bluuebunny/crossref_metadata_2025 huggingface dataset:
Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module
Authors: Arce Nicholas A. , Markham-Lee Zoe , Liang Qian , Najmudin Shabir , Legan Emily R. , Dean Gabrielle , Su Ally J. , Wilson Moriah S. , Sidonio Robert F. , Lollar Pete , Emsley Jonas , Li Renhao
Published: January 2024

Activation of von Willebrand factor (VWF) is a tightly controlled process governed primarily by local elements around its A1 domain. Recent studies suggest that the O-glycosylated sequences flanking the A1 domain constitute a discontinuous and force-sensitive autoinhibitory module (AIM), although its extent and conformation remains controversial. Here, we used a targeted screening strategy to identify 2 groups of nanobodies. One group, represented by clone 6D12, is conformation insensitive and binds the N-terminal AIM (NAIM) sequence that is distal from A1; 6D12 activates human VWF and induces aggregation of platelet-rich plasma at submicromolar concentrations. The other group, represented by clones Nd4 and Nd6, is conformation sensitive and targets the C-terminal AIM (CAIM). Nd4 and Nd6 inhibit ristocetin-induced platelet aggregation and reduce VWF-mediated platelet adhesion under flow. A crystal structure of Nd6 in complex with AIM-A1 shows a novel conformation of both CAIM and NAIM that are primed to interact, providing a model of steric hindrance stabilized by the AIM as the mechanism for regulating GPIbα binding to VWF. Hydrogen-deuterium exchange mass spectrometry analysis shows that binding of 6D12 induces the exposure of the GPIbα-binding site in the A1 domain, but binding of inhibitory nanobodies reduces it. Overall, these results suggest that the distal portion of NAIM is involved in specific interactions with CAIM, and binding of nanobodies to the AIM could either disrupt its conformation to activate VWF or stabilize its conformation to upkeep VWF autoinhibition. These reported nanobodies could facilitate future studies of VWF functions and related pathologies.
A novel diabetic foot ulcer diagnostic model: identification and analysis of genes related to glutamine metabolism and immune infiltration
Authors: Shi Hongshuo , Yuan Xin , Yang Xiao , Huang Renyan , Fan Weijing , Liu Guobin
Published: January 2024

Background

Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis.

Methods

We downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset.

Results

In both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929).

Conclusion

This study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.
CT features based preoperative predictors of aggressive pathology for clinical T1 solid renal cell carcinoma and the development of nomogram model
Authors: Wang Keruo , Dong Liang , Li Songyang , Liu Yaru , Niu Yuanjie , Li Gang
Published: January 2024

Background

We aimed to identify preoperative predictors of aggressive pathology for cT1 solid renal cell carcinoma (RCC) by combining clinical features with qualitative and quantitative CT parameters, and developed a nomogram model.

Methods

We conducted a retrospective study of 776 cT1 solid RCC patients treated with partial nephrectomy (PN) or radical nephrectomy (RN) between 2018 and 2022. All patients underwent four-phase contrast-enhanced CT scans and the CT parameters were obtained by two experienced radiologists using region of interest (ROI). Aggressive pathology was defined as patients with nuclear grade III-IV; upstage to pT3a; type II papillary renal cell carcinoma (pRCC), collecting duct or renal medullary carcinoma, unclassified RCC or sarcomatoid/rhabdoid features. Univariate and multivariate logistic analyses were used to determine significant predictors and develop the nomogram model. To evaluate the accuracy and clinical utility of the nomogram model, we used the receiver operating characteristic (ROC) curve, calibration plot, decision curve analysis (DCA), risk stratification, and subgroup analysis.

Results

Of the 776 cT1 solid RCC patients, 250 (32.2%) had aggressive pathological features. The interclass correlation coefficient (ICC) of CT parameters accessed by two reviewers ranged from 0.758 to 0.982. Logistic regression analyses showed that neutrophil-to-lymphocyte ratio (NLR), distance to the collecting system, CT necrosis, tumor margin irregularity, peritumoral neovascularity, and RER-NP were independent predictive factors associated with aggressive pathology. We built the nomogram model using these significant variables, which had an area under the curve (AUC) of 0.854 in the ROC curve.

