bluuebunny/crossref_metadata_2025 huggingface dataset:
Responsiveness to change in health status of the EQ-5D in patients treated for depression and anxiety
Authors: Sandin Kenneth , Shields Gemma , Gjengedal Ragne G.H. , Osnes Kåre , Bjørndal Marianne T. , Reme Silje E. , Hjemdal Odin
Published: April 2023

Background

The EQ-5D is a commonly used generic measure of health but evidence on its responsiveness to change in mental health is limited. This study aimed to explore the responsiveness of the five-level version of the instrument, the EQ-5D-5 L, in patients receiving treatment for depression and anxiety.

Methods

Patient data (N = 416) were collected at baseline and at end of treatment in an observational study in a Norwegian outpatient clinic. Patients were adults of working age (18–69 years) and received protocol-based metacognitive or cognitive therapy for depression or anxiety according to diagnosis. Responsiveness in the EQ-5D was compared to change in the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). Effect sizes (Cohen’s d), Standardised response mean (SRM), and Pearson’s correlation were calculated. Patients were classified as “Recovered”, “Improved”, or “Unchanged” during treatment using the BDI-II and the BAI. ROC analyses determined whether the EQ-5D could correctly classify patient outcomes.

Results

Effect sizes were large for the BAI, the BDI-II, the EQ-5D value and the EQ VAS, ranging from d = 1.07 to d = 1.84. SRM were also large (0.93-1.67). Pearson’s correlation showed strong agreement between change scores of the EQ-5D value and the BDI-II (rs -0.54) and moderate between the EQ-5D value and the BAI (rs -0.43). The EQ-5D consistently identified “Recovered” patients versus “Improved” or “Unchanged” in the ROC analyses with AUROC ranging from 0.72 to 0.84.

Conclusion

The EQ-5D showed good agreement with self-reported symptom change in depression and anxiety, and correctly identified recovered patients. These findings indicate that the EQ-5D may be appropriately responsive to change in patients with depression and anxiety disorders, although replication in other clinical samples is needed.
Protease secretions by the invading blastocyst induce calcium oscillations in endometrial epithelial cells via the protease-activated receptor 2
Authors: Hennes Aurélie , Devroe Johanna , De Clercq Katrien , Ciprietti Martina , Held Katharina , Luyten Katrien , Van Ranst Nele , Maenhoudt Nina , Peeraer Karen , Vankelecom Hugo , Voets Thomas , Vriens Joris
Published: April 2023

Background

Early embryo implantation is a complex phenomenon characterized by the presence of an implantation-competent blastocyst and a receptive endometrium. Embryo development and endometrial receptivity must be synchronized and an adequate two-way dialogue between them is necessary for maternal recognition and implantation. Proteases have been described as blastocyst-secreted proteins involved in the hatching process and early implantation events. These enzymes stimulate intracellular calcium signaling pathways in endometrial epithelial cells (EEC). However, the exact molecular players underlying protease-induced calcium signaling, the subsequent downstream signaling pathways and the biological impact of its activation remain elusive.

Methods

To identify gene expression of the receptors and ion channels of interest in human and mouse endometrial epithelial cells, RNA sequencing, RT-qPCR and in situ hybridization experiments were conducted. Calcium microfluorimetric experiments were performed to study their functional expression.

Results

We showed that trypsin evoked intracellular calcium oscillations in EEC of mouse and human, and identified the protease-activated receptor 2 (PAR2) as the molecular entity initiating protease-induced calcium responses in EEC. In addition, this study unraveled the molecular players involved in the downstream signaling of PAR2 by showing that depletion and re-filling of intracellular calcium stores occurs via PLC, IP3R and the STIM1/Orai1 complex. Finally, in vitro experiments in the presence of a specific PAR2 agonist evoked an upregulation of the ‘Window of implantation’ markers in human endometrial epithelial cells.

Conclusions

These findings provide new insights into the blastocyst-derived protease signaling and allocate a key role for PAR2 as maternal sensor for signals released by the developing blastocyst.

Graphical Abstract
Transesophageal echocardiography-guided percutaneous patent ductus arteriosus closure without fluoroscopy
Authors: Wang Gang , Wu Yuhao , Pan Zhengxia , Wu Chun , Li Yonggang , Li Hongbo , Wang Quan , Liu Bo , Dai Jiangtao
Published: April 2023

Objectives

A retrospective study was performed to summarize the experience of transcatheter closure of patent ductus arteriosus (PDA) through the right femoral vein under the guidance of transesophageal echocardiography (TEE).

Methods

From January 2019 to September 2021, 75 children who underwent PDA closure through the right femoral vein under the guidance of TEE were included. The guide wire and delivery sheath were inserted through the ductus arteriosus into the descending aorta via the right femoral vein, and the occluder was subsequently deployed. After discharge, all patients were required for outpatient follow-ups at 1, 3, 6 and 12 months.

