bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI Prognostic Factors in Multiple Sclerosis, Neuromyelitis Optica Spectrum Disorder, and Myelin Oligodendrocyte Antibody Disease
Authors: Cortese Rosa , Giorgio Antonio , Severa Gianmarco , De Stefano Nicola
Published: November 2021

Several MRI measures have been developed in the last couple of decades, providing a number of imaging biomarkers that can capture the complexity of the pathological processes occurring in multiple sclerosis (MS) brains. Such measures have provided more specific information on the heterogeneous pathologic substrate of MS-related tissue damage, being able to detect, and quantify the evolution of structural changes both within and outside focal lesions. In clinical practise, MRI is increasingly used in the MS field to help to assess patients during follow-up, guide treatment decisions and, importantly, predict the disease course. Moreover, the process of identifying new effective therapies for MS patients has been supported by the use of serial MRI examinations in order to sensitively detect the sub-clinical effects of disease-modifying treatments at an earlier stage than is possible using measures based on clinical disease activity. However, despite this has been largely demonstrated in the relapsing forms of MS, a poor understanding of the underlying pathologic mechanisms leading to either progression or tissue repair in MS as well as the lack of sensitive outcome measures for the progressive phases of the disease and repair therapies makes the development of effective treatments a big challenge. Finally, the role of MRI biomarkers in the monitoring of disease activity and the assessment of treatment response in other inflammatory demyelinating diseases of the central nervous system, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte antibody disease (MOGAD) is still marginal, and advanced MRI studies have shown conflicting results. Against this background, this review focused on recently developed MRI measures, which were sensitive to pathological changes, and that could best contribute in the future to provide prognostic information and monitor patients with MS and other inflammatory demyelinating diseases, in particular, NMOSD and MOGAD.
Trihydroxyethyl Rutin Provides Neuroprotection in Rats With Cervical Spinal Cord Hemi-Contusion
Authors: Liu Yapu , Liu Qi , Yang Zhou , Li Rong , Huang Zhiping , Huang Zucheng , Liu Junhao , Wu Xiuhua , Lin Junyu , Wu Xiaoliang , Zhu Qingan
Published: November 2021

Objective: To investigate the neuroprotective effects of trihydroxyethyl rutin in rats with cervical spinal cord hemi-contusion.

Methods: Adult male Sprague–Dawley rats were subjected to hemi-contusion at a stroke depth of 1.2 mm, and then intraperitoneally injected with 50 or 100 mg/kg trihydroxyethyl rutin per day for 12 weeks (T50 and T100 groups, respectively). Changes in somatosensory evoked potentials (SEPs), motor evoked potentials (MEPs), and behavior were continuously monitored. At 12 weeks post-injury, immunohistochemical staining was performed to assess changes in cervical spinal cord microvascular morphology. Magnetic resonance imaging (MRI) scans were performed to examine end-stage injury in the cervical spinal cord, and Eriochrome cyanine-stained slices of spinal cord tissue were evaluated for injury.

Results: There were no significant differences in biomechanical parameters among the spinal cord injury, T50 and T100 rat groups. At 3 days-post-injury, there was a significant decrease in grip strength. At 12 weeks post-injury, grip strength recovery was significantly better in the T50 and T100 groups than in the injury group. Compared with the injury group, the total limb placement frequency was significantly higher in the T50 group at 2, 4, 6, 10, and 12 weeks post-injury and in the T100 group at 2, 6, 8, and 10 weeks post-injury. Ipsilateral SEPs and MEPs were dynamic, increasing in latency and decreasing in amplitude in the injury compared with sham group. MRI scanning demonstrated that the coronal, sagittal, and transversal lesion areas were smaller in the T50 and T100 groups than in the injury group. Microvascular density showed a greater reduction in the injury group compared with the T50 and T100 groups. Eriochrome cyanine staining showed that the ipsilateral side, residual parenchyma, and gray matter areas were larger in the T50 and T100 groups than in the injury group.

Conclusion: Trihydroxyethyl rutin exhibits robust neuroprotective effects, improving limb motor function and nerve electrophysiological parameters after spinal cord injury, maintaining microvascular density, and reducing the area of injury and degree of demyelination.
It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
Authors: Wakasugi Noritaka , Hanakawa Takashi
Published: November 2021

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.
The Use of High-Intensity Focused Ultrasound (HIFU) Plus 150mg Bicalutamide as First Line Salvage Therapy for Local Recurrent Prostate Cancer
Authors: Cao Jian-zhou , Su Rui , Pan Jin-feng , Yan Ze-jun , Ma Qi
Published: November 2021

