bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Jones et al.’s method for extending Bland-Altman plots to limits of agreement with the mean for multiple observers
Authors: Christensen Heidi S. , Borgbjerg Jens , Børty Lars , Bøgsted Martin 
Published: December 2020

Abstract
Background
To assess the agreement of continuous measurements between a number of observers, Jones et al. introduced limits of agreement with the mean (LOAM) for multiple observers, representing how much an individual observer can deviate from the mean measurement of all observers. Besides the graphical visualisation of LOAM, suggested by Jones et al., it is desirable to supply LOAM with confidence intervals and to extend the method to the case of multiple measurements per observer.

Methods
We reformulate LOAM under the assumption the measurements follow an additive two-way random effects model. Assuming this model, we provide estimates and confidence intervals for the proposed LOAM. Further, this approach is easily extended to the case of multiple measurements per observer.

Results
The proposed method is applied on two data sets to illustrate its use. Specifically, we consider agreement between measurements regarding tumour size and aortic diameter. For the latter study, three measurement methods are considered.

Conclusions
The proposed LOAM and the associated confidence intervals are useful for assessing agreement between continuous measurements.
The curious incident of a cavum velum interpositum cyst in twins of a mother carrying May-Hegglin anomaly: a case report and short literature review
Authors: Giordano Giulio , Tiscia Giovanni L. , Favuzzi Giovanni , Chinni Elena , Intrieri Mariano , Mastroianno Mario , Di Meglio Letizia , Margaglione Maurizio , Grandone Elvira 
Published: December 2020

Abstract
Background
May-Hegglin anomaly is an autosomal dominant inherited condition, characterized by thrombocytopenia, giant platelets and Dohle-like bodies. Incidence is unknown and affected individuals can show from mild to moderate-severe haemorrhagic symptoms. The cyst of cavum veli interpositi (a virtual space filled with fluid within the third ventricle) is rarely reported in the foetal period. Furthermore, it is unclear whether isolated cavum veli interpositi cysts are a normal variant or developmental malformations. The simultaneous presence of these two anomalies was never described.

Case presentation
We describe a very rare case of a twin monochorionic pregnancy in a woman with the May-Hegglin anomaly, whose foetuses carried cavum veli interpositi cysts. Since childhood, our patient had shown macro-thrombocytopenia, deafness and bleeding (epistaxis and menorrhagia), but she was misdiagnosed until the age of 30 years when our Centre identified a de novo allelic variant in the gene MYH9 coding for the non-muscle myosin heavy chain IIa. Our patient bled neither during the pregnancy, nor in the peripartum period. Children are now eight-months-old and have never bled, although both inherited the MYH9 variant and have thrombocytopenia with giant platelets. Furthermore, none of them developed psychomotor disorders.

Conclusions
To the best of our knowledge, this is the sixth case of twin pregnancy in a woman carrying May-Hegglin anomaly and the first one with cavum veli interpositi cysts in the neonates. We speculate that MYH9 could have, at least in part, played a role in the development of both conditions, as this gene has a pleiotropic effect.
Network meta-analysis of targeted therapies for diffuse large B cell lymphoma
Authors: Wang Jie , Huang Jun , Zeng Qing 
Published: December 2020

AbstractBackgroundThe purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma (DLBCL).MethodsThe PubMed, EmBase, and Cochrane library electronic databases were systematically searched throughout December 2019. Direct and indirect evidence from relevant RCTs was identified for network meta-analysis. The pooled results for grade 3 or greater adverse events between targeted therapies and chemotherapy were calculated using a random-effects model.ResultsA total of 18 RCTs enrolling 8207 DLBCL patients were selected for the final meta-analysis. The results of the network analysis indicated that the addition of dacetuzumab (74.8%) to rituximab-based regimens or lenalidomide (77.1%) was associated with better therapeutic effects on overall survival, whereas dacetuzumab (80.4%) or bortezomib (70.8%) added to rituximab was most likely to improve events-free survival. Moreover, lenalidomide (93.8%) and I-tositumomab (77.2%) were associated with higher overall response rates. Finally, patients receiving targeted therapies were associated with an increased risk of diarrhea (RR: 2.63; 95%CI: 1.18–5.86;P = 0.019), and thrombocytopenia (RR: 1.41; 95%CI: 1.05–1.90;P = 0.023).ConclusionsThis study provides the best treatment strategy for DLBCL patients in terms of overall survival, events-free survival, and overall response rate. The findings of this study require validation with further large-scale RCTs.
Survival rate of patients with bladder cancer and its related factors in Kurdistan Province (2013–2018): a population-based study
Authors: Amiri Mozhdeh , Heshmatollah Sofimajidpour , Esmaeilnasab Nader , Khoubi Jamshid , Ghaderi Ebrahim , Roshani Daem 
Published: December 2020