Results

In this group, patients were older than 10 months of age and body weight greater than 8 kg. Among 75 cases with PDA, 63 were tubular type and 12 were conical type. The mean operative time was 40.2 ± 7.3 min. The size of PDA occluder ranged from 4–6 to 12–14 mm. The mean hospital stay was 5.5 ± 0.5 days. One month after discharge, there were 4 cases with a mild residual shunt. Eventually, the residual shunt was not observed during 3, 6, and 12 months of follow-up.

Conclusions

PDA closure under the guidance of TEE can be performed through the right femoral vein successfully and effectively. This procedure has no contrast agent usage, radiation exposure, or open incisions.
Localisation of digital health tools used by displaced populations in low and middle-income settings: a scoping review and critical analysis of the Participation Revolution
Authors: Benson Jennifer , Brand Tilman , Christianson Lara , Lakeberg Meret
Published: April 2023

Background

Forced displacement is a crucial determinant of poor health. With 31 people displaced every minute worldwide, this is an important global issue. Addressing this, the Participation Revolution workstream from the World Humanitarian Summit’s Localisation commitments has gained traction in attempting to improve the effectiveness of humanitarian aid. Simultaneously, digital health initiatives have become increasingly ubiquitous tools in crises to deliver humanitarian assistance and address health burdens.

Objective

This scoping review explores how the localisation agenda’s commitment to participation has been adopted within digital health interventions used by displaced people in low-and-middle-income countries.

Methods

This review adopted the Arksey and O’Malley approach and searched five academic databases and three online literature repositories with aPopulation,ConceptandContextinclusion criteria. Data were synthesised and analysed through a critical power lens from the perspective of displaced people in low-and-middle-income-countries.

Results

27 papers demonstrated that a heterogeneous group of health issues were addressed through various digital health initiatives, principally through the use of mobile phones. The focus of the literature lay largely within technical connectivity and feasibility assessments, leaving a gap in understanding potential health implications. The varied conceptualisation of the localisation phenomenon has implications for the future of participatory humanitarian action: Authorship of reviewed literature primarily descended from high-income countries exposing global power dynamics leading the narrative. However, power was not a central theme in the literature: Whilst authors acknowledged the benefit of local involvement, participatory activities were largely limited to informing content adaptations and functional modifications within pre-determined projects and objectives.

Conclusion

With over 100 million people displaced globally, effective initiatives that meaningfully address health needs without perpetuating harmful inequalities are an essential contribution to the humanitarian arena. The gap in health outcomes evidence, the limited constructions of health, and the varying and nuanced digital divide factors are all indicators of unequal power in the digital health sphere. More needs to be done to address these gaps meaningfully, and more meaningful participation could be a crucial undertaking to achieve this.

Registration The study protocol was registered before the study (10.17605/OSF.IO/9D25R) athttps://osf.io/9d25r.
Understanding the roles and regulation patterns of circRNA on its host gene in tumorigenesis and tumor progression
Authors: Wei Jianxia , Li Mengna , Xue Changning , Chen Shipeng , Zheng Lemei , Deng Hongyu , Tang Faqing , Li Guiyuan , Xiong Wei , Zeng Zhaoyang , Zhou Ming
Published: April 2023

Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs, which are covalently closed loop structures formed by precursor mRNAs (pre-mRNAs) through back-splicing. CircRNAs are abnormally expressed in many tumors, and play critical roles in a variety of tumors as oncogenes or tumor suppressor genes by sponging miRNAs, regulating alternative splicing and transcription, cis-regulating host genes, interacting with RNA binding proteins (RBPs) or encoding polypeptides. Among them, the regulation of circRNAs on their corresponding host genes is a critical way for circRNAs to exit their functions. Accumulating evidence suggests that circRNAs are able to regulate the expression of host genes at the transcriptional level, post-transcriptional level, translational level, post-translational level, or by encoding polypeptides. Therefore, this paper mainly summarized the roles and association of circRNAs and their corresponding host genes in tumorigenesis and tumor progression, generalized the circRNAs that function synergistically or antagonistically with their host genes, and elaborated the mechanisms of mutual regulation between circRNAs and their host genes. More importantly, this review provides specific references for revealing the potential application of circRNAs combined with their host genes in tumor diagnosis, treatment and prognosis.
How to measure children's feet: 3D foot scanning compared with established 2D manual or digital methods
Authors: Mueller Juliane , Richter Monika , Schaefer Kathrin , Ganz Jonathan , Lohscheller Jörg , Mueller Steffen
Published: April 2023

Background

In infants and young children, a wide heterogeneity of foot shape is typical. Therefore, children, who are additionally influenced by rapid growth and maturation, are a very special cohort for foot measurements and the footwear industry. The importance of foot measurements for footwear fit, design, as well as clinical applications has been sufficiently described. New measurement techniques (3D foot scanning) allow the assessment of the individual foot shape. However, the validity in comparison to conventional methods remains unclear. Therefore, the purpose of this study was to compare 3D foot scanning with two established measurement methods (2D digital scanning/manual foot measurements).

