bluuebunny/crossref_metadata_2025 huggingface dataset:
Usability and ease of use of long-term remote monitoring of physical activity for individuals with acquired brain injury in community: a qualitative analysis
Authors: Mazzeo Marie , Hernan Gabriel , Veerubhotla Akhila
Published: September 2023

Introduction

Objective and continuous monitoring of physical activity over the long-term in the community is perhaps the most important step in the paradigm shift toward evidence-based practice and personalized therapy for successful community integration. With the advancement in technology, physical activity monitors have become the go-to tools for objective and continuous monitoring of everyday physical activity in the community. While these devices are widely used in many patient populations, their use in individuals with acquired brain injury is slowly gaining traction. The first step before using activity monitors in this population is to understand the patient perspective on usability and ease of use of physical activity monitors at different wear locations. However, there are no studies that have looked at the feasibility and patient perspectives on long-term utilization of activity monitors in individuals with acquired brain injury.

Methods

This pilot study aims to fill this gap and understand patient-reported aspects of the feasibility of using physical activity monitors for long-term use in community-dwelling individuals with acquired brain injury.

Results

This pilot study found that patients with acquired brain injury faced challenges specific to their functional limitations and that the activity monitors worn on the waist or wrist may be better suited in this population.

Discussion

The unique wear location-specific challenges faced by individuals with ABI need to be taken into account when selecting wearable activity monitors for long term use in this population.
Sex, myelin, and clinical characteristics of Parkinson’s disease
Authors: Cai Jiayue , Kim Jowon L. , Wang Yuheng , Baumeister Tobias R. , Zhu Maria , Liu Aiping , Lee Soojin , McKeown Martin J.
Published: September 2023

Objective

To determine if there are sex differences in myelin in Parkinson’s disease, and whether these explain some of the previously-described sex differences in clinical presentation.

Methods

Thirty-three subjects (23 males, 10 females) with Parkinson’s disease underwent myelin water fraction (MWF) imaging, an MRI scanning technique of in vivo myelin content. MWF of 20 white matter regions of interest (ROIs) were assessed. Motor symptoms were assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS). Principal component analysis, logistic and multiple linear regressions, and t-tests were used to determine which white matter ROIs differed between sexes, the clinical features associated with these myelin changes, and if overall MWF and MWF laterality differed between males and females.

Results

Consistent with prior reports, tremor and bradykinesia were more likely seen in females, whereas rigidity and axial symptoms were more likely seen in males in our cohort. MWF of the thalamic radiation, cingulum, cingulum hippocampus, inferior fronto-occipital fasciculi, inferior longitudinal fasciculi, and uncinate were significant in predicting sex. Overall MWF and asymmetry of MWF was greater in males. MWF differences between sexes were associated with tremor symptomatology and asymmetry of motor performance.

Conclusion

Sex differences in myelin are associated with tremor and asymmetry of motor presentation. While preliminary, our results suggest that further investigation of the role of biological sex in myelin pathology and clinical presentation in Parkinson’s disease is warranted.
High-dose liraglutide improves metabolic syndrome in poor responders to bariatric surgery
Authors: Vinciguerra Federica , Piazza Luigi , Di Stefano Carla , Degano Claudia , Pulvirenti Alfredo , Baratta Roberto , Frittitta Lucia
Published: September 2023

Background

Bariatric surgery (BS) represents the most effective therapy for obesity class III, or class II with at least one weight-related comorbidity. However, some patients have insufficient weight loss or clinically relevant weight regain after a successful primary procedure. This study aimed to assess the efficacy of liraglutide treatment on weight loss, body composition and improvement of metabolic syndrome (MS) in patients defined as poor responders after BS.

Methods

The study involved 59 non-diabetic adults with obesity (M/F: 17/42, age: 38.6 ± 11.8 years, BMI 38.3 ± 5.5 kg/m2) who had been treated with BS and experienced a poor response, categorized as either IWL (insufficient weight loss) or WR (weight regain). All patients were prescribed pharmacological therapy with liraglutide and attended nutritional counseling. Anthropometric and clinical measurements, body composition and the presence of MS defined according to the ATP-III classification were evaluated before starting liraglutide and after 24 weeks of treatment.

Results

After 24 weeks of treatment with liraglutide, the mean weight loss was 8.4% ± 3.6% with no difference between gender, bariatric procedure, or type of poor response (IWL or WR). A significant decrease in fat mass, free-fat mass and total body water was documented. After 24 weeks, patients presented significantly lowered fasting glucose, total cholesterol, triglycerides, AST and ALT. The prevalence of MS was reduced from 35% at baseline to 1.6% after 24 weeks. No patients discontinued the treatment during the study.

