypothetical speaking up vignettes, where participants were the receivers of speaking up messages. Analysis of variance was used to explore any potential differences between receiver groups.

Results

Findings indicated that the level of perceived accommodation and group membership, whether defined by speaker discipline or seniority, collectively influenced how the receiver of a speaking up message evaluated the interaction, which influenced their anticipated response to the speaker.

Conclusions

The receiver’s perceptions and evaluations of the message, their own professional identity and the presence of others, influenced receivers’ anticipated responses. This has direct implications on healthcare speaking up training and provision of care, as the varying clinical disciplines received and responded to the same messages differently.
Identification of ferroptosis related markers by integrated bioinformatics analysis and In vitro model experiments in rheumatoid arthritis
Authors: Xia Jinjun , Zhang Lulu , Gu Tao , Liu Qingyang , Wang Qiubo
Published: January 2023

Background

Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive and symmetrical joint diseases and synovitis. This research attempted to explore the mechanisms involving ferroptosis in RA, and find the biological markers by integrated analysis.

Methods

Gene expression data (GSE55235 and GSE55457) of synovial tissues from healthy and RA individuals were downloaded. By filtering the differentially expressed genes (DEGs) and intersecting them with the 484 ferroptosis-related genes (FRGs), the overlapping genes were identified. After the enrichment analysis, the machine learning-based approaches were introduced to screen the potential biomarkers, which were further validated in other two datasets (GSE77298 and GSE93272) and cell samples. Besides, we also analyze the infiltrating immune cells in RA and their correlation with the biomarkers.

Results

With the criteria, 635 DEGs in RA were included, and 29 of them overlapped in the reported 484 FRGs. The enrichments of the 29 differentially expressed ferroptosis-related genes indicated that they may involve in the FoxO signaling pathway and inherited metabolic disorder. RRM2, validating by the external datasets and western blot, were identified as the biomarker with the high diagnostic value, whose associated immune cells, such as Neutrophils and Macrophages M1, were also further evaluated.

Conclusion

We preliminary explored the mechanisms between ferroptosis and RA. These results may help us better comprehend the pathophysiological changes of RA in basic research, and provide new evidences for the clinical transformation.
Loop pathways are responsible for tuning the accumulation of C19- and C22-sterol intermediates in the mycobacterial phytosterol degradation pathway
Authors: Song Shikui , He Jianxin , Gao Meng , Huang Yongqi , Cheng Xiyao , Su Zhengding
Published: January 2023

4-Androstene-3,17-dione (4-AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (BA) are the most important and representative C19- and C22-steroidal materials. The optimalization of sterol production with mycobacterial phytosterol conversion has been investigated for decades. One of the major challenges is that current industrial mycobacterial strains accumulate unignorable impurities analogous to desired sterol intermediates, significantly hampering product extractions and refinements. Previously, we identified Mycobacterium neoaurum HGMS2 as an efficient 4-AD-producing strain (Wang et al. in Microb Cell Fact. 19:187, 2020). Recently, we have genetically modified the HGMS2 strain to remove its major impurities including ADD and 9OH-AD (Li et al. in Microb Cell Fact. 20:158, 2021). Unexpectedly, the modified mutants started to significantly accumulate BA compared with the HGMS2 strain. In this work, while we attempted to block BA occurrence during 4-AD accumulation in HGMS2 mutants, we identified a few loop pathways that regulated metabolic flux switching between 4-AD and BA accumulations and found that both the 4-AD and BA pathways shared a 9,10-secosteroidial route. One of the key enzymes in the loop pathways was Hsd4A1, which played an important role in determining 4-AD accumulation. The inactivation of the hsd4A1 gene significantly blocked the 4-AD metabolic pathway so that the phytosterol degradation pathway flowed to the BA metabolic pathway, suggesting that the BA metabolic pathway is a complementary pathway to the 4-AD pathway. Thus, knocking out the hsd4A1 gene essentially made the HGMS2 mutant (HGMS2Δhsd4A1) start to efficiently accumulate BA. After further knocking out the endogenous kstd and ksh genes, an HGMS2Δhsd4A1 mutant, HGMS2Δhsd4A1/Δkstd1, enhanced the phytosterol conversion rate to BA in 1.2-fold compared with the HGMS2Δhsd4A1 mutant in pilot-scale fermentation. The final BA yield increased to 38.3 g/L starting with 80 g/L of phytosterols. Furthermore, we knocked in exogenous active kstd or ksh genes to HGMS2Δhsd4A1/Δ kstd1 to construct DBA- and 9OH-BA-producing strains. The resultant DBA- and 9OH-BA-producing strains, HGMS2Δhsd4A1/kstd2 and HGMS2Δkstd1/Δhsd4A1/kshA1B1, efficiently converted phytosterols to DBA- and 9OH-BA with the rates of 42.5% and 40.3%, respectively, and their final yields reached 34.2 and 37.3 g/L, respectively, starting with 80 g/L phytosterols. Overall, our study not only provides efficient strains for the industrial production of BA, DBA and 9OH-BA but also provides insights into the metabolic engineering of the HGMS2 strain to produce other important steroidal compounds.
In silico profiling of nonsynonymous SNPs of fat mass and obesity-associated gene: possible impacts on the treatment of non-alcoholic fatty liver disease
Authors: Patnaik Damini , Jena Atala Bihari , Kerry Rout George , Duttaroy Asim K.
Published: January 2023

