bluuebunny/crossref_metadata_2025 huggingface dataset:
A case of ANCA-associated vasculitis in a 16-year-old female following SARS-COV-2 infection and a systematic review of the literature
Authors: Bryant Maria C. , Spencer L. Terry , Yalcindag Ali
Published: August 2022

Background

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare form of vasculitis in children. SARS-CoV-2, the virus that causes COVID-19 infection, seems to trigger autoimmunity and new-onset autoimmune disease in pediatric and adult patients. We present a case of new-onset AAV following COVID-19 infection in an adolescent patient, and we review the literature of AAV following COVID-19 infection.

Case presentation

An adolescent female with a history of asthma was diagnosed with mild COVID-19 infection and subsequently developed persistent cough, wheezing, hearing loss, arthralgias, and rash. Her imaging and laboratory workup showed pulmonary nodules and cavitary lesions, elevated inflammatory markers, negative infectious testing, and positive ANCA. She was treated with glucocorticoids, rituximab, and mycophenolate mofetil. At six-month follow-up, she had improvement in her symptoms, pulmonary function tests, imaging findings, and laboratory markers.

Conclusions

We report the second case of new-onset anti-PR3, C-ANCA vasculitis and the fourth case of pediatric-onset AAV following COVID-19 infection. A systematic review of the literature found 6 cases of new-onset AAV in adults after COVID-19 infection. Pediatric and adult patients who develop AAV post COVID-19 infection have few, if any, comorbidities, and show marked radiographic and symptomatic improvement after treatment. There is increasing evidence for COVID-19-induced autoimmunity in children and our case highlights the importance of considering AAV in a child following a recent COVID-19 infection because timely treatment may improve clinical outcomes.
Comparison of global indicators for severe maternal morbidity among South Korean women who delivered from 2003 to 2018: a population-based retrospective cohort study
Authors: Nam Jin Young
Published: August 2022

Background

Even though several severe maternal morbidity (SMM) indicators exist globally, indicators that can serve as international standards are needed. Therefore, this study aimed to compare the SMM risk assessment using four international indicators and identify the factors underlying the differences among the risk assessments obtained by the various indicators.

Methods

This study used the National Health Insurance delivery cohort in South Korea from 2003 to 2018. SMM was estimated using four indicators: the United States Centers for Disease Control and Prevention (US-CDC) SMM algorithm, the American College of Obstetricians and Gynecologists (ACOG) gold standard guidelines, Zwart et al.’s indicators for the Netherlands, and the European Network on Severe Acute Maternal Morbidity (EURONET-SAMM) index. Generalized estimating equations models were used to identify the relationships between SMM indicators and risk factors.

Results

The SMM incidence rates in 6,421,091 deliveries, were 2.36%, 3.12%, 0.31%, and 1.36% using the US-CDC, ACOG, Zwart et al.’s, and EURONET SAMM indicators, respectively. In sub indicators, hemorrhage-related codes constituted the highest proportion of all SMM indicators. Advanced maternal age was related to high risk in all four SMM indicators (US-CDC: 40–44 years, RR 1.67, 95% CI 1.63–1.71; ACOG’s guidelines: 40–44 years, RR 1.52, 95% CI 1.49–1.56; Zwart’s indicators: RR 2.72, 95% CI 2.55–2.90; EURONET-SAMM: RR 2.04, 95% CI 1.97–2.11) compared to those aged 25–29 years. In residential area, women who lived in rural area had approximately 1.2- to 1.5-fold higher risk of SMM compared to those who lived in Seoul. Additionally, inadequate prenatal care was associated with a 1.1- to 1.4-fold higher risk of SMM compared to adequate prenatal care.

Conclusions

SMM was associated with maternal age, socioeconomic status, and adverse obstetric factors using various international SMM indicators. Further studies are needed to further determine risk and preventable factors for SMM and to identify more specific causes associated with the frequent sub-indicators of SMM.
Simultaneous versus staged bilateral total hip arthroplasty: a systematic review and meta-analysis
Authors: Ramezani Akam , Ghaseminejad Raeini Amirhossein , Sharafi Amirmohammad , Sheikhvatan Mehrdad , Mortazavi Seyed Mohammad Javad , Shafiei Seyyed Hossein
Published: August 2022

Background

Total hip arthroplasty is a common orthopedic surgery for treating primary or secondary hip osteoarthritis. Bilateral total hip replacement could be performed in a single stage or two separate stages. Each surgical procedure's reliability, safety, and complications have been reported controversially. This study aimed to review the current evidence regarding the outcomes of simultaneous and staged bilateral total hip arthroplasty.

Methods

We conducted a meta-analysis using MEDLINE, EMBASE, Web of Science, and Scopus databases. Eligible studies compared complications and related outcomes between simultaneous and staged bilateral THA. Two reviewers independently screened initial search results, assessed methodological quality, and extracted data. We used the Mantel–Haenszel method to perform the meta-analysis.

Results

In our study, we included 29,551 patients undergoing simBTHA and 74,600 patients undergoing stgBTHA. In favor of the simBTHA, a significant reduction in deep vein thrombosis (DVT) and systemic, local, and pulmonary complications was documented. However, we evidenced an increased pulmonary embolism (PE) and periprosthetic fracture risk in simBTHA. In the simBTHA, total blood loss, length of hospital stay, and total cost were lower.