Patients with localized prostate cancer (PCa) are often treated with radical prostatectomy (RP). However, more than 30% of such patients have high risk of recurrence. Salvage radiotherapy (SRT), androgen deprivation therapy (ADT) and combination of radiotherapy and ADT are the standard care for recurrent PCa. Recently, high intensity focused ultrasound (HIFU) has gradually applied in the treatment of recurrent PCa. Here, we proposed a hypothesis that combined HIFU and bicalutamide 150mg as first line salvage therapy to treat patients with local recurrent PCa with visible lesions due to the following advantages: (1) HIFU is effective in reducing local tumor load, and bicalutamide 150mg is a feasible and safety option to combine with HIFU. (2) Compared with radiotherapy, HIFU plus 150mg bicalutamide is minimal invasiveness with fewer adverse effects and better quality of life(QOL); (3) Radiotherapy can be preserved as the second-line salvage method in the cases who are failure to HIFU and 150mg bicalutamide combination. More clinical trials are warranted to confirm this hypothesis in treatment with recurrent PCa.
Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma
Authors: Cui Lixuan , Yan Liang , Guan Xiaoya , Dong Bin , Zhao Min , Lv Ang , Liu Daoning , Wang Zhen , Liu Faqiang , Wu Jianhui , Tian Xiuyun , Hao Chunyi
Published: November 2021

Background

Primary retroperitoneal liposarcomas (RLPSs) are rare heterogeneous tumors for which there are few effective therapies. Certain anti-angiogenic tyrosine kinase inhibitors have demonstrated efficacy against various solid tumors. The aims of this study were to investigate the effect of Apatinib against retroperitoneal liposarcoma cells and its underlying mechanism and to explore the anti-tumor efficacy of a combination of Apatinib and Epirubicin.

Methods

CD34 immunohistochemical staining was used to measure microvessel density (MVD) in 89 retroperitoneal liposarcoma tissues. We used CCK-8 cell proliferation, clone formation, Transwell migration, invasion assays and flow cytometry to evaluate the effects of Apatinib alone and the combination of Apatinib and Epirubicin on liposarcoma cells. High-throughput RNA sequencing and western-blotting was used to identify key differentially expressed genes (DEGs) in SW872 cell line after application of Apatinib. Murine patient-derived tumor xenograft (PDX) was established to assess the efficacy and safety of Apatinib monotherapy and the combination of Apatinib and Epirubicin in RLPS.

Results

The microvessel density (MVD) varied widely among retroperitoneal liposarcoma tissues. Compared with the low-MVD group, the high-MVD group had poorer overall survival. Apatinib inhibited the liposarcoma cell proliferation, invasion and migration, increased the proportion of apoptosis, and induced G1 phase arrest. In addition, the combination of Apatinib and Epirubicin enhanced the foregoing inhibitory effects. High-throughput RNA sequencing showed that Apatinib downregulated the expression of TYMS and RRM2. Western blotting verified that Apatinib downregulated the TYMS/STAT3/PD-L1 pathway and inhibited liposarcoma proliferation by suppressing the RRM2/PI3K/AKT/mTOR pathway. In the murine PDX model of retroperitoneal liposarcoma, Apatinib and its combination with Epirubicin significantly inhibited microvessel formation and repressed tumor growth safely and effectively.

Conclusions

Apatinib and its combination with Epirubicin showed strong efficacy against liposarcoma both in vitro and in vivo. Apatinib might inhibit liposarcoma cell proliferation through the RRM2/PI3K/AKT/mTOR signaling pathway and downregulate PD-L1 via the TYMS/STAT3 signaling pathway.
Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors
Authors: Imodoye Sikiru O. , Adedokun Kamoru A. , Muhammed Abdurrasheed Ola , Bello Ibrahim O. , Muhibi Musa A. , Oduola Taofeeq , Oyenike Musiliu A.
Published: November 2021

Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs via a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but also resistant to several cytotoxic agents during treatment, owing to their anatomically diffuse localisation in the body system. As the quest to find an effective method of addressing metastasis in cancer intervention heightens, understanding the molecular interplay involving the signalling pathways, downstream effectors, and their interactions with the EMT would be an important requisite while the challenges of metastasis continue to punctuate. Unfortunately, the molecular underpinnings that govern this process remain to be completely illuminated. However, it is becoming increasingly clear that EMT, which initiates every episode of metastasis, significantly requires some master regulators called EMT transcription factors (EMT-TFs). Thus, this review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation. In addition, it discusses the interaction of various signalling molecules and effector proteins with these factors. It also provides insight into promising therapeutic targets that may inhibit the metastatic process to overcome the limitation of “undruggable” cancer targets in therapeutic design and upturn the current spate of drug resistance. More so, it extends the discussion from the basic understanding of the EMT binary switch model, and ultimately unveiling the E/M cellular plasticity along a phenotypic spectrum via multiple trans-differentiations. It wraps up on how this knowledge update shapes the diagnostic and clinical approaches that may demand a potential shift in investigative paradigm using novel technologies such as single-cell analyses to improve overall patient survival.
The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment
Authors: Jia Wentao , Liang Shufang , Cheng Binbin , Ling Changquan
Published: November 2021