AbstractBackgroundBladder cancer is one of the most common urinary tract cancers. This study aims to estimate the survival rate of patients with bladder cancer according to the Cox proportional hazards model based on some key relevant variables.MethodsIn this retrospective population-based cohort study that explores the survival of patients with bladder cancer and its related factors, we first collected demographic information and medical records of 321 patients with bladder cancer through in-person and telephone interviews. Then, in the analysis phase, Kaplan–Meier method and log-rank test were used to draw the survival curve, compare the groups, and explore the effect of risk factors on the patient survival rate using Cox proportional hazards model.ResultsThe median survival rate of patients was 63.2 (54.7–72) months and one, three and five-year survival rates were 87%, 68% and 54%, respectively. The results of multiple analyses using Cox's proportional hazards model revealed that variables of sex (male gender) (HR = 11.8, 95% CI: 0.4–100.7), more than 65 year of age (HR = 4.1, 95% CI: 0.4–11), occupation, income level, (HR = 0.4, 95% CI: 0.2–0.8), well differentiated tumor grade (HR = 3.2, 95% CI: 1.7–6) and disease stage influenced the survival rate of patients (p < 0.05).ConclusionThe survival rate of patients with bladder cancer in Kurdistan province is relatively low. Given the impact of the disease stage on the survival rate, adequate access to appropriate diagnostic and treatment services as well as planning for screening and early diagnosis, especially in men, can increase the survival rate of patients.
Hugan Qingzhi medication ameliorates free fatty acid-induced L02 hepatocyte endoplasmic reticulum stress by regulating the activation of PKC-δ
Authors: Yang Miaoting , Chen Zhijuan , Xiang Shijian , Xia Fan , Tang Waijiao , Yao Xiaorui , Zhou Benjie 
Published: December 2020

Abstract
Background
Previous studies have found that Hugan Qingzhi tablet (HQT) has significant lipid-lowering and antioxidant effects on non-alcoholic fatty liver disease (NAFLD). Moreover, the results of proteomic analysis confirmed that various proteins in endoplasmic reticulum stress (ERS) pathway were activated and recovered by HQT. However, its mechanism remains confused. The purpose of this study was to explore the effects of HQT-medicated serum on hepatic ERS and its relevant mechanisms.

Methods
L02 cells were induced by Free Fatty Acid (FFA) for 24 h to establish a model of hepatic ERS and pretreated with the drug-medicated rat serum for 24 h. Accumulation of intracellular lipid was evaluated using Oil Red O staining and Triglyceride detection kit. The morphological changes of ER were observed by TEM. PKC-δ was silenced by specific siRNA. Western blot and RT-qPCR were applied to detect the expression of markers related to ERS, calcium disorder, steatosis and insulin resistance. The fluorescence of Ca2+ influx was recorded using fluorescence spectrophotometer.

Results
HQT-medicated serum significantly decreased the intracellular TG content. Furthermore, it caused significant reduction in the expression of ERS markers and an improvement in ER structure of L02 cells. PKC-δ was activated into phosphorylated PKC-δ in FFA-induced L02 hepatocytes while these changes can be reversed by HQT-medicated serum. Silencing PKC-δ in L02 cells can restore the expression and activity of SERCA2 in ER and down-regulate the expression of IP3R protein to maintain intracellular calcium homeostasis, so as to relieve FFA-induced ERS and its lipid accumulation and insulin resistance.

