bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of Population Pharmacokinetic Models for Clozapine Dosage Prediction
Authors: Berneri Massimo , Jha Uma , O'Halloran Seán , Salman Sam , Wickramasinghe Shanek , Kendrick Kevin , Nguyen Jessica , Joyce David A. 
Published: March 2024

Background:
Clozapine is unique in its capacity to ameliorate severe schizophrenia but at high risk of toxicity. A relationship between blood concentration and clinical response and evidence for concentration–response relationships to some adverse effects justify therapeutic drug monitoring of clozapine. However, the relationship between drug dose and blood concentration is quite variable. This variability is, in part, due to inductive and inhibitory interactions varying the activity of cytochrome P450 1A2 (CYP1A2), the principal pathway for clozapine elimination. Several population pharmacokinetic models have been presented to facilitate dose selection and to identify poor adherence in individual patients. These models have faced little testing for validity in independent populations or even for persisting validity in the source population.

Methods:
Therefore, we collected a large population of clozapine-treated patients (127 patients, 1048 timed plasma concentrations) in whom dosing and covariate information could be obtained with high certainty. A population pharmacokinetic model was constructed with data collected in the first 6 weeks from study enrolment (448 plasma concentrations), to estimate covariate influences and to allow alignment with previously published models. The model was tested for its performance in predicting the concentrations observed at later time intervals up to 5 years. The predictive performances of 6 published clozapine population models were then assessed in the entire population.

Results:
The population pharmacokinetic model based on the first 6 weeks identified significant influences of sex, smoking, and cotreatment with fluvoxamine on clozapine clearance. The model built from the first 6 weeks had acceptable predictive performance in the same patient population up to the first 26 weeks using individual parameters, with a median predictive error (PE) of −0.1% to −15.9% and median absolute PE of 22.9%–27.1%. Predictive performance fell progressively with time after 26 weeks. Bayesian addition of plasma concentration observations within each prediction period improved individual predictions. Three additional observations extended acceptable predictive performance into the second 6 months of therapy. When the published models were tested with the entire data set, median PE ranged from −8% to +35% with a median absolute PE of >39% in all models. Thus, none of the tested models was successful in external validation. Bayesian addition of single patient observations improved individual predictions from all models but still without achieving acceptable performances.

Conclusions:
We conclude that the relationship between covariates and blood clozapine concentrations differs between populations and that relationships are not stable over time within a population. Current population models for clozapine are not capturing influential covariates.
Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy
Authors: Ampuero Javier , Lucena Ana , Berenguer Marina , Hernández-Guerra Manuel , Molina Esther , Gómez-Camarero Judith , Valdivia Carlos , Gómez Elena , Casado Marta , Álvarez-Navascuez Carmen , Jorquera Francisco , García-Buey Luisa , Díaz-González Álvaro , Morillas Rosa , García-Retortillo Montserrat , Sousa Jose M. , Pérez-Medrano Indhira , Simón Miguel Á. , Martínez Javier , Arenas Juan , Londoño María Carlota , Olveira Antonio , Fernández-Rodríguez Conrado ,   on behalf of ColHai Registry
Published: March 2024

Background and Aims:
The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients.

Approach and Results:
Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score–matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06–0.73]) and AST (OR 0.97 [95% CI: 0.95–0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95–0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08–0.64]), diabetes (sHR 5.62 [95% CI: 2.02–15.68]), albumin (sHR 0.34 [95% CI: 0.13–0.89]), and platelets (sHR 0.99 [95% CI: 0.98–1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14–0.95]), albumin (sHR 0.36 (95% CI: 0.16–0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17–11.70]) were associated with decompensated cirrhosis.

Conclusions:
Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation.
Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort
Authors: Pandurangi Sindhu , Mourya Reena , Nalluri Shreya , Fei Lin , Dong Shun , Harpavat Sanjiv , Guthery Stephen L. , Molleston Jean P. , Rosenthal Philip , Sokol Ronald J. , Wang Kasper S. , Ng Vicky , Alonso Estella M. , Hsu Evelyn K. , Karpen Saul J. , Loomes Kathleen M. , Magee John C. , Shneider Benjamin L. , Horslen Simon P. , Teckman Jeffrey H. , Bezerra Jorge A. ,   for the Childhood Liver Disease Research Network
Published: March 2024

Background and Aims:
High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated the accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort.