Background

Nonalcoholic fatty liver, or NAFLD, is the most common chronic liver ailment. It is characterized by excessive fat deposition in hepatocytes of individuals who consume little or no alcohol and are unaffected by specific liver damaging factors. It is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease, and sleep apnea. The global burden of NAFLD is increasing at an alarming rate. However, no pharmacologically approved drugs against NAFLD are available owing to their complex pathophysiology. Genome-wide association studies have uncovered SNPs in the fat mass and obesity-associated gene (FTO) that are robustly associated with obesity and higher BMI. The prevalence of NAFLD increases in parallel with the increasing prevalence of obesity. Since FTO might play a crucial role in NAFLD development, the current study identified five potentially deleterious mutations from 383 ns-SNPs in the human FTO gene using various in silico tools.

Methods

This study aims to identify potentially deleterious nonsynonymous SNPs (ns-SNPs) employing various in silico tools. Additionally, molecular modeling approaches further studied the structural changes caused by identified SNPs. Moreover, molecular dynamics studies finally investigated the binding potentials of the phytochemicals resveratrol, rosmarinic acid, and capsaicin with different mutant forms of FTO.

Results

The current investigation has five potentially deleterious mutations from 383 ns-SNPs in the human FTO gene using various in silico tools. The present study identified five nsSNPs of the human gene FTO, Gly103Asp, Arg96Pro, Tyr295Cys, and Arg322Gln, with an apparent connection to the disease condition. Modulation of demethylation activity by phytomolecule scanning explains the hepatoprotective action of molecules. The current investigation also suggested that predicted mutations did not affect the binding ability of three polyphenols: rosamarinic acid, resveratrol, and capsaicin.

Conclusion

This study showed that the predicted mutations in FTO did not affect the binding of three polyphenols. Thus, these three molecules can significantly aid drug development against FTO and NAFLD.
Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy
Authors: Zhao Yading , Shi Dandan , Guo Lu , Shang Mengmeng , Sun Xiao , Meng Dong , Xiao Shan , Wang Xiaoxuan , Li Jie
Published: January 2023

Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy.

Graphical Abstract
Synovial sarcoma with intra-abdominal metastasis causing hemoperitoneum: a case-report
Authors: Thompson Joshua J. , Koch Rachel A. , Keedy Vicki L. , Magge Deepa R.
Published: January 2023

Synovial sarcoma is a rare soft tissue sarcoma which frequently involves the upper or lower extremities. Soft tissue sarcomas including synovial sarcoma have a propensity to metastasize to the lungs, and there are very few reports of metastatic lesions in other locations.

Here, we report a case of a 49-year-old patient who underwent neoadjuvant chemoradiation for an upper extremity synovial sarcoma and presented approximately 4 years later with abdominal pain and hemoperitoneum and was ultimately found to have metastatic synovial sarcoma involving the greater curvature of the stomach and surrounding peri-gastric soft tissue. We describe the multidisciplinary management of this complex patient presentation and propose that expanded surveillance imaging beyond that of the local tumor resection bed and the chest may be beneficial especially in tumors with high-risk features.
Safety, efficacy and prognosis of anticoagulant therapy for portal vein thrombosis in cirrhosis: a retrospective cohort study
Authors: Zhang Zhiqi , Zhao Ying , Li Dandan , Guo Mingxing , Li Hongyu , Liu Ranjia , Cui Xiangli
Published: January 2023

Background

The role of anticoagulants in the treatment of cirrhotic PVT remains controversial. This study aimed to analyze the safety and efficacy of anticoagulant therapy in patients with cirrhotic portal vein thrombosis (PVT) and its impact on prognosis.

