bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory Information and Guidance on Biosimilars and Their Use Across Europe: A Call for Strengthened One Voice Messaging
Authors: Barbier Liese , Mbuaki Allary , Simoens Steven , Declerck Paul , Vulto Arnold G. , Huys Isabelle 
Published: March 2022

BackgroundBeyond evaluation and approval, European and national regulators have a key role in providing reliable information on biosimilars and the science underpinning their development, approval, and use.ObjectivesThis study aims to (i) review biosimilar information and guidance provided by EMA and national medicines agencies and (ii) explore stakeholder perspectives on the role of regulators in enabling acceptance and use of biosimilars.MethodsThis study consists of (i) a comparative review of regulatory information and position statements across medicine agencies (n = 32) and (ii) qualitative interviews with stakeholders in Europe (n = 14).ResultsThe comparative analysis showed that regulatory information and guidance about biosimilars offered by national medicines agencies in Europe varies, and is limited or absent in multiple instances. Approximately 40% (13/31) of the national medicines agencies' websites did not offer any information regarding biosimilars, and for about half (15/31) no educational materials were provided. Only less than half of national medicines agencies provided guidance on biosimilar interchangeability and switching (8/31 and 12/31, respectively). Among the national medicines agencies that did offer guidance, the extent (e.g., elaborate position vs. brief statement) and content (e.g., full endorsement vs. more cautious) of the guidance differed substantially. Countries that have a strong involvement in EU level biosimilar regulatory activities generally had more elaborate information nationally. Interviewees underwrote the need for (national) regulators to intensify biosimilar stakeholder guidance, especially in terms of providing clear positions regarding biosimilar interchangeability and switching, which in turn can be disseminated by the relevant professional societies more locally.ConclusionThis study revealed that, despite strong EU-level regulatory biosimilar guidance, guidance about biosimilars, and their use differs considerably across Member States. This heterogeneity, together with the absence of a clear EU-wide position on interchangeability, may instill uncertainty among stakeholders about the appropriate use of biosimilars in practice. Regulators should strive for a clear and common EU scientific position on biosimilar interchangeability to bridge this gap and unambiguously inform policy makers, healthcare professionals, and patients. Furthermore, there is a clear opportunity to expand information at the national level, and leverage EU-developed information materials more actively in this regard.
Identification of Key Biomarkers and Pathways for Maintaining Cognitively Normal Brain Aging Based on Integrated Bioinformatics Analysis
Authors: Xu Jinling , Zhou Hui , Xiang Guangda 
Published: March 2022

BackgroundGiven the arrival of the aging population has caused a series of social and economic problems, we aimed to explore the key genes underlying cognitively normal brain aging and its potential molecular mechanisms.MethodsGSE11882 was downloaded from Gene Expression Omnibus (GEO). The data from different brain regions were divided into aged and young groups for analysis. Co-expressed differentially expressed genes (DEGs) were screened. Functional analysis, protein–protein interaction (PPI) network, microRNA (miRNA)-gene, and transcription factor (TF)-gene networks were performed to identify hub genes and related molecular mechanisms. AlzData database was used to elucidate the expression of DEGs and hub genes in the aging brain. Animal studies were conducted to validate the hub genes.ResultsCo-expressed DEGs contained 7 upregulated and 87 downregulated genes. The enrichment analysis indicated DEGs were mainly involved in biological processes and pathways related to immune-inflammatory responses. From the PPI network, 10 hub genes were identified: C1QC, C1QA, C1QB, CD163, FCER1G, VSIG4, CD93, CD14, VWF, and CD44. CD44 and CD93 were the most targeted DEGs in the miRNA-gene network, and TIMP1, HLA-DRA, VWF, and FGF2 were the top four targeted DEGs in the TF-gene network. In AlzData database, the levels of CD44, CD93, and CD163 in patients with Alzheimer’s disease (AD) were significantly increased than those in normal controls. Meanwhile, in the brain tissues of cognitively normal mice, the expression of CD44, CD93, and CD163 in the aged group was significantly lower than those in the young group.ConclusionThe underlying molecular mechanisms for maintaining healthy brain aging are related to the decline of immune-inflammatory responses. CD44, CD93, and CD 163 are considered as potential biomarkers. This study provides more molecular evidence for maintaining cognitively normal brain aging.
Risk of Dementia or Cognitive Impairment in Sepsis Survivals: A Systematic Review and Meta-Analysis
Authors: Lei Siyuan , Li Xuanlin , Zhao Hulei , Feng Zhenzhen , Chun Liu , Xie Yang , Li Jiansheng 
Published: March 2022