Conclusion

This meta-analysis shows that simultaneous bilateral THA accompanies fewer complications and lower total cost. Well-designed randomized controlled trials are needed to provide robust evidence.
CD147 mediates epidermal malignant transformation through the RSK2/AP-1 pathway
Authors: Zhang Xu , Guo Yeye , Xiao Ta , Li Jie , Guo Aiyuan , Lei Li , Jin Chong , Long Qi , Su Juan , Yin Mingzhu , Liu Hong , Chen Chao , Zhou Zhe , Zhu Susi , Tao Juan , Hu Shuo , Chen Xiang , Peng Cong
Published: August 2022

Background

Malignant transformation of the epidermis is an essential process in the pathogenesis of cutaneous squamous-cell carcinoma (cSCC). Although evidence has demonstrated that CD147 plays key roles in various tumors, the role of CD147 in epidermal malignant transformation in vivo remains unclear.

Methods

Epidermal CD147-overexpression or knockout (EpiCD147-OE or EpiCD147-KO) transgenic mouse models were generated for in vivo study. RNA-sequencing and q-PCR were performed to identify the differentially expressed genes. Immunohistochemistry and flow cytometry were performed to investigate the role of CD147 in regulating myeloid-derived suppressor cells (MDSCs). Immunoprecipitation, EMSA and ChIP assays were performed to investigate the mechanism of CD147 in cell transformation.

Results

We found that specific overexpression of CD147 in the epidermis (EpiCD147-OE) induces spontaneous tumor formation; moreover, a set of chemokines and cytokines including CXCL1, which play essential function in MDSC recruitment, were significantly upregulated in EpiCD147-OE transgenic mice. As expected, overexpression of CD147 in the epidermis remarkably facilitated tumorigenesis by increasing the rate of tumor initiation and the number and size of tumors in the DMBA/TPA mouse model. Interestingly, the expression of CXCL1 and the infiltration of MDSCs were dramatically increased in EpiCD147-OE transgenic mice. Our findings also showed that knockdown of CD147 attenuated EGF-induced malignant transformation as well as CXCL1 expression in HaCaT cells. Consistently, CD147 was found overexpressed in cutaneous squamous cell carcinoma (cSCC), and positively related with the expression of CD33, a myeloid-associated marker. We further identified RSK2, a serine/threonine kinase, as an interacting partner of CD147 at the binding site of CD147D207-230. The interaction of CD147 and RSK2 activated RSK2, thus enhancing AP-1 transcriptional activation. Furthermore, EMSAs and ChIP assays showed that AP-1 could associate with the CXCL1 promoter. Importantly, RSK2 inhibitor suppressed the tumor growth in DMBA/TPA mouse model by inhibiting the recruitment of MDSCs.

Conclusion

Our findings demonstrate that CD147 exerts a key function in epidermal malignant transformation in vivo by activating keratinocytes and recruiting MDSCs via the RSK2/AP-1 pathway.
Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment
Authors: Jiang Jianyun , Ying Hongmei
Published: August 2022

Nasopharyngeal carcinoma (NPC) arises from the epithelial cells located in the nasopharynx and has a distinct geographic distribution. Chronic Epstein-Barr virus (EBV) infection, as its most common causative agents, can be detected in 100% of NPC types. In-depth studies of the cellular and molecular events leading to immunosuppression in NPC have revealed new therapeutic targets and diverse combinations that promise to benefit patients with highly refractory, advanced and metastatic NPC. This paper reviews the mechanisms by which NPC cells to circumvent immune surveillance and approaches being attempted to restore immunity. We integrate existing insights into anti-NPC immunity and molecular signaling pathways as well as targeting therapies in anticipation of broader applicability and effectiveness in advanced metastatic NPC.
The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma
Authors: Morra Francesco , Merolla Francesco , Damia Giovanna , Ricci Francesca , Varricchio Silvia , Ilardi Gennaro , Arenare Laura , Califano Daniela , Napolitano Virginia , Fruscio Robert , Melillo Rosa Marina , Palazzo Luca , Celetti Angela
Published: August 2022

Background

Treatment with PARP inhibitors (PARPi) is primarily effective against high-grade serous ovarian cancers (HGSOC) withBRCA1/2mutations or other deficiencies in homologous recombination (HR) repair mechanisms. However, resistance to PARPi frequently develops, mostly as a result ofBRCA1/2reversion mutations. The tumour suppressor CCDC6 is involved in HR repair by regulating the PP4c phosphatase activity on γH2AX. In this work, we reported that in ovarian cancer cells, a physical or functional loss of CCDC6 results synthetic lethal with the PARP-inhibitors drugs, by affecting the HR repair. We also unravelled a role for CCDC6 as predictive marker of PARPi sensitivity in ovarian cancer, and the impact of CCDC6 downregulation in overcoming PARPi resistance in these tumours.

Methods

A panel of HGSOC cell lines (eitherBRCA-wild type or mutant) were treated with PARPi after CCDC6 was attenuated by silencing or by inhibiting USP7, a CCDC6-deubiquitinating enzyme, and the effects on cell survival were assessed. At the cellular and molecular levels, the processes underlying the CCDC6-dependent modification of drugs’ sensitivity were examined. Patient-derived xenografts (PDXs) were immunostained for CCDC6, and the expression of the protein was analysed statistically after digital or visual means.