Conclusions

Our research demonstrated that preoperative four-phase contrast-enhanced CT was critical for predicting aggressive pathology in cT1 solid RCC, and the constructed nomogram was useful in guiding patient treatment and postoperative follow-up.
Physician-brief advice for promoting smoking cessation among cancer patients on treatment in low and middle-income countries: a scoping review
Authors: Ilesanmi Olayinka Stephen , Faseru Babalola , Afolabi Aanuoluwapo Adeyimika , Odukoya Olukemi , Ayo-Yusuf Olalekan , Akinsolu Folahanmi , Adebiyi Akindele Olupelumi , Evans William K.
Published: January 2024

Introduction

Physician-brief advice has been utilized in high-income countries to promote smoking cessation among cancer patients. Empirical evidence on its effectiveness among cancer patients in low and middle-income countries (LMICs) is lacking. The gap could be due to inadequate training, and competing healthcare priorities, leading to insufficient implementation of targeted smoking cessation interventions in oncology settings. We undertook this scoping review to determine if physician-brief advice is effective in promoting smoking cessation among cancer patients in LMICs.

Methods

We conducted a literature search of all relevant articles across five databases: Cochrane Central Register of Controlled Trials, Cochrane Library (Tobacco Addiction Group trials), World Conference on Lung Cancer proceedings, PubMed, and Google Scholar up to November 2023, using pre-defined inclusion criteria and keywords. The study population was cancer survivors in LMICs, the intervention was smoking cessation advice by a physician in a clinic or oncology center during a consultation, and the outcome was the effect of smoking cessation programs in discontinuing smoking among cancer survivors in LMICs.

Results

Overall, out of every 10 cancer patients in LMICs, about seven were smokers, and one-half had received physician-brief advice for smoking cessation. Physician-brief advice was more likely to be delivered to patients with smoking-related cancer (Cohen’s d = 0.396). This means that there is a noticeable difference between patients with smoking-related cancer compared to those with cancer unrelated to smoking. Smoking cessation failure was due to the inability to cope with the symptoms of withdrawal, missed smoking cessation clinic visits, mental health disorders, limited time and resources, and minimal patient-physician contact.

Conclusion

There is very little literature on the frequency of use or the efficacy of physician-brief advice on smoking cessation in LMICs. The literature suggests that cancer patients in LMICs have low self-efficacy to quit smoking, and smoking cessation is rarely part of cancer care in LMICs. Physicians in LMICs should be trained to use motivational messages and good counseling techniques to improve smoking cessation among cancer patients. Policymakers should allocate the resources to implement physician-brief advice and design training programs for physicians focusing on physician-brief advice tailored to cancer patients.
Impact of chronic obstructive pulmonary disease on the efficacy and safety of neoadjuvant immune checkpoint inhibitors combined with chemotherapy for resectable non-small cell lung cancer: a retrospective cohort study
Authors: Dong Weigang , Yin Yan , Yang Shengnan , Liu Bin , Chen Xi , Wang Lina , Su Yue , Jiang Yan , Shi Dongsheng , Sun Daqiang , Qin Jianwen
Published: January 2024

Background

Neoadjuvant immune checkpoint inhibitors(ICIs) combined with chemotherapy can improve non-small cell lung cancer(NSCLC) patients' pathological responses and show promising improvements in survival. Chronic obstructive pulmonary disease (COPD) is a systemic inflammatory disease, and its associated abnormal inflammatory response affects not only the immunotherapy efficacy but also immune-related adverse events. It remains unclear whether NSCLC patients with COPD can benefit from neoadjuvant ICIs combined with chemotherapy.

Methods

A retrospective observational clinical study was conducted on 105 consecutive NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy at the Department of Thoracic Surgery of Tianjin Chest Hospital between April 2020 and April 2023.

Results

A total of 74 NSCLC patients were included in the study, including 30 patients with COPD and 44 patients without COPD. The percentage of patients with a pathological complete response (PCR) was higher in the COPD group than in the non-COPD group (43.3% vs. 20.5%, P = 0.042). Multivariate logistic regression analysis of factors associated with PCR showed that the adjusted odds ratio (OR) was statistically significant for presence of COPD (OR = 3.020, 95%CI: 1.042–8.757; P = 0.042). Major pathological response (66.7% vs. 50%, P = 0.155), R0 resection rate (96.7% vs.93.2%, P = 0.642), N2 lymph node downstaging(92.3% vs. 66.7%, P = 0.182) and objective response rate (70% vs. 63.6%, P = 0.57) were not significantly different between the groups. Progression-free survival(PFS) was not reached in the COPD group and 17 months (95%CI: 12.1–21.9) in the non-COPD group, with statistically significance (χ2 = 6.247, P = 0.012). Multivariate Cox’s regression analysis showed that the adjusted hazard ratio (HRadj) was statistically significant for presence of COPD (HRadj = 0.321, 95%CI: 0.111–0.930; P = 0.036). The grade 3 and grade 4 adverse events in the COPD group were leukopenia (3.3%, 6.7%), neutropenia (3.3%, 6.7%), fatigue (6.7%, 0%), gastrointestinal reactions (3.3%, 0%), and hypothyroidism (3.3%, 0%). In the non-COPD group, the corresponding adverse events were leukopenia (6.8%, 6.8%), neutropenia (3.3%, 6.8%), fatigue (2.3%, 0%), gastrointestinal reactions (2.3%, 0%), and hypothyroidism (2.3%, 0%), respectively.