Conclusion

In patients who experience poor response after BS, liraglutide is well tolerated and promotes significant weight loss, ameliorates cardiometabolic comorbidities, and reduces the prevalence of MS.
Single-cell analysis of bovine muscle-derived cell types for cultured meat production
Authors: Messmer Tobias , Dohmen Richard G. J. , Schaeken Lieke , Melzener Lea , Hueber Rui , Godec Mary , Didoss Carin , Post Mark J. , Flack Joshua E.
Published: September 2023

Cultured meat technologies leverage the proliferation and differentiation of animal-derived stem cells ex vivo to produce edible tissues for human consumption in a sustainable fashion. However, skeletal muscle is a dynamic and highly complex tissue, involving the interplay of numerous mono- and multinucleated cells, including muscle fibers, satellite cells (SCs) and fibro-adipogenic progenitors (FAPs), and recreation of the tissue in vitro thus requires the characterization and manipulation of a broad range of cell types. Here, we use a single-cell RNA sequencing approach to characterize cellular heterogeneity within bovine muscle and muscle-derived cell cultures over time. Using this data, we identify numerous distinct cell types, and develop robust protocols for the easy purification and proliferation of several of these populations. We note overgrowth of undesirable cell types within heterogeneous proliferative cultures as a barrier to efficient cultured meat production, and use transcriptomics to identify conditions that favor the growth of SCs in the context of serum-free medium. Combining RNA velocities computed in silico with time-resolved flow cytometric analysis, we characterize dynamic subpopulations and transitions between active, quiescent, and committed states of SCs, and demonstrate methods for modulation of these states during long-term proliferative cultures. This work provides an important reference for advancing our knowledge of bovine skeletal muscle biology, and its application in the development of cultured meat technologies.
Selenium intake and multiple health-related outcomes: an umbrella review of meta-analyses
Authors: Wang Puze , Chen Bo , Huang Yin , Li Jin , Cao Dehong , Chen Zeyu , Li Jinze , Ran Biao , Yang Jiahao , Wang Ruyi , Wei Qiang , Dong Qiang , Liu Liangren
Published: September 2023

Selenium is an essential trace metalloid element that is associated with fundamental importance to human health. Our umbrella review aimed to evaluate the quality of evidence, validity, and biases in the relationship between selenium intake and health-related outcomes according to published systematic reviews with pooled data and meta-analyses. Selenium intake is associated with a decreased risk of digestive system cancers, all-cause mortality, depression, and Keshan disease, when in children reduce the risk of Kashin-Beck disease. Additionally, selenium supplementation can improve sperm quality, polycystic ovary syndrome, autoimmune thyroid disease, cardiovascular disease, and infective outcomes. Selenium supplementation also has relationship with a decreased concentration of serum lipids including total cholesterol and very low-density lipoprotein cholesterol. However, no evidence has shown that selenium is associated with better outcomes among patients in intensive care units. Furthermore, selenium intake may be related with a higher risk of type 2 diabetes and non-melanoma skin cancers. Moreover, most of included studies are evaluated as low quality according to our evidence assessment. Based on our study findings and the limited advantages of selenium intake, it is not recommended to receive extra supplementary selenium for general populations, and selenium supplementation should not be continued in patients whose selenium-deficient status has been corrected.
Whole-exome sequencing of calcitonin-producing pancreatic neuroendocrine neoplasms indicates a unique molecular signature
Authors: Döring Claudia , Peer Katharina , Bankov Katrin , Bollmann Carmen , Ramaswamy Annette , Di Fazio Pietro , Wild Peter Johannes , Bartsch Detlef Klaus
Published: September 2023

Introduction

Calcitonin-producing pancreatic neuroendocrine neoplasms (CT-pNENs) are an extremely rare clinical entity, with approximately 60 cases reported worldwide. While CT-pNENs can mimic the clinical and diagnostic features of medullary thyroid carcinoma, their molecular profile is poorly understood.

Methods

Whole-exome sequencing (WES) was performed on tumor and corresponding serum samples of five patients with increased calcitonin serum levels and histologically validated calcitonin-positive CT-pNENs. cBioPortal analysis and DAVID gene enrichment analysis were performed to identify dysregulated candidate genes compared to control databases. Immunohistochemistry was used to detect the protein expression of MUC4 and MUC16 in CT-pNEN specimens.

Results

Mutated genes known in the literature in pNENs like MEN1 (35% of cases), ATRX (18-20% of cases) and PIK3CA (1.4% of cases) were identified in cases of CT-pNENs. New somatic SNVs in ATP4A, HES4, and CAV3 have not been described in CT- pNENs, yet. Pathogenic germline mutations in FGFR4 and DPYD were found in three of five cases. Mutations of CALCA (calcitonin) and the corresponding receptor CALCAR were found in all five tumor samples, but none of them resulted in protein sequelae or clinical relevance. All five tumor cases showed single nucleotide variations (SNVs) in MUC4, and four cases showed SNVs in MUC16, both of which were membrane-bound mucins. Immunohistochemistry showed protein expression of MUC4 in two cases and MUC16 in one case, and the liver metastasis of a third case was double positive for MUC4 and MUC16. The homologous recombination deficiency (HRD) score of all tumors was low.

