bluuebunny/crossref_metadata_2025 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.
Guidelines for Application of High-Content Screening in Traditional Chinese Medicine: Concept, Equipment, and Troubleshooting
Authors: Chen Xuechun , Li Lu , Zhang Mingxu , Yang Jian , Lyu ChunMing , Xu Yizhou , Yang Yang , Wang Yi
Published: March 2024

High-content screening (HCS) technology combines automated high-speed imaging hardware and single-cell quantitative analysis. It can greatly accelerate data acquisition in cellular fluorescence imaging and is a powerful research technique in traditional Chinese medicine (TCM). An increasing number of laboratories and platforms, including TCM laboratories, have begun utilizing HCS systems. However, this technology is still in its infancy in TCM research and there is a lack of sufficient experience with the associated concepts, instrument configurations, and analysis methods. To improve the understanding of HCS among researchers in the field of TCM, this paper summarizes the concept of HCS, software and hardware configuration, the overall research process, as well as common problems and related solutions of HCS in TCM research based on our team’s previous research experience, providing several research examples and an outlook on future perspectives, aiming to provide a technical guide for HCS in TCM research.
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.
Metabolic flux analysis in adipose tissue reprogramming
Authors: Medina Ashley , Bruno Joanne , Alemán José O.
Published: March 2024

Obesity is a growing epidemic in the United States and worldwide and is associated with insulin resistance and cardiovascular disease, among other comorbidities. Understanding of the pathology that links overnutrition to these disease processes is ongoing. Adipose tissue is a heterogeneous organ comprised of multiple different cell types and it is likely that dysregulated metabolism within these cell populations disrupts both inter- and intracellular interactions and is a key driver of human disease. In recent years, metabolic flux analysis, which offers a precise quantification of metabolic pathway fluxes in biological systems, has emerged as a candidate strategy for uncovering the metabolic changes that stoke these disease processes. In this mini review, we discuss metabolic flux analysis as an experimental tool, with a specific emphasis on mass spectrometry with isotope tracing as this is the technique most frequently used for metabolic flux analysis in adipocytes. Furthermore, we examine existing literature that uses metabolic flux analysis to further our understanding of adipose tissue biology. Our group has a specific interest in understanding the role of white adipose tissue inflammation in the progression of cardiometabolic disease, as we know that in obesity the accumulation of pro-inflammatory adipose tissue macrophages is associated with significant morbidity, so we use this as a paradigm throughout our review for framing the application of these experimental techniques. However, there are many other biological applications to which they can be applied to further understanding of not only adipose tissue biology but also systemic homeostasis.
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.
Prospective evaluation of 68Ga-NODAGA-RGD PET-CT in patients of carcinoma thyroid with thyroglobulin elevated negative radioiodine scintigraphy (TENIS) with a head-to-head comparison with FDG-PET/CT
Authors: Gondhane Abhay , Verma Priyanka , Chandak Ashok , Basu Sandip
Published: March 2024

Background and aim

This study aimed to examine the expression of RGD binding integrins in patients of elevated serum thyroglobulin (Tg) level with negative radioiodine scintigraphy (TENIS) employing 68Ga-NODAGA-RGD PET-CT.

Material and methods

This was a prospective study involving 30 proven cases of TENIS with histopathological diagnosis of differentiated thyroid carcinoma post-surgery. In addition to observing the lesional concentration on 68Ga-NODAGA-RGD PET-CT, a 4-point visual grading system (grade I–IV), was undertaken to estimate the degree of radiotracer avidity, for potential of theranostics.

Results

On 18F-FDG-PET/CT, the uptake was seen in 182 lesions out of a total of 200 (91%). 68Ga-NODAGA-RGD PET-CT showed expression in a total of 110/200 (55%) lesions. On patient-specific analysis, 68Ga-NODAGA-RGD PET-CT was positive for the disease in 21/30 patients (70%) and negative in 9/30 (30%) patients. The overall patient-specific sensitivity and specificity of 68Ga-NODAGA-RGDPET-CT were 75% and 100%, respectively. 18F-FDG PET-CT was positive for the disease in 26/30 patients (86.66%) and negative in 4/30 (13.33%) patients. The overall patient-specific sensitivity and specificity of 18F-FDG-PET/CT were 92.86% and 100%, respectively. The 4-point visual grading system revealed 14/200 (7%) lesions demonstrating Grade I uptake, 49/200 (24.5%) lesions grade II uptake, 17/200 (8.5%) lesions grade III uptake and 40/200 (20%) lesions grade IV uptake.