Conclusions

The present study indicates that the presence of COPD may improve PCR, prolong PFS, and have an acceptable safety profile in NSCLC patients receiving neoadjuvant ICIs combined with chemotherapy.
Development and validation of a 18F-FDG PET/CT radiomics nomogram for predicting progression free survival in locally advanced cervical cancer: a retrospective multicenter study
Authors: Liu Huiling , Cui Yongbin , Chang Cheng , Zhou Zichun , Zhang Yalin , Ma Changsheng , Yin Yong , Wang Ruozheng
Published: January 2024

Background

The existing staging system cannot meet the needs of accurate survival prediction. Accurate survival prediction for locally advanced cervical cancer (LACC) patients who have undergone concurrent radiochemotherapy (CCRT) can improve their treatment management. Thus, this present study aimed to develop and validate radiomics models based on pretreatment 18Fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computed tomography (CT) images to accurately predict the prognosis in patients.

Methods

The data from 190 consecutive patients with LACC who underwent pretreatment 18F-FDG PET-CT and CCRT at two cancer hospitals were retrospectively analyzed; 176 patients from the same hospital were randomly divided into training (n = 117) and internal validation (n = 50) cohorts. Clinical features were selected from the training cohort using univariate and multivariate Cox proportional hazards models; radiomic features were extracted from PET and CT images and filtered using least absolute shrinkage and selection operator and Cox proportional hazard regression. Three prediction models and a nomogram were then constructed using the previously selected clinical, CT and PET radiomics features. The external validation cohort that was used to validate the models included 23 patients with LACC from another cancer hospital. The predictive performance of the constructed models was evaluated using receiver operator characteristic curves, Kaplan Meier curves, and a nomogram.

Results

In total, one clinical, one PET radiomics, and three CT radiomics features were significantly associated with progression-free survival in the training cohort. Across all three cohorts, the combined model displayed better efficacy and clinical utility than any of these parameters alone in predicting 3-year progression-free survival (area under curve: 0.661, 0.718, and 0.775; C-index: 0.698, 0.724, and 0.705, respectively) and 5-year progression-free survival (area under curve: 0.661, 0.711, and 0.767; C-index, 0.698, 0.722, and 0.676, respectively). On subsequent construction of a nomogram, the calibration curve demonstrated good agreement between actually observed and nomogram-predicted values.

Conclusions

In this study, a clinico-radiomics prediction model was developed and successfully validated using an independent external validation cohort. The nomogram incorporating radiomics and clinical features could be a useful clinical tool for the early and accurate assessment of long-term prognosis in patients with LACC patients who undergo concurrent chemoradiotherapy.
Effect of single-administration of d-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial
Authors: Wada Shuhei , Iwamoto Kunihiro , Okumura Hiroki , Hida Hirotake , Hiraoka Shuichi , Kamei Aya , Mori Daisuke , Yamada Kiyofumi , Ando Masahiko , Ozaki Norio , Ikeda Masashi
Published: January 2024

Background

Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of d-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia.

Methods

Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of d-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point).

Results

d-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste.

Conclusion

Our findings indicate that single-administration of d-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste.

Trial registration

This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.
Chronic kidney disease incidences in Thai outpatients diagnosed with psychiatric illnesses receiving lithium maintenance therapy: a university hospital-based study
Authors: Pitanupong Jarurin , Jittpratoom Chavisa , Anantapong Kanthee
Published: January 2024

Background

There has been no previous study in Thailand regarding the incidence of lithium-induced abnormal renal function. Hence, this study aimed to assess the effect of lithium maintenance therapy on chronic kidney disease, and associated factors among outpatients diagnosed with a psychiatric illness within Southern Thailand.

Methods

This was a retrospective study, using an information review from the electronic medical records of Songklanagarind Hospital computer system in the last ten years; from 1 January 2013 until 31 September 2022. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 and persisted for three months or more. There were 461 outpatients diagnosed with a psychiatric illness who received lithium maintenance therapy. From this, 154 outpatients were excluded: 153 received lithium therapy for less than three months and 1 presented with a baseline chronic kidney disease. All data were analyzed using Rstudio 4.3.1. The incidence of lithium-induced chronic kidney disease was analyzed by survival analysis.

