bluuebunny/crossref_metadata_2025_split huggingface dataset:
A review of patient-reported outcomes used for regulatory approval of oncology medicinal products in the European Union between 2017 and 2020
Authors: Teixeira Maria Manuel , Borges Fábio Cardoso , Ferreira Paula Sousa , Rocha João , Sepodes Bruno , Torre Carla 
Published: August 2022

IntroductionCancer and corresponding available treatments are associated with substantial symptoms and functional limitations. In this context, collection of patient-reported outcomes (PRO) in clinical trials gained special interest and is recommended by regulatory authorities. Within clinical trials framework, PRO may provide evidence to support medicines approval, labeling and marketing claims. This study aims to analyze the existing evidence based on PRO as part of new oncology indications receiving positive opinions issued by the European Medicines Agency (EMA) between 2017 and 2020 and to identify PRO related label claims granted.MethodologyOncology medicinal products and indications approved by the European Commission following a positive opinion from the EMA between 2017 and 2020 were identified. European Public Assessment Report (EPAR) and Summary of Product Characteristics (SmPC) were reviewed for each medicinal product to identify use of PRO and PRO label claims.ResultsA total of 128 oncology indications, corresponding to 76 medicines, were approved; of those, 100 (78.1%) included PRO in the confirmatory clinical trials. Thirty-seven indications were supported by double-blind randomized trials and the remainder 63 by open-label trials. Out of the 104 confirmatory trials analyzed, PRO were defined as a secondary endpoint in 60 studies (57.7%), exploratory in 31 (29.8%) and as both in 13 (12.5%). In total, 54 different PRO measures (PROM) were used, of those 41 (75.9%) were disease-specific measures. Nevertheless, PROM selected relied on the EORTC (41.3%), FACIT (17.1%) and EQ-5D (29.2%) measures. A total of 76 indications (59.4%) had PRO reviewers comments included in the EPAR, however only 22 indications (17.8%) included label claims in the SmPC. The reasons identified in the EMA assessment supporting the exclusion of PRO claims were described for 34 indications (44.7%).ConclusionsDespite growing recognition of the value of PRO data for the development of improved cancer therapies, PRO implementation remains challenging. The main reasons identified in our study are related with study design, missing data, study conduct and PROM selection.
Residual reserve index modifies the effect of amyloid pathology on fluorodeoxyglucose metabolism: Implications for efficiency and capacity in cognitive reserve
Authors: McKenzie Cathryn , Bucks Romola S. , Weinborn Michael , Bourgeat Pierrick , Salvado Olivier , Gavett Brandon E. 
Published: August 2022

BackgroundThe residual approach to measuring cognitive reserve (using the residual reserve index) aims to capture cognitive resilience conferred by cognitive reserve, but may be confounded by factors representing brain resilience. We sought to distinguish between brain and cognitive resilience by comparing interactions between the residual reserve index and amyloid, tau, and neurodegeneration [“AT(N)”] biomarkers when predicting executive function. We hypothesized that the residual reserve index would moderate at least one path from an AT(N) biomarker to executive function (consistent with cognitive resilience), as opposed to moderating a path between two AT(N) biomarkers (suggestive of brain resilience).MethodsParticipants (N = 332) were from the Alzheimer’s Disease Neuroimaging Initiative. The residual reserve index represented the difference between observed and predicted memory performance (a positive residual reserve index suggests higher cognitive reserve). AT(N) biomarkers were: CSF β-amyloid1–42/β-amyloid1–40 (A), plasma phosphorylated tau-181 (T), and FDG metabolism in AD-specific regions ([N]). AT(N) biomarkers (measured at consecutive time points) were entered in a sequential mediation model testing the indirect effects from baseline amyloid to executive function intercept (third annual follow-up) and slope (baseline to seventh follow-up), via tau and/or FDG metabolism. The baseline residual reserve index was entered as a moderator of paths between AT(N) biomarkers (e.g., amyloid-tau), and paths between AT(N) biomarkers and executive function.ResultsThe residual reserve index interacted with amyloid pathology when predicting FDG metabolism: the indirect effect of amyloid → FDG metabolism → executive function intercept and slope varied as a function of the residual reserve index. With lower amyloid pathology, executive function performance was comparable at different levels of the residual reserve index, but a higher residual reserve index was associated with lower FDG metabolism. With higher amyloid pathology, a higher residual reserve index predicted better executive function via higher FDG metabolism.ConclusionThe effect of the residual reserve index on executive function performance via FDG metabolism was consistent with cognitive resilience. This suggests the residual reserve index captures variation in cognitive reserve; specifically, neural efficiency, and neural capacity to upregulate metabolism to enhance cognitive resilience in the face of greater amyloid pathology. Implications for future research include the potential bidirectionality between neural efficiency and amyloid accumulation.
The nomogram for the prediction of overall survival in patients with metastatic lung adenocarcinoma undergoing primary site surgery: A retrospective population-based study
Authors: Ma Chao , Peng Shuzhen , Zhu Boya , Li Siying , Tan Xiaodong , Gu Yaohua 
Published: August 2022