Methods

A retrospective cohort study was conducted for PVT patients with liver cirrhosis in our hospital. The primary outcome of the study was the PVT recanalization rate. Other outcomes included bleeding rate, liver function, and mortality. Cox and Logistic regression were used to explore the risk factors of outcomes.

Results

This study included 77 patients that 27 patients in the anticoagulant group and 50 in the non-anticoagulant group. Anticoagulant therapy was associated with higher rate of PVT recanalization (44.4% vs 20.0%, log-rank P = 0.016) and lower rate of PVT progression (7.4% vs 30.0%, log-rank P = 0.026), and without increasing the rate of total bleeding (14.8% vs 24%, P = 0.343), major bleeding (3.7% vs 6%, P = 0.665) and variceal bleeding (3.7% vs 16%, P = 0.109). The safety and efficacy of different anticoagulants were similar. The Child-Pugh grade of the anticoagulant therapy group was better than that of the non-anticoagulant therapy group (P = 0.030). There was no significant difference in the 2-year survival rate of the two groups.

Conclusion

Anticoagulants could increase the PVT recanalization rate and reduce the PVT progression rate without increasing the rate of bleeding. Anticoagulants may be beneficial to improving the liver function of patients with cirrhotic PVT. There was no significant difference in the safety and efficacy of different anticoagulants in the treatment of cirrhotic PVT.
Chronic anti-coagulation therapy reduced mortality in patients with high cardiovascular risk early in COVID-19 pandemic
Authors: Zaghloul Mohamed S. , Jammeh Momodou , Gibson Andrew , Luo Suhong , Chadwick-Mansker Kelley , Liu Qianjin , Yan Yan , Zayed Mohamed A.
Published: January 2023

Background

Coronavirus disease 2019 (COVID-19) is associated with provoked thrombo-inflammatory responses. Early in the COVID-19 pandemic this was thought to contribute to hypercoagulability and multi-organ system complications in infected patients. Limited studies have evaluated the impact of therapeutic anti-coagulation therapy (AC) in alleviating these risks in COVID-19 positive patients. Our study aimed to investigate whether long-term therapeutic AC can decrease the risk of multi-organ system complications (MOSC) including stroke, limb ischemia, gastrointestinal (GI) bleeding, in-hospital and intensive care unit death in COVID-19 positive patients hospitalized during the early phase of the pandemic in the United States.

Methods

A retrospective analysis was conducted of all COVID-19 positive United States Veterans between March 2020 and October 2020. Patients receiving continuous outpatient therapeutic AC for a least 90 days prior to their initial COVID-19 positive test were assigned to the AC group. Patients who did not receive AC were included in a control group. We analyzed the primary study outcome of MOSC between the AC and control groups using binary logistic regression analysis (Odd-Ratio; OR).

Results

We identified 48,066 COVID-19 patients, of them 879 (1.8%) were receiving continuous therapeutic AC. The AC cohort had significantly worse comorbidities than the control group. On the adjusted binary logistic regression model, therapeutic AC significantly decreased in-hospital mortality rate (OR; 0.67, p = 0.04), despite a higher incidence of GI bleeding (OR; 4.00, p = 0.02). However, therapeutic AC did not significantly reduce other adverse events.

Conclusion

AC therapy reduced in-hospital death early in the COVID-19 pandemic among patients who were hospitalized with the infection. ﻿However, it did not decrease the risk of MOSC. Additional trials are needed to determine the effectiveness of AC in preventing complications associated with ongoing emerging strains of the COVID-19 virus.
How surface acting affects turnover intention among family doctors in rural China: the mediating role of emotional exhaustion and the moderating role of occupational commitment
Authors: Wang Anqi , Tang Changhai , Zhou Lifang , Lv Haiyuan , Song Jia , Chen Zhongming , Yin Wenqiang
Published: January 2023

Background

Family doctors in rural China are the main force for primary health care, but the workforce has not been well stabilized in recent years. Surface acting is an emotional labor strategy with a disparity between inner feelings and emotional displays, provoking negative effects such as emotional exhaustion, occupational commitment reduction, and, consequently, increasing turnover rate. With the Conservation of Resources theory, this study explores how the surface acting of rural family doctors affects turnover intention through emotional exhaustion and investigates what role occupational commitment plays in this relationship.

Methods

With a valid response rate of 93.89%, 953 valid data were collected by an anonymous self-administered questionnaire survey in December 2021 in Shandong Province, China. Cronbach’s Alpha and confirmatory factor analysis (CFA) were used to estimate reliability and construct validity, respectively. The PROCESS macro in SPSS was performed to analyze the mediating and moderated mediation effects of surface acting, emotional exhaustion, occupational commitment, and turnover intention.