Results

HGSOC cells acquired PARPi sensitivity after CCDC6 depletion. Notably, CCDC6 downregulation restored the PARPi sensitivity in newly generated or spontaneously resistant cells containing either wild type- or mutant-BRCA2. When in an un-phosphorylated state, the CCDC6 residue threonine 427 is crucial for effective CCDC6-PP4 complex formation and PP4 sequestration, which maintains high γH2AX levels and effective HR. Remarkably, the PP4-dependent control of HR repair is influenced by the CCDC6 constitutively phosphorylated mutant T427D or by the CCDC6 loss, favouring PARPi sensitivity. As a result, the PP4 regulatory component PP4R3α showed to be essential for both the activity of the PP4 complex and the CCDC6 dependent PARPi sensitivity. It's interesting to note that immunohistochemistry revealed an intense CCDC6 protein staining in olaparib-resistant HGSOC cells and PDXs.

Conclusions

Our findings suggest that the physical loss or the functional impairment of CCDC6 enhances the PP4c complex activity, which causes BRCAness and PARPi sensitivity in HGSOC cells. Moreover, CCDC6 downregulation might overcome PARPi resistance in HGSOCs, thus supporting the potential of targeting CCDC6 by USP7 inhibitors to tackle PARPi resistance.
Evaluation of abdominal compression–decompression combined with chest compression CPR performed by a new device: Is the prognosis improved after this combination CPR technique?
Authors: Li Haishan , Wang Chao , Zhang Hongyuan , Cheng Fang , Zuo Shuang , Xu Liyou , Chen Hui , Wang Xiaodong
Published: August 2022

Introduction

This study was designed to compare the outcomes of standard cardiopulmonary resuscitation (STD-CPR) and combined chest compression and abdominal compression–decompression cardiopulmonary resuscitation (CO-CPR) with a new device following out-of-hospital cardiac arrest (OHCA). Moreover, we investigated whether patient prognosis improved with this combination treatment.

Methods

This trial was a single-centre, prospective, randomized trial, and a blinded assessment of the outcomes was performed. A total of 297 consecutive patients with OHCA were initially screened, and 278 were randomized to the STD-CPR group (n = 135) or the CO-CPR group (n = 143). We compared the proportions of patients who achieved a return of spontaneous circulation (ROSC), survived to hospital admission and survived to hospital discharge. In addition, we also performed the Kaplan–Meier analysis with a log-rank test at the end of the follow-up period to compare the survival curves of the two groups.

Results

The differences were not statistically significant in the proportion of patients who achieved ROSC [31/135 (23.0%) versus 35/143 (24.5%)] and survived to hospital admission [28/135 (20.7%) versus 33/143 (23.1%)] between the CO-CPR group and STD-CPR group. However, there was a significant difference in the proportion of patients who survived to hospital discharge [16/135 (11.9%) versus 7/143 (4.9%)] between the two groups. Nine patients (6.7%) in the CO-CPR group and 2 patients (1.4%) in the STD group showed good neurological outcomes according to the cerebral performance category (CPC) scale score, and the difference was statistically significant (P = 0.003). The Kaplan–Meier curves showed that the patients in the CO-CPR group achieved better survival benefits than those in the STD-CPR group at the end of the follow-up period (log-rankP = 0.007).

Conclusion

CO-CPR was more beneficial than STD-CPR in terms of survival benefits in patients who have suffered out-of-hospital cardiac arrest.

Trial registrationChinese Clinical Trial Registry, registered number:ChiCTR2100049581. Registered 30 July 2021- Retrospectively registered.http://www.medresman.org.cn/uc/index.aspx.
Open hemorrhoidectomy under local anesthesia versus saddle block in western Uganda: a study protocol for a prospective equivalence randomized, double-blind controlled trial
Authors: Sikakulya Franck Katembo , Ssebuufu Robinson , Okedi Xaviour Francis , Baluku Moris , Lule Herman , Kyamanywa Patrick
Published: August 2022

Background

While open hemorrhoidectomy under local anesthesia has been shown to be more cost-effective with shorter operation times and lower complication rates, local anesthesia is still not considered as a first-line technique in low-income countries like Uganda. The objective of this trial is to compare open hemorrhoidectomy using local anesthesia versus saddle block among patients with primary uncomplicated 3rd- or 4th-degree hemorrhoids in western Uganda.

Methods

The protocol for a prospective equivalence randomized, double-blind controlled trial was conducted among patients with primary uncomplicated 3rd- or 4th-degree hemorrhoids. Recruitment was started in December 2021 and is expected to end in May 2022. Consenting participants who require open hemorrhoidectomy indicated at Kampala International Teaching Hospital, Uganda, will be randomized into two groups of 29 patients per arm.

Discussion

The primary outcome of this study is to compare the occurrences of postoperative pain following open hemorrhoidectomy using the visual analog scale in an interval of 2, 4, and 6 h and 7 days postoperatively. Furthermore, the mean operative time from the induction of anesthesia to the end of the surgical procedure as well as the cost-effectiveness of the 2 techniques will be assessed in both groups. Open hemorrhoidectomy under local anesthesia has the potential to offer benefits to patients but most importantly expediting return to baseline and functional status, shorter hospital stay by meeting the faster discharge criteria, and reduction in costs associated with reduced length of stay and complications.