Methods

Two hundred seventy seven children (125 m / 152 f; mean ± SD: 8.0 ± 1.5yrs; 130.2 ± 10.7cm; 28.0 ± 7.3kg) were included into the study. After collection of basic data (sex, age (yrs), body height (cm), body weight (kg)) geometry of the right foot was measured in static condition (stance) with three different measurement systems (fixed order): manual foot measurement, 2D foot scanning (2D desk scanner) and 3D foot scanning (hand‐held 3D scanner). Main outcomes were foot length, foot width (projected; anatomical; instep), heel width and anatomical foot ball breadth. Analysis of variances for dependent samples was applied to test for differences between foot measurement methods (Post‐hoc analysis: Tukey‐Kramer‐Test; α=0.05).

Results

Significant differences were found for all outcome measures comparing the three methods (p<0.0001). The span of foot length differences ranged from 3 to 6mm with 2D scans showing the smallest and 3D scans the largest deviations. Foot width measurements in comparison of 3D and 2D scans showed consistently higher values for 3D measurements with the differences ranging from 1mm to 3mm.

Conclusions

The findings suggests that when comparing foot data, it is important to consider the differences caused by new measurement methods. Differences of about 0.6cm are relevant when measuring foot length, as this is the difference of a complete shoe size (Parisian point). Hence, correction factors may be required to compare the results of different measurements appropriately. The presented results may have relevance in the field of ergonomics (shoe industry) as well as clinical practice.
The struggle to stay physically active—A qualitative study exploring experiences of individuals with persistent plantar fasciopathy
Authors: Mørk Marianne , Soberg Helene Lundgaard , Hoksrud Aasne Fenne , Heide Marte , Groven Karen Synne
Published: April 2023

Background

Plantar fasciopathy is the most common cause of heel pain, and is associated with decreased physical activity level and quality of life. There has been limited research on the experiences of patients with plantar fasciopathy. This study seeks to gain more in‐depth understanding and knowledge by exploring the lived experiences of people with persistent plantar fasciopathy.

Methods

We included 15 participants with longstanding plantar fasciopathy. Face‐to‐face, semi‐structured interviews were audio recorded, transcribed verbatim and analysed using Braun and Clark's reflexive thematic analysis. We used an inductive approach led by a phenomenological theoretical framework.

Results

We identified three core themes and ten sub‐themes. The first theme was ‘Struggling to stay active’ with sub‐themes ‘Struggling with pain and how to adjust it’, ‘ Finding alternative activities' and ‘Longing for the experience of walking’. The second main theme was ‘Emotional challenges' with the sub‐themes ‘Feelings of frustration and self‐blame’ and ‘Worries of weight gain and related consequences'. The third main theme was ‘Relations to others' with the sub‐themes ‘Participation in family and social life’, ‘ Visible in new ways', ‘ Striving to avoid sick leave’ and ‘Bothering others'.

Conclusions

Participants revealed how their heel pain led to inactivity and emotional and social challenges. Pain when walking and fear of aggravating it dominated the participants' lives. They emphasised the importance of finding alternative ways to stay active and avoiding sick leave. Treatment should focus on holistic and individually tailored approaches.
De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review
Authors: Li Wei , Guo Hui
Published: April 2023

Background

The TRIM8 gene encodes a protein that participates in various biological processes. TRIM8 variants can lead to early termination of protein translation, which can cause a rare disease called neuro-renal syndrome. This syndrome is characterized by epilepsy, psychomotor retardation, and focal segmental glomerulosclerosis. However, we found that some patients may not present the above typical triad, and the reason may be related to their variant sites.

Case presentation

We report a case of a 6-year-old boy with nephrotic-range proteinuria as the first prominent manifestation of TRIM8 variant. He had stage 3 chronic kidney disease at the time of presentation, specific facial features, and a neurogenic bladder. He had not experienced seizures previously. There were no apparent abnormalities in his growth, intelligence, or motor development. The results of whole exome sequencing showed a TRIM8 variant. Renal biopsy revealed focal segmental glomerulosclerosis and renal tubular cystic dilatation. He did not respond to hormone and angiotensin-converting enzyme inhibitor treatment; however, the symptoms of neurogenic bladder were relieved after treatment with Solifenacin.

Conclusion

In this case, renal disease was the prominent manifestation; the patient had no other obvious neurological symptoms except a neurogenic bladder. Notably, the variant site is the closest to the C-terminal to date. Based on the analysis of previously reported cases, we found that as the TRIM8 variant became closer to the C-terminal, the renal lesions became more prominent, and there were fewer neurologic lesions. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. Patients may only have kidney disease as a prominent manifestation. At the same time, we found that we should also pay attention to the eye lesions of these patients. Therefore, gene analysis is helpful in identifying the etiology and guiding the prognosis of patients with hormone-resistant proteinuria. We suggest that TRIM8 should be included in gene panels designed for the genetic evaluation of hormone-resistant proteinuria.
Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis
Authors: Wiles Anna K. , Mehta Sunali , Millier Melanie , Woolley Adele G. , Li Kunyu , Parker Kim , Kazantseva Marina , Wilson Michelle , Young Katie , Bowie Sarah , Ray Sankalita , Slatter Tania L. , Stamp Lisa K. , Hessian Paul A. , Braithwaite Antony W.
Published: April 2023

Background

The p53 isoform Δ133p53β is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53β is driving aggressive disease in RA.