Results

Of the 307 outpatients diagnosed with a psychiatric illness and received lithium maintenance therapy, the most common diagnosis was bipolar disorder (59.3%). Most were female (52.8%), with the median (IQR) age of 39.0 (27.5–54.0) years. The median (IQR) age onset of lithium therapy and duration of lithium maintenance therapy were 28.0 (21.0–41.5) years, and 2.97 (0.9–9.2) years, respectively. This study identified six outpatients (1.9%) that developed chronic kidney disease stage 3 or more and one of them (0.3%) presented with chronic kidney disease stage 5 or end-stage. The incidence of lithium-induced chronic kidney disease was 0.0023 cases per exposed patient-year. When comparing outpatients who had received lithium maintenance therapy and developed chronic kidney disease with those who did not develop chronic kidney disease, this study identified that most of the group with chronic kidney disease had a lithium maintenance therapy for more than ten years, had an older age onset of lithium therapy, reported history of psychiatric hospitalization and lithium intoxication, and presented with physical illness. The associated factors between the effect of lithium maintenance therapy and chronic kidney disease could not be identified due to a limited number of outpatients having developed chronic kidney disease.

Conclusions

Lithium-induced chronic kidney disease was identified as a minor incidence, and it was likely safe for maintenance therapy with careful and regular monitoring. However, older patients or those receiving lithium for a longer time and present with comorbid physical illnesses should be prescribed with caution.

IRB / IEC certification

65-389-3-4.
Health literacy of trans and gender diverse individuals –a cross sectional survey in Germany
Authors: von der Warth Rieka , Körner Mirjam , Farin-Glattacker Erik
Published: January 2024

Introduction

To date, there has been little research on the general health literacy of trans and gender diverse individuals, even though previous research undermines the importance of good health literacy in this sample. The aim of the article is therefore to describe the general health literacy of trans and gender diverse individuals based on a German survey.

Methods

In September 2022, a survey study was conducted in which health literacy was recorded using HLS-EU-16. Data will be presented descriptively; gender differences will be explored using a Χ2- test and a univariate analysis of variance (ANOVA).

Results

Out of N = 223 participants, n = 129 individuals (57.8%) identified as non-binary; n = 49 (22.0%) identified themselves as male, while n = 45 (20.2%) identified as female. Mean age was 28.03 years. Overall, 26.4% of all the participants showed an inadequate health literacy, as proposed by the HLS-EU-16. In trend, health-related task related to media use were more often perceived as easy compared to the German general population.

Conclusion

Individuals, who identify as trans and gender diverse may have a general health literacy below average compared to the German general population. However, tasks related to media use were perceived as easy, which might be a good starting point for health literacy related interventions.

Trial registration

DRKS00026249, Date of registration: 15/03/2022.
Follicular adenoma with a papillary architecture originating from an ectopic thyroid gland: a case report
Authors: Kuba Kiyomi , Kawasaki Tomonori , Enoki Yuichiro , Inoue Hitoshi , Matsumura Satoko , Yamazaki Tomoko , Ebihara Yasuhiro , Nakahira Mitsuhiko , Sugasawa Masashi
Published: January 2024

Background

Follicular adenomas with papillary architecture are rare tumors of thyroid origin and are composed of completely encapsulated follicular cells with a papillary architecture lacking the nuclear characteristics of papillary carcinoma. Herein, we present a case of follicular adenoma with papillary architecture originating from an ectopic thyroid gland, diagnosed from a mass in the submandibular region.

Case Presentation

A 70-year-old woman was referred to our hospital with the chief complaint of a painless left submandibular mass that had been present for one year. The patient underwent left submandibular dissection for therapy and diagnosis. Microscopically, papillary lesions with fibrovascular cores were observed in the interior, and the epithelial cells were cylindrical in shape with eosinophilic cytoplasm, round or oval nuclei, with no pathological features, leading to a diagnosis of papillary carcinoma or follicular carcinoma. The mass was diagnosed as a follicular thyroid adenoma with papillary architecture. This is the first report of a follicular adenoma with a papillary architecture originating from an ectopic thyroid gland.

Conclusion

This experience suggests that follicular adenoma should be included in the differential diagnosis of ectopic thyroid tumors.
Cost modelling rehabilitation in the home for reconditioning in the Australian context
Authors: Poulos Roslyn G. , Cole Andrew M. D. , Hilvert Dan R. , Warner Kerry N. , Faux Steven G. , Nguyen Tuan-Anh , Kohler Friedbert , Un Fey-Ching , Alexander Tara , Capell Jacquelin T. , O’Connor Claire M. C. , Poulos Christopher J.
Published: January 2024

Background

Inpatient rehabilitation services are challenged by increasing demand. Where appropriate, a shift in service models towards more community-oriented approaches may improve efficiency. We aimed to estimate the hypothetical cost of delivering a consensus-based rehabilitation in the home (RITH) model as hospital substitution for patients requiring reconditioning following medical illness, surgery or treatment for cancer, compared to the cost of inpatient rehabilitation.