Invasion and metastasis are the main reasons for the high mortality of liver cancer, which involve the interaction of tumor stromal cells and malignant cells. Cancer-associated fibroblasts (CAFs) are one of the major constituents of tumor stromal cells affecting tumor growth, invasion, and metastasis. The heterogeneous properties and sources of CAFs make both tumor-supporting and tumor-suppression effects possible. The mechanisms for CAFs in supporting hepatocellular carcinoma (HCC) progression can be categorized into upregulated aggressiveness and stemness, transformed metabolism toward glycolysis and glutamine reductive carboxylation, polarized tumor immunity toward immune escape of HCC cells, and increased angiogenesis. The tumor-suppressive effect of fibroblasts highlights the functional heterogenicity of CAF populations and provides new insights into tumor–stromal interplay mechanisms. In this review, we introduced several key inflammatory signaling pathways in the transformation of CAFs from normal stromal cells and the heterogeneous biofunctions of activated CAFs. In view of the pleiotropic regulation properties of traditional Chinese medicine (TCM) and heterogeneous effects of CAFs, we also introduced the application and values of TCM in the treatment of HCC through targeting CAFs.
Mitochondria-Shaping Proteins and Chemotherapy
Authors: Xie Longlong , Zhou Tiansheng , Xie Yujun , Bode Ann M. , Cao Ya
Published: November 2021

The emergence, in recent decades, of an entirely new area of “Mitochondrial dynamics”, which consists principally of fission and fusion, reflects the recognition that mitochondria play a significant role in human tumorigenesis and response to therapeutics. Proteins that determine mitochondrial dynamics are referred to as “shaping proteins”. Marked heterogeneity has been observed in the response of tumor cells to chemotherapy, which is associated with imbalances in mitochondrial dynamics and function leading to adaptive and acquired resistance to chemotherapeutic agents. Therefore, targeting mitochondria-shaping proteins may prove to be a promising approach to treat chemotherapy resistant cancers. In this review, we summarize the alterations of mitochondrial dynamics in chemotherapeutic processing and the antitumor mechanisms by which chemotherapy drugs synergize with mitochondria-shaping proteins. These might shed light on new biomarkers for better prediction of cancer chemosensitivity and contribute to the exploitation of potent therapeutic strategies for the clinical treatment of cancers.
Downstaging Conversion Therapy in Patients With Initially Unresectable Advanced Hepatocellular Carcinoma: An Overview
Authors: Sun Hui-Chuan , Zhu Xiao-Dong
Published: November 2021

The high mortality rate associated with hepatocellular carcinoma (HCC) is partly due to the high proportion of patients who present with advanced stage disease at diagnosis, for whom there are limited treatment options. For selected patients with initially unresectable HCC, locoregional and/or systemic treatments can result in tumor downstaging and consequently provide opportunities for surgical intervention and the potential for long-term survival. Therefore, the key aim of ‘conversion therapy’ is to reduce tumor burden so that patients become amenable to surgical resection. Various therapies have been investigated as candidates for downstaging patients with potentially resectable HCC including transarterial chemoembolization, transarterial radioembolization with yttrium-90 microspheres, radiotherapy, systemic therapies and combination or multimodality treatment approaches. However, downstaging conversion therapy remains controversial and there are several challenges such as defining the criteria used to identify the population of patients who are ‘potentially resectable’, the criteria used to define successful downstaging, and the optimum treatment approach to maximize the success of downstaging therapy. In this review article, we summarize clinical experience and evidence of downstaging conversion treatment in patients identified as having ‘potentially resectable’ HCC.
A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma
Authors: Yang Hua , Zhang Mu-Zi-he , Sun Hui-wei , Chai Yan-tao , Li Xiaojuan , Jiang Qiyu , Hou Jun
Published: November 2021

BAY-876 is an effective antagonist of the Glucose transporter type 1 (GLUT1) receptor, a mediator of aerobic glycolysis, a biological process considered a hallmark of hepatocellular carcinoma (HCC) together with cell proliferation, drug-resistance, and metastasis. However, the clinical application of BAY-876 has faced many challenges. In the presence study, we describe the formulation of a novel microcrystalline BAY-876 formulation. A series of HCC tumor models were established to determine not only the sustained release of microcrystalline BAY-876, but also its long-acting antitumor activity. The clinical role of BAY-876 was confirmed by the increased expression of GLUT1, which was associated with the worse prognosis among advanced HCC patients. A single dose of injection of microcrystalline BAY-876 directly in the HCC tissue achieved sustained localized levels of Bay-876. Moreover, the single injection of microcrystalline BAY-876 in HCC tissues not only inhibited glucose uptake and prolonged proliferation of HCC cells, but also inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors. Thus, the microcrystalline BAY-876 described in this study can directly achieve promising localized effects, given its limited diffusion to other tissues, thereby reducing the occurrence of potential side effects, and providing an additional option for advanced HCC treatment.
Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research
Authors: Cogels Morgane M. , Rouas Redouane , Ghanem Ghanem E. , Martinive Philippe , Awada Ahmad , Van Gestel Dirk , Krayem Mohammad
Published: November 2021

Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”.
Did the National Lockdown in Saudi Arabia Reduce Lower Respiratory Illnesses in Children?
Authors: Alharbi Nasser S. , Alnasser Yossef , Alenizi Ahmed S. , Alanazi Alnashmi S. , Alharbi Abeer H. , AlQurashi Faisal O. , Nafisah Ibrahim , Yousef Abdullah A.
Published: November 2021

Objectives: This study aims to explore the effect of lockdown and early precautionary measures implemented in Saudi Arabia on number of pediatric hospitalizations due to lower respiratory illnesses (bronchiolitis, asthma, and pneumonia).

Methods: This is a retrospective cross-sectional study aims to review patients from four major hospitals in Saudi Arabia. All pediatric hospitalizations secondary to asthma, bronchiolitis, and pneumonia during the months of the lockdown (March, April, and May) in 2020 were documented. Then, they were compared to the previous 2 years. Variables like number of hospitalizations, oxygen requirement, mechanical ventilation, admission to the intensive care unit (ICU), length of stay, and results of viral studies were collected.

Results: We included 1,003 children from four different centers. Males were slightly higher than females (55.8% vs. 44.2%). Total number of hospitalizations in 2020 was 201, significantly lower than 399 and 403 hospitalizations in 2019 and 2018, respectively (P < 0.01). The major drop happened on the months of April and May. Although bronchiolitis hospitalizations' dropped by more than half in 2020 compared to the previous 2 years, it was not statistically significant (P = 0.07). But, asthma hospitalizations were significantly less in 2020 compared to the previous 2 years (49–65% reduction, P = 0.003). Number of pneumonia cases were lowered in 2020 compared to the previous 2 years. However, proportion of pneumonia diagnosis to total hospitalizations increased in 2020 (55% compared to 50% and 35%). There was a surge of viral testing during a period of uncertainty in the early phase of the pandemic. This total reduction in hospitalization was not associated with higher oxygen requirements, mechanical ventilation, ICU admissions or longer hospital stay.

Conclusions: Lockdown and precautionary measures executed during the early phase of COVID-19 pandemic helped decrease the number of hospitalizations due to lower respiratory illnesses in Saudi Arabia. Reduction in hospitalizations seems less likely to be secondary to hospital avoidance or delayed presentations as number of ICU admission and oxygen requirements did not increase. The post pandemic pattern of respiratory illnesses among children needs further research.
Diagnostic Errors Are Common in Acute Pediatric Respiratory Disease: A Prospective, Single-Blinded Multicenter Diagnostic Accuracy Study in Australian Emergency Departments
Authors: Porter Paul , Brisbane Joanna , Tan Jamie , Bear Natasha , Choveaux Jennifer , Della Phillip , Abeyratne Udantha
Published: November 2021

Background: Diagnostic errors are a global health priority and a common cause of preventable harm. There is limited data available for the prevalence of misdiagnosis in pediatric acute-care settings. Respiratory illnesses, which are particularly challenging to diagnose, are the most frequent reason for presentation to pediatric emergency departments.

Objective: To evaluate the diagnostic accuracy of emergency department clinicians in diagnosing acute childhood respiratory diseases, as compared with expert panel consensus (reference standard).

Methods: Prospective, multicenter, single-blinded, diagnostic accuracy study in two well-resourced pediatric emergency departments in a large Australian city. Between September 2016 and August 2018, a convenience sample of children aged 29 days to 12 years who presented with respiratory symptoms was enrolled. The emergency department discharge diagnoses were reported by clinicians based upon standard clinical diagnostic definitions. These diagnoses were compared against consensus diagnoses given by an expert panel of pediatric specialists using standardized disease definitions after they reviewed all medical records.