Discussion

CT-pNENs have a unique molecular signature compared to other pNEN subtypes, specifically involving the FGFR4, DPYD, MUC4, MUC16 and the KRT family genes. However, a major limitation of our study was the relative small number of only five cases. Therefore, our WES data should be interpreted with caution and the mutation landscape in CT-pNENs needs to be verified by a larger number of patients. Further research is needed to explain differences in pathogenesis compared with other pNENs. In particular, multi-omics data such as RNASeq, methylation and whole genome sequencing could be informative.
Anlotinib combined with whole-brain radiotherapy in non-small cell lung cancer with multiple brain metastases that progressed or developed after at least one lines of prior treatment
Authors: Kong Cheng , Yu Shaorong , Qian Pudong , Song Xue , Wen Jing , Jiang Ming , Zhu Jun , Xu Jianhua , Zhao Lijun , Guo Zhen , Wu Jianfeng , He Xia , Zhu Xiangzhi
Published: September 2023

Background

Intracranial metastasis that failed standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with whole-brain radiotherapy (WBRT) for NSCLC with brain metastases (BMs) that progressed or developed after at least one line of prior treatment and compare the outcomes with that of the contemporary institutional control.

Methods

NSCLC patients with multiple BMs that progressed or developed after at least one line of prior systematic treatment and treated with WBRT subsequently between 2019 and 2021 were selected retrospectively for analysis. Based on whether concurrent anlotinib had been used in combination with WBRT, the cases were divided into the anlotinib group and control group. The primary endpoints were intracranial progression-free survival (iPFS) and safety.

Results

A total of 76 patients met the inclusion criteria of the study. Of the 76 patients, 34 received concurrent WBRT and anlotinib followed by anlotinib maintenance and 42 were treated with WBRT alone or in combination with other systemic agents at the physicians’ discretion. The median follow-up for the entire cohort was 21 months. The median iPFS for the anlotinib and control group was 6.7 months (95% CI, 4.6–9.9) and 5.3 months (95% CI, 4.0–6.5), respectively (log-rank P = 0.04). There was no difference in overall survival between the two groups (log-rank P = 0.38). In the anlotinib group, treatment-related adverse events were reported in 15 patients (44.1%), with acute or late grade 3–5 adverse events identified in 14.7% of patients (n = 5).

Conclusions

WBRT plus anlotinib, as a convenient chemo-free regimen, may represent an overall safe and effective procedure in advanced NSCLC with multiple BMs that progressed or developed after standard systematic treatment.
Head and neck cancers survival in Europe, Taiwan, and Japan: results from RARECAREnet Asia based on a privacy-preserving federated infrastructure
Authors: Botta Laura , Matsuda Tomohiro , Charvat Hadrien , Chiang Chun-ju , Lee Wen-Chung , van Gestel Anna Jacoba , Martin Frank , Geleijnse Gijs , Cellamare Matteo , Bonfarnuzzo Simone , Marcos-Gragera Rafael , Guevara Marcela , Mousavi Mohsen , Craig Stephanie , Rodrigues Jessica , Rubió-Casadevall Jordi , Licitra Lisa , Cavalieri Stefano , Resteghini Carlo , Gatta Gemma , Trama Annalisa ,   the RARECAREnet working group
Published: September 2023

Background

The head and neck cancers (HNCs) incidence differs between Europe and East Asia. Our objective was to determine whether survival of HNC also differs between European and Asian countries.

Methods

We used population-based cancer registry data to calculate 5-year relative survival (RS) for the oral cavity, hypopharynx, larynx, nasal cavity, and major salivary gland in Europe, Taiwan, and Japan. We modeled RS with a generalized linear model adjusting for time since diagnosis, sex, age, subsite, and histological grouping. Analyses were performed using federated learning, which enables analyses without sharing sensitive data.

Findings

Five-year RS for HNC varied between geographical areas. For each HNC site, Europe had a lower RS than both Japan and Taiwan. HNC subsites and histologies distribution and survival differed between the three areas. Differences between Europe and both Asian countries persisted even after adjustments for all HNC sites but nasal cavity and paranasal sinuses, when comparing Europe and Taiwan.

Interpretation

Survival differences can be attributed to different factors including different period of diagnosis, more advanced stage at diagnosis, or different availability/access of treatment. Cancer registries did not have stage and treatment information to further explore the reasons of the observed survival differences. Our analyses have confirmed federated learning as a feasible approach for data analyses that addresses the challenges of data sharing and urge for further collaborative studies including relevant prognostic factors.
Tumorigenic effects of human mesenchymal stromal cells and fibroblasts on bladder cancer cells
Authors: Frerichs Lucie M. , Frerichs Bastian , Petzsch Patrick , Köhrer Karl , Windolf Joachim , Bittersohl Bernd , Hoffmann Michèle J. , Grotheer Vera
Published: September 2023

Background

Patients with muscle-invasive bladder cancer face a poor prognosis due to rapid disease progression and chemoresistance. Thus, there is an urgent need for a new therapeutic treatment. The tumor microenvironment (TME) has crucial roles in tumor development, growth, progression, and therapy resistance. TME cells may also survive standard treatment of care and fire up disease recurrence. However, whether specific TME components have tumor-promoting or tumor-inhibitory properties depends on cell type and cancer entity. Thus, a deeper understanding of the interaction mechanisms between the TME and cancer cells is needed to develop new cancer treatment approaches that overcome therapy resistance. Little is known about the function and interaction between mesenchymal stromal cells (MSC) or fibroblasts (FB) as TME components and bladder cancer cells.