Approach and Results:
MMP-7 was measured in serum samples of 399 infants with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays. The discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an AUROC of 0.90 (CI: 0.87–0.94). At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77–0.86), stool color = 0.68 (CI: 0.63–0.73), and pathology = 0.84 (CI: 0.76–0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+gamma-glutamyl transferase AUROC to 0.91 (CI: 0.88–0.95). Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs.

Conclusions:
Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in the evaluation of infants with cholestasis may simplify diagnostic algorithms and shorten the time to hepatoportoenterostomy.
A Modified Girth-Hitch Suture Technique to Rescue Single-Haptic Dislocation of Scleral-Fixated Intraocular Lenses
Authors: Arıkan Yorgun Mücella , Taşçı Yelda Yıldız , Yasin Toklu 
Published: March 2024

Purpose:
To describe the technique of modified girth-hitch suture for one-side transscleral fixation to rescue a single-haptic dislocation.

Methods:
In this surgical technique report, dislocated scleral-fixated posterior-chamber intraocular lenses (IOLs) were secured to the sclera using a 10-0 polypropylene suture looped around the IOL haptic. Three types of IOL were secured in this study (four cases of one-piece polymethyl methacrylate (PMMA) IOL, one case of three-piece acrylic IOL with PMMA loop, and one case of acrylic foldable IOL with a two-plate loop design).

Results:
Six patients, who had subluxation of the scleral-fixated posterior-chamber IOL due to single-knot dehiscence, underwent refixation of scleral-fixated IOL surgery using this technique. In all cases, successful repositioning with stable and central fixation of the IOLs was achieved. No intraoperative or postoperative complications were noted.

Conclusion:
Internal refixation with a girth-hitch suture is a relatively quick and convenient method for the management of a dislocated IOL haptic on one side.
Retinal Vasculitis in a Patient with Hansen’s Disease
Authors: Savant Shravan V. , Soukiasian Sarkis H. , Spaide Richard F. , Klein-Mascia Kendra A. 
Published: March 2024

Purpose:
Hansen’s disease is endemic in over 140 countries worldwide and a potentially blinding condition. We describe a case of retinal vasculitis in a patient with Hansen’s disease with concomitant positive antiphospholipid antibody serology, a potentially under-reported complication in this setting.

Methods:
A 37-year-old Brazilian man systemically stable on triple therapy (clofazimine, rifampin, dapsone) for Hansen’s disease presented for a comprehensive ophthalmic evaluation.

Results:
Dilated exam revealed diffuse peripheral intraretinal hemorrhages in his right eye. Fluorescein angiography showed peripheral non-perfusion, abnormal shunt vessels and leakage from the retinal veins in the right eye and peripheral non-perfusion and vascular leakage in the fellow eye, consistent with vasculitis. Laboratory workup was notable for positive antiphospholipid antibodies (lupus anticoagulant, anticardiolipin IgM, anti-beta-2 glycoprotein 1 IgM) and normocytic anemia.

Conclusion:
As antiphospholipid antibodies are present in a large proportion of patients with Hansen’s disease, it is possible that retinal vasculitis may be more common than previously thought. The extent to which retinal vasculitis occurs in Hansen’s disease remains uncertain and possibly underestimated due to the frequency of anterior segment scarring, which impedes retinal evaluation. Heightened surveillance for potential retinal vascular complications is warranted.
Development and validation of a deep learning radiomics model with clinical-radiological characteristics for the identification of occult peritoneal metastases in patients with pancreatic ductal adenocarcinoma
Authors: Shi Siya , Lin Chuxuan , Zhou Jian , Wei Luyong , chen Mingjie , Zhang Jian , Cao Kangyang , Fan Yaheng , Huang Bingsheng , Luo Yanji , Feng Shi-Ting 
Published: March 2024

Background:
Occult peritoneal metastases (OPM) in patients with pancreatic ductal adenocarcinoma (PDAC) are frequently overlooked during imaging. We aimed to develop and validate a CT-based deep learning-based radiomics (DLR) model to identify OPM in PDAC before treatment.

Methods:
This retrospective, bicentric study included 302 patients with PDAC (training: n=167, OPM-positive, n=22; internal test: n=72, OPM-positive, n=9: external test, n=63, OPM-positive, n=9) who had undergone baseline CT examinations between January 2012 and October 2022. Handcrafted radiomics (HCR) and DLR features of the tumor and HCR features of peritoneum were extracted from CT images. Mutual information and least absolute shrinkage and selection operator algorithms were used for feature selection. A combined model, which incorporated the selected clinical-radiological, HCR, and DLR features, was developed using a logistic regression classifier using data from the training cohort and validated in the test cohorts.