Methods

Data were drawn from the following sources: the results of a Delphi survey with health professionals working in the field of rehabilitation in Australia; publicly available data and reports; and the expert opinion of the project team. Delphi survey data were analysed descriptively. The costing model was developed using assumptions based on the sources described above and was restricted to the Australian National Subacute and Non-Acute Patient Classification (AN-SNAP) classes 4AR1 to 4AR4, which comprise around 73% of all reconditioning episodes in Australia. RITH cost modelling estimates were compared to the known cost of inpatient rehabilitation. Where weighted averages are provided, these were determined based on the modelled number of inpatient reconditioning episodes per annum that might be substitutable by RITH.

Results

The cost modelling estimated the weighted average cost of a RITH reconditioning episode (which mirrors an inpatient reconditioning episode in intensity and duration) for AN-SNAP classes 4AR1 to 4AR4, to be A$11,371, which is 28.1% less than the equivalent weighted average public inpatient cost (of A$15,820). This represents hypothetical savings of A$4,449 per RITH reconditioning substituted episode of care.

Conclusions

The hypothetical cost of a model of RITH which would provide patients with as comprehensive a rehabilitation service as received in inpatient rehabilitation, has been determined. Findings suggest potential cost savings to the public hospital sector. Future research should focus on trials which compare actual clinical and cost outcomes of RITH for patients in the reconditioning impairment category, to inpatient rehabilitation.
The impact of the affordable care act on perinatal mood and anxiety disorder diagnosis and treatment rates among Michigan Medicaid enrollees 2012–2018
Authors: Hall Stephanie V. , Zivin Kara , Piatt Gretchen A. , Weaver Addie , Tilea Anca , Zhang Xiaosong , Moyer Cheryl A.
Published: January 2024

Background

Perinatal Mood and Anxiety Disorders (PMADs) affect one in five birthing individuals and represent a leading cause of maternal mortality. While these disorders are associated with a variety of poor outcomes and generate significant societal burden, underdiagnosis and undertreatment remain significant barriers to improved outcomes. We aimed to quantify whether the Patient Protection Affordable Care Act (ACA) improved PMAD diagnosis and treatment rates among Michigan Medicaid enrollees.

Methods

We applied an interrupted time series framework to administrative Michigan Medicaid claims data to determine if PMAD monthly diagnosis or treatment rates changed after ACA implementation for births 2012 through 2018. We evaluated three treatment types, including psychotherapy, prescription medication, and either psychotherapy or prescription medication. Participants included the 170,690 Medicaid enrollees who had at least one live birth between 2012 and 2018, with continuous enrollment from 9 months before birth through 3 months postpartum.

Results

ACA implementation was associated with a statistically significant 0.76% point increase in PMAD diagnosis rates (95% CI: 0.01 to 1.52). However, there were no statistically significant changes in treatment rates among enrollees with a PMAD diagnosis.

Conclusion

The ACA may have improved PMAD detection and documentation in clinical settings. While a higher rate of PMAD cases were identified after ACA Implementation, Post-ACA cases were treated at similar rates as Pre-ACA cases.
Migrasomal autophagosomes relieve endoplasmic reticulum stress in glioblastoma cells
Authors: Lee Seon Yong , Choi Sang-Hun , Kim Yoonji , Ahn Hee-Sung , Ko Young-Gyu , Kim Kyunggon , Chi Sung Wook , Kim Hyunggee
Published: January 2024

Background

Glioblastoma (GBM) is more difficult to treat than other intractable adult tumors. The main reason that GBM is so difficult to treat is that it is highly infiltrative. Migrasomes are newly discovered membrane structures observed in migrating cells. Thus, they can be generated from GBM cells that have the ability to migrate along the brain parenchyma. However, the function of migrasomes has not yet been elucidated in GBM cells.

Results

Here, we describe the composition and function of migrasomes generated along with GBM cell migration. Proteomic analysis revealed that LC3B-positive autophagosomes were abundant in the migrasomes of GBM cells. An increased number of migrasomes was observed following treatment with chloroquine (CQ) or inhibition of the expression of STX17 and SNAP29, which are involved in autophagosome/lysosome fusion. Furthermore, depletion of ITGA5 or TSPAN4 did not relieve endoplasmic reticulum (ER) stress in cells, resulting in cell death.