Methods

We investigated the functional impact of conditioned media (CM) from primary cultures of different donors of MSC or FB on urothelial carcinoma cell lines (UCC) representing advanced disease stages, namely, BFTC-905, VMCUB-1, and UMUC-3. Underlying mechanisms were identified by RNA sequencing and protein analyses of cancer cells and of conditioned media by oncoarrays.

Results

Both FB- and MSC-CM had tumor-promoting effects on UCC. In some experiments, the impact of MSC-CM was more pronounced. CM augmented the aggressive phenotype of UCC, particularly of those with epithelial phenotype. Proliferation and migratory and invasive capacity were significantly increased; cisplatin sensitivity was reduced. RNA sequencing identified underlying mechanisms and molecules contributing to the observed phenotype changes. NRF2 and NF-κB signaling was affected, contributing to improved cisplatin detoxification. Likewise, interferon type I signaling was downregulated and regulators of epithelial mesenchymal transition (EMT) were increased. Altered protein abundance of CXCR4, hyaluronan receptor CD44, or TGFβ-signaling was induced by CM in cancer cells and may contribute to phenotypical changes. CM contained high levels of CCL2/MCP-1, MMPs, and interleukins which are well known for their impact on other cancer entities.

Conclusions

The CM of two different TME components had overlapping tumor-promoting effects and increased chemoresistance. We identified underlying mechanisms and molecules contributing to the aggressiveness of bladder cancer cells. These need to be further investigated for targeting the TME to improve cancer therapy.
Impact of circulating lymphoma cells at diagnosis on outcomes in patients with Waldenstrom macroglobulinemia
Authors: Nalin Ansel , Zhao Qiuhong , Voorhees Timothy , Bond David , Sawalha Yazeed , Hanel Walter , Sigmund Audrey , Annunzio Kaitlin , Alinari Lapo , Baiocchi Robert , Maddocks Kami , Jones Dan , Christian Beth , Epperla Narendranath
Published: September 2023

Given the paucity of data surrounding the prognostic relevance of circulating lymphoma (CL) in Waldenström macroglobulinemia (WM), we sought to evaluate the impact of CL at diagnosis on outcomes in patients with WM. Patients were divided into CL+ and CL- based on the results of flow cytometry. The endpoints included assessing progression-free survival (PFS), overall survival (OS), and diagnosis-to-treatment interval (DTI) between the two groups. Among the 308 patients with WM, 69 met the eligibility criteria with 42 and 27 in CL+ and CL- groups, respectively. The two groups were well balanced in regard to all the baseline characteristics. The ORR was numerically higher in the CL+ group compared to the CL-group (81% versus 61%, respectively), however, the CR+VGPR rates were similar between the two groups. The median PFS was not significantly different between the two groups (6.3 years in the CL- group versus not reached [NR] in the CL+ group) regardless of the first-line therapy. There was no significant difference in median OS between the CL- and CL+ groups (13 years versus NR). Although the median DTI was shorter in the CL+ group compared to CL- group, the significance was lost in the multivariable analysis. In this study (largest-to-date) evaluating the impact of CL on outcomes in patients with newly diagnosed WM, we did not find the prognostic utility of CL in WM. Future studies should explore the correlation of CL with other biological factors that impact the outcomes in WM patients.
The association between plasma osmolality and in-hospital mortality in the first 24 h after neonatal intensive care unit admission
Authors: Liu Weiqin , Xiang Lingling , Zhao Zhiwei , Lin Lu , Wei Hong , Hua Ziyu
Published: September 2023

Background

Perturbation of osmolality is associated with increased mortality in adults and children in critically ill conditions. However, it is still unclear whether osmolality imbalance impacts the prognosis of critically ill infants. This study aimed to investigate the relationship between plasma osmolality and prognosis in critically ill infants within 24 h of admission.

Methods

This retrospective study enrolled 1,042 infants who had plasma osmolality data from 2010 to 2018. The initial plasma osmolality (within 24 h after admission) was extracted from the pediatric intensive care database (PIC V1.1). The locally weighted scatter-plot smoothing (LOWESS) and restricted cubic splines (RCS) methods were used to explore the approximate relationship between plasma osmolality and in-hospital mortality. Univariate and multivariate logistic regression analyses were used to further analyse this relationship. Kaplan–Meier analysis was applied to estimate the probability of hospital mortality within 90 days of admission. Subgroup analysis was employed to assess the impact of potential confounders (including postnatal days, gender, and gestational age).