Results:
Three clinical-radiological characteristics (carcinoembryonic antigen 19-9 and CT-based T and N stages), nine HCR features of the tumor, 14 DLR features of the tumor and three HCR features of the peritoneum were retained after feature selection. The combined model yielded satisfactory predictive performance, with an area under the curve (AUC) of 0.853 (95% confidence interval [CI], 0.790–0.903), 0.845 (95% CI, 0.740–0.919), and 0.852 (95% CI, 0.740–0.929) in the training, internal test, and external test cohorts, respectively (all P<0.05). The combined model showed better discrimination than the clinical-radiological model in the training (AUC=0.853 vs. 0.612, P<0.001) and the total test (AUC=0.842 vs. 0.638, P<0.05) cohorts. The decision curves revealed that the combined model had greater clinical applicability than the clinical-radiological model.

Conclusions:
The model combining CT-based deep learning radiomics and clinical-radiological features showed satisfactory performance for predicting occult peritoneal metastases in patients with pancreatic ductal adenocarcinoma.
The effect of omentoplasty in various surgical operations: systematic review and meta-analysis
Authors: Peng Yaqi , Xiong Shan , Ding Yujin , Xie Limin , Wang Yihang , Mei Ying , Liu Wei , Deng Tuo 
Published: March 2024

Background:
Omentoplasty is commonly used in various surgeries. However, its effectiveness is unsure due to lack of convincing data and research. To clarify the impact of omentoplasty on postoperative complications of various procedures, this systematic review and meta-analysis was performed.

Methods:
A systematic review of published literatures from four databases: PubMed, Web of Science, Cochrane Library, and Embase before 14 July 2022. The authors primarily included publications on five major surgical operations performed in conjunction with omentoplasty: thoracic surgery, esophageal surgery, gastrointestinal surgery, pelvi-perineal surgery, and liver surgery. The protocol was registered in PROSPERO.

Results:
This review included 25 273 patients from 91 studies (n=9670 underwent omentoplasty). Omentoplasty was associated with a lower risk of overall complications particularly in gastrointestinal [relative risk (RR) 0.53; 95% CI: 0.39–0.72] and liver surgery (RR 0.54; 95% CI: 0.39–0.74). Omentoplasty reduced the risk of postoperative infection in thoracic (RR 0.38; 95% CI: 0.18–0.78) and liver surgery (RR 0.39; 95% CI: 0.29–0.52). In patients undergoing esophageal (RR 0.89; 95% CI: 0.80–0.99) and gastrointestinal (RR 0.28; 95% CI: 0.23–0.34) surgery with a BMI greater than 25, omentoplasty is significantly associated with a reduced risk of overall complications compared to patients with normal BMI. No significant differences were found in pelvi-perineal surgery, except infection in patients whose BMI ranged from 25 kg/m2 to 29.9 kg/m2 (RR 1.25; 95% CI: 1.04–1.50) and anastomotic leakage in patients aged over 60 (RR 0.59; 95% CI: 0.39–0.91).

Conclusion:
Omentoplasty can effectively prevent postoperative infection. It is associated with a lower incidence of multiple postoperative complications in gastrointestinal and liver surgery.
The role of early cerebral edema and hematoma assessment in aneurysmal subarachnoid hemorrhage (a-SAH) in predicting early brain injury (EBI) and cognitive impairment: a case controlled study
Authors: Wang Ming-Dong , Fu Qian-Hui , Ni Andrew , Yuan Yun-Peng , Li Chun-Hui , Wang Zhan-Xiang , Wang Hong 
Published: March 2024

Background:
Early assessment and management of cerebral edema and hematoma following aneurysmal subarachnoid hemorrhage (a-SAH) can significantly impact clinical cognitive outcomes. However, current clinical practices lack predictive models to identify early structural brain abnormalities affecting cognition. To address this gap, the authors propose the development of a predictive model termed the a-SAH Early Brain Edema/Hematoma Compression Neural (Structural Brain) Networks Score System (SEBE-HCNNSS).

Methods:
In this study, 202 consecutive patients with spontaneous a-SAH underwent initial computed tomography (CT) or MRI scans within 24 h of ictus with follow-up 2 months after discharge. Using logistic regression analysis (univariate and multivariate), the authors evaluated the association of clinically relevant factors and various traditional scale ratings with cognitive impairment (CI). Risk factors with the highest area under the curve (AUC) values were included in the multivariate analysis and least absolute shrinkage and selection operator (LASSO) analysis or Cox regression analysis.