Trial registration

Pan African Clinical Trials Registry PACTR202110667430356. Registered on 8 October 2021
Abatacept downregulates Fcγ receptor I on circulating monocytes: a potential therapeutic mechanism in patients with rheumatoid arthritis
Authors: Fukue Ryosuke , Okazaki Yuka , Gono Takahisa , Kuwana Masataka
Published: August 2022

Background

Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc portion of immunoglobulin (Ig) G. The mechanism of action of abatacept in rheumatoid arthritis (RA) is believed to be competitive inhibition of T cell costimulation mediated by the binding of CD28 to CD80/CD86 on antigen-presenting cells, and recent studies have shown that abatacept induces reverse signaling in macrophages and osteoclast precursors in a T cell-independent manner. This study aimed to investigate the therapeutic effects of abatacept on circulating monocytes that contribute to RA pathogenesis.

Methods

Purified circulating monocytes derived from RA patients and controls were cultured in the absence or presence of abatacept or CD28-Ig for 24 h. The recovered cells were subjected to flow cytometry to evaluate the expression levels of cell surface molecules, and cytokines and chemokines in the culture supernatant were measured by multiplex bead arrays. The expression of candidate molecules was further examined by immunoblotting using total cellular extracts of the cultured monocytes. Finally, the effects of abatacept on cytokine production in monocytes stimulated with the immune complex of anti-citrullinated peptide antibodies (ACPAs) were examined.

Results

CD64/FcγRI was identified as a monocyte-derived molecule that was downregulated by abatacept but not CD28-Ig. This effect was observed in both RA patients and controls. The abatacept-induced downregulation of CD64/FcγRI was abolished by treatment with anti-CD86 antibodies but not anti-CD80 antibodies. Abatacept suppressed the production of interleukin (IL)-1β, IL-6, C-C motif chemokine ligand 2, and tumor necrosis factor-α in cultured monocytes stimulated with the ACPA immune complex.

Conclusions

The therapeutic effects of abatacept on RA are mediated, in part, by the downregulation of CD64/FcγRI on circulating monocytes via direct binding to CD86 and the suppression of immune complex-mediated inflammatory cytokine production.
Multimodality imaging of renal lymphoma and its mimics
Authors: Nguyen Trinh , Gupta Akshya , Bhatt Shweta
Published: August 2022

Lymphomatous involvement of the genitourinary system, particularly the kidneys, is commonly detected on autopsies; yet on conventional diagnostic imaging renal lymphoma is significantly underestimated and underreported, in part due to its variable imaging appearance and overlapping features with other conditions. We present a spectrum of typical and atypical appearances of renal lymphoma using multimodality imaging, while reviewing the roles of imaging in the detection, diagnosis, staging, and surveillance of patients with lymphoma. We also illustrate a breadth of benign and malignant entities with similar imaging features confounding the diagnosis of renal lymphoma, emphasizing the role of percutaneous image-guided biopsy. Understanding the spectrum of appearances of renal lymphoma and recognizing the overlapping entities will help radiologists improve diagnostic confidence and accuracy.
Cost-effectiveness of the implementation of [68Ga]Ga-PSMA-11 PET/CT at initial prostate cancer staging
Authors: van der Sar Esmée C. A. , Keusters Willem R. , van Kalmthout Ludwike W. M. , Braat Arthur J. A. T. , de Keizer Bart , Frederix Geert W. J. , Kooistra Anko , Lavalaye Jules , Lam Marnix G. E. H. , van Melick Harm H. E.
Published: August 2022

Background

Despite its high specificity, PSMA PET/CT has a moderate to low sensitivity of 40–50% for pelvic lymph node detection, implicating that a negative PSMA PET/CT cannot rule out lymph node metastases. This study investigates a strategy of implementing PSMA PET/CT for initial prostate cancer staging and treatment planning compared to conventional diagnostics. In this PSMA PET/CT strategy, a bilateral extended pelvic lymph node dissection (ePLND) is only performed in case of a negative PSMA PET/CT; in case of a positive scan treatment planning is solely based on PSMA PET/CT results.

Method

A decision table and lifetime state transition model were created. Quality-adjusted life years and health care costs were modelled over lifetime.

Results

The PSMA PET/CT strategy of treatment planning based on initial staging with [68Ga]Ga-PSMA-11 PET/CT results in cost-savings of €674 and a small loss in quality of life (QoL), 0.011 QALY per patient. The positive effect of [68Ga]Ga-PSMA-11 PET/CT was caused by abandoning both an ePLND and unnecessary treatment in iM1 patients, saving costs and resulting in higher QoL. The negative effect was caused by lower QoL and high costs in the false palliative state, due to pN1lim patients (≤ 4 pelvic lymph node metastases) being falsely diagnosed as iN1ext (> 4 pelvic lymph node metastases). These patients received subsequently palliative treatment instead of potentially curative therapy.

Conclusion

Initial staging and treatment planning based on [68Ga]Ga-PSMA-11 PET/CT saves cost but results in small QALY loss due to the rate of false positive findings.
Mesenchymal stromal cells pretreated with proinflammatory cytokines enhance skin wound healing via IL-6-dependent M2 polarization
Authors: Liu Chenyang , Xu Yan , Lu Yichi , Du Pan , Li Xiaoxiao , Wang Chengchun , Guo Peng , Diao Ling , Lu Guozhong
Published: August 2022

Background

Numerous studies have shown that mesenchymal stromal cells (MSCs) promote cutaneous wound healing via paracrine signaling. Our previous study found that the secretome of MSCs was significantly amplified by treatment with IFN-γ and TNF-α (IT). It has been known that macrophages are involved in the initiation and termination of inflammation, secretion of growth factors, phagocytosis, cell proliferation, and collagen deposition in wound, which is the key factor during wound healing. In this study, we aim to test whether the supernatant of MSCs pretreated with IT (S-IT MSCs) possesses a more pronounced effect on improving wound healing and describe the interplay between S-IT MSCs and macrophages as well as the potential mechanism in skin wound healing.