BackgroundLung adenocarcinoma (LUAD) is the most common type of Non-small-cell lung cancer (NSCLC). Distant metastasis of lung adenocarcinoma reduces the survival rate. we aim to develop a nomogram in order to predict the survival of patients with metastatic lung adenocarcinoma.MethodsWe retrospectively collected patients who were initially diagnosed as metastatic LUAD from 2010 to 2015 from SEER database. Based on the multivariate and univariate Cox regression analysis of the training cohorts, independent prognostic factors were assessed. The nomogram prediction model was then constructed based on these prognostic factors to predict the overall survival at 12, 24 and 36 months after surgery. Nomogram were identified and calibrated by c-index, time-dependent receiver operating characteristic curve (time-dependent AUC) and calibration curve. Decision curve analysis (DCA) was used to quantify the net benefit of the nomogram at different threshold probabilities, and to better compare with the TNM staging system, we calculated the c-index of this nomogram as well as the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI).ResultA total of 1102 patients with metastatic LUAD who met the requirements were included for analysis. They were randomly divided into 774 in the training cohorts and 328 in the validation cohorts. As can be seen from the calibration plots, the predicted nomogram and the actual observations in both of the training and validation cohorts were generally consistent. The time dependent AUC values of 12 months, 24 months and 36 months were 0.707, 0.674 and 0.686 in the training cohorts and 0.690, 0.680 and 0.688 in the verification cohorts, respectively. C-indexes for the training and validation cohorts were 0.653 (95%CI 0.626-0.68)and 0.663 (95%CI 0.626-1), respectively. NRI and IDI show that the model is more clinical applicable than the existing staging system. In addition, our risk scoring system based on Kaplan Meier (K-M) survival curve can accurately divide patients into three hierarchy risk groups.ConclusionThis has led to the development and validation of a prognostic nomogram to assist clinicians in determining the prognosis of patients with metastatic lung adenocarcinoma after primary site surgery.
The global research status and trends of the application of endoscopic ultrasonography in pancreatic tumors over the last decades: A bibliometric study
Authors: Xia Chuanchao , Yin Hua , Zhang Kecheng , Wang Zhenhuan , Yang Xiaoli , Huang Haojie 
Published: August 2022

BackgroundTo describe the development process and structural relationships of scientific achievements in endoscopic ultrasonography (EUS) in pancreatic tumors over the past decades and to reveal the key research topics using bibliometric analysis.MethodsAll relevant publications covering the research of EUS in pancreatic tumors from 1984 to 2021 were involved through the Web of Science Core Collection. R-bibliometrix was used to conduct the bibliometric analysis, and VOSviewer software was used to explore the hot spots and networks related to this field.ResultsBetween 1984 and 2021, 4071 publications were involved. The number of annual publications increased from 1 to 310. The United States contributed the most publications to this field (n=1433, 35.20%), followed by Japan (n=827, 20.31%) and Germany (n=319, 7.84%). There was active cooperation between countries/regions. Gastrointestinal Endoscopy (GIE) was the most productive journal and the most influential journal. Professor Giovannini M, who produced the most publications, had a great influence on this research. The focus in this field was clarified by analyzing the top 10 citations and co-citations publications. Moreover, the analysis of the keywords showed Important topics: “Classification of pancreatic tumor disease” “Development of EUS in the diagnosis of pancreatic tumor diseases,” and “Development of EUS in the treatment of pancreatic tumor diseases.”ConclusionFor the first time, bibliometric analysis was used to gain a deep understanding of the global trends of studies investigating EUS in pancreatic tumor diseases. The EUS field is rapidly evolving, and our study may be a critical reference for clinical researchers related to this field.
A prospective comparison between multidisciplinary healthcare providers' clinical examination and a validated pain scale
Authors: Menezes Rodrigo C. , Silva Raissa L. O. , Arriaga María B. , Ferreira Isabella B. B. , Carmo Thomas A. , da Silva Victor R. , Otero Matheus L. , Gobatto André L. N. , Agareno Sydney , Filgueiras Filho Nivaldo M. , Akrami Kevan M. , Andrade Bruno B. 
Published: August 2022