Results

Reliability and validity indicated that the measurement instruments were acceptable. Surface acting had a direct positive effect on turnover intention (β = 0.481, 95% CI [0.420, 0.543]). Emotional exhaustion partially mediated the effect of surface acting on turnover intention (indirect effect: 0.214, 95% CI [0.175, 0.256]). Occupational commitment moderated the effect of emotional exhaustion on turnover intention (β = − 0.065, 95% CI [− 0.111, − 0.019]), and moderated the indirect effect of surface acting on turnover intention via emotional exhaustion (index of moderated mediation: − 0.035).

Conclusions

Emotional exhaustion partially mediates the relationship between surface acting and turnover intention among family doctors in rural China, and occupational commitment moderates the direct effect of emotional exhaustion on turnover intention and further moderates the mediating effect. Policymakers should pay more attention to the effects of emotional labor and emotional resource depletion on the stability of rural health human resources.
Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma: a systematic review and meta-analysis
Authors: Goudarzi Zahra , Mostafavi Mehrdad , Salesi Mahmood , Jafari Mojtaba , Mirian Iman , Hashemi Meshkini Amir , Keshavarz Khosro , Ghasemi Younes
Published: January 2023

Objective

Renal cell carcinoma (RCC) is the most common type of kidney cancer. VEGF inhibitors and mTORs are the most common therapeutic options among the different classes of available treatments. In this study, the effectiveness of Everolimus was compared to Temsirolimus, and Everolimus plusLenvatinib in renal cell carcinoma patients by review of the international clinical evidence.

Materials and methods

A systematic review was conducted and all relevant published clinical studies on the efficacy and cost-effectiveness of Everolimus, Temsirolimus, and Lenvatinib plus Everolimus were searched comprehensively in electronic databases including Pubmed, Scopus, Medline, Cochrane Library, and ISI web of science. The Q score and I2 test checked the Heterogeneity and publication bias test, respectively. Egger’s test and Begg’s test were used to checking publication bias. The hazard ratio (HR) of included studies and subclass analysis were estimated by fixed and random effect models.

Results

Out of 1816 found studies, ultimately, were included considering inclusion and exclusion criteria. None of these studies evaluated all three treatment strategies together and each study was about one strategy. Only one study was found for Everolimus plus Lenvatinib, so it was excluded from meta-analysis. Overall, data from 526 patients on Temsirolimus and 648 patients on Everolimus were included in Meta-Analysis. Accordingly, the efficacy of Everolimus and Temsirolimus was not statistically significant in assessed outcomes (PFS, TTSF, and death). However, Everlimus is superior to Temsirolimus in OS (Q = 3.61, p-value: 0.462, I2 = 0%). No heterogeneity or bias was detected.

Conclusion

According to the results of this study, Everolimus could be related to an increase of OS versus Temsirolimus as a second line treatment of ORCC patients.
A prediction model for the impact of environmental and genetic factors on cardiovascular events: development in a salt substitutes population
Authors: Zhao Dan , Sun Hao , Li Huamin , Li Chaoxiu , Zhou Bo
Published: January 2023

Background

Cardiovascular disease (CVD) has evolved into a serious public health issue that demands the use of suitable methods to estimate the risk of the disease. As a result, in a sample of individuals who completed a 3-year low-sodium salt or conventional salt intervention in a hypertensive environment, we constructed a 13-year cardiovascular (CV) event risk prediction model with a 10-year follow-up.

Methods

A Cox proportional hazards model was used to build a prediction model based on data from 306 participants who matched the inclusion criteria. Both the discriminating power and the calibration of the prediction models were assessed. The discriminative power of the prediction model was measured using the area under the curve (AUC). Brier scores and calibration plots were used to assess the prediction model's calibration. The model was internally validated using the tenfold cross-validation method. The nomogram served as a tool for visualising the model.

Results

Among the 306 total individuals, there were 100 cases and 206 control. In the model, there were six predictors including age, smoking, LDL-C (low-density lipoprotein cholesterol), baseline SBP (systolic blood pressure), CVD (cardiovascular history), and CNV (genomic copy number variation) nsv483076. The fitted model has an AUC of 0.788, showing strong model discrimination, and a Brier score of 0.166, indicating that it was well-calibrated. According to the results of internal validation, the prediction model utilised in this study had a good level of repeatability. According to the model integrating the interaction of CNVs and baseline blood pressure, the effect of baseline SBP on CV events may be greater when nsv483076 was normal double copies than when nsv483076 was copy number variation.