BackgroundThere is growing evidence that sepsis survivors are at increased risk of developing new-onset atrial fibrillation, acute kidney injury, and neurological diseases. However, whether sepsis survivals increase the risk of dementia or cognitive impairment remains to be further explored.ObjectiveThe objective of this study was to determine whether sepsis survivals increase the risk of dementia or cognitive impairment.MethodsWe searched PubMed, Cochrane Library, Web of Science, and EMBASE databases for cohort studies or case-control studies from their inception to November 5, 2021. The quality of this study was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). The Stata software (version 15.1) was used to calculate the odds ratio (OR) of dementia or cognitive impairment in sepsis survivals. Subgroup and sensitivity analyses were performed to assess the source of heterogeneity. Funnel plots and Egger’s test were used to detect the publication bias.ResultsEight studies (i.e., seven cohort studies and one case-control study) involving 891,562 individuals were included. The quality assessment results showed that the average score of NOS was over 7, and the overall quality of the included studies was high. Pooled analyses indicated that sepsis survivals were associated with an increased risk of all-cause dementia (OR = 1.62, 95% CI = 1.23–2.15, I2 = 96.4%, p = 0.001). However, there was no obvious association between sepsis survivals and the risk of cognitive impairment (OR = 1.77, 95% CI = 0.59–5.32, I2 = 87.4%, p = 0.306). Subgroup analyses showed that severe sepsis was associated with an increased risk of dementia or cognitive impairment (OR = 1.99, 95% CI = 1.19–3.31, I2 = 75.3%, p = 0.008); such risk was higher than that of other unspecified types of sepsis (OR = 1.47, 95% CI = 1.04–2.09, I2 = 97.6%, p = 0.029).ConclusionSepsis survivals are associated with an increased risk of all-cause dementia but not with cognitive impairment. Appropriate management and prevention are essential to preserve the cognitive function of sepsis survivors and reduce the risk of dementia.
Preventing Sleep Disruption With Bright Light Therapy During Chemotherapy for Breast Cancer: A Phase II Randomized Controlled Trial
Authors: Rissling Michelle , Liu Lianqi , Youngstedt Shawn D. , Trofimenko Vera , Natarajan Loki , Neikrug Ariel B. , Jeste Neelum , Parker Barbara A. , Ancoli-Israel Sonia 
Published: March 2022

PurposeThe goal of this study was to examine whether daily increased morning light exposure would maintain or improve sleep and the circadian pattern of relatively more activity in the day and less during the night in women undergoing chemotherapy for breast cancer.Patients and MethodsParticipants were 39 women with newly diagnosed breast cancer, randomized to either 30-mins of daily morning bright white light (BWL) or dim red light (DRL). Sleep/wake was measured objectively for 72-h with wrist actigraphy and subjectively with the Pittsburgh Sleep Quality Index (PSQI) prior to and during chemotherapy cycles 1 and 4. The study was registered with the National Institutes of Health ClinicalTrials.gov (Clinical Trials number: NCT00478257).ResultsResults from actigraphy suggested that compared to the DRL group, women in the BWL group had longer night-time sleep, fewer sleep disturbances during the night, and had fewer and shorter daytime naps at the end of cycle 4 of chemotherapy as well as exhibiting less activity at night and more activity during the day by the end of cycle 4. Results from PSQI indicated that components of sleep quality improved but daytime dysfunction deteriorated during cycle 4 treatment in the BWL group; meanwhile the DRL group used more sleep medications in the treatment weeks which might have led to the improved sleep quality during the recovery weeks of both cycles.ConclusionThese results suggest that bright white light therapy administered every morning on awakening may protect women undergoing chemotherapy for breast cancer from nighttime sleep and daytime wake disruption. Randomized clinical trials in larger samples are needed to confirm these findings.
Radial Data Mining to Identify Density–Dose Interactions That Predict Distant Failure Following SABR
Authors: Davey Angela , van Herk Marcel , Faivre-Finn Corinne , McWilliam Alan 
Published: March 2022

