bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preeclampsia: A Review of Early Predictors
Authors: Abbas Riwa A. , Ghulmiyyah Labib , Hobeika Elie , Usta Ihab M. , Mirza Fadi , Nassar Anwar H. 
Published: February 2021

Abstract
Preeclampsia is a progressive, multi-system disorder of pregnancy associated with morbidity and mortality on both the mother and the fetus. Currently, research is directed at identifying early biomarkers of preeclampsia in order to predict its occurrence. This is important because it helps understand the pathophysiology of the disease, and thus, promises new treatment modalities. Although a clear understanding of the pathogenesis of PE remains elusive, the currently most accepted theory suggests a two-stage process. The first stage results in inadequate remodeling of the spiral arteries and leads to the second stage, whereby the clinical features of the syndrome are featured. In this review, we summarize the modalities that have been studies so far to predict preeclampsia. The use of uterine artery Doppler and several other biomarkers such as vitamin D, soluble fms-like tyrosine kinase 1/placental growth factor (sFLT1/PlGF) ratio, soluble endoglin, and a subset of T-lymphocytes has shown promising results. We are still at early stages in this advance, and no clear recommendations have been made about their clinical use to date. Further studies are still needed to improve screening strategies and evaluate the cost-effectiveness of any intervention.
The Gut Microbiome During Pregnancy
Authors: Jiang Guoqing , Zhou Zhiyi , Li Xiaojuan , Qian Yuan , Wang Kunhua 
Published: February 2021

Abstract
Gut microbiota is symbiotic and interdependent with human body. Intestinal probiotics are colonized in the human gastrointestinal tract, which can improve the host intestinal microenvironment and enhance the intestinal function and immune function of the human body. A small number of opportunistic pathogens exist in the intestinal tract. Once the number of pathogens exceeds the threshold of intestinal tolerance, the intestinal micro-ecological balance can be destroyed, and various diseases may thus develop. Pregnancy is a special status with different physiologic changing stages. In the meanwhile, alterations in the gut microbiome populations occur, which can promote the differentiation, development, and maturation of fetal organs by affecting maternal metabolism. Compared with normal pregnant women, great changes in the gastrointestinal function and gut microbiome may take place in pregnant women with pregnancy-related complications, in which these changes include the number, species, and intestinal translocation. The composition of the maternal gut microbiome could contribute to pregnancy and obstetric outcomes, and long-term health of mother and child. The relationships of pregnancy to gut microbiome have attracted an increasing attention in recent years. This article will provide a summary review of the research studies of gut microbiome in normal pregnant women versus abnormal pregnancy women with complications.
Perinatal Management and Outcomes of Pregnancy Following Sheehan Syndrome: A Case Report and Literature Review
Authors: Zhan Yongchi , Xu Tingting , Wang Xiaodong 
Published: February 2021

Abstract
Pregnancy is rare and difficult in Sheehan syndrome patients. With the help of assisted reproductive technology, the patients even with panhypopituitarism can get pregnant again. Moreover, women with hypopituitarism have increased risk of pregnancy complications. Here we report a patient who suffered acute and severe Sheehan syndrome with panhypopituitarism and central diabetes insipidus got pregnant again by in vitro fertilization and embryo transfer. A regular and careful antenatal care was given by the cooperation between obstetricians and endocrinologists. Finally, she delivered a healthy female baby at 37+6 weeks of gestation with Apgar scores of 10 and 10 at 1 and 5 minutes, respectively. The patient and her baby were doing well at postpartum follow-up. The related articles were also reviewed. This case report is aimed to help clinical practitioners to make better decisions on the management of Sheehan syndrome or other type of hypopituitarism during pregnancy.
Can We Predict Individual Concentrations of Tacrolimus After Liver Transplantation? Application and Tweaking of a Published Population Pharmacokinetic Model in Clinical Practice
Authors: Decrocq-Rudler Marie-Astrid , Chan Kwong Anna H-X. P. , Meunier Lucy , Fraisse Julien , Ursic-Bedoya José , Khier Sonia 
Published: February 2021

Background:
Various population pharmacokinetic models have been developed to describe the pharmacokinetics of tacrolimus in adult liver transplantation. However, their extrapolated predictive performance remains unclear in clinical practice. The purpose of this study was to predict concentrations using a selected literature model and to improve these predictions by tweaking the model with a subset of the target population.