Conclusions
The results concluded that HQT-medicated serum exerts protective effects against hepatic ERS, steatosis and insulin resistance in FFA-induced L02 hepatocyte. And its potential mechanism might be down-regulating the activation of PKC-δ and stabilization of intracellular calcium.
Applying SF-6D to measure health state utilities among the middle and old aged patients with hypertension in China
Authors: Liu Xiaohan , Bai Guannan , Li Hui , Li Shunping 
Published: December 2020

Abstract
Purpose
Hypertension is a growing public health problem in China; however, little is known about health-related quality of life (HRQoL) especially health state utility (HSU) of patients with hypertension in rural China. This study aimed to examine the HSU as measured by SF-6D and to investigate its associated factors among middle and old aged patients with hypertension in rural China.

Methods
Data were collected from twelve villages in Shandong Province in 2016. SF-36 was administrated to measure HRQoL of middle and old aged patients with hypertension and was got to the SF-6D values using Hong Kong’s tariff. Descriptive analyses, such as demographic characteristics, socio-economic status, and utility, were stratified by hypertension classification. Multiple linear regression models were applied to assess the associated factors of HSU.

Results
A total of 933 (response rate:86.4%) middle and old aged patients (69.1 ± 8.2 years) with hypertension participated in the study. 39.4% of participants were male; 44.2% had stage I hypertension; 26.4% had stage II and above. The mean score of SF-6D utility score was 0.743 (SD: 0.14, range: 0.32–1.00, median: 0.756, Interquartile range:0.634–0.859). Being female (β = −0.046), having two or more comorbidities (2 vs. 1 β = −0.066; > 3 vs. 1 β = −0.098) and the health expenditure higher than 2000 RMB (2000–3999 vs.< 2000 β = −0.042; 4000–5999 vs. < 2000 β = −0.046; > 6000 vs. < 2000 β = −0.071) were significantly associated with lower SF-6D overall score; while being farmer (β = 0.032), having high household income (10,000–14,999 vs. < 5000 β = 0.045; > 15,000 vs. < 5000 β = 0.064) and having stage I and above hypertension (stage I vs. Normotensive β = 0.047; stage II vs. Normotensive β = 0.079; stage III vs. Normotensive β = 0.095) were significantly associated with higher SF-6D overall score.

Conclusion
SF-6D was capable to measure quality of life middle and old aged patients with hypertension in China. And multiple factors were demonstrated to be significantly associated with quality of life.
Quality assessment of the guidelines for the management of malignant pleural effusions and ascites
Authors: Li Jia-Xi , Shi Yan-Mei , An Li-Ya , Yang Jin-Xu , Qi Yu-Xing , Yang Ting , Cen Yun-Yun , Lin Yue-Ying , Sun Da-Li 
Published: December 2020

Abstract
Objectives
To fully assess the quality of the guidelines for the management of malignant pleural effusions (MPE) and ascites and reveal the heterogeneity of recommendations and possible reasons among guidelines.

Methods
A systematic search was performed in the database to obtain guidelines for the management of MPE and ascites. The AGREE IIGtool was used to assess the quality of these guidelines. The Measurement Scale of Rate of Agreement (MSRA) was introduced to assess the scientific agreement of formulated recommendations for the management of MPE and ascites among guidelines, and evidence supporting these recommendations was extracted and analyzed.

Results
Nine guidelines were identified. Only 4 guidelines scored more than 60% and are worth recommending. Recommendations were also heterogeneous among guidelines for the management of MPE, and the main reasons were the different emphases of the recommendations for the treatment of MPE, the contradictions in recommendations, and the unreasonably cited evidence for MPE.