Methods

In the present study, we used a unique supernatant of MSCs from human umbilical cord-derived MSCs (UC-MSCs) pretreated with IT, designated S-IT MSCs, subcutaneously injected into a mice total skin excision. We evaluated the effect of S-IT MSCs on the speed and quality of wound repair via IT MSCs-derived IL-6-dependent M2 polarization in vivo by hematoxylin–eosin staining (H&E), immunohistochemistry (IHC), immunofluorescence (IF), Masson’s trichrome staining, Sirius red staining, quantitative real-time PCR (qPCR). In addition, the effect of S-IT MSCs on the polarization of macrophages toward M2 phenotype and the potential mechanism of it were also investigated in vitro by flow cytometry (FCM), enzyme-linked immunosorbent assay (ELISA), tube formation assay, and western blot analysis.

Results

Compared with control supernatant (S-MSCs), our H&E and IF results showed that S-IT MSCs were more effectively in promoting macrophages convert to the M2 phenotype and enhancing phagocytosis of M2 macrophages. Meanwhile, the results of tube formation assay, IHC, Masson’s trichrome staining, Sirius red staining showed that the abilities of M2 phenotype to promote vascularization and collagen deposition were significantly enhanced by S-IT MSCs-treated, thereby accelerating higher quality wound healing. Further, our ELISA, FCM, qPCR and western blot results showed that IL-6 was highly enriched in S-IT MSCs and acted as a key regulator to induce macrophages convert to the M2 phenotype through IL-6-dependent signaling pathways, ultimately achieving the above function of promoting wound repair.

Conclusions

These findings provide the first evidence that the S-IT MSCs is more capable of eliciting M2 polarization of macrophages via IL-6-dependent signaling pathways and accelerating wound healing, which may represent a new strategy for optimizing the therapeutic effect of MSCs on wound healing.
How the mechanical microenvironment of stem cell growth affects their differentiation: a review
Authors: Zhang Xiaofang , Zhang Sibo , Wang Tianlu
Published: August 2022

Stem cell differentiation is of great interest in medical research; however, specifically and effectively regulating stem cell differentiation is still a challenge. In addition to chemical factors, physical signals are an important component of the stem cell ecotone. The mechanical microenvironment of stem cells has a huge role in stem cell differentiation. Herein, we describe the knowledge accumulated to date on the mechanical environment in which stem cells exist, which consists of various factors, including the extracellular matrix and topology, substrate stiffness, shear stress, hydrostatic pressure, tension, and microgravity. We then detail the currently known signalling pathways that stem cells use to perceive the mechanical environment, including those involving nuclear factor-kB, the nicotinic acetylcholine receptor, the piezoelectric mechanosensitive ion channel, and hypoxia-inducible factor 1α. Using this information in clinical settings to treat diseases is the goal of this research, and we describe the progress that has been made. In this review, we examined the effects of mechanical factors in the stem cell growth microenvironment on stem cell differentiation, how mechanical signals are transmitted to and function within the cell, and the influence of mechanical factors on the use of stem cells in clinical applications.
Single-cell transcriptomics reveals the cell fate transitions of human dopaminergic progenitors derived from hESCs
Authors: Liang Lingmin , Tian Yao , Feng Lin , Wang Chaoqun , Feng Guihai , Stacey Glyn Nigel , Shyh-Chang Ng , Wu Jun , Hu Baoyang , Li Wei , Hao Jie , Wang Liu , Wang Yukai
Published: August 2022

Background

Midbrain dopaminergic (DA) progenitors derived from human pluripotent stem cells are considered to be a promising treatment for Parkinson’s disease (PD). However, the differentiation process produces undesired cell types, which influence the in vivo evaluation of DA cells. In this paper, we analyze the cell fate choice during differentiation and provide valuable information on cell preparation.

Methods

Human embryonic stem cells were differentiated into DA progenitors. We applied single-cell RNA sequencing (scRNA-seq) of the differentiation cells at different time points and investigated the gene expression profiles. Based on the differentially expressed genes between DA and non-DA cells, we investigated the impact of LGI1 (DA enriched) overexpression on DA differentiation and the enrichment effect of CD99 (non-DA enriched) sorting.

Results

Transcriptome analyses revealed the DA differentiation trajectory as well as non-DA populations and three key lineage branch points. Using genetic gain- and loss-of-function approaches, we found that overexpression of LGI1, which is specific to EN1+ early DA progenitors, can promote the generation of TH+ neurons. We also found that choroid plexus epithelial cells and DA progenitors are major components of the final product (day 25), and CD99 was a specific surface marker of choroid plexus epithelial cells. Sorting of CD99− cells eliminated major contaminant cells and improved the purity of DA progenitors.

Conclusions

Our study provides the single-cell transcriptional landscape of in vitro DA differentiation, which can guide future improvements in DA preparation and quality control for PD cell therapy.
Biological activity reduction and mitochondrial and lysosomal dysfunction of mesenchymal stem cells aging in vitro
Authors: Zhang Ge , Wang Yuli , Lin Jianhua , Wang Bo , Mohsin Ali , Cheng Zhimin , Hao Weijie , Gao Wei-Qiang , Xu Huiming , Guo Meijin
Published: August 2022

Background

Mesenchymal stem cells (MSCs) have been extensively used for the treatment of various diseases in preclinical and clinical trials. In vitro propagation is needed to attain enough cells for clinical use. However, cell aging and viability reduction caused by long-time culture have not been thoroughly investigated, especially for the function of mitochondria and lysosomes. Therefore, this study was designed to detect mitochondrial and lysosomal activity, morphological and functional changes in human umbilical cord MSCs (UMSCs) after long-time culture.