Results

An approximately“U”-shaped relationship between plasma osmolality and mortality was detected. In the logistic regression model, plasma osmolality <270 mmol/L (low osmolality group) was significantly associated with in-hospital mortality (P < 0.05; OR 2.52; 95% CI, 1.15–5.06). Plasma osmolality >300 mmol/L (high osmolality group) was also significantly associated with mortality (P < 0.05; OR 3.52; 95% CI, 1.16–8.83). This association remained even after multivariable adjustments. The 90-day survival rate was lower in the abnormal plasma osmolality group (including high or low osmolality groups) than in the intermediate group (log-rank test, P < 0.05). The abnormal plasma osmolality group had a significantly higher incidence of all-cause mortality in the 0–7 postnatal days subgroup (high osmolality group, P < 0.05; OR 5.25; low osmolality group, P < 0.05; OR 3.01). Infants with abnormal osmolality had a significantly higher mortality rate in the female group (P < 0.05). High osmolality was associated with a higher mortality rate in the preterm group (P < 0.05).

Conclusions

Both hypoosmolality and hyperosmolality were shown to be independently associated with increased risk of in-hospital infant mortality in NICUs.
Case report: Novel insights into hemorrhagic destruction of the brain, subependymal calcification, and cataracts disease
Authors: Abdallah Moady Tameemi , Odeh Marwan , Fedida Ayalla , Segal Zvi , Gruber Maayan , Goldfeld Moshe , Kalfon Limor , Falik-Zaccai Tzipora C.
Published: September 2023

Introduction

Pathogenic variants of the junctional adhesion molecule 3 (JAM3/JAM-C; OMIM#606871) is the cause of the rare recessive disorder called hemorrhagic destruction of the brain, subependymal calcification, and cataracts (HDBSCC, OMIM#613730) disease. A similar phenotype is universal, including congenital cataracts and brain hemorrhages with high mortality rate in the first few weeks of life and with a poor neurologic outcome in survivors. We aim to describe and enlighten novel phenotype and genotype of a new patient and review the literature regarding all reported patients worldwide.

Case report

We report the case of a prenatal and postnatal phenotype of a new patient with a novel pathogenic loss-of-function variant in JAM3, who presented prenatally with cataracts and brain anomalies and postnatally with brain hemorrhages, failure to thrive (FTT), progressive microcephaly, recurrent posterior capsule opacities, and auditory neuropathy.

Discussion

This study enlightens novel possible functions of JAM3 in the normal development of the brain, the ocular lenses, the auditory system, and possibly the gastrointestinal tract. This study is the first to report of cataracts evident in as early as 23 weeks of gestation and a rare phenomenon of recurrent posterior capsule opacities despite performing recurrent posterior capsulectomy and anterior vitrectomy. We suggest that auditory neuropathy, which is reported here for the first time, is part of the phenotype of HDBSCC, probably due to an endothelial microvasculature disruption of the peripheral eighth nerve or possibly due to impaired nerve conduction from the synapse to the brainstem.

Conclusions

Prenatal cataracts, brain anomalies, FTT, and auditory neuropathy are part of the phenotype of the HDBSCC disease. We suggest including JAM3 in the gene list known to cause congenital cataracts, brain hemorrhages, and hearing loss. Further studies should address the auditory neuropathy and FTT phenomena in knockout mice models. We further suggest performing comprehensive ophthalmic, audiologic, and gastroenterologic evaluations for living patients worldwide to further confirm these novel phenomena in this rare entity.
Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005–2021)
Authors: Foley C. M. , McKenna D. , Gallagher K. , McLellan K. , Alkhdher H. , Lacassagne S. , Moraitis E. , Papadopoulou C. , Pilkington C. , Al Obaidi M. , Eleftheriou D. , Brogan P.
Published: September 2023

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005–October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6–14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.
Risk factors for death associated with severe influenza in children and the impact of the COVID-19 pandemic on clinical characteristics
Authors: Hu Qian , Liang Wen , Yi Qiuwei , Zheng Yuejie , Wang Wenjian , Wu Yuhui
Published: September 2023

Background

To summarize the clinical features of severe influenza in children and the high-risk factors for influenza-related deaths and to raise awareness among pediatricians.

Methods

A retrospective study of clinical manifestations, laboratory tests, and diagnosis and treatment of 243 children with severe influenza admitted to Shenzhen Children's Hospital from January 2009 to December 2022 was conducted. Univariate logistic regression analysis and Boruta analysis were also performed to identify potentially critical clinical characteristics associated with death, and clinically significant were used in further multivariate logistic regression analysis. Subject receiver operating characteristic (ROC) curves were applied to assess the efficacy of death-related independent risk factors to predict death from severe influenza.

Results

There were 169 male and 74 female patients with severe influenza, with a median age of 3 years and 2 months and 77.4% of patients under six. There were 46 cases (18.9%) in the death group. The most common pathogen was Influenza A virus (IAV) (81.5%). The most common complication in the death group was influenza-associated acute necrotizing encephalopathy (ANE [52.2%]). Severe influenza in children decreased significantly during the COVID-19 pandemic, with a median age of 5 years, a high predominance of neurological symptoms such as ANE (P = 0.001), and the most common pathogen being H3N2 (P < 0.001). D-dimer, acute respiratory distress syndrome (ARDS), and acute necrotizing encephalopathy (ANE) were significant independent risk factors for severe influenza-associated death. Furthermore, the ROC curves showed that the combined diagnosis of independent risk factors had significant early diagnostic value for severe influenza-related deaths.