PurposeLower dose outside the planned treatment area in lung stereotactic radiotherapy has been linked to increased risk of distant metastasis (DM) possibly due to underdosage of microscopic disease (MDE). Independently, tumour density on pretreatment computed tomography (CT) has been linked to risk of MDE. No studies have investigated the interaction between imaging biomarkers andincidentaldose. The interaction would showcase whether the impact of dose on outcome is dependent on imaging and, hence, if imaging could inform which patients require dose escalation outside the gross tumour volume (GTV). We propose an image-based data mining methodology to investigate density–dose interactions radially from the GTV to predict DM with noa prioriassumption on location.MethodsDose and density were quantified in 1-mm annuli around the GTV for 199 patients with early-stage lung cancer treated with 60 Gy in 5 fractions. Each annulus was summarised by three density and three dose parameters. For parameter combinations, Cox regressions were performed including adose–densityinteraction in independent annuli. Heatmaps were created that described improvement in DM prediction due to the interaction. Regions of significant improvement were identified and studied in overall outcome models.ResultsDose–density interactions were identified that significantly improved prediction for over 50% of bootstrap resamples. Dose and density parameters werenotsignificant when the interaction was omitted. Tumour density variance and high peritumour density were associated with DM for patients with more cold spots (less than 30-Gy EQD2) and non-uniform dose about 3 cm outside of the GTV. Associations identified were independent of the mean GTV dose.ConclusionsPatients with high tumour variance and peritumour density have increased risk of DM if there is a low and non-uniform dose outside the GTV. The dose regions are independent of tumour dose, suggesting thatincidentaldose may play an important role in controlling occult disease. Understanding such interactions is key to identifying patients who will benefit from dose-escalation. The methodology presented allowed spatial dose–density interactions to be studied at the exploratory stage for the first time. This could accelerate the clinical implementation of imaging biomarkers by demonstrating the impact ofincidentaldose for tumours of varying characteristics in routine data.
Elucidating the Synergistic Effect of Multiple Chinese Herbal Prescriptions in the Treatment of Post-stroke Neurological Damage
Authors: Xu Anqi , Wen Zhuo-Hua , Su Shi-Xing , Chen Yu-Peng , Liu Wen-Chao , Guo Shen-Quan , Li Xi-Feng , Zhang Xin , Li Ran , Xu Ning-Bo , Wang Ke-Xin , Li Wen-Xing , Guan Dao-Gang , Duan Chuan-Zhi 
Published: March 2022

Background: Traditional Chinese medicine (TCM) has been widely used in the treatment of human diseases. However, the synergistic effects of multiple TCM prescriptions in the treatment of stroke have not been thoroughly studied.Objective of the study: This study aimed to reveal the mechanisms underlying the synergistic effects of these TCM prescriptions in stroke treatment and identify the active compounds.Methods: Herbs and compounds in the Di-Tan Decoction (DTD), Xue-Fu Zhu-Yu Decoction (XFZYD), and Xiao-Xu-Ming Decoction (XXMD) were acquired from the TCMSP database. SEA, HitPick, and TargetNet web servers were used for target prediction. The compound-target (C-T) networks of three prescriptions were constructed and then filtered using the collaborative filtering algorithm. We combined KEGG enrichment analysis, molecular docking, and network analysis approaches to identify active compounds, followed by verification of these compounds with an oxygen-glucose deprivation and reoxygenation (OGD/R) model.Results: The filtered DTD network contained 39 compounds and 534 targets, the filtered XFZYD network contained 40 compounds and 508 targets, and the filtered XXMD network contained 55 compounds and 599 targets. The filtered C-T networks retained approximately 80% of the biological functions of the original networks. Based on the enriched pathways, molecular docking, and network analysis results, we constructed a complex network containing 3 prescriptions, 14 botanical drugs, 26 compounds, 13 targets, and 5 pathways. By calculating the synergy score, we identified the top 5 candidate compounds. The experimental results showed that quercetin, baicalin, and ginsenoside Rg1 independently and synergistically increased cell viability.Conclusion: By integrating pharmacological and chemoinformatic approaches, our study provides a new method for identifying the effective synergistic compounds of TCM prescriptions. The filtered compounds and their synergistic effects on stroke require further research.
Diabetes, Metformin and the Clinical Course of Covid-19: Outcomes, Mechanisms and Suggestions on the Therapeutic Use of Metformin
Authors: Bailey Clifford J. , Gwilt Mike 
Published: March 2022