Methods

First, we examined cell activities, including proliferation and immigration ability, differentiation potential, and immunosuppressive capacity of UMSCs at an early and late passages as P4 (named UMSC-P4) and P9 (named UMSC-P9), respectively. Then, we compared the mitochondrial morphology of UMSC-P4 and UMSC-P9 using the electronic microscope and MitoTracker Red dyes. Furthermore, we investigated mitochondrial function, including mitochondrial membrane potential, antioxidative ability, apoptosis, and ferroptosis detected by respective probe. Cell energy metabolism was tested by mass spectrometry. In addition, we compared the lysosomal morphology of UMSC-P4 and UMSC-P9 by electronic microscope and lysoTracker Red dyes. Finally, the transcriptome sequence was performed to analyze the total gene expression of these cells.

Results

It was found that UMSC-P9 exhibited a reduced biological activity and showed an impaired mitochondrial morphology with disordered structure,  reduced mitochondrial crista, and mitochondrial fragments. They also displayed decreased mitochondrial membrane potential, antioxidative ability, tricarboxylic acid cycle activity and energy production. At the same time, apoptosis and ferroptosis were increased. In addition, UMSC-P9, relative to UMSC-P4, showed undegraded materials in their lysosomes, the enhancement in lysosomal membrane permeability, the reduction in autophagy and phagocytosis. Moreover, transcriptome sequence analysis also revealed a reduction of cell function, metabolism, mitochondrial biogenesis, DNA replication and repair, and an increase of gene expression related to cell senescence, cancer, diseases, and infection in UMSC-P9.

Conclusion

This study indicates that in vitro long-time culturing of MSCs can cause mitochondrial and lysosomal dysfunction, probably contributing to the decline of cell activity and cell aging. Therefore, the morphology and function of mitochondria and lysosomes can be regarded as two important parameters to monitor cell viability, and they can also serve as two important indicators for optimizing in vitro culture conditions.
Using Jupyter Notebooks for re-training machine learning models
Authors: Smajić Aljoša , Grandits Melanie , Ecker Gerhard F.
Published: August 2022

Machine learning (ML) models require an extensive, user-driven selection of molecular descriptors in order to learn from chemical structures to predict actives and inactives with a high reliability. In addition, privacy concerns often restrict the access to sufficient data, leading to models with a narrow chemical space. Therefore, we propose a framework of re-trainable models that can be transferred from one local instance to another, and further allow a less extensive descriptor selection. The models are shared via a Jupyter Notebook, allowing the evaluation and implementation of a broader chemical space by keeping most of the tunable parameters pre-defined. This enables the models to be updated in a decentralized, facile, and fast manner. Herein, the method was evaluated with six transporter datasets (BCRP, BSEP, OATP1B1, OATP1B3, MRP3, P-gp), which revealed the general applicability of this approach.
OpenVar: functional annotation of variants in non-canonical open reading frames
Authors: Brunet Marie A. , Leblanc Sébastien , Roucou Xavier
Published: August 2022

Background

Recent technological advances have revealed thousands of functional open reading frames (ORF) that have eluded reference genome annotations. These overlooked ORFs are found throughout the genome, in any reading frame of transcripts, mature or non-coding, and can overlap annotated ORFs in a different reading frame. The exploration of these novel ORFs in genomic datasets and of their role in genetic traits is hindered by a lack of software.

Results

Here, we present OpenVar, a genomic variant annotator that mends that gap and fosters meaningful discoveries. To illustrate the potential of OpenVar, we analysed all variants within SynMicDB, a database of cancer-associated synonymous mutations. By including non-canonical ORFs in the analysis, OpenVar yields a 33.6-fold, 13.8-fold and 8.3-fold increase in high impact variants over Annovar, SnpEff and VEP respectively. We highlighted an overlapping non-canonical ORF in the HEY2 gene where variants significantly clustered.

Conclusions

OpenVar integrates non-canonical ORFs in the analysis of genomic variants, unveiling new research avenues to better understand the genotype–phenotype relationships.
Kinetics of capillary refill time after fluid challenge
Authors: Raia Lisa , Gabarre Paul , Bonny Vincent , Urbina Tomas , Missri Louai , Boelle Pierre-Yves , Baudel Jean-Luc , Guidet Bertrand , Maury Eric , Joffre Jeremie , Ait-Oufella Hafid
Published: August 2022

Background

Capillary refill time (CRT) is a valuable tool for triage and to guide resuscitation. However, little is known about CRT kinetics after fluid infusion.

Methods

We conducted a prospective observational study in a tertiary teaching hospital. First, we analyzed the intra-observer variability of CRT. Next, we monitored fingertip CRT in sepsis patients during volume expansion within the first 24 h of ICU admission. Fingertip CRT was measured every 2 min during 30 min following crystalloid infusion (500 mL over 15 min).