Conclusions

Taken together, our study suggests that increasing the number of autophagosomes, through inhibition of autophagosome/lysosome fusion, generates migrasomes that have the capacity to alleviate cellular stress.
The m6A methyltransferase METTL3 drives thyroid cancer progression and lymph node metastasis by targeting LINC00894
Authors: Zhou Xiang , Chang Lisha , Liang Qiaoqiao , Zhao Rongjie , Xiao Yong , Xu Zheng , Yu Leitao
Published: January 2024

Background

Long noncoding RNAs (lncRNAs) are significant contributors to various human malignancies. The aberrant expression of lncRNA LINC00894 has been reported in various human malignancies. We aimed to illustrate the role of LINC00894 and its underlying mechanism in the development of papillary thyroid carcinoma (PTC).

Methods

We performed bioinformatics analysis of differentially expressed RNAs from TCGA and GEO datasets and selected the target lncRNA LINC00894. SRAMP analysis revealed abundant M6A modification sites in LINC00894. Further analysis of StarBase, GEPIA, and TCGA datasets was performed to identify the related differentially expressed genes METTL3. Colony formation and CCK-8 assays confirmed the relationship between LINC00894, METTL3, and the proliferative capacity of PTC cells. The analysis of AnnoLnc2, Starbase datasets, and meRIP-PCR and qRT‒PCR experiments confirmed the influence of METTL3-mediated m6A modification on LINC00894. The study employed KEGG enrichment analysis as well as Western blotting to investigate the impact of LINC00894 on the expression of proteins related to the Hippo signalling pathway.

Results

LINC00894 downregulation was detected in PTC tissues and cells and was even further downregulated in PTC with lymphatic metastasis. LINC00894 inhibits the lymphangiogenesis of vascular endothelial cells and the proliferation of cancer cells. METTL3 enhances PTC progression by upregulating LINC00894 by enhancing LINC00894 mRNA stability through the m6A-YTHDC2-dependent pathway. LINC00894 may inhibit PTC malignant phenotypes through the Hippo signalling pathway.

Conclusion

The METTL3-YTHDC2 axis stabilizes LINC00894 mRNA in an m6A-dependent manner and subsequently inhibits tumour malignancy through the Hippo signalling pathway.
Are institutional deliveries equitable in the southern states of India? A benefit incidence analysis
Authors: Sharma Santosh Kumar , Nambiar Devaki
Published: January 2024

Background

Despite a commendable rise in the number of women seeking delivery care at public health institutions in South India, it is unclear if the benefit accrues to wealthier or poorer socio-economic groups. The study’s aim was to investigate at how the public subsidy is distributed among Indian women who give birth in public hospitals in the southern regions.

Methods

Data from the Indian Demographic Health Survey’s fifth wave (NFHS-5, 2019–21) was used in this study. A total of 22, 403 were institutional deliveries across all the southern states of India were included. Out-of-pocket expenditure (OOPE) on childbirth in health institutions was the outcome variable. We used summary statistics, Benefits Incidence Analysis (BIA), concentration index (CI), and concentration curve (CC) were used.

Results

Most women in the lowest, poorest, and medium quintiles of wealth opted to give birth in public facilities. In contrast, about 69% of mothers belonging to highest quintile gave birth in private health institutions. The magnitude of CI and CC of institutional delivery indicates that public sector usage was concentrated among poorer quintiles [CIX: − 0.178; SE: 0.005; p < 0.001] and private sector usage was concentrated among wealthier quintiles [CIX: 0.239; SE: 0.006; p < 0.001]. Benefit incidence analyses suggest that middle quintile of women received the maximum public subsidy in primary health centres (33.23%), followed by richer quintile (25.62%), and poorer wealth quintiles (24.84%). These pattern in the secondary health centres was similar.

Conclusion

Poorer groups utilize the public sector for institutional delivery in greater proportions than the private sector. Middle quintiles seem to benefit the most from public subsidy in terms of the median cost of service and non-payment. Greater efforts must be made to understand how and why these groups are being left behind and what policy measures can enhance their inclusion and financial risk protection.
Health-related quality of life in mild-to-moderate COVID-19 in the UK: a cross-sectional study from pre- to post-infection
Authors: Soare Ioana-Alexandra , Ansari Wajeeha , Nguyen Jennifer L. , Mendes Diana , Ahmed Waqas , Atkinson Joanna , Scott Amie , Atwell Jessica E. , Longworth Louise , Becker Frauke
Published: January 2024

Background

The aim of this study was to estimate the impact of mild-to-moderate COVID-19 on health-related quality of life (HRQoL) over time among individuals in the United Kingdom, adding to the evidence base that had focussed on severe COVID-19.