Methods:
A literature review was conducted to select an adequate population pharmacokinetic model (L). Pharmacokinetic data from therapeutic drug monitoring of tacrolimus in liver-transplanted adults were retrospectively collected. A subset of these data (70%) was exploited to tweak the L-model using the $PRIOR subroutine of the NONMEM software, with 2 strategies to weight the prior information: full informative (F) and optimized (O). An external evaluation was performed on the remaining data; bias and imprecision were evaluated for predictions a priori and Bayesian forecasting.

Results:
Seventy-nine patients (851 concentrations) were enrolled in the study. The predictive performance of L-model was insufficient for a priori predictions, whereas it was acceptable with Bayesian forecasting, from the third prediction (ie, with ≥2 previously observed concentrations), corresponding to 1 week after transplantation. Overall, the tweaked models showed a better predictive ability than the L-model. The bias of a priori predictions was −41% with the literature model versus −28.5% and −8.73% with tweaked F and O models, respectively. The imprecision was 45.4% with the literature model versus 38.0% and 39.2% with tweaked F and O models, respectively. For Bayesian predictions, whatever the forecasting state, the tweaked models tend to obtain better results.

Conclusions:
A pharmacokinetic model can be used, and to improve the predictive performance, tweaking the literature model with the $PRIOR approach allows to obtain better predictions.
Therapeutic Drug Monitoring of Psychotropics as a Diagnostic Tool for CYP2D6 Poor Metabolizer Phenotype
Authors: Ganesh Soraya V. , Beunk Lianne , Nikolik Bojan , van der Weide Jan , Bet Pierre M. 
Published: February 2021

Background:
Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective.

Methods:
In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated.

Results:
Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%–99.6%), 93.0% (88.8%–97.2%), 97.8% (95.4%–100.0%), and 85.6% (78.0%–93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity.

Conclusions:
If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications.
A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma
Authors: Sueshige Yoshio , Shiraiwa Ken , Honda Koichi , Tanaka Ryota , Saito Tomoko , Tokoro Masanori , Iwao Masao , Endo Mizuki , Arakawa Mie , Tatsuta Ryosuke , Seike Masataka , Murakami Kazunari , Itoh Hiroki 
Published: February 2021

Background:
Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future.

Methods:
After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode.

Results:
The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2–1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib.

Conclusions:
A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.
Therapeutic Drug Monitoring and Pharmacokinetic Analysis of Cyclosporine in a Pediatric Patient with Hemophagocytic Lymphohistiocytosis Complicated by Diabetes Insipidus: A Grand Round
Authors: Liang Yujian , Wu Zhaoyi , Zhao Liyan , Wu Jingjing , Chen Xiao , Tang Wen , Zeng Jiawei 
Published: February 2021

Background:
Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease. Initial therapy is based on etoposide, dexamethasone, and cyclosporine (CSA). The pharmacokinetics (PKs) of CSA and other drugs are sometimes altered in patients with HLH complicated by diabetes insipidus (DI) but the precise mechanisms remain unknown.

Methods:
In this study, the authors present a case of a 4-year-old boy with HLH complicated by DI. CSA concentrations were determined by enzyme multiplied immunoassay technique; noncompartmental PK analysis of the plasma concentration–time data was performed using PKSolver; and linear regression analysis was performed to determine linearity of relationship between urine output and C0 levels of CSA.

Results:
Although C0 values of CSA were lower than the target levels, the patient was successfully treated and a good clinical outcome was achieved. Linear regression analysis showed a strong negative correlation between urine output and the serum trough concentration (C0) of CSA, pharmacokinetic analysis showed the main PK parameters of CSA as follows: C0, 50.2 mcg/L; peak concentration (Cmax), 723.4 mcg/L; area under the curve0–24, 7478.2 mcg·h/L; clearance, 0.77 L/h/kg, elimination half-life, 5.3 hours, and volume of distribution, 6.0 L/kg.

Conclusions:
To the best of the authors' knowledge, this is the first report of the CSA PK profile in a patient with HLH complicated by DI. The authors suppose that a large fluid output and input leads to extensive CSA distribution. These results suggest that the monitoring of the Cmax and area under the curve of CSA might be more clinically and pharmacokinetically significant than that of C0 in patients with HLH complicated by DI. This case highlights the importance of therapeutic drug monitoring and demonstrates PK parameters of CSA in a pediatric patient with HLH complicated by DI.
A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication
Authors: Elkayal Omar , Spriet Isabel , Uyttebroeck Anne , Colita Anca , Annaert Pieter , Allegaert Karel , Smits Anne , Van Daele Ruth , Dreesen Erwin 
Published: February 2021

Background:
Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients.