Conclusions

The efficacy of risk prediction models for CV events that include environmental and genetic components is excellent, and they may be utilised as risk assessment tools for CV events in specific groups to offer a foundation for tailored intervention strategies.
Characterization of large extracellular vesicles (L-EV) derived from human regulatory macrophages (Mreg): novel mediators in wound healing and angiogenesis?
Authors: Albrecht Martin , Hummitzsch Lars , Rusch Rene , Heß Katharina , Steinfath Markus , Cremer Jochen , Lichte Frank , Fändrich Fred , Berndt Rouven , Zitta Karina
Published: January 2023

Background

Large extracellular vesicles (L-EV) with a diameter between 1 and 10 µm are released by various cell types. L-EV contain and transport active molecules which are crucially involved in cell to cell communication. We have shown that secretory products of human regulatory macrophages (Mreg) bear pro-angiogenic potential in-vitro and our recent findings show that Mreg cultures also contain numerous large vesicular structures similar to L-EV with so far unknown characteristics and function.

Aim of this study

To characterize the nature of Mreg-derived L-EV (L-EVMreg) and to gain insights into their role in wound healing and angiogenesis.

Methods

Mreg were differentiated using blood monocytes from healthy donors (N = 9) and L-EVMreg were isolated from culture supernatants by differential centrifugation. Characterization of L-EVMreg was performed by cell/vesicle analysis, brightfield/transmission electron microscopy (TEM), flow cytometry and proteome profiling arrays. The impact of L-EVMreg on wound healing and angiogenesis was evaluated by means of scratch and in-vitro tube formation assays.

Results

Mreg and L-EVMreg show an average diameter of 13.73 ± 1.33 µm (volume: 1.45 ± 0.44 pl) and 7.47 ± 0.75 µm (volume: 0.22 ± 0.06 pl) respectively. Flow cytometry analyses revealed similarities between Mreg and L-EVMreg regarding their surface marker composition. However, compared to Mreg fewer L-EVMreg were positive for CD31 (P < 0.01), CD206 (P < 0.05), CD103 (P < 0.01) and CD45 (P < 0.05). Proteome profiling suggested that L-EVMreg contain abundant amounts of pro-angiogenic proteins (i.e. interleukin-8, platelet factor 4 and serpin E1). From a functional point of view L-EVMreg positively influenced in-vitro wound healing (P < 0.05) and several pro-angiogenic parameters in tube formation assays (all segment associated parameters, P < 0.05; number of meshes, P < 0.05).

Conclusion

L-EVMreg with regenerative and pro-angiogenic potential can be reproducibly isolated from in-vitro cultured human regulatory macrophages. We propose that L-EVMreg could represent a putative therapeutic option for the treatment of chronic wounds and ischemia-associated diseases.
Inhibition of 2-arachidonoylglycerol degradation enhances glial immunity by single-cell transcriptomic analysis
Authors: Zhu Dexiao , Zhang Jian , Hashem Jack , Gao Fei , Chen Chu
Published: January 2023

Background

2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid. Inhibition of 2-AG metabolism by inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that degrades 2-AG in the brain, produces anti-inflammatory and neuroprotective effects in neurodegenerative diseases. However, the molecular mechanisms underlying these beneficial effects are largely unclear.

Methods

Hippocampal and cortical cells were isolated from cell type-specific MAGL knockout (KO) mice. Single-cell RNA sequencing was performed by 10 × Genomics platform. Cell Ranger, Seurat (v3.2) and CellChat (1.1.3) packages were used to carry out data analysis.

Results

Using single-cell RNA sequencing analysis, we show here that cell type-specific MAGL KO mice display distinct gene expression profiles in the brain. Inactivation of MAGL results in robust changes in expression of immune- and inflammation-related genes in microglia and astrocytes. Remarkably, upregulated expression of chemokines in microglia is more pronounced in mice lacking MAGL in astrocytes. In addition, expression of genes that regulate other cellular functions and Wnt signaling in astrocytes is altered in MAGL KO mice.