Conclusion

The results suggested that RGD-binding integrin is expressed in a sizeable fraction of metastatic lesions of TENIS cases, albeit demonstrating a varying degree of uptake. Out of the soft tissue, lung, and bone lesions, metastatic bone lesions showed more RGD affinity than other sites. The patients with substantial RGD uptake on a 4-point visual grading system may be potential targets for RGD–based therapy.
Caring for screenagers (Part 1): a pediatrician's primer on popular social media platforms
Authors: Cason Grace , Margolis Alex , Barile Joseph , Milanaik Ruth Lynn
Published: March 2024

Purpose of review

Since the inception of social media, children have used platforms in manners unbeknownst to their parents. Just when parents feel they may finally understand what platform is relevant or trend is “in,” the landscape evolves, and children shift to something new. It is therefore critical that pediatricians stay informed about what is popular in youth populations. This enables the recognition of the potential dangers of contemporary social media engagement.

Recent findings

Short-form content and livestreaming continue to rise in popularity while certain older forms of social media have retained relevancy in youth circles. YouTube is the dominant social media force, with both livestreaming and short-form offerings. Twitch and TikTok provide alternatives to YouTube for livestreaming and short-form content, respectively. Instagram and Snapchat – two social media apps that have existed for over 10 years – remain as the most popular mechanisms for children to interact with their friends online.

Issues related to body image, attention deficits, cyberbullying, and other potential harms have many parents wary of their child's presence on social media. Social media sites have in-place mechanisms to prevent the likelihood of harm, but pediatricians and parents should still counsel children on best social media practices.
Use of Maribavir for Multidrug Resistant Cytomegaloviremia in a Pediatric Oncology Patient
Authors: Fisher James E. , Mulieri Kevin , Finch Elizabeth , Ericson Jessica E.
Published: March 2024

Resistant and refractory cytomegalovirus (CMV) viremia can limit the provision of chemotherapy due to myelosuppression and end-organ dysfunction. Few therapies are available for children with clinically significant CMV viremia. We successfully used maribavir for a 4-year-old patient with lymphoma to complete his chemotherapy course. Resistance to maribavir did result after many months of therapy.
Nasopharyngeal Carcinoma in Children, Current Treatment Approach
Authors: Ben-Ami Tal
Published: March 2024

Nasopharyngeal carcinoma (NPC) is a rare and locally aggressive form of childhood cancer. Treatment of pediatric NPC includes chemotherapy and radiotherapy. Most studies on the treatment of pediatric NPC are single-arm studies. With current treatment protocols survival rates for patients with nonmetastatic disease exceed 80%, although most children will have long-term treatment-related late effects. Efforts to reduce early and late toxicities include reduced radiotherapy doses in children with good responses to induction chemotherapy. Further studies are needed to evaluate the role of immunotherapy in both the primary setting and in children with progressive or relapsed disease. This review summarizes current clinical approaches to the treatment of pediatric NPC.
Risk Factors for Blunt Cerebrovascular Injury in a Cohort of Pediatric Patients With Cervical Seat Belt Sign
Authors: Najar Daniel A. , Cardenas-Turanzas Marylou , King Jadeyn , Shah Manish N. , Cox Charles S. , Ugalde Irma T.
Published: March 2024

Background

Three-point seat belt restraints have been attributed to blunt cerebrovascular injury (BVCI), injury to the carotid or vertebral arteries. Although previous studies have not found a seat belt sign to be a significant predictor for BCVI, it is still used to screen patients for BCVI.