Objectives: Pre-existing or new diabetes confers an adverse prognosis in people with Covid-19. We reviewed the clinical literature on clinical outcomes in metformin-treated subjects presenting with Covid-19.Methods: Structured PubMed search: metformin AND [covid (ti) OR covid-19 (ti) OR covid19 (ti) OR coronavirus (ti) OR SARS-Cov2 (ti)], supplemented with another PubMed search: “diabetes AND [covid OR covid-19 OR covid19 OR coronavirus (i) OR SARS-Cov2 (ti)]” (limited to “Clinical Study”, “Clinical Trial”, “Controlled Clinical Trial”, “Meta-Analysis”, “Observational Study”, “Randomized Controlled Trial”, “Systematic Review”).Results: The effects of metformin on the clinical course of Covid-19 were evaluated in retrospective analyses: most noted improved clinical outcomes amongst type 2 diabetes patients treated with metformin at the time of hospitalisation with Covid-19 infection. These outcomes include reduced admission into intensive care and reduced mortality in subgroups with versus without metformin treatment.Conclusion: The pleiotropic actions of metformin associated with lower background cardiovascular risk may mediate some of these effects, for example reductions of insulin resistance, systemic inflammation and hypercoagulability. Modulation by metformin of the cell-surface ACE2 protein (a key binding target for SARS-CoV 2 spike protein) via the AMP kinase pathway may be involved. While pre-existing metformin treatment offers potentially beneficial effects and can be continued when Covid-19 infection is not severe, reports of increased acidosis and lactic acidosis in patients with more severe Covid-19 disease remind that metformin should be withdrawn in patients with hypoxaemia or acute renal disease. Prospective study of the clinical and metabolic effects of metformin in Covid-19 is warranted.
Evaluation and Application of Population Pharmacokinetic Models for Identifying Delayed Methotrexate Elimination in Patients With Primary Central Nervous System Lymphoma
Authors: Mao Junjun , Li Qing , Li Pei , Qin Weiwei , Chen Bobin , Zhong Mingkang 
Published: March 2022

Objective: Several population pharmacokinetic (popPK) models have been developed to determine the sources of methotrexate (MTX) PK variability. It remains unknown if these published models are precise enough for use or if a new model needs to be built. The aims of this study were to 1) assess the predictability of published models and 2) analyze the potential risk factors for delayed MTX elimination.Methods: A total of 1458 MTX plasma concentrations, including 377 courses (1–17 per patient), were collected from 77 patients who were receiving high-dose MTX for the treatment of primary central nervous system lymphoma in Huashan Hospital. PopPK analysis was performed using the NONMEM® software package. Previously published popPK models were selected and rebuilt. A new popPK model was then constructed to screen potential covariates using a stepwise approach. The covariates were included based on the combination of theoretical mechanisms and data properties. Goodness-of-fit plots, bootstrap, and prediction- and simulation-based diagnostics were used to determine the stability and predictive performance of both the published and newly built models. Monte Carlo simulations were conducted to qualify the influence of risk factors on the incidence of delayed elimination.Results: Among the eight evaluated published models, none presented acceptable values of bias or inaccuracy. A two-compartment model was employed in the newly built model to describe the PK of MTX. The estimated mean clearance (CL/F) was 4.91 L h−1 (relative standard error: 3.7%). Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F. The median and median absolute prediction errors of the final model were -10.2 and 36.4%, respectively. Results of goodness-of-fit plots, bootstrap, and prediction-corrected visual predictive checks indicated the high predictability of the final model.Conclusions: Current published models are not sufficiently reliable for cross-center use. The elderly patients and those with renal dysfunction, hypoalbuminemia are at higher risk of delayed elimination.
Subchronic Oral Toxicity of Sodium p-Hydroxybenzoate in Sprague-Dawley Rats
Authors: Fan Xiaoli , Song Hengzhi , Xu Xiaotian , Lu Xi , Wang Yuhui , Duan Xiaoqun 
Published: March 2022

