bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the nlmixr R package for population pharmacokinetic modeling: A metformin case study
Authors: Mak Wen Yao , Ooi Qing Xi , Cruz Cintia Valeria , Looi Irene , Yuen Kah Hay , Standing Joseph F. 
Published: August 2022

Aimnlmixr offers first‐order conditional estimation (FOCE), FOCE with interaction (FOCEi) and stochastic approximation estimation‐maximisation (SAEM) to fit nonlinear mixed‐effect models (NLMEM). We modelled metformin's pharmacokinetic data using nlmixr and investigated SAEM and FOCEi's performance with respect to bias and precision of parameter estimates, and robustness to initial estimates.MethodCompartmental models were fitted. The final model was determined based on the objective function value and inspection of goodness‐of‐fit plots. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re‐estimated as the initial estimates were perturbed 100 times and resultant changes evaluated.ResultsThe absorption kinetics of metformin depend significantly on food status. Under the fasted state, the first‐order absorption into the central compartment was preceded by zero‐order infusion into the depot compartment, whereas for the fed state, the absorption into the depot was instantaneous followed by first‐order absorption from depot into the central compartment. The means of relative mean estimation error (rMEE) (
) and rRMSE (
) were 0.48 and 0.35, respectively. All parameter estimates given by SAEM appeared to be narrowly distributed and were close to the true value used for simulation. In contrast, the distribution of estimates from FOCEi were skewed and more biased. When initial estimates were perturbed, FOCEi estimates were more biased and imprecise.Discussionnlmixr is reliable for NLMEM. SAEM was superior to FOCEi in terms of bias and precision, and more robust against initial estimate perturbations.
The impact of histological grade on outcomes in follicular lymphoma: An analysis of patients in the SEER database in the context of evolving disease classification and treatment
Authors: Naik Anisha , Gooley Ted , Loeb Keith , Soma Lorinda , Smith Stephen D. , Gopal Ajay , Naresh Kikkeri N. 
Published: August 2022

SummaryCurrently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992–2018 in the SEER database with disease‐specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1–2. During 1992–2005, the 10‐year DSS for patients with FL grades 3 and grades 1–2 were 68.6%, and 71.4%, respectively, and in 2006–2018, they were 77.7% and 82.6%, respectively. The 10‐year OS estimates in 1992–2005 were 49.9% and 54.2% for grade 3 and grades 1–2 respectively, and in 2006–2018, they were 59.1% and 63.5% for grade 3 and grades 1–2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992–2005 were 1.09 (1.02–1.16) and 1.07 (1.02–1.12), respectively, compared to FL grades 1–2; and during 2006–2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22–1.45) and 1.16 (1.10–1.23), respectively compared to FL grades 1–2. The grade of FL is an important determinant of disease biology.
Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment
Authors: Ochiai Ryosuke , Hayashi Kentaro , Yamamoto Hiroshi , Fujii Risa , Saichi Naomi , Shinchi Hiroki , Ishida Tsuyoshi , Honda Takeshi , Shimizu Tetsuo , Matsutani Noriyuki , Seki Nobuhiko , Kawamura Masafumi , Ueda Koji 
Published: August 2022

AbstractTo identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI), we enrolled patients with EGFR gene mutation‐positive non–small‐cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression‐free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| > 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long‐lasting effects of gefitinib may be due to the antitumor effects of CD8+ T cells, as well as the induction of immunogenic apoptosis of tumor cells by blocking the EGFR signaling pathway. Notably, Doking Protein 3 (DOK3), a molecule involved in B‐cell receptor signaling, and some immunoglobulin and complement molecules exhibited a clear correlation with PFS longevity of gefitinib treatment. Indeed, the strong expression of DOK3 in B cells was confirmed within tertiary lymphoid structures of lung cancer tissues derived from patients with long PFS. These findings suggest that the patients with active B‐cell and T‐cell immunity as a host immunological feature are more likely to benefit from gefitinib therapy. Circulating exosomal DOK3 has the potential as a predictive marker of response to gefitinib indicating this immunological feature.
Learning the rules of the game: The role of generic “you” and “we” in shaping children's interpretations of norms
Authors: Orvell Ariana , Elli Giulia , Umscheid Valerie , Simmons Ella , Kross Ethan , Gelman Susan A. 
Published: August 2022