Results

First, the accuracy of repetitive fingertip CRT measurements was evaluated on 40 critically ill patients. Reproducibility was excellent, with an intra-class correlation coefficient of 99.5% (CI 95% [99.3, 99.8]). A CRT variation larger than 0.2 s was considered as significant. Next, variations of CRT during volume expansion were evaluated on 29 septic patients; median SOFA score was 7 [5–9], median SAPS II was 57 [45–72], and ICU mortality rate was 24%. Twenty-three patients were responders as defined by a CRT decrease  > 0.2 s at 30 min after volume expansion, and 6 were non-responders. Among responders, we observed that fingertip CRT quickly improved with a significant decrease at 6–8 min after start of crystalloid infusion, the maximal improvement being observed after 10–12 min (−0.7 [−0.3;−0.9] s) and maintained at 30 min. CRT variations significantly correlated with baseline CRT measurements (R = 0.39, P = 0.05).

Conclusions

CRT quickly improved during volume expansion with a significant decrease 6–8 min after start of fluid infusion and a maximal drop at 10–12 min.
Thoracolumbar retrolaminar block in seven dogs undergoing spinal surgery
Authors: Pentsou Kyratsoula , Huuskonen Vilhelmiina
Published: August 2022

Background

Thoracolumbar intervertebral disc extrusion is a common neurologic complaint in dogs and is associated with debilitating pain that requires careful analgesic management to avoid the transition to a chronic pain state. Recently, there has been an increased effort to incorporate regional anaesthetic techniques whenever possible, both for perioperative analgesia management and for prevention of chronic pain. A novel regional anaesthetic technique named retrolaminar block is a fascial plane block where the local anaesthetic is injected directly on top of the dorsal aspect of the vertebral lamina, in the fascial plane between the lamina and the epaxial muscles. The technique was recently described in humans and it is claimed to provide analgesia in patients undergoing thoracic and lumbar procedures. To the authors’ knowledge, the retrolaminar block has not been previously reported in live dogs.

Case presentation

Seven dogs presented to our hospital for suspected thoracolumbar intervertebral disc extrusion were anaesthetised using an anaesthetic premedication and induction protocol tailored for each individual animal. Once the suspected diagnosis was confirmed, all seven dogs were placed in sternal recumbency, and the target thoracolumbar vertebral spinous process was identified with palpation. A unilateral retrolaminar block was performed in all dogs with 2 mg/kg of 0.25% bupivacaine. Physiologic parameters, as well as responses to nociceptive stimuli, were monitored throughout the anaesthetic event.

Intraoperatively, one dog required a bolus of fentanyl to control nociceptive stimulation while the epaxial muscles were retracted. No further intraoperative rescue analgesia was required in any of the cases. The postoperative pain was assessed using the Short Form of Glasgow Composite Measure Pain Scale for dogs every four hours for the duration of the dogs’ hospitalization. The retrolaminar block reduced the intraoperative requirement for systemic opioids and other adjunct analgesic agents and all dogs were comfortable throughout their hospitalization and up until the time of their discharge.

Conclusions

This case report presents the performance of the retrolaminar block technique as part of multimodal analgesia management in seven dogs undergoing thoracolumbar spinal surgery.
Impact of CCI on performance analysis of downlink satellite-terrestrial systems: outage probability and ergodic capacity perspective
Authors: Nguyen Nhat-Tien , Nguyen Hong-Nhu , Le Anh-Tu , Nguyen Nhan Duc , Do Dinh-Thuan , Voznak Miroslav
Published: August 2022

The evolution of non-orthogonal multiple access (NOMA) has raised many opportunities for massive connectivity with less latency in signal transmissions at great distances. We aim to integrate NOMA with a satellite communications network to evaluate system performance under the impacts of imperfect channel state information and co-channel interference from nearby systems. In our considered system, two users perform downlink communications under power-domain NOMA. We analyzed the performance of this system with two modes of shadowing effect: heavy shadowing and average shadowing. The detailed performance was analyzed in terms of the outage probability and ergodic capacity of the system. We derive closed-form expressions and performed a numerical analysis. We discover that the performance of two destinations depends on the strength of the transmit power at the satellite. However, floor outage occurs because the system depends on other parameters, such as satellite link modes, noise levels, and the number of interference sources. To verify the authenticity of the derived closed-form expressions, we also perform Monte-Carlo simulations.
Effects of aerobic, resistance, and combined training on endothelial function and arterial stiffness in older adults: study protocol for a systematic review and meta-analysis
Authors: da Silva Raphael S. N. , da Silva Diego S. , Waclawovsky Gustavo , Schaun Maximiliano I.
Published: August 2022

Introduction

Aging is an independent risk factor for cardiovascular events. It promotes vascular dysfunction which is associated with risk factors for cardiovascular diseases (CVDs). Exercise can modulate vascular function parameters, but little is known about the effects of different modalities of training (aerobic, resistance, and combined) on endothelial function and arterial stiffness in older adults.

Methods

This systematic review study will include randomized controlled trials (RCTs) selected from the electronic databases MEDLINE (PubMed), Cochrane, LILACS, EMBASE, and Web of Science. We will follow the PRISMA guidelines and PICOS framework. Studies involving both male and female older adults (≥60 years old) with or without comorbidities undergoing aerobic, resistance, and/or combined training compared to a control group (no exercise) will be eligible. We will use the Cochrane Risk of Bias 2 (RoB 2) tool to evaluate the quality of individual studies and GRADE to assess the strength of evidence. Statistical analyses will be conducted with RStudio for Windows (v1.3.959) using R package meta.

Discussion

A systematic review and meta-analysis involving data from studies of older adults would deepen our understanding of vascular adaptations to exercise training in this population. It could provide new insights into how health providers can improve patient management and prevention of cardiovascular events in older adults.