Methods

A bespoke online survey was administered to individuals who self-reported a positive COVID-19 test. An amended version of a validated generic HRQoL instrument (EQ-5D-5L) was used to measure HRQoL retrospectively at different timepoints over the course of an infection: pre-COVID-19, acute COVID-19, and long COVID. In addition, HRQoL post-COVID-19 was captured by the original EQ-5D-5L questionnaire. A mixed-effects model was used to estimate changes in HRQoL over time, adjusted for a range of variables correlated with HRQoL.

Results

The study recruited 406 participants: (i) 300 adults and 53 adolescents with mild-to-moderate COVID-19 who had not been hospitalised for COVID-19 during acute COVID-19, and (ii) 53 adults who had been hospitalised for COVID-19 in the acute phase and who had been recruited for validation purposes. Data were collected between January and April 2022. Among participants included in the base-case analysis, EQ-5D-5L utility scores were lower during both acute COVID-19 (β=-0.080, p = 0.001) and long COVID (β=-0.072, p < 0.001) compared to pre COVID-19. In addition, EQ-5D-5L utility scores post-COVID-19 were found to be similar to the EQ-5D-5L utility scores before COVID-19, including for patients who had been hospitalised for COVID-19 during the acute phase or for those who had experienced long COVID. Moreover, being hospitalised in the acute phase was associated with additional utility decrements during both acute COVID-19 (β=-0.147, p = 0.026) and long (β=-0.186, p < 0.001) COVID.

Conclusion

Patients perceived their HRQoL to have varied significantly over the course of a mild-to-moderate COVID-19 infection. However, HRQoL was found to return to pre-COVID-19 levels, even for patients who had been hospitalised for COVID-19 during the acute phase or for those who had experienced long COVID.
Where are the links? Using a causal loop diagram to assess interactions in healthcare coordination for youth experiencing homelessness in Toronto, Canada
Authors: Hudani Alzahra , Long Janet , Labonté Ronald , Yaya Sanni
Published: January 2024

Background

Youth experiencing homelessness (YEH) suffer from poorer physical and mental health outcomes than stably housed youth. Additionally, YEH are forced to navigate fragmented health and social service systems on their own, where they often get lost between systems when transitioning or post-discharge. Inevitably, YEH require support with health system navigation and healthcare coordination. The aim of this study is to understand interactions within and between the emergency youth shelter (EYS) and health systems that affect healthcare coordination for YEH in Toronto, Canada, and how these interactions can be targeted to improve healthcare coordination for YEH.

Methods

This study is part of a larger qualitative case study informed by the framework for transformative systems change. To understand interactions in healthcare coordination for YEH within and between the EYS and health systems, we developed a causal loop diagram (CLD) using in-depth interview data from 24 key informants at various levels of both systems. Open and focused codes developed during analysis using Charmaz’s constructivist grounded theory methodology were re-analysed to identify key variables, and links between them to create the CLD. The CLD was then validated by six stakeholders through a stakeholder forum.

Results

The CLD illustrates six balancing and one reinforcing feedback loop in current healthcare coordination efforts within the EYS and health systems, respectively. Increasing EYS funding, building human resource capacity, strengthening inter and intra-systemic communication channels, and establishing strategic partnerships and formal referral pathways were identified among several other variables to be targeted to spiral positive change in healthcare coordination for YEH both within and between the EYS and health systems.

Conclusions

The CLD provides a conceptual overview of the independent and integrated systems through which decision-makers can prioritize and guide interventions to strengthen healthcare coordination within and between the EYS and health systems. Overall, our research findings suggest that key variables such as streamlining communication and improving staff–youth relationships be prioritized, as each of these acts interdependently and influences YEH’s access, quality and coordination of healthcare.
Enhanced meningeal lymphatic drainage ameliorates lipopolysaccharide-induced brain injury in aged mice
Authors: Dong Hongquan , Dai Xiaonan , Zhou Yin , Shi Chonglong , Bhuiyan Piplu , Sun Zhaochu , Li Nana , Jin Wenjie
Published: January 2024

Background

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced by sepsis is considered a potential mechanism of SAE; however, very little is known about the role of the meningeal lymphatic system in SAE.