Results: For 620 participants, the sensitivity and specificity (%, [95% CI]) of the emergency department compared with the expert panel diagnoses were generally poor: isolated upper respiratory tract disease (64.9 [54.6, 74.4], 91.0 [88.2, 93.3]), croup (76.8 [66.2, 85.4], 97.9 [96.2, 98.9]), lower respiratory tract disease (86.6 [83.1, 89.6], 92.9 [87.6, 96.4]), bronchiolitis (66.9 [58.6, 74.5], 94.3 [80.8, 99.3]), asthma/reactive airway disease (91.0 [85.8, 94.8], 93.0 [90.1, 95.3]), clinical pneumonia (63·9 [50.6, 75·8], 95·0 [92·8, 96·7]), focal (consolidative) pneumonia (54·8 [38·7, 70·2], 86.2 [79.3, 91.5]). Only 59% of chest x-rays with consolidation were correctly identified. Between 6.9 and 14.5% of children were inappropriately prescribed based on their eventual diagnosis.

Conclusion: In well-resourced emergency departments, we have identified a previously unrecognized high diagnostic error rate for acute childhood respiratory disorders, particularly in pneumonia and bronchiolitis. These errors lead to the potential of avoidable harm and the administration of inappropriate treatment.
Designing Support Structures Post Sepsis in Children: Perspectives of the Queensland Paediatric Sepsis Program
Authors: Raman Sainath , English Alana , O'Keefe Meagan , Harley Amanda , Steele Mary , Minogue Jess , Weller Kate , Long Debbie , Irwin Adam , Lister Paula
Published: November 2021

Introduction: Paediatric post sepsis syndrome is poorly defined and causes physical, neurocognitive, psychosocial morbidity, and family dysfunction. Families of sepsis survivors report unmet needs during care. Worldwide, the provision of post sepsis care is in its infancy with limited evidence to design clinical support pathways.

Perspective: The Queensland Paediatric Sepsis Program (QPSP) developed a family support structure (FSS) to improve care during all stages of childhood sepsis. It was designed in partnership with consumers guided by information from consumers and it is partly delivered by consumers. Key areas include online, multimodal education for families and the ability to connect with other families affected by sepsis. The FSS is delivered by a multidisciplinary team (MDT) acting with clinicians local to the child. Families can join the FSS registry at any stage of their sepsis journey which connects them to our MDT team and opens opportunities to participate in future research and other initiatives. Improving public awareness is a critical outcome for our consumers and they have co-designed media and digital campaigns.

Discussion: The ideal FSS for post sepsis syndrome management is a clinical pathway designed in partnership with consumers of interventions proven to improve outcomes from sepsis that meets their requirements. The QPSP FSS is novel as it is co-designed with, and partly delivered by, consumers with interventions aimed to improve the entire spectrum of morbidities suffered by survivors and their families, not just physical sequelae. Evaluation is embedded in the program and outcomes will guide evolution of the FSS.
Safety of Inulin and Sinistrin: Combining Several Sources for Pharmacovigilance Purposes
Authors: Bui T-V. , Prot-Bertoye C. , Ayari H. , Baron S. , Bertocchio J-P. , Bureau C. , Davis P. , Blanchard A. , Houillier P. , Prie D. , Lillo-Le Louet A. , Courbebaisse M.
Published: November 2021

Introduction: Inulin and its analog sinistrin are fructose polymers used in the food and pharmaceutical industries. In 2018, The French National Agency for the Safety of Medicines and Health Products (ANSM) decided to withdraw products containing sinistrin and inulin due to several reports of serious hypersensitivity reactions, including a fatal outcome.

Objective: To assess the safety of inulin and sinistrin use in France.

Methods: We searched multiple sources to identify adverse reactions (ARs) to inulin or sinistrin: first, classical pharmacovigilance databases including the French Pharmacovigilance (FPVD) and the WHO Database (VigiBase); second, data from a clinical trial, MultiGFR; third, data regarding current use in an hospital. All potential ARs to inulin or sinistrin were analyzed with a focus on hypersensitivity reactions and relationships to batches of sinistrin.

Results: From 1991 to 2018, 134 ARs to inulin or sinistrin were registered in the FPVD or VigiBase. Sixty-three cases (47%) were classified as serious, and 129 cases (96%) were hypersensitivity reactions. We found an association between a batch of sinistrin and the occurrence of hypersensitivity reactions. During the MultiGFR clinical trial, 7 patients (7/163 participants) had an Adverse reaction; of these, 4 were hypersensitivity reactions including one case of grade 4 anaphylactic shock. In the hospital, no ARs were observed. In the literature, ARs to inulin and sinistrin are very rarely reported and mostly benign.

Conclusion: Most ARs to inulin and sinistrin are hypersensitivity reactions that appear to be associated with sinistrin batches.
Prevalence of Chronic Polypharmacy in Community-Dwelling Elderly People in Poland: Analysis of National Real-World Database Helps to Identify High Risk Group
Authors: Kardas Przemysław , Lichwierowicz Aneta , Urbański Filip , Chudzyńska Ewa , Czech Marcin , Kardas Grzegorz
Published: November 2021

Introduction: Multimorbidity often comes with age, making elderly people particularly prone to polypharmacy. Polypharmacy, in turn, is a risk factor for adverse drug reactions, drug-drug interactions, non-adherence to medication, negative health outcomes, and increased healthcare services utilization. The longer the exposure to polypharmacy is, the higher the risk of these consequences is. Therefore, a detailed assessment of the prevalence and drivers of chronic polypharmacy in the elderly is particularly important.