Conclusions

Our results provide transcriptomic evidence that cell type-specific inactivation of MAGL induces differential expression of immune-related genes and other fundamental cellular pathways in microglia and astrocytes. Upregulation of the immune/inflammatory genes suggests that tonic levels of immune/inflammatory vigilance are enhanced in microglia and astrocytes, particularly in microglia, by inhibition of 2-AG metabolism, which likely contribute to anti-inflammatory and neuroprotective effects produced by inactivation of MAGL in neurodegenerative diseases.
Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of Alzheimer’s disease via modulating neuropathology and gut microbiota through suppressing C/EBPβ/AEP pathway
Authors: Xu Qing-Qing , Su Zi-Ren , Yang Wen , Zhong Mei , Xian Yan-Fang , Lin Zhi-Xiu
Published: January 2023

Background

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive dysfunctions and behavioral impairments. Patchouli alcohol (PA), isolated from Pogostemonis Herba, exhibits multiple pharmacological properties, including neuroprotective effects. This study aimed to investigate the therapeutic effects of PA against AD using the TgCRND8 transgenic AD mouse model, and to explore the underlying mechanisms targeting CCAAT/enhancer-binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling pathway.

Methods

After genotyping to confirm the transgenicity, drug treatments were administered intragastrically once daily to 3-month-old TgCRND8 mice for 4 consecutive months. Several behavioral tests were applied to assess different aspects of neurological functions. Then the brain and colon tissues were harvested for in-depth mechanistic studies. To further verify whether PA exerts anti-AD effects via modulating C/EBPβ/AEP signaling pathway in TgCRND8 mice, adeno-associated virus (AAV) vectors encoding CEBP/β were bilaterally injected into the hippocampal CA1 region in TgCRND8 mice to overexpress C/EBPβ. Additionally, the fecal microbiota transplantation (FMT) experiment was performed to verify the potential role of gut microbiota on the anti-AD effects of PA.

Results

Our results showed that PA treatment significantly improved activities of daily living (ADL), ameliorated the anxiety-related behavioral deficits and cognitive impairments in TgCRND8 mice. PA modulated the amyloid precursor protein (APP) processing. PA also markedly reduced the levels of beta-amyloid (Aβ) 40 and Aβ42, suppressed Aβ plaque burdens, inhibited tau protein hyperphosphorylation at several sites and relieved neuroinflammation in the brains of TgCRND8 mice. Moreover, PA restored gut dysbiosis and inhibited the activation of the C/EBPβ/AEP signaling pathway in the brain and colon tissues of TgCRND8 mice. Interestingly, PA strikingly alleviated the AD-like pathologies induced by the overexpression of C/EBPβ in TgCRND8 mice. Additionally, the FMT of fecal microbiota from the PA-treated TgCRND8 mice significantly alleviated the cognitive impairments and AD-like pathologies in the germ-free TgCRND8 mice.

Conclusion

All these findings amply demonstrated that PA could ameliorate the cognitive deficits in TgCRND8 mice via suppressing Aβ plaques deposition, hyperphosphorylation of tau protein, neuroinflammation and gut dysbiosis through inhibiting the activation of C/EBPβ/AEP pathway, suggesting that PA is a promising naturally occurring chemical worthy of further development into the pharmaceutical treatment of AD.
The 18-month efficacy of an Intensive LifeStyle Modification Program (ILSM) to reduce type 2 diabetes risk among rural women: a cluster randomized controlled trial
Authors: Zhong Qinyi , Chen Yao , Luo Mengchun , Lin Qian , Tan Jianghong , Xiao Shuiyuan , Willey James Allen , Chen Jyu-Lin , Whittemore Robin , Guo Jia
Published: January 2023

Background

Many lifestyle interventions have demonstrated efficacy up to one-year follow-up, yet maintaining improvements at longer-term follow-up is a well-recognized worldwide challenge, especially in underserved areas. The purpose of this study is to compare the 18-month efficacy of an Intensive LifeStyle Modification Program to usual care in reducing the risk for type 2 diabetes (T2D) among women with a history of gestational diabetes mellitus (GDM).

Methods

We conducted a two-arm, cluster randomized controlled trial among women with a history of GDM in China. A total of 16 towns (clusters) in two distinct rural areas in south-central China were randomly selected (8 towns per area) and assigned (1:1) to the intervention (Intensive LifeStyle Modification Program) or control (usual care) group with stratification in the two rural areas. The strategies for maintaining intervention effects were used (including setting recursive goals and providing a supportive environment, etc.) under the guidance of social cognitive theory. The primary outcome was a change in T2D risk; secondary outcomes included glycemic, weight-related, behavioral, and psychological variables. All outcomes were collected at baseline, 6, and 18 months. All participants entered the intention-to-treat analysis. Data were analyzed via generalized estimation equation models (accounting for clusters) at the individual level, with subgroup analysis included in the model.