Methods

Using RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53β. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software.

Results

Elevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53β mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of ‘activated fibroblasts’ together with elevated levels of Δ133p53β.

Conclusions

Induction of Δ133p53β in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53β could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53β could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.
A deep learning model using chest X-ray for identifying TB and NTM-LD patients: a cross-sectional study
Authors: Liu Chia-Jung , Tsai Cheng Che , Kuo Lu-Cheng , Kuo Po-Chih , Lee Meng-Rui , Wang Jann-Yuan , Ko Jen-Chung , Shih Jin-Yuan , Wang Hao-Chien , Yu Chong-Jen
Published: April 2023

Background

Timely differentiating between pulmonary tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD), which are radiographically similar, is important because infectiousness and treatment differ. This study aimed to evaluate whether artificial intelligence could distinguish between TB or NTM-LD patients by chest X-rays (CXRs) from suspects of mycobacterial lung disease.

Methods

A total of 1500 CXRs, including 500 each from patients with pulmonary TB, NTM-LD, and patients with clinical suspicion but negative mycobacterial culture (Imitator) from two hospitals, were retrospectively collected and evaluated in this study. We developed a deep neural network (DNN) and evaluated model performance using the area under the receiver operating characteristic curves (AUC) in both internal and external test sets. Furthermore, we conducted a reader study and tested our model under three scenarios of different mycobacteria prevalence.

Results

Among the internal and external test sets, the AUCs of our DNN model were 0.83 ± 0.005 and 0.76 ± 0.006 for pulmonary TB, 0.86 ± 0.006 and 0.64 ± 0.017 for NTM-LD, and 0.77 ± 0.007 and 0.74 ± 0.005 for Imitator. The DNN model showed higher performance on the internal test set in classification accuracy (66.5 ± 2.5%) than senior (50.8 ± 3.0%, p < 0.001) and junior pulmonologists (47.5 ± 2.8%, p < 0.001). Among different prevalence scenarios, the DNN model has stable performance in terms of AUC to detect TB and mycobacterial lung disease.

Conclusion

DNN model had satisfactory performance and a higher accuracy than pulmonologists on classifying patients with presumptive mycobacterial lung diseases. DNN model could be a complementary first-line screening tool.
Intra- and peri-tumoral MRI radiomics features for preoperative lymph node metastasis prediction in early-stage cervical cancer
Authors: Zhang Zhenhua , Wan Xiaojie , Lei Xiyao , Wu Yibo , Zhang Ji , Ai Yao , Yu Bing , Liu Xinmiao , Jin Juebin , Xie Congying , Jin Xiance
Published: April 2023

Background

Noninvasive and accurate prediction of lymph node metastasis (LNM) is very important for patients with early-stage cervical cancer (ECC). Our study aimed to investigate the accuracy and sensitivity of radiomics models with features extracted from both intra- and peritumoral regions in magnetic resonance imaging (MRI) with T2 weighted imaging (T2WI) and diffusion weighted imaging (DWI) for predicting LNM.

Methods

A total of 247 ECC patients with confirmed lymph node status were enrolled retrospectively and randomly divided into training (n = 172) and testing sets (n = 75). Radiomics features were extracted from both intra- and peritumoral regions with different expansion dimensions (3, 5, and 7 mm) in T2WI and DWI. Radiomics signature and combined radiomics models were constructed with selected features. A nomogram was also constructed by combining radiomics model with clinical factors for predicting LNM.

Results

The area under curves (AUCs) of radiomics signature with features from tumors in T2WI and DWI were 0.841 vs. 0.791 and 0.820 vs. 0.771 in the training and testing sets, respectively. Combining radiomics features from tumors in the T2WI, DWI and peritumoral 3 mm expansion in T2WI achieved the best performance with an AUC of 0.868 and 0.846 in the training and testing sets, respectively. A nomogram combining age and maximum tumor diameter (MTD) with radiomics signature achieved a C-index of 0.884 in the prediction of LNM for ECC.

Conclusions

 Radiomics features extracted from both intra- and peritumoral regions in T2WI and DWI are feasible and promising for the preoperative prediction of LNM for patients with ECC.
Expansion and characterization of human limbus-derived stromal/mesenchymal stem cells in xeno-free medium for therapeutic applications
Authors: Sahoo Abhishek , Damala Mukesh , Jaffet Jilu , Prasad Deeksha , Basu Sayan , Singh Vivek
Published: April 2023

Background

Mesenchymal stem cells (MSCs) have been proven to prevent and clear corneal scarring and limbal stem cell deficiency. However, using animal-derived serum in a culture medium raises the ethical and regulatory bar. This study aims to expand and characterize human limbus-derived stromal/mesenchymal stem cells (hLMSCs) for the first time in vitro in the xeno-free medium.