Objective

This study aims to determine risk factors for BCVI within a cohort of patients with seat belt signs.

Methods

We conducted a retrospective cohort study using our institutional trauma registry and included patients younger than 18 years with blunt trauma who both had a computed tomography angiography (CTA) of the neck performed and had evidence of a seat belt sign per the medical record. We reported frequencies, proportions, and measures of central tendency and conducted univariate analysis to evaluate factors associated with BCVI. We estimated the magnitude of the effect of each variable associated with the study outcome by conducting logistic regression and reporting odds ratios and 95% confidence intervals.

Results

Among all study patients, BCVI injuries were associated with Injury Severity Score higher than 15 (P = 0.04), cervical spinal fractures (P = 0.007), or basilar skull fractures (P = 0.01). We observed higher proportions of children with BCVI when other motorized and other blunt mechanisms were reported as the mechanisms of injury (P = 0.002) versus motor vehicle collision.

Conclusions

Significant risk factors for BCVI in the presence of seat belt sign are: Injury severity score greater than 15, cervical spinal fracture, basilar skull fracture, and the other motorized mechanism of injury, similar to those in all children at risk of BCVI.
Can Ischemia-Modified Albumin Be a Helpful Marker in the Diagnosis and Follow-Up of Childhood Intussusception?
Authors: Kocaoğlu Çelebi , Kocaoğlu Canan , Madenci Hasan
Published: March 2024

Objectives

Intussusception is the invagination of a proximal segment of the intestine into a more distal segment. The present study aimed to determine the sensitivity of the ischemia-modified albumin (IMA) and the correlation between IMA and the severity of intestinal ischemia in intussusception cases.

Methods

Thirty-six consecutive children aged between 0 and 16 years presenting with the clinical and radiological features of intestinal obstruction caused by intussusception were enrolled in the study. The age- and sex-matched control group was composed of patients undergoing outpatient surgery. The patients were categorized as cases of type I (ileoileal), type II (ileocecal), and type III (colocolic) based on the ultrasonography findings.

Results

The mean IMA level of the intussusception group was 179.13 ± 220.33 ng/mL, whereas the mean level was found as 89 ± 70.9 ng/mL in the control group. When the patients were categorized as ileoileal, ileocecal, and colocolic, the mean IMA levels were detected as 235.65 ± 268.14 ng/mL, 174.46 ± 212.8 ng/mL, and 46.95 ± 19.56 ng/mL, respectively. There was a moderate correlation between the invaginated segment lengths measured by the surgeon during the operation and IMA levels.

Conclusions

Our study findings reveal that IMA can be used as an auxiliary diagnostic marker in patients presenting with symptoms and signs suggestive of intussusception. Thus, patients can be screened for mechanical bowel obstruction due to intussusception and may be referred to pediatric surgery centers earlier for further examination.
Pitfall of Monobloc Advancement in Beare-Stevenson Syndrome
Authors: Sakamoto Yoshiaki , Miwa Tomoru
Published: March 2024

Beare-Stevenson syndrome (BSS) is an extremely rare form of craniosynostosis. Half of patients with BSS died within the first year of life due to cardiorespiratory arrest or unexpected sudden death. In addition, there have only been fewer than 30 cases, which limits prognostication for clinicians. We currently have an 8-year-old patient who is being followed up. She underwent tracheostomy, cranioplasty, and shunting. After waiting for growth, for improvement of ocular herniation, monobloc advancement was performed at the age of 5 years. The temporal fossa was quite narrow due to severe midface hypoplasia. In addition, even though midface advancement, it was difficult to remove tracheostomy. This was because midfacial hypoplasia was so severe that it was hard to notice, but there was also micrognathia. We report our experience with this midface treatment.
Defining the Problem: 53 Years of Firearm Violence Afflicting America’s Schools
Authors: Joseph Bellal , Hosseinpour Hamidreza , Sakran Joseph , Anand Tanya , Colosimo Christina , Nelson Adam , Stewart Collin , Spencer Audrey L , Zhang Bo , Magnotti Louis J
Published: March 2024

BACKGROUND:

Firearm violence and school shootings remain a significant public health problem. This study aimed to examine how publicly available data from all 50 states might improve our understanding of the situation, firearm type, and demographics surrounding school shootings.