Results:
A total of 177 patients were enrolled in the study, and 43 patients were classified with a high SEBE-HCNNSS grade (3–5). After a mean follow-up of 2 months, 121 individuals (68.36%) with a-SAH and three control subjects developed incident CI. The CT interobserver reliability of the SEBE-HCNNSS scale was high, with a Kappa value of 1. Furthermore, ROC analysis identified the SEBE-HCNNSS scale (OR 3.322, 95% CI: 2.312–7.237, P=0.00025) as an independent predictor of edema, CI, and unfavorable prognosis. These results were also replicated in a validation cohort.

Conclusion:
Overall, the SEBE-HCNNSS scale represents a simple assessment tool with promising predictive value for CI and clinical outcomes post-a-SAH. Our findings indicate its practical utility as a prognostic instrument for risk evaluation after a-SAH, potentially facilitating early intervention and treatment.
Analyzing circulating tumor cells and epithelial-mesenchymal transition status of papillary thyroid carcinoma patients following thyroidectomy: a prospective cohort study
Authors: Yu Hyeong Won , Park Eunju , Lee Ja Kyung , Kim Woochul , Kong Ju Hyun , Sunoo Joseph , Hong Soon-Cheol , Choi June Young 
Published: March 2024

Background:
This study investigated the prevalence and subtype distribution of circulating tumor cells (CTCs) in patients with papillary thyroid cancer (PTC) before and after thyroidectomy to determine the potential of CTC count as a noninvasive marker of the efficacy of surgical treatment in PTC.

Materials and methods:
Between January 2021 and January 2022, 62 PTC patients who underwent thyroidectomy at Seoul National University Bundang Hospital were prospectively evaluated. Peripheral blood samples (7.5 ml) were collected from each patient for CTC analysis before surgery and at 2 weeks and 3 months after surgery. CTC count and the distribution of CTC subtypes, including epithelial, epithelial-mesenchymal, and mesenchymal phenotypes, were analyzed using the negative selection method and immunofluorescence staining. The relationship between CTC count and clinicopathological characteristics was analyzed before and after surgery.

Results:
Before surgery, CTCs were detected in 87% (54/62) of patients; the mean CTC count was 8.0 and the median was 5.0 in 7.5 ml of peripheral blood. The mesenchymal or epithelial-mesenchymal phenotypes were predominant. After thyroidectomy, the mean and median CTC count values decreased to 5.3 and 2.5, respectively, at 2 weeks and to 4.3 and 3.0, respectively, at 3 months. This postoperative reduction in CTCs was more pronounced in patients with lymphatic invasion, lymph node metastasis, or BRAF V600E mutation.

Conclusion:
CTCs were detected in patients with PTC with a predominance of cells undergoing epithelial-mesenchymal transition. The CTC count decreased postoperatively, suggesting that liquid biopsy with CTC detection could be a valuable noninvasive tool for monitoring the efficacy of surgery in PTC.
Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus
Authors: Clarke Megan A. , Wentzensen Nicolas , Perkins Rebecca B. , Garcia Francisco , Arrindell Deborah , Chelmow David , Cheung Li C. , Darragh Teresa M. , Egemen Didem , Guido Richard , Huh Warner , Locke Alexander , Lorey Thomas S. , Nayar Ritu , Risley Carolann , Saslow Debbie , Smith Robert A. , Unger Elizabeth R. , Massad L. Stewart ,   for the Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee
Published: March 2024

Objectives
The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results.

Methods
Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines. Resource usage metrics were calculated to support decision-making. Risk estimates in relation to clinical action thresholds were reviewed and used as the basis for draft recommendations. After an open comment period, recommendations were finalized and ratified through a vote by the Consensus Stakeholder Group.

Results
For triage of positive HPV results from screening with primary HPV testing (with or without genotyping) or with cytology cotesting, colposcopy is recommended for individuals testing DS-positive. One-year follow-up with HPV-based testing is recommended for individuals testing DS-negative, except for HPV16- and HPV18-positive results, or high-grade cytology in cotesting, where immediate colposcopy referral is recommended. Risk estimates were similar between the Kaiser Permanente Northern California and STudying Risk to Improve DisparitiES populations. In general, resource usage metrics suggest that compared with cytology, DS requires fewer colposcopies and detects cervical intraepithelial neoplasia grade 3 or worse earlier.

Conclusions
Dual stain testing with CINtec PLUS Cytology is acceptable for triage of HPV-positive test results. Risk estimates are portable across different populations.