Aim of study: To find out the prevalence of chronic polypharmacy in the elderly population of Poland, and to characterize the subgroup with the highest risk of this problem, using real-world data.

Methodology: A retrospective analysis of data on dispensation and healthcare services utilization held by the national payer organization for the year 2018. Chronic polypharmacy was defined as possession, as a result of dispensation, of five or more prescribed drugs within 80% of each of the consecutive 6 months.

Results: Chronic polypharmacy was found in 554.1 thousand patients, i.e. in 19.1% of the national 65+ cohort. On average, those patients were 76 years old, and 49.3% of them were female. The vast majority (68.6%) continued their polypharmacy for the period of the whole year. There was a marked variation in geographical distribution of chronic polypharmacy with the highest value of 1.7 thousand per 100,000 inhabitants in the Łódź Voivodeship. Patients exposed to chronic polypharmacy filled prescriptions from 4.5±2.36 healthcare professionals. The average number of drugs they used was 8.3±3.84 DDD per patient per day. The most often prescribed drugs were Metformin, Atorvastatin and Pantoprazole. The average annual hospitalisation rate in those patients was 1.03±2.4.

Conclusion: This study was the first of this kind involving a nationwide assessment of chronic polypharmacy in Polish elderly people. We found that this problem affected one fifth of Polish older adults and it remains stable due to its direct relation to chronic conditions. Thus, our results confirm that this phenomenon is highly important for the national health policy and requires relevant interventions. The planned introduction of pharmaceutical care in Poland is expected to help in solving the problem.
Exogenous Carbon Monoxide Produces Rapid Antidepressant- and Anxiolytic-Like Effects
Authors: Luo Yixiao , Ullah Rafi , Wang Jinfeng , Du Yuru , Huang Shihao , Meng Li , Gao Yuan , Gong Miao , Galaj Ewa , Yin Xi , Shi Haishui
Published: November 2021

Carbon monoxide (CO), a byproduct of heme catalyzed by heme oxygenase (HO), has been reported to exert antioxidant and anti-inflammatory actions, and to produce significant neuroprotective effects. The potential effects of CO and even HO on depressive-like behaviors are still poorly understood. Utilizing several approaches including adeno-associated virus (AAV)-mediated overexpression of HO-1, systemic CO-releasing molecules (CO-RMs), CO-rich saline or CO gas treatment procedures in combination with hydrogen peroxide (H2O2)-induced PC12 cell injury model, and lipopolysaccharide (LPS)-induced depression mouse model, the present study aimed to investigate the potential antidepressant- and anxiolytic-like effects of endogenous and exogenous CO administration in vivo and in vitro. The results of in vitro experiments showed that both CO-RM-3 and CO-RM-A1 pretreatment blocked H2O2-induced cellular injuries by increasing cell survival and decreasing cell apoptosis and necrosis. Similar to the effects of CO-RM-3 and CO-RM-A1 pretreatment, AAV-mediated HO-1 overexpression in the dorsal hippocampus produced significant antidepressant-like activities in mice under normal conditions. Further investigation showed that the CO gas treatment significantly blocked LPS-induced depressive- and anxiety-like behaviors in mice. Taken together, our results suggest that the activation of HO-1 and/or exogenous CO administration produces protective effects and exerts antidepressant- and anxiolytic-like effects. These data uncover a novel function of the HO-1/CO system that appears to be a promising therapeutic target for the treatment of depression and anxiety.
Receptor Interacting Protein Kinases 1/3: The Potential Therapeutic Target for Cardiovascular Inflammatory Diseases
Authors: Leng Yiming , Zhang Ying , Li Xinyu , Wang Zeyu , Zhuang Quan , Lu Yao
Published: November 2021

The receptor interacting protein kinases 1/3 (RIPK1/3) have emerged as the key mediators in cell death pathways and inflammatory signaling, whose ubiquitination, phosphorylation, and inhibition could regulate the necroptosis and apoptosis effectually. Recently, more and more studies show great interest in the mechanisms and the regulator of RIPK1/3-mediated inflammatory response and in the physiopathogenesis of cardiovascular diseases. The crosstalk of autophagy and necroptosis in cardiomyocyte death is a nonnegligible conversation of cell death. We elaborated on RIPK1/3-mediated necroptosis, pathways involved, the latest regulatory molecules and therapeutic targets in terms of ischemia reperfusion, myocardial remodeling, myocarditis, atherosclerosis, abdominal aortic aneurysm, and cardiovascular transplantation, etc.
Cardiovascular Protective Effects of Plant Polysaccharides: A Review
Authors: Dong Xinli , Zhou Mengze , Li Yehong , Li Yuxin , Ji Hui , Hu Qinghua
Published: November 2021