Conclusion

Neurological disorders such as ANE are more significant in children with severe influenza after the COVID-19 pandemic. Influenza virus infection can cause serious multisystem complications such as ARDS and ANE, and D-dimer has predictive value for early diagnosis and determination of the prognosis of children with severe influenza.
Pathological role of methionine in the initiation and progression of biliary atresia
Authors: Jiachen Zheng , Paul Kwong Hang Tam , Kenneth Kak Yuen Wong , Vincent Chi Hang Lui
Published: September 2023

Methionine (Met) is an essential amino acid, and its excessive dietary intake and/or its metabolism disturbance could lead to accumulation/depletion of hepatic Met and some of the key intermediates of these pathways, which would interfere normal liver function and would be associated with liver diseases. Biliary atresia (BA) is a life-threatening disease characterized by inflammatory fibrosclerosing changes of the intrahepatic and extrahepatic biliary systems and is the primary cause of obstructive neonatal cholestasis with a rapid course of liver failure. However, its pathogenesis remains unknown. Previous studies reported elevated Met level in patients with obstructive cholestasis, suggesting a potential link between Met and BA. This paper reviews the Met metabolism in normal conditions and its dysregulation under abnormal conditions, the possible causes of hypermethioninemia, and its connection to BA pathogenesis: Abnormal hepatic level of Met could lead to a perturbation of redox homeostasis and mitochondrial functions of hepatocytes, enhancement of viral infectivity, and dysregulation of innate and adaptative immune cells in response to infection/damage of the liver contributing to the initiation/progression of BA.
SGLT2 inhibitors for patients with heart failure with preserved ejection fraction in China: a cost-effectiveness study
Authors: Lu He , Shang Pingping , Zhou Dexing
Published: September 2023

Background: The potential benefits of intervention with empagliflozin or dapagliflozin for patients with heart failure with preserved ejection fraction (HFpEF) were first demonstrated in the EMPEROR-Preserved and DELIVER studies. However, the cost-effectiveness of this intervention (empagliflozin or dapagliflozin) is yet to be established.

Methods: In the context of Chinese healthcare, a Markov model was proposed, which incorporates clinical outcomes from the EMPEROR-Preserved and DELIVER studies, to predict the utility and costs over a lifetime. The time horizon was 20 years, and a 5% discount rate was applied to the costs and utilities. The incremental cost-effectiveness ratio (ICER) threshold against willingness to pay (WTP) was set as the primary outcome. The robustness of the decision was evaluated using sensitivity analyses.

Results: After a simulated 20-year lifetime, a 72-year-old patient with HFpEF in the intervention group (empagliflozin) showed an increase of 0.44 quality-adjusted life years (QALYs) and $1,623.58 with an ICER of $3,691.56 per QALY, which was lower than the WTP threshold of $12,032.10 per QALY. A 72-year-old patient with HFpEF in the intervention group (dapagliflozin) showed an increase of 0.34 QALYs and $2,002.13 with an ICER of $5,907.79 per QALY, which was lower than the WTP threshold of $12,032.10 per QALY. One-way sensitivity analyses showed that cardiovascular (CV) mortality in the intervention and comparator groups was the most sensitive to the decision. Cost-effectiveness was demonstrated in the intervention group (empagliflozin or dapagliflozin) in 67.9% or 62.2% of 1000 Monte Carlo simulations, respectively.

Conclusion: In Chinese healthcare, the interventions (empagliflozin or dapagliflozin) for HFpEF were more cost-effective than the comparators. Our study has provided a quantitative evaluation of the costs and benefits of such interventions for a lifetime using the model.
A physiologically based pharmacokinetic model for V937 oncolytic virus in mice
Authors: Peribañez-Dominguez Sara , Parra-Guillen Zinnia P. , Freshwater Tomoko , Troconiz Iñaki F.
Published: September 2023

Introduction: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes.

Materials and methods: Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4.

Results: Viral levels showed a drop from 108 to 105 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration.

Conclusion: To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.
Drugs for treating myocardial fibrosis
Authors: Ren Zhanhong , Zhang Zixuan , Ling Li , Liu Xiufen , Wang Xin
Published: September 2023