Results

The sample included 320 women from 16 clusters (20 women per cluster). At 18 months, the intervention group demonstrated a significant improvement in T2D risk score, fasting blood glucose, body mass index (BMI), waist circumference, intention to eat low glycemic index food, perceived stress, quality of life in psychological and environmental domains, and social support over time (p < 0.05) based on the intention-to-treat analysis set. Subgroup analysis showed a significant interaction effect on T2D risk score in subgroups of different BMI, waist circumference, and blood glucose (p < 0.05).

Conclusions

Over 18 months, the Intensive LifeStyle Modification Program reduced T2D risk among rural women with a history of GDM in China. Women who were overweight, had high abdominal adiposity, or had blood glucose intolerance benefited more from this intervention. This program serves as a potential diabetes prevention model for women with a history of GDM in low-resource settings worldwide.

Trial registration

Registered on Chinese Clinical Trial Registry (ChiCTR1800015023) on 1st March 2018, http://www.chictr.org.cn/showproj.aspx?proj=25569
Buccal rotation for wholly impacted maxillary third molar extraction
Authors: Ye Zhou-Xi , Qian Wen-Hao , Wu Yu-Bo , Yang Chi
Published: January 2023

Background

Extracting wholly impacted maxillary 3rd molars faces difficulty due to the narrow surgical field, adjacent teeth resistances and risk of oroantral communication. This study is designed to introduce and evaluate the applicability of a novel method-buccal rotation to extract maxillary 3rd molars.

Materials and methods

In this cohort study, from October 1st 2020 to September 30th 2021, 72 wholly impacted maxillary 3rd molars were included. Based on the crowns with coronal 1/3, middle 1/3, apical 1/3 of the adjacent teeth roots, teeth were classified into position I, II, III. Based on the angles < 30°, ≥ 30°but < 60°, ≥ 60° to the adjacent teeth, teeth were classified into angulation A, B, C. Traditional method and novel method-buccal rotation were applied based on the surgical simulations. Surgical results were recorded. To analyze the data, Chi-square test was applied.

Results

82.00% of teeth in position I and 50.00% in position II were designed to use traditional method, 83.33% in position III were using the novel method (p < 0.05). 81.25% of teeth in angulation A and 52.63% in angulation B were designed to use traditional method, 80.00% in angulation C were using the novel method (p < 0.05). Four cases got temporary complications.

Conclusion

Buccal rotation was applicable to extract the deep impacted maxillary third molars with large angles towards the adjacent teeth.
Evaluating remote facilitation intensity for multi-national translation of nurse-initiated stroke protocols (QASC Australasia): a protocol for a cluster randomised controlled trial
Authors: Fasugba O. , Dale S. , McInnes E. , Cadilhac D. A. , Noetel M. , Coughlan K. , McElduff B. , Kim J. , Langley T. , Cheung N. W. , Hill K. , Pollnow V. , Page K. , Sanjuan Menendez E. , Neal E. , Griffith S. , Christie L. J. , Slark J. , Ranta A. , Levi C. , Grimshaw J. M. , Middleton S.
Published: January 2023

Background

Facilitated implementation of nurse-initiated protocols to manage fever, hyperglycaemia (sugar) and swallowing difficulties (FeSS Protocols) in 19 Australian stroke units resulted in reduced death and dependency for stroke patients. However, a significant gap remains in translating this evidence-based care bundle protocol into standard practice in Australia and New Zealand. Facilitation is a key component for increasing implementation. However, its contribution to evidence translation initiatives requires further investigation. We aim to evaluate two levels of intensity of external remote facilitation as part of a multifaceted intervention to improve FeSS Protocol uptake and quality of care for patients with stroke in Australian and New Zealand acute care hospitals.

Methods

A three-arm cluster randomised controlled trial with a process evaluation and economic evaluation. Australian and New Zealand hospitals with a stroke unit or service will be recruited and randomised in blocks of five to one of the three study arms—high- or low-intensity external remote facilitation or a no facilitation control group—in a 2:2:1 ratio. The multicomponent implementation strategy will incorporate implementation science frameworks (Theoretical Domains Framework, Capability, Opportunity, Motivation – Behaviour Model and the Consolidated Framework for Implementation Research) and include an online education package, audit and feedback reports, local clinical champions, barrier and enabler assessments, action plans, reminders and external remote facilitation. The primary outcome is implementation effectiveness using a composite measure comprising six monitoring and treatment elements of the FeSS Protocols. Secondary outcome measures are as follows: composite outcome of adherence to each of the combined monitoring and treatment elements for (i) fever (n=5); (ii) hyperglycaemia (n=6); and (iii) swallowing protocols (n=7); adherence to the individual elements that make up each of these protocols; comparison for composite outcomes between (i) metropolitan and rural/remote hospitals; and (ii) stroke units and stroke services. A process evaluation will examine contextual factors influencing intervention uptake. An economic evaluation will describe cost differences relative to each intervention and study outcomes.