IntroductionUnrecognized pain in the Intensive Care Unit (ICU), due to inadequate assessment and therapeutic management, is associated with increased morbidity and mortality. Despite the availability of validated pain monitoring tools, such as the Critical-Care Pain Observational Tool (CPOT), these scales are not commonly used in clinical practice, with healthcare professionals often relying on their clinical impression. Our study aims to determine the agreement between the pain examination performed by ICU professionals and the CPOT.MethodsProspective cohort study that included critically ill patients and physicians, nurses and physiotherapists from an ICU in Bahia, Brazil. During bedside clinical rounds, the CPOT score was applied to assess the pain of hospitalized patients, and health professionals were interviewed to ascertain their perception of the patient's pain for a maximum of five consecutive days. Correlations were assessed using the Spearman rank tests. Hierarchical cluster analysis was employed to show the results of CPOT score and pain assessment by healthcare professionals at each study time. And the Kappa statistic was calculated to assess the agreement between the CPOT score vs. the pain assessment by healthcare providers.ResultsOne hundred one patients were included in the study with median age of 74 years (IQR 61.5–83.5), a predominance of women (55.4%) and a median SAPS 3 score of 45 (IQR 39.5–53.0). The correlation between the professional's pain assessment and the CPOT were mostly statistically significant, ranged from negligible to weak, being the highest index obtained in the evaluation of nurses on day 5 (Kappa index = 0.43, p = 0.005). Physician assessments were significant only in day 1. On the presence of pain, the professionals' assessments and CPOT revealed mild to a moderate agreement.ConclusionHealthcare professional's pain assessment displayed a weak positive correlation with a validated pain scale and poor agreement amongst members of the ICU team, particularly when the pain was felt to be absent. Thus, this study highlights the importance of routine tools for pain assessment in the ICU for all members of multidisciplinary teams.
Associations of self-reported residential noise exposure with obesity and hypertension in children and adolescents
Authors: Liang Xiaohua , Tang Xian , Liu Mingliang , Liang Xiaoyue , Chen Li , Chen Xia , Zuo Lei , Ren Yanling , Hao Guang 
Published: August 2022

BackgroundEpidemiologic evidence linking environmental noise to obesity and hypertension remains scarce, especially in children, and the results remain inconclusive. This study aims to examine the cross-sectional associations of self-reported residential noise exposure with obesity and hypertension in children and adolescents.MethodsAs an ongoing study, a representative sample of the children aged 6–9 years in Chongqing were selected in 2014. In 2019, self-reported residential noise (answer categories: “very quiet,” “moderately quiet,” “slightly quiet,” and “not at all quiet”) data were collected, and 3,412 participants with completed data were included in the analyses.ResultsParticipants living in a quieter area had a significantly lower risk of obesity than those living in a noisy area (very quiet: OR = 0.50, 95%CI: 0.29–0.88, P = 0.015; moderately quiet: OR = 0.61, 95%CI: 0.36–1.02, P = 0.059). Similar associations were observed for abdominal obesity, although did not reach statistical significance. Consistently, residential noise exposure was significantly associated with body mass index (BMI) and waist-to-height ratio. Self-reported residential noise exposure was positively associated with systolic blood pressure (β = −1.808; 95%CI = −3.495, −0.110; P = 0.037). When sleep quality, study stress, BMI, and vegetable/fruits consumption were further adjusted, all effect estimates decreased, and no statistical association was observed between noise exposure and blood pressure. Furthermore, we found that the mediating effects of obesity on the associations of self-reported residential noise exposure with hypertension were 6.8% (% of total effect mediated = 0.068, 95%CI: −2.58, 3.99), although did not reach statistical significance.ConclusionsSelf-reported residential noise exposure was associated with a higher risk of obesity or abdominal obesity. Also, self-reported residential noise exposure was positively associated with hypertension, and obesity may partially mediate this association, but did not reach statistical significance.
Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition
Authors: Ushio Soichiro , Wada Yudai , Nakamura Mizuki , Matsumoto Daiki , Hoshika Kota , Shiromizu Shoya , Iwata Naohiro , Esumi Satoru , Kajizono Makoto , Kitamura Yoshihisa , Sendo Toshiaki 
Published: August 2022

Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 μg/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 releasein vivoandin vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior.
Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity
Authors: Karathanasis Dimitris K. , Rapti Anna , Nezos Adrianos , Skarlis Charalampos , Kilidireas Constantinos , Mavragani Clio P. , Evangelopoulos Maria Eleftheria 
Published: August 2022