Myocardial fibrosis, which is a common pathological manifestation of many cardiovascular diseases, is characterized by excessive proliferation, collagen deposition and abnormal distribution of extracellular matrix fibroblasts. In clinical practice, modern medicines, such as diuretic and β receptor blockers, and traditional Chinese medicines, such as salvia miltiorrhiza and safflower extract, have certain therapeutic effects on myocardial fibrosis. We reviewed some representative modern medicines and traditional Chinese medicines (TCMs) and their related molecular mechanisms for the treatment of myocardial fibrosis. These drugs alleviate myocardial fibrosis by affecting related signaling pathways and inhibiting myocardial fibrosis-related protein synthesis. This review will provide more references and help for the research and treatment of myocardial fibrosis.
Dipyridamole activates adenosine A2B receptor and AMPK/cAMP signaling and promotes myogenic differentiation of myoblastic C2C12 cells
Authors: Marco-Bonilla Miguel , Herencia Raquel , Fresnadillo María , Huete-Toral Fernando , Carracedo Gonzalo , Largo Raquel , Herrero-Beaumont Gabriel , Mediero Aránzazu
Published: September 2023

Introduction: Sarcopenia is defined as a loss of muscle mass and strength. ATP homeostasis is crucial during myogenesis. We determined how the purinergic system modulates myogenesis using dipyridamole (blocks adenosine taken up by the cells) and tenofovir (inhibits ATP release) in a myoblast cell line.

Methods: C2C12 cells were differentiated in the presence/absence of tenofovir/dipyridamole, with/without the A2B selective inhibitor PSB-603. Extra-/intracellular nucleotides were examined via HPLC. The expression of muscle differentiation proteins (Pax7, Mif5, MyoD, MyoG, and MHC), PKA/CREB, adenosine receptors (A1, A2A, A2B, and A3), ATP-channel pannexin-1 and the P2X7 receptor was analyzed via WB and RT-PCR. cAMP and AMPK activation was measured.

Results: Tenofovir increased intracellular ATP and reduced extracellular adenosine, decreasing Pax7 expression and increasing MHC expression prematurely. Dipyridamole increased intracellular AMP and extracellular adenosine, counteracting the premature myogenesis promoted by tenofovir. All adenosine receptors were expressed during differentiation with dipyridamole, increasing A2B expression. Tenofovir maintained inactive AMPK and decreased cAMP levels, as well as PKAα and pCREB expression, which were recovered with dipyridamole.

Discussion: Adenosine and ATP act as mediators in muscle myogenesis. The blockade of ATP release by tenofovir promotes premature myogenesis, with dipyridamole counteracting the premature differentiation promoted by tenofovir via the adenosine A2B receptor and cAMP/AMPK pathways. Therefore, dipyridamole might be of interest as a therapeutic approach in sarcopenia.
A strong-field THz light source based on coherent transition radiation
Authors: Kang Yin , Wang Ruoyu , Chen Wei , Tu Lingjun , Zhang Kaiqing , Feng Chao
Published: September 2023

Terahertz (THz) radiation is a powerful tool for exploring various scientific frontiers through THz pump–probe experiments. However, different experiments may require THz radiation with different spectral properties, such as broad-band or narrow-band, which are difficult to be generated by a single light source. In this paper, we propose a THz light source that can produce both types of THz radiation by manipulating the longitudinal profile of an electron beam and exploiting coherent transition radiation. We perform theoretical analysis and numerical simulations based on the parameters of the Shanghai soft X-ray Free-Electron Laser facility, and the results show that the proposed light source can generate broad-band THz radiation with a pulse energy of 342 µJ and narrow-band THz radiation with a pulse energy of 91 µJ. The proposed light source can offer more flexibility and versatility for free-electron laser (FEL) users to conduct THz pump–probe experiments.
Defining the glucosylceramide population of C. elegans
Authors: Xatse Mark A. , Olsen Carissa Perez
Published: September 2023

Glucosylceramides (GlcCer) are lipids that impact signaling pathways, serve as critical components of cellular membranes, and act as precursors for hundreds of other complex glycolipid species. Abnormal GlcCer metabolism is linked to many diseases, including cancers, diabetes, Gaucher disease, neurological disorders, and skin disorders. A key hurdle to fully understanding the role of GlcCer in disease is the development of methods to accurately detect and quantify these lipid species in a model organism. This will allow for the dissection of the role of this pool in vivo with a focus on all the individual types of GlcCer. In this review, we will discuss the analysis of the GlcCer population specifically in the nematode Caenorhabditis elegans, focusing on the mass spectrometry-based methods available for GlcCer quantification. We will also consider the combination of these approaches with genetic interrogation of GlcCer metabolic genes to define the biological role of these unique lipids. Furthermore, we will explore the implications and obstacles for future research.
Fermented Astragalus membranaceus could promote the liver and intestinal health of juvenile tiger grouper (Epinephelus fuscoguttatus)
Authors: Yang Jingru , Zhou Shengjie , Fu Zhengyi , Xiao Bo , Li Minghao , Yu Gang , Ma Zhenhua , Zong Humin
Published: September 2023