Methods

Limbal tissue was obtained from therapeutic grade corneoscleral rims and subjected to explant culture till tertiary passage in media with and without serum (STEM MACS XF; SM), to obtain pure hLMSCs. Population doubling time, cell proliferation, expression of phenotypic markers, tri-lineage differentiation, colony-forming potential and gene expression analysis were carried out to assess the retention of phenotypic and genotypic characteristics of hLMSCs.

Results

The serum-free medium supported the growth of hLMSCs, retaining similar morphology but a significantly lower doubling time of 23 h (*p < 0.01) compared to the control medium. FACS analysis demonstrated ≥ 90% hLMSCs were positive for CD90+, CD73+, CD105+, and ≤ 6% were positive for CD45−, CD34−andHLA-DR−. Immunofluorescence analysis confirmed similar expression of Pax6+, COLIV+, ABCG2+, ABCB5+, VIM+, CD90+, CD105+, CD73+, HLA-DR−andCD45−, αSMA− in both the media. Tri-lineage differentiation potential and gene expression of hLMSCs were retained similarly to that of the control medium.

Conclusion

The findings of this study demonstrate successful isolation, characterization and culture optimization of hLMSCs for the first time in vitro in a serum-free environment. This will help in the future pre-clinical and clinical applications of MSCs in translational research.
A beginner’s guide on the use of brain organoids for neuroscientists: a systematic review
Authors: Mulder Lance A. , Depla Josse A. , Sridhar Adithya , Wolthers Katja , Pajkrt Dasja , Vieira de Sá Renata
Published: April 2023

Background

The first human brain organoid protocol was presented in the beginning of the previous decade, and since then, the field witnessed the development of many new brain region-specific models, and subsequent protocol adaptations and modifications. The vast amount of data available on brain organoid technology may be overwhelming for scientists new to the field and consequently decrease its accessibility. Here, we aimed at providing a practical guide for new researchers in the field by systematically reviewing human brain organoid publications.

Methods

Articles published between 2010 and 2020 were selected and categorised for brain organoid applications. Those describing neurodevelopmental studies or protocols for novel organoid models were further analysed for culture duration of the brain organoids, protocol comparisons of key aspects of organoid generation, and performed functional characterisation assays. We then summarised the approaches taken for different models and analysed the application of small molecules and growth factors used to achieve organoid regionalisation. Finally, we analysed articles for organoid cell type compositions, the reported time points per cell type, and for immunofluorescence markers used to characterise different cell types.

Results

Calcium imaging and patch clamp analysis were the most frequently used neuronal activity assays in brain organoids. Neural activity was shown in all analysed models, yet network activity was age, model, and assay dependent. Induction of dorsal forebrain organoids was primarily achieved through combined (dual) SMAD and Wnt signalling inhibition. Ventral forebrain organoid induction was performed with dual SMAD and Wnt signalling inhibition, together with additional activation of the Shh pathway. Cerebral organoids and dorsal forebrain model presented the most cell types between days 35 and 60. At 84 days, dorsal forebrain organoids contain astrocytes and potentially oligodendrocytes. Immunofluorescence analysis showed cell type-specific application of non-exclusive markers for multiple cell types.

Conclusions

We provide an easily accessible overview of human brain organoid cultures, which may help those working with brain organoids to define their choice of model, culture time, functional assay, differentiation, and characterisation strategies.
Tissue engineering modalities in skeletal muscles: focus on angiogenesis and immunomodulation properties
Authors: Namjoo Atieh Rezaei , Abrbekoh Fateme Nazary , Saghati Sepideh , Amini Hassan , Saadatlou Mohammad Ali Ebrahimi , Rahbarghazi Reza
Published: April 2023

Muscular diseases and injuries are challenging issues in human medicine, resulting in physical disability. The advent of tissue engineering approaches has paved the way for the restoration and regeneration of injured muscle tissues along with available conventional therapies. Despite recent advances in the fabrication, synthesis, and application of hydrogels in terms of muscle tissue, there is a long way to find appropriate hydrogel types in patients with congenital and/or acquired musculoskeletal injuries. Regarding specific muscular tissue microenvironments, the applied hydrogels should provide a suitable platform for the activation of endogenous reparative mechanisms and concurrently deliver transplanting cells and therapeutics into the injured sites. Here, we aimed to highlight recent advances in muscle tissue engineering with a focus on recent strategies related to the regulation of vascularization and immune system response at the site of injury.
Overexpression of KCNJ2 enhances maturation of human-induced pluripotent stem cell-derived cardiomyocytes
Authors: Zhou Jingjun , Cui Baiping , Wang Xiaochen , Wang Hongkun , Zheng Junnan , Guo Fengfeng , Sun Yaxun , Fan Hangping , Shen Jiaxi , Su Jun , Wang Jue , Zhao Haige , Tang Yiquan , Gong Tingyu , Sun Ning , Liang Ping
Published: April 2023

Background

Although human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising cell resource for cardiovascular research, these cells exhibit an immature phenotype that hampers their potential applications. The inwardly rectifying potassium channel Kir2.1, encoded by the KCNJ2 gene, has been thought as an important target for promoting electrical maturation of iPSC-CMs. However, a comprehensive characterization of morphological and functional changes in iPSC-CMs overexpressing KCNJ2 (KCNJ2 OE) is still lacking.