Discussion

We will generate new evidence on the most effective facilitation intensity to support implementation of nurse-initiated stroke protocols nationwide, reducing geographical barriers for those in rural and remote areas.

Trial registration

ACTRN12622000028707. Registered 14 January, 2022.
Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients
Authors: Kuntz L. , Le Fèvre C. , Jarnet D. , Keller A. , Meyer P. , Thiery A. , Cebula H. , Noel G. , Antoni D.
Published: January 2023

Purpose

Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs.

Methods and materials

The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated.

Results

184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1–6), for a median of 4 BMs treated during all sessions (range: 2–19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001).

Conclusion

Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.
A survey exploring caregiver burden and health-related quality of life in hereditary transthyretin amyloidosis
Authors: Acaster Sarah , Lo Siu Hing , Nestler-Parr Sandra
Published: January 2023

Background

Hereditary transthyretin amyloidosis (ATTRv) is an ultra-rare, life-shortening disease with a high unmet need. This study examined ATTRv caregiver health-related quality of life (HRQoL) and productivity.

Methods

A cross-sectional online survey, including EQ-5D-3L, Hospital anxiety and depression scale (HADS), and caregiver and patient characteristics questions, was developed to assess ATTRv caregiver burden. A companion general population survey collected EQ-5D-3L, HADS and chronic health conditions data. Caregiver-control group differences in HRQoL were assessed using t-tests and chi-square tests. Ordinary Least Squares regression was used to estimate the disutility of being a caregiver compared to controls stratified by patient ambulatory status.

Results

Thirty-six caregivers and matched controls completed the survey (n = 72). The disease severity of patients they cared for was varied: 33% required no assistance walking, 58% required assistance with walking and 9% required a wheelchair/were bedridden. On average, caregivers spent 6 h daily on practical care and 4 h daily on emotional support. Fifty-six percent indicated that they had changed their employment due to providing ATTRv care. Caregivers reported lower HRQoL, as indicated by lower EQ-5D 3L utility scores (M = 0.772, SD = 0.178 vs. M = 0.849, SD = 0.218) and higher HADS anxiety (9.3 vs. 6.1, p < 0.01) and depression (7.6 vs. 4.4, p < 0.01) scores, compared with matched controls. Caregivers were also more likely to report sleep problems (33% vs. 8%, p < 0.01) and stress (42% vs. 0%, p < 0.001) as chronic conditions than controls.

Conclusions

The study results indicate that caring for a person with ATTRv can have a considerable negative impact on caregivers’ HRQoL and productivity. The study findings provide important information for economic evaluations of ATTRv treatments.
Underestimating attacks: comparing two sources of publicly-available data about attacks on health care in 2017
Authors: Parada Vanessa , Fast Larissa , Briody Carolyn , Wille Christina , Coninx Rudi
Published: January 2023

Background

Attacks on health care represent an area of growing international concern. Publicly available data are important in documenting attacks, and are often the only easily accessible data source. Data collection processes about attacks on health and their implications have received little attention, despite the fact that datasets and their collection processes may result in differing numbers. Comparing two separate datasets compiled using publicly-available data revealed minimal overlap. This article aims to explain the reasons for the lack of overlap, to better understand the gaps and their implications.

Methods

We compared the data collection processes for datasets comprised of publicly-reported attacks on health care from the World Health Organization (WHO) and Insecurity Insight’s Security in Numbers Database (SiND). We compared each individual event to compile a comparable dataset and identify unique and matched events in order to determine the overlap between them. We report descriptive statistics for this comparison.

Results

We identified a common dataset of 287 events from 2017, of which only 33 appeared in both datasets, resulting in a mere 12.9% (n = 254) overlap. Events affecting personnel and facilities appeared most often in both, and 22 of 31 countries lacked any overlap between datasets.

Conclusions

We conclude that the minimal overlap suggests significant underreporting of attacks on health care, and furthermore, that dataset definitions and parameters affect data collection. Source variation appears to best explain the discrepancies and closer comparison of the collection processes reveal weaknesses of both automated and manual data collection that rely on hidden curation processes. To generate more accurate datasets compiled from public sources requires systematic work to translate definitions into effective online search mechanisms to better capture the full range of events, and to increase the diversity of languages and local sources to better capture events across geographies.