Cardiovascular disease is a kind of heart, brain, and blood vessel injury disease by the interaction of various pathological factors. The pathogenesis of cardiovascular disease is complex with various risk factors, including abnormally elevated blood pressure, glucose, and lipid metabolism disorders, atherosclerosis, thrombosis, etc. Plant polysaccharides are a special class of natural products derived from plant resources, which have the characteristics of wide sources, diverse biological activities, and low toxicity or side effects. Many studies have shown that plant polysaccharides improve cardiovascular diseases through various mechanisms such as anti-oxidative stress, restoring the metabolism of biological macromolecules, regulating the apoptosis cascade to reduce cell apoptosis, and inhibiting inflammatory signal pathways to alleviate inflammation. This article reviews the pharmacological effects and protective mechanisms of some plant polysaccharides in modulating the cardiovascular system, which is beneficial for developing more effective drugs with low side effects for management of cardiovascular diseases.
Computing Edge Metric Dimension of One-Pentagonal Carbon Nanocone
Authors: Sharma Sunny Kumar , Raza Hassan , Bhat Vijay Kumar
Published: November 2021

Minimum resolving sets (edge or vertex) have become an integral part of molecular topology and combinatorial chemistry. Resolving sets for a specific network provide crucial information required for the identification of each item contained in the network, uniquely. The distance between an edge e = cz and a vertex u is defined by d(e, u) = min{d(c, u), d(z, u)}. If d(e1, u) ≠ d(e2, u), then we say that the vertex u resolves (distinguishes) two edges e1 and e2 in a connected graph G. A subset of vertices RE in G is said to be an edge resolving set for G, if for every two distinct edges e1 and e2 in G we have d(e1, u) ≠ d(e2, u) for at least one vertex u ∈ RE. An edge metric basis for G is an edge resolving set with minimum cardinality and this cardinality is called the edge metric dimension edim(G) of G. In this article, we determine the edge metric dimension of one-pentagonal carbon nanocone (1-PCNC). We also show that the edge resolving set for 1-PCNC is independent.
Displacement Transformations as a Tool to Study Many-Body Localization
Authors: Serna Pablo , Ortuño Miguel , Somoza Andrés M.
Published: November 2021

We obtain eigenstates of interacting disorder Hamiltonians using unitary displacement transformations that rotate the state of the system. The method generates excited states if the strength of these transformations is chosen to optimize the energy, while decreasing the energy variance. We apply the method to analyse the localization properties of one-dimensional spinless fermions with short range interactions, reaching relatively large system sizes. We quantify the degree of localization through the size and disorder dependence of the inverse participation ratio.
Age-Related Exosomal and Endogenous Expression Patterns of miR-1, miR-133a, miR-133b, and miR-206 in Skeletal Muscles
Authors: Mytidou Chrystalla , Koutsoulidou Andrie , Zachariou Margarita , Prokopi Marianna , Kapnisis Konstantinos , Spyrou George M. , Anayiotos Andreas , Phylactou Leonidas A.
Published: November 2021

Skeletal muscle growth and maintenance depend on two tightly regulated processes, myogenesis and muscle regeneration. Both processes involve a series of crucial regulatory molecules including muscle-specific microRNAs, known as myomiRs. We recently showed that four myomiRs, miR-1, miR-133a, miR-133b, and miR-206, are encapsulated within muscle-derived exosomes and participate in local skeletal muscle communication. Although these four myomiRs have been extensively studied for their function in muscles, no information exists regarding their endogenous and exosomal levels across age. Here we aimed to identify any age-related changes in the endogenous and muscle-derived exosomal myomiR levels during acute skeletal muscle growth. The four endogenous and muscle-derived myomiRs were investigated in five skeletal muscles (extensor digitorum longus, soleus, tibialis anterior, gastrocnemius, and quadriceps) of 2-week–1-year-old wild-type male mice. The expression of miR-1, miR-133a, and miR-133b was found to increase rapidly until adolescence in all skeletal muscles, whereas during adulthood it remained relatively stable. By contrast, endogenous miR-206 levels were observed to decrease with age in all muscles, except for soleus. Differential expression of the four myomiRs is also inversely reflected on the production of two protein targets; serum response factor and connexin 43. Muscle-derived exosomal miR-1, miR-133a, and miR-133b levels were found to increase until the early adolescence, before reaching a plateau phase. Soleus was found to be the only skeletal muscle to release exosomes enriched in miR-206. In this study, we showed for the first time an in-depth longitudinal analysis of the endogenous and exosomal levels of the four myomiRs during skeletal muscle development. We showed that the endogenous expression and extracellular secretion of the four myomiRs are associated to the function and size of skeletal muscles as the mice age. Overall, our findings provide new insights for the myomiRs’ significant role in the first year of life in mice.
Autologous Bone Marrow Cell Infusion for the Treatment of Decompensated Liver Cirrhosis Patients With Type 2 Diabetes Mellitus
Authors: Liu Baochi , Cheng Mingrong , Lang Lin , Li Lei , Si Yanhui , Wang Guangmian
Published: November 2021