AbstractA critical skill of childhood is learning social norms. We examine whether the generic pronouns “you” and “we,” which frame information as applying to people in general rather than to a specific individual, facilitate this process. In one pre‐registered experiment conducted online between 2020 and 2021, children 4‐ to 9‐year‐old primarily living in the midwestern U.S. (N = 146, 75 girls, 71 boys,Mage = 7.14,SD = 1.69, 82% White) interpreted actions described with generic pronouns (vs. “I”) as normatively correct and selected the speaker who used generic pronouns as the rule‐follower, particularly when generic pronouns were presented first. There were no significant effects of age. These results illustrate how generic pronouns influence how children discern unfamiliar norms and form interpersonal judgments.
Regular support provided by dermatological nurses improves outcomes in patients with psoriasis treated with topical drugs: a randomized controlled trial
Authors: Svendsen Mathias Tiedemann , Feldman Steven R. , Mejldal Anna , Möller Sören , Kongstad Line Planck , Andersen Klaus E. 
Published: August 2022

Abstract

Background
Patient adherence to topical antipsoriatic drugs is often poor, leading to poor efficacy. Use of long-term support delivered by dermatological nurses to patients treated with topical drugs may improve outcome.

Aim
To evaluate whether regular support from dermatological nurses improves outcome and treatment adherence in patients with psoriasis receiving topical medications.

Methods
We conducted a randomized controlled trial (RCT) (clinicaltrials.gov registration NCT04220554), in which patients received once-daily topical medications (containing corticosteroids and/or calcipotriol) for as long as their psoriasis was visible. The patients were randomly allocated to standard care by the dermatologist either with (n = 51) or without (n = 52) support from dermatological nurses. The nurse support intervention consisted of a structured dermatological consultation at baseline and Week 1, followed by contact with a nurse each month (in the outpatient clinic or by telephone). The primary outcome was severity of psoriasis, which was measured by the Lattice System Physician's Global Assessment (LS-PGA) and assessed by intention-to-treat analyses using linear mixed regression models for longitudinal data. Secondary outcomes were quality of life (measured by the Dermatology Life Quality Index; DLQI) and good adherence (defined as use of ≥ 80% of recommended doses).

Results
In total, 92 patients (89%) completed the 48-week trial period. The intervention group improved more than the nonintervention group from baseline to Week 24 in LS-PGA (2.21 vs. 1.28, P = 0.001) and in DLQI at Week 12 (6.50 vs. 1.55, P &lt; 0.001). Differences between the two groups in favour of the intervention were observed throughout the study period. More participants in the intervention group had good adherence compared with the nonintervention group (36% vs. 14%, P &lt; 0.001).

Conclusion
Regular, continued patient support from dermatological nurses increased the efficacy of psoriasis treatment, improved quality of life and enhanced long-term adherence to topical antipsoriatic drugs. However, there is still room for more improvement.
Long‐term outcome of cerebral amyloid angiopathy‐related hemorrhage
Authors: Che Ruiwen , Zhang Mengke , Sun Hailiang , Ma Jin , Hu Wenbo , Liu Xin , Ji Xunming 
Published: August 2022

AbstractObjectThe long‐term functional outcome of cerebral amyloid angiopathy‐related hemorrhage (CAAH) patients is unclear. We sought to assess the long‐term functional outcome of CAAH and determine the prognostic factors associated with unfavorable outcomes.MethodsWe enrolled consecutive CAAH patients from 2014 to 2020 in this observational study. Baseline characteristics and clinical outcomes were presented. Multivariable logistic regression analysis was performed to identify the prognostic factors associated with long‐term outcome.ResultsAmong the 141 CAAH patients, 76 (53.9%) achieved favorable outcomes and 28 (19.9%) of them died at 1‐year follow‐up. For the longer‐term follow‐up with a median observation time of 19.0 (interquartile range, 12.0–26.5) months, 71 (50.4%) patients obtained favorable outcomes while 33 (23.4%) died. GCS on admission (OR, 0.109; 95% CI, 0.021–0.556;p = 0.008), recurrence of ICH (OR, 2923.687; 95% CI, 6.282–1360730.14;p = 0.011), WML grade 3–4 (OR, 31.007; 95% CI, 1.041–923.573;p = 0.047), severe central atrophy (OR, 4220.303; 95% CI, 9.135–1949674.84;p = 0.008) assessed by CT was identified as independent predictors for long‐term outcome.InterpretationNearly 50% of CAAH patients achieved favorable outcomes at long‐term follow‐up. GCS, recurrence of ICH, WML grade and cerebral atrophy were identified as independent prognostic factors of long‐term outcome.
Pancreaticoduodenectomy with right hemicolectomy for advanced malignancy: a single UK hepatopancreaticobiliary centre experience
Authors: Das Bibek , Fehervari Matyas , Hamrang‐Yousefi Sahar , Jiao Long R. , Pai Madhava , Jenkins John T. , Spalding Duncan R. C. 
Published: August 2022