Conclusions
The quality of the management guidelines for patients with MPE and malignant ascites was highly variable. Specific improvement of the factors leading to the heterogeneity of recommendations will be a reasonable and effective way for developers to upgrade the recommendations in the guidelines for MPE.
Risk of birth defects in children conceived by artificial oocyte activation and intracytoplasmic sperm injection: a meta-analysis
Authors: Long Rui , Wang Meng , Yang Qi Yu , Hu Shi Qiao , Zhu Li Xia , Jin Lei 
Published: December 2020

AbstractBackgroundWhether artificial oocyte activation (ICSI-AOA) will increase the risk of birth defects remains controversial. Thus, we performed this study to evaluate the risk of birth defects and further compare the incidence of different birth defects types (chromosomal aberrations and non-chromosomal aberrations) in children conceived by ICSI-AOA and conventional intracytoplasmic sperm injection (ICSI) in an enlarged sample size.MethodA comprehensive review of the literatures comparing birth defects in children conceived by ICSI-AOA and conventional ICSI by October 2020 was performed in PubMed, Embase, Cochrane Libraries, Web of Science, and Chinese databases including China National Knowledge Infrastructure, China Biology Medicine disc and Wan Fang. Risk ratios (RR) and 95% confidence intervals (CI) were calculated.ResultsFive studies were included in the final analysis. Compared with conventional ICSI, ICSI-AOA did not increase the birth defects rate (RR = 1.27, 95%CI 0.70–2.28) of children. Furthermore, in a subgroup analysis, birth defects were classified into two types (chromosomal aberrations and non-chromosomal aberrations) in four studies and no statistical difference were revealed.ConclusionOur analysis indicates that ICSI-AOA represents no significant difference in the prevalence of major birth defects or types of birth defects (chromosomal aberrations and non-chromosomal aberrations) comparing with conventional ICSI. This conclusion may provide clinicians evidence-based support in patient counseling and instruction of the application and safety concern about ICSI-AOA.
The potential of real-time analytics to improve care for mechanically ventilated patients in the intensive care unit: an early economic evaluation
Authors: Bakker Lytske , Vaporidi Katerina , Aarts Jos , Redekop William 
Published: December 2020

Abstract
Background
Mechanical ventilation services are an important driver of the high costs of intensive care. An optimal interaction between a patient and a ventilator is therefore paramount. Suboptimal interaction is present when patients repeatedly demand, but do not receive, breathing support from a mechanical ventilator (> 30 times in 3 min), also known as an ineffective effort event (IEEV). IEEVs are associated with increased hospital mortality prolonged intensive care stay, and prolonged time on ventilation and thus development of real-time analytics that identify IEEVs is essential. To assist decision-making about further development we estimate the potential cost-effectiveness of real-time analytics that identify ineffective effort events.

Methods
We developed a cost-effectiveness model combining a decision tree and Markov model for long-term outcomes with data on current care from a Greek hospital and literature. A lifetime horizon and a healthcare payer perspective were used. Uncertainty about the results was assessed using sensitivity and scenario analyses to examine the impact of varying parameters like the intensive care costs per day and the effectiveness of treatment of IEEVs.

Results
Use of the analytics could lead to reduced mortality (3% absolute reduction), increased quality adjusted life years (0.21 per patient) and cost-savings (€264 per patient) compared to current care. Moreover, cost-savings for hospitals and health improvements can be incurred even if the treatment’s effectiveness is reduced from 30 to 10%. The estimated savings increase to €1,155 per patient in countries where costs of an intensive care day are high (e.g. the Netherlands). There is considerable headroom for development and the analytics generate savings when the price of the analytics per bed per year is below €7,307. Furthermore, even when the treatment’s effectiveness is 10%, the probability that the analytics are cost-effective exceeds 90%.