This study aimed to indicate whether autologous bone marrow cell infusion (ABMI) via the right omental vein (ROV) could have a regulatory effect on decompensated liver cirrhosis (DLC) patients with type 2 diabetes mellitus (T2DM). For this purpose, 24 DLC patients with T2DM were divided into observation group (n=14) and control group (n=10). Patients in the observation group were given ABMI through the ROV and right omental artery (ROA), and cases in the control group received ABMI through the ROV. At 1, 3, 6, and 12months after ABMI, it was revealed that the prothrombin time, the total bilirubin levels, and the amount of ascites were significantly lower, while the serum albumin levels in the two groups were markedly higher compared with those before ABMI (p<0.01), and there was no significant difference between the two groups at each time point (p>0.05). The fasting blood glucose and glycosylated hemoglobin levels at 6 and 12months after ABMI in the two groups significantly decreased compared with those before ABMI (p<0.05 or p<0.01), while the decreased levels in the observation group were more obvious than those in the control group at each time point (p<0.01). The amount of insulin in the observation group at 3, 6, and 12months after ABMI was significantly less than that before ABMI in the control group (p<0.01). In summary, ABMI showed a significant therapeutic efficacy for DLC patients with T2DM through ROV and ROA.
Association Between Mechanical, Physiological, and Technical Parameters With Canoe Slalom Performance: A Systematic Review
Authors: Messias Leonardo Henrique Dalcheco , Reis Ivan Gustavo Masselli Dos , Bielik Viktor , Garbuio Ana Luíza Paula , Gobatto Claudio Alexandre , Manchado-Gobatto Fúlvia Barros
Published: November 2021

This study aimed to systematically review studies that evaluated and compared mechanical, physiological, and technical parameters with the performance of slalom athletes. PubMed, SPORTDiscuss, and Scopus databases were searched until September 10, 2021, with no restriction of published data. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guided the study's screening and quality assessment performed by an external reviewer using a 16-checklist item. A search of the databases identified 125 studies, but only eight were eligible, including a total sample of 117 male athletes. Four reports only associated mechanical or technical parameters with the performance of the paddler. Concerning the remaining studies, only one correlated physiological data, and the others associated more than one parameter with race time. Most of the eligible reports presented significant associations between mechanical/physiological components and slalom performance. Eligible studies support that high-force development during a slalom race is a relevant parameter for performance. Aerobic metabolism is highly required during slalom tasks and is inversely associated with race time, although it may not increase the chances of winning medals. Few reports have associated canoe slalom performance with technical components, and further research should focus on this matter.
The Association Between Force-Velocity Relationship in Countermovement Jump and Sprint With Approach Jump, Linear Acceleration and Change of Direction Ability in Volleyball Players
Authors: Pleša Jernej , Kozinc Žiga , Šarabon Nejc
Published: November 2021

The force-velocity (FV) relationship allows the identification of the mechanical capabilities of musculoskeletal system to produce force, power and velocity. The aim of this study was to assess the associations of the mechanical variables derived from the FV relationship with approach jump, linear sprint and change of direction (CoD) ability in young male volleyball players. Thirty-seven participants performed countermovement jumps with incremental loads from bodyweight to 50–100 kg (depending on the individual capabilities), 25-m sprint with split times being recorded for the purpose of FV relationship calculation, two CoD tests (505 test and modified T-test) and approach jump. Results in this study show that approach jump performance seems to be influenced by maximal power output (r = 0.53) and horizontal force production (r = 0.51) in sprinting, as well as force capacity in jumping (r = 0.45). Only the FV variables obtained from sprinting alone contributed to explaining linear sprinting and CoD ability (r = 0.35–0.93). An interesting finding is that sprinting FV variables have similar and some even stronger correlation with approach jump performance than jumping FV variables, which needs to be considered for volleyball training optimization. Based on the results of this study it seems that parameters that refer to horizontal movement capacity are important for volleyball athletic performance. Further interventional studies are needed to check how to implement specific FV-profile-based training programs to improve specific mechanical capabilities that determine volleyball athletic performance and influence the specific physical performance of volleyball players.