Objective: While multiple sclerosis (MS) is considered the cornerstone of autoimmune demyelinating CNS disorders, systemic autoimmune diseases (SADs) are important MS mimickers. We sought to explore whether distinct clinical, laboratory, and imaging characteristics along with quantitation of peripheral blood type I interferon (IFN) activity could aid in differentiating between them.Methods: A total of 193 consecutive patients with imaging features suggesting the presence of CNS demyelinating disease with or without relevant clinical manifestations underwent full clinical, laboratory, and imaging evaluation, including testing for specific antibodies against 15 cellular antigens. Expression analysis of type I IFN-inducible genes (MX-1, IFIT-1, and IFI44) was performed by real-time PCR, and a type I IFN score, reflecting type I IFN peripheral activity, was calculated. After joint neurological/rheumatological evaluation and 1 year of follow-up, patients were classified into MS spectrum and CNS autoimmune disorders.Results: While 66.3% (n = 128) of the patients were diagnosed with MS spectrum disorders (predominantly relapsing–remitting MS), 24.9% (n = 48) were included in the CNS autoimmune group, and out of those, one-fourth met the criteria for SAD (6.7% of the cohort, n = 13); the rest (18.1% of the cohort, n = 35), despite showing evidence of systemic autoimmunity, did not fulfill SAD criteria and comprised the “demyelinating disease with autoimmune features” (DAF) subgroup. Compared to the MS spectrum, CNS autoimmune patients were older, more frequently females, with increased rates of hypertension/hyperlipidemia, family history of autoimmunity, cortical dysfunction, anti-nuclear antibody titers ≥1/320, anticardiolipin IgM positivity, and atypical for MS magnetic resonance imaging lesions. Conversely, lower rates of infratentorial and callosal MRI lesions, CSF T2 oligoclonal bands, and IgG-index positivity were observed in CNS autoimmune patients. Patients fulfilling SAD criteria, but not the DAF group, had significantly higher peripheral blood type I IFN scores at baseline compared to MS spectrum [median (IQR)]: 50.18 (152.50) vs. −0.64 (6.75), p-value: 0.0001.Conclusion: Our study suggests that underlying systemic autoimmunity is not uncommon in patients evaluated for possible CNS demyelination. Distinct clinical, imaging and laboratory characteristics can aid in early differentiation between MS and CNS-involving systemic autoimmunity allowing for optimal therapeutic strategies. Activated type I IFN pathway could represent a key mediator among MS-like-presenting SADs and therefore a potential therapeutic target.
Active optical clock lasing on the Cs 7S1/2-6P3/2 transition under a weak magnetic field
Authors: Shi Tiantian , Miao Jianxiang , Zhang Jia , Chen Jingbiao 
Published: August 2022

In the bad-cavity limit, the collective atomic dipole is highly coherent, resulting in the phase information of an active optical clock (AOC) laser primarily stored in the atomic gain medium. Therefore, compared with the good-cavity laser, the sensitivity of an AOC laser to cavity fluctuations is greatly reduced, as characterized by the suppressed cavity-pulling effect. In this work, the AOC lasing on the cesium 7S1/2-6P3/2 clock transition with a natural linewidth of 1.81 MHz under a weak magnetic field is achieved. We calculate the Zeeman spectra of upper and lower states of clock transition, and measure the beat-note spectrum between different Zeeman-sublevel transitions of 7S1/2-6P3/2. Moreover, the cavity-pulling, temperature, power, and linewidth characteristics of the AOC laser are demonstrated under a weak magnetic field. Such an emerging laser can be applied as a narrow-linewidth local oscillator, as well as an active optical frequency standard, which is promising for the field of precision measurement.
Pain acceptance and illness intrusiveness in low-back pain: A longitudinal study
Authors: Simoncsics Eszter , Konkolý Thege Barna , Stauder Adrienne 
Published: August 2022

BackgroundIn chronic pain syndromes, acceptance of pain may be a better approach than pain control. So far, little data have been available on how pain and its acceptance affect illness intrusiveness among patients with low-back pain (LBP).ObjectiveThe present longitudinal study evaluates the impact of pain acceptance on illness intrusiveness in patients with LBP.MethodsStudy participants were asked to complete the following questionnaires during their visit (T1) at one of four diverse rheumatologic outpatient clinics, and then 2–3 months later (T2) via phone or online: Chronic Pain Acceptance Questionnaire (CPAQ), Illness Intrusiveness Rating Scale (IIRS), Roland-Morris Disability Questionnaire (RMDQ), Patient Health Questionnaire Depression subscale (PHQ9), and socioeconomic data.ResultsOne hundred and twenty-seven individuals completed the questionnaires at baseline (31 having acute, 15 subacute and 81 chronic low back pain) and 97 at follow-up. Illness intrusiveness was negatively correlated with chronic pain acceptance both at T1 (r = −0.39) and T2 (r = –0.44). Illness intrusiveness scores have not changed significantly from T1 (M = 28.59 SD = 13.08) to T2 (M = 28.24, SD = 15.76). In a multiple regression model—including pain intensity, functional status, pain acceptance, depression severity, age, sex and educational level—the independent predictors of follow-up illness intrusiveness scores were lower pain acceptance and higher depression scores.ConclusionsIn our study, patients with acute, subacute and chronic low back pain reported similar levels of illness intrusiveness. In addition, illness intrusiveness scores have not changed significantly during the 2-month follow-up period and pain acceptance proved to be a significant independent predictor of illness intrusiveness among patients with chronic low-back pain.