AbstractAimLocally advanced intestinal neoplasms including colon cancer may require radical en bloc pancreaticoduodenectomy and right hemicolectomy (PD‐RC) to achieve curative, margin‐negative resection, but the safety and benefit of this uncommon procedure has not been established. The Association of Coloproctology of Great Britain and Ireland IMPACT initiative has also highlighted a lack of awareness about current services available within the UK for patients with advanced colorectal cancer and concerns about low‐volume centres managing complex cases. Thus, we aimed to review the feasibility, safety and long‐term outcomes of this procedure at a single high‐volume hepatopancreaticobiliary surgery unit in the UK.MethodA retrospective cohort study was performed using a database of all consecutive patients with intestinal cancer who had been referred to our regional advanced multidisciplinary team and undergone PD‐RC in a 7‐year period (2013–2020). Clinico‐pathological and outcome data were reviewed.ResultsTen patients (mean age 54 ± 13, 8/10 men) were identified. Final histology revealed the primary tumour sites were colon (n = 7) and duodenum (n = 3). R0 resection was achieved in all cases. The major complication rate (Clavien–Dindo ≥ 3) was 10% (1/10) with no deaths within 90 days of surgery. The Kaplan–Meier estimated 5‐year overall survival was 83.3% (95% CI 58.3%–100%). Univariate survival analysis identified perineural invasion and extra‐colonic origin as predictors of poor survival (log‐rank P < 0.05).ConclusionEn bloc PD‐RC for locally advanced intestinal cancer can be performed safely with a high proportion of margin‐negative resections and resultant long‐term survival in carefully selected patients.
Genomewide association study identifies a novel variant associated with tacrolimus trough concentration in Chinese renal transplant recipients
Authors: Yang Siyao , Jiang Haixia , Li Chengcheng , Lu Huijie , Li Chuanjiang , Ye Demei , Qi Huana , Xu Wenbin , Bao Xiaojie , Maseko Nicola , Zhang Siqi , Shao Ruifan , Li Liang 
Published: August 2022

AbstractTacrolimus (TAC) is an immunosuppressant widely used in kidney transplantation. TAC displays considerable interindividual variability in pharmacokinetics (PKs). Genetic and clinical factors play important roles in TAC PKs. We enrolled a total of 251 Chinese renal transplant recipients and conducted a genomewide association study (GWAS), linkage disequilibrium (LD), and one‐way analysis of variance (ANOVA) to find genetic variants affecting log‐transformed TAC trough blood concentration/dose ratio (log[C0/D]). In addition, we performed dual luciferase reporter gene assays and multivariate regression models to evaluate the effect of the genetic variants. The GWAS results showed that all 23 genomewide significant single‐nucleotide polymorphisms (p < 5 × 10−8) were located on chromosome 7, includingCYP3A5*3. LD, conditional association analysis, and one‐way ANOVA showed that rs75125371 T > C independently influenced TAC log(C0/D). Dual luciferase reporter gene assays indicated that rs75125371 minor allele (C) was significantly associated with increased normalized luciferase activity than the major allele (T) in the Huh7 cells (p = 1.2 × 10−5) and HepaRG cells (p = 0.0097). A model inclusive of age, sex, hematocrit,CYP3A5*3, and rs75125371 explained 37.34% variance in TACC0. These results suggest that rs75125371 T > C is a functional and population‐specific variant affecting TACC0in Chinese renal transplant recipients.
The fibrosis‐4 score is associated with long‐term mortality in different phenotypes of acute heart failure
Authors: Tseng Chih‐Hsueh , Huang Wei‐Min , Yu Wen‐Chung , Cheng Hao‐Min , Chang Hao‐Chih , Hsu Pai‐Feng , Chiang Chern‐En , Chen Chen‐Huan , Sung Shih‐Hsien 
Published: August 2022