Methods:
Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation.

Results:
Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour−1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day).

Conclusions:
Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.
Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson’s Disease?
Authors: Baumeister Alan A. 
Published: February 2021

Abstract
Recent epidemiological evidence indicates that diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk for diseases of the basal ganglia and cerebellum, including Parkinson’s disease (PD). The evidence reviewed here indicates that deficits in striatal dopamine are a shared component of the causal chains that produce these disorders. Neuropsychological studies of adult ADHD, prodromal PD, and early-stage PD reveal similar deficits in executive functions, memory, attention, and inhibition that are mediated by similar neural substrates. These and other findings are consistent with the possibility that ADHD may be part of the PD prodrome. The mechanisms that may mediate the association between PD and ADHD include neurotoxic effects of stimulants, other environmental exposures, and Lewy pathology. Understanding the nature of the association between PD and ADHD may provide insight into the etiology and pathogenesis of both disorders. The possible contribution of stimulants to this association may have important clinical and public health implications.
CORRELATION BETWEEN ATROPHY-TRACTION-NEOVASCULARIZATION GRADE FOR MYOPIC MACULOPATHY AND CLINICAL SEVERITY
Authors: Ruiz-Medrano Jorge , Flores-Moreno Ignacio , Ohno-Matsui Kyoko , Cheung Chui Ming Gemmy , Silva Rufino , Ruiz-Moreno José M. 
Published: February 2021

Purpose:
To assess the reliability of the atrophy-traction-neovascularization (ATN) classification in patients with pathologic myopia (PM) and its correlation with best-corrected visual acuity (BCVA).

Methods:
Cross-sectional study. Hundred highly myopic eyes with a spherical equivalent of >−6.0 diopters or axial length of >26 mm and a total ATN score of ≥3 underwent a complete ophthalmological examination, including fundus photography and swept-source optical coherence tomography. Five observers graded each eye using the ATN system. Mean A, T, and N scores were calculated and correlated with age, BCVA (in logarithm of the minimum angle of resolution), and axial length. Patients were considered to present severe PM if either A or T components were ≥3 and/or N was ≥2.

Results:
Hundred eyes (53 left) from 91 patients (78 women) were classified. Mean age, BCVA, and axial length values were, respectively, 65.1 ± 11.7 years (range, 36–97 years), −0.63 ± 0.62 (−3.00 to 0.00), and 29.26 ± 2.7 mm (26.01–37.66 mm). Mean ATN grades for each component were as follows: A = 2.51 ± 0.78 (0.6–4.0), T = 0.88 ± 1.14 (0.0–5.0), and N = 1.31 ± 1.40 (0.0–3.0). Weighted interobserver agreement was 98.1%, 98.7%, and 94.6%, for A, T and N, respectively. In eyes with severe PM, BCVA was significantly lower and axial length was significantly longer.

Conclusion:
The excellent interobserver rate in this study demonstrates that the updated ATN grading system is an accurate and reliable tool to classify patients with PM. These findings show that BCVA is more compromised in eyes with severe PM, particularly those graded ≥A3 and/or T3.
FULL-THICKNESS MACULAR HOLE IN AGE-RELATED MACULAR DEGENERATION PATIENTS WITH TWO DISTINCT ENTITIES
Authors: Rabina Gilad , Pillar Shani , Nemet Achia , Mimouni Michael , Levinger Nadav , Chowers Itay , Ehrlich Rita , Gal-Or Orly , Barequet Dana , Rosenblatt Amir , Moisseiev Elad , Greifner Hillel , Magal Itay , Segal Ori 
Published: February 2021

Purpose:
To describe optical coherence tomography characteristics of full-thickness macular holes (FTMHs) in age-related macular degeneration patients.

Methods:
A multicenter, retrospective, observational case series of patients diagnosed with age-related macular degeneration and FTMHs seen between January 1, 2009, and January 3, 2020. Clinical charts and spectral-domain optical coherence tomography images were reviewed. Optical coherence tomography findings included FTMH-inverted trapezoid or hourglass appearance, central macular thickness (CMT), complete retinal pigment epithelium and complete retinal outer retinal atrophy, and presence of pigment epithelium detachment and epiretinal membrane. The mean outcome was the morphologic and functional characterization of different subtypes of FTMHs.