Conclusions
Implementing real-time analytics to identify ineffective effort events can lead to health and financial benefits. Therefore, it will be worthwhile to continue assessment of the effectiveness of the analytics in clinical practice and validate our findings. Eventually, their adoption in settings where costs of an intensive care day are high and ineffective efforts are frequent could yield a high return on investment.
Physical health examination in outpatients with schizophrenia: the cost effectiveness of laboratory screening tests
Authors: Eskelinen Saana , Suvisaari Janne V. J. , Suvisaari Jaana M. 
Published: December 2020

AbstractBackgroundGuidelines on laboratory screening in schizophrenia recommend annual monitoring of fasting lipids and glucose. The utility and the cost effectiveness of more extensive laboratory screening have not been studied.MethodsThe Living Conditions and the Physical Health of Outpatients with Schizophrenia Study provided a comprehensive health examination, including a laboratory test panel for 275 participants. We calculated the prevalence of the results outside the reference range for each laboratory test, and estimated the cost effectiveness to find an aberrant test result using the number needed to screen to find one abnormal result (NNSAR) and the direct cost spent to find one abnormal result (DCSAR, NNSAR x direct cost per test) formulas. In addition, we studied whether patients who were obese or used clozapine had more often abnormal results.ResultsA half of the sample had 25-hydroxyvitamin D below, and almost one-fourth cholesterol, triglycerides or glucose above the reference range. One-fifth had sodium below and gamma glutamyltransferase above the reference range. NNSAR was highest for potassium (137) and lowest for 25-hydroxyvitamin D (2). DCSAR was below 5€ for glucose, all lipids and sodium, and below 10€ for creatinine and gamma glutamyltransferase. Potassium (130€), pH-adjusted ionized calcium (33 €) and thyroid stimulating hormone (33€) had highest DCSARs. Several abnormal results were more common in obese and clozapine using patients.ConclusionsAn annual laboratory screening panel for an outpatient with schizophrenia should include fasting glucose, lipids, sodium, creatinine, a liver function test and complete blood count, and preferably 25-hydroxyvitamin D.
A pilot protocol to assess the feasibility of a virtual multiple crossover, randomized controlled trial design using methylphenidate in mild cognitive impairment
Authors: DesRuisseaux Libby A. , Williams Victoria J. , McManus Alison J. , Gupta Anoopum S. , Carlyle Becky C. , Azami Hamed , Gerber Jessica A. , Bolling Anna M. , Cook Carolyn L. , Betensky Rebecca A. , Arnold Steven E. 
Published: December 2020

Abstract
Background
The conventional clinical trial design in Alzheimer’s disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an “average” patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level (“N-of-1”) regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design.

Methods
Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments.

Discussion
This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research.

Trial registration
ClinicalTrials.gov, NCT03811847. Registered on 21 January 2019.
Extracts of medicinal plants with natural deep eutectic solvents: enhanced antimicrobial activity and low genotoxicity
Authors: Grozdanova Tsvetinka , Trusheva Boryana , Alipieva Kalina , Popova Milena , Dimitrova Lyudmila , Najdenski Hristo , Zaharieva Maya M. , Ilieva Yana , Vasileva Bela , Miloshev George , Georgieva Milena , Bankova Vassya 
Published: December 2020

AbstractNatural deep eutectic solvents (NADES) are a new alternative to toxic organic solvents. Their constituents are primary metabolites, non-toxic, biocompatible and sustainable. In this study four selected NADES were applied for the extraction of two medicinal plants: Sideritis scardica, and Plantago major as an alternative to water-alcohol mixtures, and the antimicrobial and genotoxic potential of the extracts were studied. The extraction efficiency was evaluated by measuring the extracted total phenolics, and total flavonoids. Best extraction results for total phenolics for the studied plants were obtained with choline chloride-glucose 5:2 plus 30% water; but surprisingly these extracts were inactive against all tested microorganisms. Extracts with citric acid-1,2-propanediol 1:4 and choline chloride-glycerol 1:2 showed good activity against S. pyogenes, E. coli, S. aureus, and C. albicans. Low genotoxicity and cytotoxicity were observed for all four NADES and the extracts with antimicrobial activity. Our results confirm the potential of NADESs for extraction of bioactive constituents of medicinal plants and further suggest that NADES can improve the effects of bioactive extracts. Further studies are needed to clarify the influence of the studied NADES on the bioactivity of dissolved substances, and the possibility to use such extracts in the pharmaceutical and food industry.