AbstractBackgroundFibrosis‐4 score (FIB4) was a non‐invasive surrogate to estimate the amount of liver scarring in chronic hepatitis. Considering the presence of increased central venous pressure and congestive hepatopathy in patients with decompensated heart failure, we therefore investigated the prognostic values of FIB4 in acute heart failure (AHF) patients.MethodPatients hospitalised primarily for HF were drawn from an intramural registry. FIB4 was calculated according to age, aspartate aminotransferase, alanine aminotransferase and platelet count. All‐cause mortality up to 5 years after discharge was obtained by linking to the national death registry.ResultsAmong a total of 1854 participants, 940 patients died during a mean follow‐up of 28.3 ± 21.8 months. FIB4 score was related to mortality and the composite of cardiovascular death or HF rehospitalisation, independent of age, sex, left ventricular ejection fraction, left atrial dimension, sodium and haemoglobin levels, estimated glomerular filtration rate, comorbidities, and medications [hazard ratio and 95% confidence interval of mortality: 1.009 (1.002–1.015), and the composite of cardiovascular death or HF hospitalisation: 1.020 (1.010–1.031)]. The prognostic value of FIB4 was predominantly in the subjects with heart failure and preserved or mildly reduced ejection fraction (HFpEF and HFmrEF), or coronary artery disease (CAD) than the counterparts [interaction p‐value <0.001, and 0.004, respectively].ConclusionsFIB4 was an independent predictor of survival in AHF patients, irrespective of the phenotypes of HF. The higher predictive value of mortality of FIB4 was observed in the subjects with HFpEF, HFmrEF or CAD.
Uncovering bias in order assignment
Authors: Grant Darren 
Published: August 2022

AbstractTo mitigate sequencing effects in decision‐making, many situations require a set of items to be considered in a random order. When such orderings are repeated, one can test whether randomization indeed obtains, or whether some orderings have been manipulated in order to achieve a favorable result. This paper articulates the key features of this problem and presents three general tests for randomness. These methods are used to analyze the order in which lottery numbers are drawn in Powerball, contestants perform on American Idol, and candidates are placed on election ballots. This last application features frequent manipulation, with potentially serious consequences.
Numerical simulation of fatigue behavior of flexible metal films in multiphysics fields
Authors: Zheng Yichuan , Huang Xingzhen , Li Zhaoxia 
Published: August 2022

AbstractThe operating ambient of flexible electronics interconnects is a complex environment that includes mechanical deformation, electric current, and temperature. It is a potential threat to the long‐term service reliability of flexible electronic devices. This paper aims to develop a multiphysics fatigue model for flexible metal films. The effect of multiphysics fields is considered in the Coffin–Manson relationship based on reasonable simplification. The fatigue behavior of copper films of various thicknesses on a flexible substrate was investigated when electrical current and mechanical displacement loads were applied simultaneously. The developed model is validated to compare with experimental results. The numerical results show that it can analyze the effect of multiphysics fields and predict the fatigue life of copper films. Therefore, it could be a means to assess the fatigue performance of metal films on flexible substrates in multiphysics fields.
Three‐dimensional fatigue crack growth simulation and fatigue life assessment based on finite element analysis
Authors: Ilie Paul , Ince Ayhan 
Published: August 2022

AbstractDamage tolerance design allows manufactures to assess fatigue crack propagation of components containing initial defects. A new modeling approach is proposed to carry out a systematic crack growth analysis based on an analytical method using reduced order models and three‐dimensional (3D) finite element (FE)‐based fatigue crack growth (FCG) analysis. 3D FE‐based FCG analysis is adopted as an advanced modeling approach for component geometries without any simplifications with respect to crack front shape or planarity of the crack path. The FE‐based FCG approach was verified and validated in two different stages: Ti‐6Al‐4V plate geometry with three different single elliptical crack configurations and Al 2024‐T3 specimens with two different multiple crack configurations. The analytical FCG approach was developed to estimate crack front evolution and crack growth life for three different elliptical cracks to verify the FE‐based approach. Experimental data of Al 2024‐T3 specimens with multi‐edge cracks was used to further validate the FE‐based FCG approach. The FE‐based FCG approach proved to be both accurate and powerful in assessing crack propagation life and crack paths of structural parts.
Insights into the role of external layers in cyanobacteria at varying temperatures and their regulatory mechanism
Authors: Cheng Yuran , Li Zhe , Xiao Yan , Wu Xinghua , Liu Liming 
Published: August 2022