Methods

iPSC-CMs were generated using a 2D in vitro monolayer differentiation protocol. Human KCNJ2 construct with green fluorescent protein (GFP) tag was created and overexpressed in iPSC-CMs via lentiviral transduction. The mixture of iPSC-CMs and mesenchymal cells was cocultured with decellularized natural heart matrix for generation of 3D human engineered heart tissues (EHTs).

Results

We showed that mRNA expression level of KCNJ2 in iPSC-CMs was dramatically lower than that in human left ventricular tissues. KCNJ2 OE iPSC-CMs yielded significantly increased protein expression of Kir2.1 and current density of Kir2.1-encoded IK1. The larger IK1 linked to a quiescent phenotype that required pacing to elicit action potentials in KCNJ2 OE iPSC-CMs, which can be reversed by IK1 blocker BaCl2. KCNJ2 OE also led to significantly hyperpolarized maximal diastolic potential (MDP), shortened action potential duration (APD) and increased maximal upstroke velocity. The enhanced electrophysiological maturation in KCNJ2 OE iPSC-CMs was accompanied by improvements in Ca2+ signaling, mitochondrial energy metabolism and transcriptomic profile. Notably, KCNJ2 OE iPSC-CMs exhibited enlarged cell size and more elongated and stretched shape, indicating a morphological phenotype toward structural maturation. Drug testing using hERG blocker E-4031 revealed that a more stable MDP in KCNJ2 OE iPSC-CMs allowed for obtaining significant drug response of APD prolongation in a concentration-dependent manner. Moreover, KCNJ2 OE iPSC-CMs formed more mature human EHTs with better tissue structure and cell junction.

Conclusions

Overexpression of KCNJ2 can robustly enhance maturation of iPSC-CMs in electrophysiology, Ca2+ signaling, metabolism, transcriptomic profile, cardiomyocyte structure and tissue engineering, thus providing more accurate cellular model for elucidating cellular and molecular mechanisms of cardiovascular diseases, screening drug-induced cardiotoxicity, and developing personalized and precision cardiovascular medicine.
Apoptotic vesicles resist oxidative damage in noise-induced hearing loss through activation of FOXO3a-SOD2 pathway
Authors: Huang Xiaotong , Kou Xiaoxing , Zhan Ting , Wei Guokun , He Feinan , Mao Xueli , Yang Haidi
Published: April 2023

Background

Mesenchymal stem cell (MSC) transplantation is a promising therapeutic approach for noise-induced hearing loss (NIHL). As the indispensable role of apoptosis in MSC transplantation was raised, the benefits of MSC-derived apoptotic vesicles (apoVs) in several disease models have been proved. However, whether apoVs benefit in NIHL have not been studied yet.

Methods

Female CBA/J mice and HEI-OC1 cells were used in this study. Flow cytometry, nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were used to characterize apoVs. Proteomic analysis was used to identify function proteins in apoVs. Immunofluorescence was used to reveal distribution pattern. Auditory brainstem response (ABR) test was used to measure the effect of apoVs treatment. DCFH-DA staining and MitoSOX staining were used to indicate oxidative damage. Western-blot and qRT-PCR were used to study the signaling pathways.

Results

We found that apoVs can be endocytosed by hair cells through systemic administration. Importantly, apoVs administration effectively attenuated NIHL and reduced hair cell loss by resisting oxidative damage in vivo. Further, apoVs application activated forkhead box o3 (FOXO3a)—mitochondrial superoxide dismutase 2(SOD2) pathway, which may relate to signal transduction and activators of transcription 3 (STAT3) in apoVs.

Conclusions

These findings uncovered the role of apoVs in preventing NIHL and resisting oxidative damage, indicating that apoVs is a promising way for inner ear delivery and a prospective cell-free therapy for NIHL.
Sex differences in the transcriptome of extracellular vesicles secreted by fetal neural stem cells and effects of chronic alcohol exposure
Authors: Chung Dae D. , Mahnke Amanda H. , Pinson Marisa R. , Salem Nihal A. , Lai Michael S. , Collins Natalie P. , Hillhouse Andrew E. , Miranda Rajesh C.
Published: April 2023

Background

Prenatal alcohol (ethanol) exposure (PAE) results in brain growth restriction, in part, by reprogramming self-renewal and maturation of fetal neural stem cells (NSCs) during neurogenesis. We recently showed that ethanol resulted in enrichment of both proteins and pro-maturation microRNAs in sub-200-nm-sized extracellular vesicles (EVs) secreted by fetal NSCs. Moreover, EVs secreted by ethanol-exposed NSCs exhibited diminished efficacy in controlling NSC metabolism and maturation. Here we tested the hypothesis that ethanol may also influence the packaging of RNAs into EVs from cell-of-origin NSCs.