Methods

Sepsis was established in male C57BL/6J mice by intraperitoneal injection of 5 mg/kg lipopolysaccharide, and the function of meningeal lymphatic drainage was assessed. Adeno-associated virus 1-vascular endothelial growth factor C (AAV1-VEGF-C) was injected into the cisterna magna to induce meningeal lymphangiogenesis. Ligation of deep cervical lymph nodes (dCLNs) was performed to induce pre-existing meningeal lymphatic dysfunction. Cognitive function was evaluated by a fear conditioning test, and inflammatory factors were detected by enzyme-linked immunosorbent assay.

Results

The aged mice with SAE showed a significant decrease in the drainage of OVA-647 into the dCLNs and the coverage of the Lyve-1 in the meningeal lymphatic, indicating that sepsis impaired meningeal lymphatic drainage and morphology. The meningeal lymphatic function of aged mice was more vulnerable to sepsis in comparison to young mice. Sepsis also decreased the protein levels of caspase-3 and PSD95, which was accompanied by reductions in the activity of hippocampal neurons. Microglia were significantly activated in the hippocampus of SAE mice, which was accompanied by an increase in neuroinflammation, as indicated by increases in interleukin-1 beta, interleukin-6 and Iba1 expression. Cognitive function was impaired in aged mice with SAE. However, the injection of AAV1-VEGF-C significantly increased coverage in the lymphatic system and tracer dye uptake in dCLNs, suggesting that AAV1-VEGF-C promotes meningeal lymphangiogenesis and drainage. Furthermore, AAV1-VEGF-C reduced microglial activation and neuroinflammation and improved cognitive dysfunction. Improvement of meningeal lymphatics also reduced sepsis-induced expression of disease-associated genes in aged mice. Pre-existing lymphatic dysfunction by ligating bilateral dCLNs aggravated sepsis-induced neuroinflammation and cognitive impairment.

Conclusion

The meningeal lymphatic drainage is damaged in sepsis, and pre-existing defects in this drainage system exacerbate SAE-induced neuroinflammation and cognitive dysfunction. Promoting meningeal lymphatic drainage improves SAE. Manipulation of meningeal lymphangiogenesis could be a new strategy for the treatment of SAE.
Reminiscent music therapy combined with robot-assisted rehabilitation for elderly stroke patients: a pilot study
Authors: Liu Qian , Liu Li , Liu Zuoyan , Xu Yang , Wang Fang , Cheng Hong , Hu Xiuying
Published: January 2024

Background

Although some studies suggest that robot-assisted technology can significantly improve upper limb function in stroke patients compared to traditional rehabilitation training, it is still necessary to incorporate an auxiliary intervention to alleviate negative emotions, thereby alleviating the post-stroke fatigue and encouraging patients to actively respond to rehabilitation. However, the effect of the auxiliary intervention is unknown.

Objective

To evaluate the effect of reminiscent music therapy combined with robot-assisted rehabilitation in elderly patients with upper limb dysfunction.

Methods

From November 2022 to March 2023, elderly patients with upper limb dysfunction after stroke were assigned to one of three groups, with group A receiving usual rehabilitation treatment and care plus robot-assisted rehabilitation and reminiscent music therapy, group B receiving usual rehabilitation treatment and care plus robot-assisted rehabilitation, and group C receiving only usual rehabilitation treatment and care. Thirty patients completed this study, with 10 participants in each group. Activities of daily living, self-esteem, rehabilitation self-efficacy, positive emotion and upper limb function were measured before and after the intervention. One-way analysis of variance, paired-sample t-test, Kruskal-Wallis H test, Wilcoxon signed rank sum test and Chi-square test were used to analyze the data.

Results

According to the intragroup comparisons, in the three groups, all outcome measurements were significantly higher than those at baseline (all P < 0.05). After the intervention, the differences in the self-management effectiveness, rehabilitation self-efficacy, and positive emotion score were statistically significant among the three groups (all P < 0.05). In accordance with the results of Bonferroni analysis, the self-management effectiveness score of group A was significantly higher than that of Group B and Group C (all P < 0.05). The rehabilitation self-efficacy score of group A was significantly higher than that of Group B and Group C (P < 0.05). The positive emotion score of group A was significantly higher than that of Group B and Group C (P < 0.05).

Conclusion

Reminiscent music therapy combined with robot-assisted rehabilitation is a promising approach to improve rehabilitation self-efficacy and positive emotion, which is evidence that reminiscent music therapy may be an effective auxiliary intervention to improve rehabilitation outcomes.
Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma
Authors: Büttner Thomas , Maerevoet Marielena K. E. , Giordano Frank A. , Veldwijk Marlon R. , Herskind Carsten , Ruder Arne Mathias
Published: January 2024

Background

Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB.

Methods

We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine.

Results

The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4–8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2–8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy.

Conclusion

The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.