In order to understand the effects of fermented Astragalus membranaceus (FAM) on the liver and intestinal health of tiger grouper (Epinephelus fuscoguttatus), this study was conducted. This study evaluates the effects of different levels of FAM on liver and intestinal tissue structure, serum biochemical parameters, intestinal digestive enzyme, and microbiota structure of tiger grouper. Fish were fed with diets (crude protein ≥ 48.0%, crude fat ≥ 10.0%) with five levels of FAM (L1:0.25%, L2: 0.5%, L3: 1%, L4: 2% and L5: 4%) in the experimental groups and a regular diet was used as the control (L0: 0%) for 8 weeks. Compared with AM, the protein content of FAM was significantly changed by 34.70%, indicating that a large amount of bacterial protein was produced after AM fermentation, and its nutritional value was improved. FAM had significant effects on the growth performance of tiger grouper (p < 0.05). The high-density lipoprotein cholesterol (HDL-C) was highest in L4 group, being significantly different from L0 group. The area and diameter of hepatocytes were lowest in L3 and L4, and the density of hepatocyte was highest in L4 group and relatively decreased in L5 group. The mucosal height and muscular thickness were highest in L3 group. The intestinal microbiota structure of tiger grouper was changed under the intervention of FAM. The lower abundance of potential pathogenic bacteria and higher abundance of probiotics colonization in the L4 group showed that the dose of FAM had the best effect on improving the health of intestinal microbiota. This study indicates that the addition of FAM in the feed contributes to liver health, improves intestinal morphology, and regulates the intestinal microbiota of tiger grouper. The addition ratio of 1%–2% is better for intestinal and liver health, and a high addition ratio will cause liver damage. Our work will provide a reference for the addition and management of FAM in the aquaculture industry.
Sensorimotor integration is affected by acute whole-body vibration: a coherence study
Authors: Lecce E. , Nuccio S. , Del Vecchio A. , Conti A. , Nicolò A. , Sacchetti M. , Felici F. , Bazzucchi I.
Published: September 2023

Introduction: Several whole-body vibration (WBV) effects on performance have been related to potential changes in the neural drive, motor unit firing rate, and sensorimotor integration. In the present paper, motor unit coherence analysis was performed to detect the source of neural modulation based on the frequency domain.

Methods: Thirteen men [25 ± 2.1 years; Body Mass Index (BMI) = 23.9 ± 1.3 kg m2; maximal voluntary force (MVF): 324.36 ± 41.26 N] performed sustained contractions of the Tibialis Anterior (TA) at 10%MVF before and after acute WBV. The vibrating stimulus was applied barefoot through a platform to target the TA. High-Density surface Electromyography (HDsEMG) was used to record the myoelectrical activity of TA to evaluate coherence from motor unit cumulative spike-trains (CSTs).

Results: Mean coherence showed a significant decrease in the alpha and low-beta bandwidths (alpha: from 0.143 ± 0.129 to 0.132 ± 0.129, p = 0.035; low-beta: from 0.117 ± 0.039 to 0.086 ± 0.03, p = 0.0001), whereas no significant changes were found in the other ones (p > 0.05). The discharge rate (DR) and the Force Covariance (CovF%) were not significantly affected by acute WBV exposure (p > 0.05).

Discussion: According to the significant effects found in alpha and low-beta bandwidths, which reflect sensorimotor integration parameters, accompanied by no differences in the DR and CovF%, the present results underlined that possible neural mechanisms at the base of the previously reported performance enhancements following acute WBV are likely based on sensorimotor integration rather than direct neural drive modulation.
Genetic diversity and signature of divergence in the genome of grapevine clones of Southern Italy varieties
Authors: Villano Clizia , Procino Silvia , Blaiotta Giuseppe , Carputo Domenico , D’Agostino Nunzio , Di Serio Ermanno , Fanelli Valentina , La Notte Pierfederico , Miazzi Monica Marilena , Montemurro Cinzia , Taranto Francesca , Aversano Riccardo
Published: September 2023

Sexual reproduction has contributed to a significant degree of variability in cultivated grapevine populations. However, the additional influence of spontaneous somatic mutations has played a pivotal role in shaping the diverse landscape of grapevine agrobiodiversity. These naturally occurring selections, termed 'clones,' represent a vast reservoir of potentially valuable traits and alleles that hold promise for enhancing grape quality and bolstering plant resilience against environmental and biotic challenges. Despite their potential, many of these clones remain largely untapped.In light of this context, this study aims to delve into the population structure, genetic diversity, and distinctive genetic loci within a collection of 138 clones derived from six Campanian and Apulian grapevine varieties, known for their desirable attributes in viticulture and winemaking. Employing two reduced representation sequencing methods, we extracted Single-Nucleotide Polymorphism (SNP) markers. Population structure analysis and fixation index (FST) calculations were conducted both between populations and at individual loci. Notably, varieties originating from the same geographical region exhibited pronounced genetic similarity.The resulting SNP dataset facilitated the identification of approximately two hundred loci featuring divergent markers (FST ≥ 0.80) within annotated exons. Several of these loci exhibited associations with essential traits like phenotypic adaptability and environmental responsiveness, offering compelling opportunities for grapevine breeding initiatives. By shedding light on the genetic variability inherent in these treasured traditional grapevines, our study contributes to the broader understanding of their potential. Importantly, it underscores the urgency of preserving and characterizing these valuable genetic resources to safeguard their intra-varietal diversity and foster future advancements in grapevine cultivation.