Methods

Sex-specified fetal murine iso-cortical neuroepithelia from three separate pregnancies were maintained ex vivo, as neurosphere cultures to model the early neurogenic niche. EVs were isolated by ultracentrifugation from NSCs exposed to a dose range of ethanol. RNA from paired EV and cell-of-origin NSC samples was processed for ribosomal RNA-depleted RNA sequencing. Differential expression analysis and exploratory weighted gene co-expression network analysis (WGCNA) identified candidate genes and gene networks that were drivers of alterations to the transcriptome of EVs relative to cells.

Results

The RNA content of EVs differed significantly from cell-of-origin NSCs. Biological sex contributed to unique transcriptome variance in EV samples, where > 75% of the most variant transcripts were also sex-variant in EVs but not in cell-of-origin NSCs. WGCNA analysis also identified sex-dependent enrichment of pathways, including dopamine receptor binding and ectoderm formation in female EVs and cell-substrate adhesion in male EVs, with the top significant DEGs from differential analysis of overall individual gene expressions, i.e., Arhgap15, enriched in female EVs, and Cenpa, enriched in male EVs, also serving as WCGNA hub genes of sex-biased EV WGCNA clusters. In addition to the baseline RNA content differences, ethanol exposure resulted in a significant dose-dependent change in transcript expression in both EVs and cell-of-origin NSCs that predominantly altered sex-invariant RNAs. Moreover, at the highest dose, ~ 73% of significantly altered RNAs were enriched in EVs, but depleted in NSCs.

Conclusions

The EV transcriptome is distinctly different from, and more sex-variant than, the transcriptome of cell-of-origin NSCs. Ethanol, a common teratogen, results in dose-dependent sorting of RNA transcripts from NSCs to EVs which may reprogram the EV-mediated endocrine environment during neurogenesis.
Multiparametric dynamic whole-body PSMA PET/CT using [68Ga]Ga-PSMA-11 and [18F]PSMA-1007
Authors: Dias André H. , Jochumsen Mads R. , Zacho Helle D. , Munk Ole L. , Gormsen Lars C.
Published: April 2023

Background

Routine prostate-specific membrane antigen (PSMA) positron emission tomography (PET) performed for primary staging or restaging of prostate cancer patients is usually done as a single static image acquisition 60 min after tracer administration. In this study, we employ dynamic whole-body (D-WB) PET imaging to compare the pharmacokinetics of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 in various tissues and lesions, and to assess whether Patlak parametric images are quantitative and improve lesion detection and image readability.

Methods

Twenty male patients with prostate cancer were examined using a D-WB PSMA PET protocol. Ten patients were scanned with [68Ga]Ga-PSMA-11 and ten with [18F]PSMA-1007. Kinetic analyses were made using time-activity curves (TACs) extracted from organs (liver, spleen, bone, and muscle) and lesions. For each patient, three images were produced: SUV + Patlak parametric images (Ki and DV). All images were reviewed visually to compare lesion detection, image readability was quantified using target-to-background ratios (TBR), and Ki and DV values were compared.

Results

The two PSMA tracers exhibited markedly different pharmacokinetics in organs: reversible for [68Ga]Ga-PSMA-11 and irreversible for [18F]PSMA-1007. For both tracers, lesions kinetics were best described by an irreversible model. All parametric images were of good visual quality using both radiotracers. In general, Ki images were characterized by reduced vascular signal and increased lesion TBR compared with SUV images. No additional malignant lesions were identified on the parametric images.

Conclusion

D-WB PET/CT is feasible for both PSMA tracers allowing for direct reconstruction of parametric Ki images. The use of multiparametric PSMA images increased TBR but did not lead to the detection of more lesions. For quantitative whole-body Ki imaging, [18F]PSMA-1007 should be preferred over [68Ga]Ga-PSMA-11 due to its irreversible kinetics in organs and lesions.
Usefulness of machine learning softwares to screen titles of systematic reviews: a methodological study
Authors: dos Reis Ana Helena Salles , de Oliveira Ana Luiza Miranda , Fritsch Carolina , Zouch James , Ferreira Paulo , Polese Janaine Cunha
Published: April 2023

Objective

To investigate the usefulness and performance metrics of three freely-available softwares (Rayyan®, Abstrackr® and Colandr®) for title screening in systematic reviews.

Study design and setting

In this methodological study, the usefulness of softwares to screen titles in systematic reviews was investigated by the comparison between the number of titles identified by software-assisted screening and those by manual screening using a previously published systematic review. To test the performance metrics, sensitivity, specificity, false negative rate, proportion missed, workload and timing savings were calculated. A purposely built survey was used to evaluate the rater's experiences regarding the softwares’ performances.

Results

Rayyan® was the most sensitive software and raters correctly identified 78% of the true positives. All three softwares were specific and raters correctly identified 99% of the true negatives. They also had similar values for precision, proportion missed, workload and timing savings. Rayyan®, Abstrackr® and Colandr® had 21%, 39% and 34% of false negatives rates, respectively. Rayyan presented the best performance (35/40) according to the raters.