Abstract

The dominance of cyanobacteria and their adaptability to changing climates might be attributed to their morphological plasticity related to external layers. The content of exopolysaccharides in cyanobacterial external layers has been shown to increase at elevated temperatures. However, the answers to the questions of why and how cyanobacteria adapt to varying temperatures by adjusting the physiological and biophysical properties of their external layers are still not clear.

We cultivated three cyanobacterial strains, Nostoc sp. FACHB‐2009, Dolichospermum sp. FACHB‐82 and Microcystis sp. FACHB‐3296, which are embedded in three typical types of external layers—sheath, capsule and slime, respectively––and each grown at three different temperatures (10°C, 25°C and 35°C).

The results showed that varying the temperature significantly changed the physicochemical properties of the external layers. High temperature conditions promoted increases in colony sizes compared to the control, with the external layers becoming thicker, looser and more adhesive, whereas cell sizes did not significantly change. Additionally, the expression patterns of related genes varied with temperature; it represents several temp dependent genes related to synthesis of nucleotide sugars were upregulated at high temperature but downregulated at low temperature.

As the external layers are wrapped outside cells, we assumed a “spherical shell heat conduction model”. Through that, we inferred that the presence of external layers influenced heat transfer in the cyanobacteria, thereby playing a role in stabilising cell activity at various temperatures.

Transcriptome tests showed that the use of intracellularly stored nucleotide sugars for external layer synthesis was the preferred process for cyanobacteria at low temperature, whereas de novo external layer synthesis was the preferred process for cyanobacteria at high temperature.
Effect of metabolic dysfunction‐associated fatty liver disease on liver cancer risk in a population with chronic hepatitis B virus infection: A nationwide study
Authors: Yun Byungyoon , Ahn Sang Hoon , Oh Juyeon , Yoon Jin‐Ha , Kim Beom Kyung 
Published: August 2022

AbstractBackgroundThe association between metabolic dysfunction‐associated fatty liver disease (MAFLD) and hepatocellular carcinoma (HCC) lacks clinical validation in at‐risk populations. We assessed this relationship among chronic hepatitis B (CHB) patients.MethodsData was collected from the National Health Insurance System database in South Korea. Chronic hepatitis B patients aged over 40 years receiving health examinations between 2011 and 2012 were recruited. The primary outcome was HCC. Metabolic dysfunction‐associated fatty liver disease was defined as hepatic steatosis in combination with at least one of the following: (i) overweight, (ii) diabetes, or (iii) lean/normal weight with two or more metabolic components. Multivariable Cox regression analysis was used to estimate adjusted hazard ratios (aHRs).ResultsOf 197 346 participants, 66 149 had MAFLD; 19 149, 44 475, and 2525 fulfilled diabetes (regardless of overweight), overweight alone, and lean/normal weight with two or more metabolic components, respectively. During follow‐up (median 7 years), 13 771 developed HCC. Metabolic dysfunction‐associated fatty liver disease was independently associated with increased risk of HCC, with aHR of 1.36 (p < 0.001). Propensity score matching confirmed the same phenomena, with aHR of 1.37 (p < 0.001). Furthermore, when stratified by liver cirrhosis and/or antiviral therapy, independent significances of MAFLD for HCC risk were maintained (all p < 0.001). Compared with the persistent non‐MAFLD subgroup during the entire follow‐up, diagnosis of MAFLD from at least one health examination significantly increased HCC risk with aHRs of 1.41, 1.37, and 1.14 among subgroups with persistent MAFLD, MAFLD to non‐MAFLD, and non‐MAFLD to MAFLD, respectively (all p < 0.05).ConclusionsMetabolic dysfunction‐associated fatty liver disease consistently increases HCC risk among CHB patients. Further studies are needed to develop an effective preventive strategy through control of metabolic health.