Results:
A total of 86 eyes of 85 consecutive patients, with mean age of 80.31 ± 8.06 and mean best-corrected visual acuity of 1.17 ± 0.58 logarithm of the minimal angle of resolution. Two different subtypes of FTMHs were identified: tractional and degenerative. Fifty (58%) degenerative FTMHs characterized with inverted trapezoid appearance and 36 (42%) tractional FTMHs characterized with hourglass appearance. Degenerative FTMHs presented with 66% of CMT < 240 µm, 14% of CMT > 320, and 70% of complete retinal outer retinal atrophy, in comparison with 41% of CMT < 240 µm, 42.9% of CMT > 320%, and 20% of complete retinal outer retinal atrophy in the tractional FTMH group (P = 0.002, 0.003, <0.001, respectively). The presence of epiretinal membrane and pigment epithelium detachment where significantly higher in tractional FTMHs (P = 0.02, 0.03, respectively).

Conclusion:
Degenerative and tractional FTMHs may be two distinct clinical entities. Discerning degenerative from tractional FTMHs is possible by using optical coherence tomography features including shape of the FTMHs, CMT, internal–external ratio of FTMHs, and presence of complete retinal outer retinal atrophy, pigment epithelium detachment, and epiretinal membrane.
Insect Fungus Metarhizium robertsii Is a Rare Causative Agent of Keratitis
Authors: Palazzolo Laura , Kowalski Regis P. , Nayyar Shannon V. , Jhanji Vishal , Prakash Gaurav 
Published: February 2021

Purpose:
This study aimed to describe a case of keratitis secondary to Metarhizium robertsii, a soil-dwelling fungus with typical insect pathogenicity.

Methods:
A Case report.

Results:
A 58-year-old man with a ocular history of soft contact lens overwear, poor contact lens hygiene, and ocular exposure to ground well water supplying his house was referred to our university practice for a central corneal ulcer with 40% thinning. Same-day rapid microscopic detection with Giemsa stain identified the presence of many hyphae elements, and he was ultimately diagnosed with M. robertsii keratitis. The patient's course involved severe and progressive corneal thinning that stabilized over a 3-month course of antifungal therapy.

Conclusions:

Metarhizium robertsii seems more aggressive than other forms of fungal keratitis; therefore, this infection may be watched more closely with the risk for quick progressive corneal thinning, even while on antifungal management.
COL14A1 promotes self-renewal of human liver cancer stem cells through activation of ERK signaling
Authors: Kong Ruijiao , Liu Haidong , Shi Yi , Man Qiuhong , Liu Shanrong 
Published: February 2021

Objective:
Liver cancer stem cells (CSCs) are the culprits of hepatocellular carcinoma metastasis and recurrence. Only by eliminating tumor stem cells can malignant tumors be fundamentally cured. This study aimed to identify the role and underlying mechanism of aberrant Collagen Type XIV Alpha 1 Chain (COL14A1) overexpression in liver CSCs, and improve understanding of the molecular basis of hepatocellular carcinoma metastasis and recurrence.

Methods:
First, quantitative real-time polymerase chain reaction was used to confirm aberrant high-expression of COL14A1 in liver CSCs. Next, interference experiments were performed to determine the key role of COL14A1. To explore the mechanism of COL14A1 overexpression in liver CSCs, putative microRNA (miRNAs) targeting COL14A1 were analyzed using the miRTarBase database. Next, quantitative real-time polymerase chain reaction, western blotting, and luciferase reporter assays were performed to verify the interaction between miR-7108-3p and COL14A1. Lastly, key target proteins of the COL14A1-extracellular-regulated signal kinase (ERK) signaling pathway were identified through western blotting analysis. This study was approved by the Ethics Committee of Shanghai Fourth People’s Hospital, Tongji University School of Medicine, China (approval No. 2019tjdx17) on February 21, 2019.

Results:
COL14A1 is abnormally highly expressed in liver CSCs, which is necessary for liver CSCs to maintain their self-renewal capability. Mechanistically, COL14A1 is post-transcriptionally regulated by miR-7108-3p in a negative manner. Low expression of miR-7108-3p increased translation of COL14A1, which subsequently activated ERK signaling, ultimately maintaining the self-renewal and stem cell-like properties of liver CSCs.

Conclusion:
COL14A1, which is negatively regulated by miR-7108-3p, was found to play a crucial role in maintaining the self-renewal and stem cell-like properties of liver CSCs through activation of ERK signaling.