Conclusion

Rayyan®, Abstrackr® and Colandr® are useful tools and provided good metric performance results for systematic title screening. Rayyan® appears to be the best ranked on the quantitative and on the raters’ perspective evaluation. The most important finding of this study is that the use of software to screen titles does not remove any title that would meet the inclusion criteria for the final review, being valuable resources to facilitate the screening process.
Robust-PAC time-critical workflow offloading in edge-to-cloud continuum among heterogeneous resources
Authors: Liu Hongyun , Xin Ruyue , Chen Peng , Gao Hui , Grosso Paola , Zhao Zhiming
Published: April 2023

Edge-to-cloud continuum connects and extends the calculation from edge side via network to cloud platforms, where diverse workflows go back and forth, getting executed on scheduled calculation resources. To better utilize the calculation resources from all sides, workflow offloading problems have been investigating lately. Most works focus on optimizing constraints like: latency requirements, resource utilization rate limits, and energy consumption bounds. However, the dynamics among the offloading environment have hardly been researched, which easily results in uncertain Quality of Service(QoS) on the user side. Any part of the workload change, resource availability change or network latency could incur dynamics in an offloading environment. In this work, we propose a robust PAC (probably approximately correct) offloading algorithm to address this dynamic issue together with optimization. We train an LSTM-based sequence-to-sequence neural network to learn how to offload workflows in edge-to-cloud continuum. Comprehensive implementations and corresponding comparison against state-of-the-art methods demonstrate the robustness of our proposed algorithm. More specifically, our algorithm achieves better offloading performance regarding dynamic heterogeneous offloading environment and faster adaptation to newly changed environments than fine-tuned state-of-the-art RL-based offloading methods.
User communities: from nice-to-have to must-have
Authors: Costa Joana , Amorim Inês , Reis João , Melão Nuno
Published: April 2023

With Industry 5.0 already on the horizon, firms need to adapt their strategies to better cater to an increasingly demanding and sustainability-conscious customer base. At the same time, the role of customers has shifted from being mere passive buyers to active users, who not only demand personalized products and services to suit their needs and preferences, but also actively engage other users and stakeholders, thereby grounding the Quadruple Helix model. The objective of this paper is to assess the role of user communities in fostering firms’ innovation in all types of innovation. Econometric estimations identified the user community as a driver of innovation propensity. Additionally, the relevance of these communities across all types of innovation (mainly for product and process innovation) was proven. Robustness analysis confirmed the results obtained in different dimensions and established a connection to human capital. This finding revealed that absorptive capacity serves not only as a facilitator of innovation, but also as a moderator. The empirical contributions point towards the urgency of policy actions that consistently involve these agents as vehicles of responsible innovation, which can fine-tune the innovation paths towards an eco-friendlier innovation ecosystem. Further testing the connection between human capital and the user community is required, as the establishment of efficient communication channels promoting the knowledge flows inside the firm will leverage innovation outputs in the different innovation types.
Hospital sanitary facilities on wards with high antibiotic exposure play an important role in maintaining a reservoir of resistant pathogens, even over many years
Authors: Neidhöfer Claudio , Sib Esther , Neuenhoff Marcel , Schwengers Oliver , Dummin Tobias , Buechler Christian , Klein Niklas , Balks Julian , Axtmann Katharina , Schwab Katjana , Holderried Tobias A. W. , Feldmann Georg , Brossart Peter , Engelhart Steffen , Mutters Nico T. , Bierbaum Gabriele , Parčina Marijo
Published: April 2023

Background

Hospitals with their high antimicrobial selection pressure represent the presumably most important reservoir of multidrug-resistant human pathogens. Antibiotics administered in the course of treatment are excreted and discharged into the wastewater system. Not only in patients, but also in the sewers, antimicrobial substances exert selection pressure on existing bacteria and promote the emergence and dissemination of multidrug-resistant clones. In previous studies, two main clusters were identified in all sections of the hospital wastewater network that was investigated, one K. pneumoniae ST147 cluster encoding NDM- and OXA-48 carbapenemases and one VIM-encoding P. aeruginosa ST823 cluster. In the current study, we investigated if NDM- and OXA-48-encoding K. pneumoniae and VIM-encoding P. aeruginosa isolates recovered between 2014 and 2021 from oncological patients belonged to those same clusters.

Methods

The 32 isolates were re-cultured, whole-genome sequenced, phenotypically tested for their antimicrobial susceptibility, and analyzed for clonality and resistance genes in silico.

Results

Among these strains, 25 belonged to the two clusters that had been predominant in the wastewater, while two others belonged to a sequence-type less prominently detected in the drains of the patient rooms.

Conclusion

Patients constantly exposed to antibiotics can, in interaction with their persistently antibiotic-exposed sanitary facilities, form a niche that might be supportive for the emergence, the development, the dissemination, and the maintenance of certain nosocomial pathogen populations in the hospital, due to antibiotic-induced selection pressure. Technical and infection control solutions might help preventing transmission of microorganisms from the wastewater system to the patient and vice versa, particularly concerning the shower and toilet drainage. However, a major driving force might also be antibiotic induced selection pressure and parallel antimicrobial stewardship efforts could be essential.