Systematic review registration

PROSPERO 42021275451
Primary stent implantation for bilateral spontaneous cervical ICA dissections with hypoperfusion after 72 h from onset: a case report
Authors: Chen Yijie , Zhang Ningyuan , Chen Yigang , Zheng Xu , Jin Xing , Zhang Jinhua
Published: August 2022

Background

Spontaneous cervical internal carotid artery dissection (cICAD) is a common cause of stroke in young adults. Endovascular therapy is an indispensable treatment for cICAD in some cases, but it faces great challenges.

Case presentation

A bilateral spontaneous cICADs with hypoperfusion-related AIS after 72 h from the onset was presented herein. The patient responded well to primary Solitaire stent detachment at the critical flow-limiting site.

Conclusions

Primary stent implantation at the critical flow-limiting site rather than covering the entire dissection may be a therapeutic option in spontaneous cICAD complicated with cerebral hypoperfusion. The Solitaire stent may be a good choice at the acute and subacute stages of cICAD.
Modeling of corona virus and its application in confocal microscopy
Authors: Hamed Abdallah Mohamed
Published: August 2022

Background

The proposal of spiky apertures showed resolution improvement compared with the circular apertures. Three models of corona virus are given. The 1st model consists of uniform circular aperture provided with 8 spikes while the 2nd model has 16 spikes for the same uniform circular aperture. The 3rd model has circular linear distribution with 8 spikes.

Results

The Normalized Point Spread Function (PSF) or the impulse response is computed for the three models using fast Fourier transform technique. In addition, the autocorrelation function corresponding to these apertures is calculated and compared with that corresponding to the ordinary circular and conic apertures. Coronavirus image is used as an object in the formation of images using confocal scanning laser microscope provided with suggested models. The fabricated MATLAB code is used to compute and plot all images and line plots.

Conclusions

The PSF plots are computed from Eqs. (8) and (12) using MATLAB code showing narrower cutoff in the PSF for spiky aperture compared with that corresponding to the uniform circular aperture and modulated linear and quadratic apertures. Hence, I reached resolution improvement in the case of spiky aperture.
Prevalence of minor physical anomalies in children with autism spectrum disorder reporting to a tertiary care hospital Lahore-Pakistan
Authors: RABIA ANSA , Mahmood Saqib , Maqbool Shazia
Published: August 2022

Objective: To assess the frequency and type of minor physical anomalies (MPAs) in subjects with autism spectrum disorder (ASD).

Methods: This descriptive cross-sectional study was conducted from September, 2016 to October, 2020. Using purposive sampling technique, 147 subjects with ASD were recruited from Children’s Hospital and Institute of Child Health (CH & ICH) Lahore, with a confirmed clinical diagnosis by developmental pediatrician, using Diagnostic and Statistical Manual of Mental Disorders (DSM-V). For morphology assessment, 12 body regions of ASD subjects were examined using Autism Dysmorphology Measure (ADM) manual after taking informed consent. Physical measurements (height, weight, head circumference, ear length, philtrum, hand, finger and foot length) were also taken and were compared with the available standard charts.

Results: A total of 381 dysmorphologies were identified in 131 (89.1%) ASD subjects whereas 16 subjects had no dysmorphology at all. Microcephaly was exhibited by 14 (9.5%) subjects, out of which 13 had variable number of dysmorphologies while one had no dysmorphology in other body regions. Out of 131 subjects exhibiting dysmorphologies, there were 108 male and 23 female subjects, with a M:F ratio 4.7:1 whereas microcephaly was observed in 12 male and two female subjects, with a M:F ratio 6:1. The highest number of dysmorphic features were noted in the ears, followed by feet and hair growth pattern.

Conclusions: MPAs associated with ASD are frequently found in, but are clearly not limited to, the head or facial region.

doi: https://doi.org/10.12669/pjms.38.7.6639

How to cite this:Rabia A, Mahmood S, Maqbool S. Prevalence of minor physical anomalies in children with autism spectrum disorder reporting to a tertiary care hospital Lahore-Pakistan. Pak J Med Sci. 2022;38(7):---------. doi: https://doi.org/10.12669/pjms.38.7.6639

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Modulators of CFTR protein function in the treatment of cystic fibrosis - a literature review
Authors: Chojęta Dariusz , Mierzwa Monika , Wróblewski Hubert , Zimna Aleksandra , Zygmunt Ewelina , Kozłowska Anna , Łysiak Katarzyna
Published: August 2022

Cystic fibrosis (CF) is a multi-system genetic disease with an autosomal recessive inheritance mechanism. The breakthroughs in the therapy of patients with CF turned out to be modulators of CFTR protein function. These small-molecule substances, influencing the basic pathogenetic defect, became a model example of precise targeted therapy, thus showing a significant advantage over symptomatic treatment. For modulators of CFTR protein function, numerous therapeutic benefits have been demonstrated with an acceptable safety profile - improved lung function and reduced frequency of pulmonary exacerbations, reduced hospitalization rate, and disease-related improvement in quality of life. The use of these drugs changes the perception of CF from a fatal pediatric disease significantly shortening the life expectancy of patients into a chronic disease in young adults. The subject of further research interest is the development of alternative therapeutic strategies based on new modulators and gene therapy. The publication is a review of the literature and summarizes the current scientific reports on the effectiveness of the use of modulators of CFTR protein function in the treatment of cystic fibrosis.