p-Hydroxybenzoic acid (p-HBA), which exists extensively in plants, is well known for its anti-inflammatory effects, but various adverse side effects have also been reported. Previous research has found that acid translated to its sodium salt improves the safety profile of compounds. Therefore, we hypothesized that p-HBA translated to sodium p-hydroxybenzoate would improve its safety profile. In the present study, we evaluated the toxicity of sodium p-hydroxybenzoate after 90 days of repeated oral toxicity experiments according to OECD guidelines in male and female Sprague–Dawley rats. Sodium p-hydroxybenzoate was administered orally to SD rats at doses of 0, 125, 250, and 500 mg/kg body weight (BW)/day for 90 days. All animals survived to the end of the study, and no sodium p-hydroxybenzoate treatment-associated mortality or clinical changes were observed during the study period. Sodium p-hydroxybenzoate did not promote any clinical signs of toxicologically relevant effects, including changes in body weight, food intake and urinalysis parameters, in male or female SD rats. Dose-related alterations in hematological parameters, organ weights and histopathological findings in hepatic tissue were examined in animals of both sexes in the 500 mg/kg BW/day group. Based on the study, the no-observed-adverse-effect level (NOAEL) for sodium p-hydroxybenzoate was determined to be 250 mg/kg BW/day in both male and female rats.
Low FODMAP Diet and Probiotics in Irritable Bowel Syndrome: A Systematic Review With Network Meta-analysis
Authors: Xie Chao-Rong , Tang Bin , Shi Yun-Zhou , Peng Wen-Yan , Ye Kun , Tao Qing-Feng , Yu Shu-Guang , Zheng Hui , Chen Min 
Published: March 2022

Background: Probiotic and low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet are two commonly used management approaches for patients with irritable bowel syndrome (IBS). We aimed to evaluate the most effective combinations and components among different probiotics or low FODMAP diet through component network meta-analysis (NMA).Methods: We searched Embase, Ovid Medline, and Web of Science from inception to 21 January 2021. Randomized controlled trials (RCTs) examining the efficacy of probiotics and low FODMAP diet for IBS were included, with placebo, sham diet, or conventional treatments as controls. Binary outcomes were compared among treatments using the relative ratio (RR). A minimally contextualized framework recommended by the GRADE group was used to evaluate the certainty of evidence. The primary efficacy outcome was the relief of global IBS symptoms, and the secondary efficacy outcome was the reduction in IBS symptom scores or abdominal pain scores.Key Results: We included 76 RCTs (n = 8058) after screening 1940 articles. Eight RCTs were classified as low risk of bias. Standard network meta-analysis (NMA) showed that Lactobacillus (RR 1.74, 95% CI 1.22–2.48) and Bifidobacterium (RR 1.76, 95% CI 1.01–3.07) were the most effective for the primary efficacy outcome (high certainty evidence); component NMA showed that Bacillus (RR 5.67, 95% CI 1.88 to 17.08, p = 0.002) and Lactobacillus (RR 1.42, 95% CI 1.07 to 1.91, p = 0.017) were among the most effective components. The results of standard NMA and CNMA analysis of the improvement of overall IBS symptom scores or abdominal pain scores were consistent with this finding.Conclusion:Lactobacillus was the most effective component for the relief of IBS symptoms; Bifidobacterium and Bacillus were possibly effective and need further verification.Systematic Review Registration: website, identifier registration number.