STUDY DESIGN:

School shootings occurring in the US for 53 years ending in May 2022 were analyzed, using primary data files that were obtained from the Center for Homeland Defense and Security. Data analyzed included situation, injury, firearm type, and demographics of victims and shooters. We compared the ratio of fatalities per wounded after stratifying by type of weapon. Rates (among children) of school shooting victims, wounded, and fatalities per 1 million population were stratified by year and compared over time.

RESULTS:

A total of 2,056 school shooting incidents involving 3,083 victims were analyzed: 2,033 children, 5 to 17 years, and 1,050 adults, 18 to 74 years. Most victims (77%) and shooters (96%) were male individuals with a mean age of 18 and 19 years, respectively. Of the weapons identified, handguns, rifles, and shotguns accounted for 84%, 7%, and 4%, respectively. Rifles had a higher fatality-to-wounded ratio (0.45) compared with shooters using multiple weapons (0.41), handguns (0.35), and shotguns (0.30). Linear regression analysis identified a significant increase in the rate of school shooting victims (β = 0.02, p = 0.0003), wounded (β = 0.01, p = 0.026), and fatalities (β = 0.01, p = 0.0003) among children over time.

CONCLUSIONS:

Despite heightened public awareness, the incidence of school shooting victims, wounded, and fatalities among children has steadily and significantly increased over the past 53 years. Understanding the epidemic represents the first step in preventing continued firearm violence in our schools.
Baseline Characteristics and Use of Pretherapeutic 18F-Fluorodeoxyglucose-PET for Pancreatic Cancer
Authors: Carlson Danielle M , Abdelrahman Amro M , Adjei Antwi Stella K , Tomlinson Jennifer L , Trivedi Kamaxi , Karbhari Aashna , Patnam Gopal Chetty Nandakumar , Halfdanarson Thor R , Goenka Ajit H , Truty Mark J
Published: March 2024

BACKGROUND:

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy. Surgical resection is the only curative modality combined with neoadjuvant chemotherapy to improve survival. Given the limitations of traditional responses such as cross-sectional imaging (CT/MRI) or tumor markers, carbohydrate antigen 19-9 (CA19-9), the 2023 National Comprehensive Cancer Network guidelines included18F-fluorodeoxyglucose (FDG)-PET as an adjunct to assess response to neoadjuvant chemotherapy. There are common misconceptions on the metabolic activity (tumor avidity) in PDAC so we aimed to describe the baseline characteristics and use of FDG-PET in a cohort of treatment-naive patients with PDAC.

STUDY DESIGN:

A single-center retrospective study was conducted capturing all biopsy-proven, treatment-naive patients with PDAC who underwent either baseline FDG-PET/CT or FDG-PET/MRI imaging between 2008 and 2023. Baseline FDG-PET characteristics were collected, including primary tumors’ maximum standardized uptake value defined as metabolic activity (FDG uptake) of tumor compared with surrounding pancreatic parenchymal background, and the identification of extrapancreatic metastatic disease.

RESULTS:

We identified 1,095 treatment-naive patients with PDAC who underwent baseline FDG-PET imaging at diagnosis. CA19-9 was elevated in 76% of patients. Overall, 96.3% (1,054) of patients had FDG-avid tumors with a median maximum standardized uptake value of 6.4. FDG-PET also identified suspicious extrapancreatic metastatic lesions in 50% of patients, with a higher proportion (p < 0.001) in PET/MRI (59.9%) vs PET/CT (44.3%). After controlling for CA19-9 elevation, PET/MRI was superior in detection of extrapancreatic lesions compared with PET/CT.

CONCLUSIONS:

FDG-PET has significant use in PDAC as a baseline imaging modality earlier neoadjuvant therapy given the majority of tumors are FDG-avid. FDG-PET can identify additional extrapancreatic suspicious lesions allowing for optimal initial staging, with PET/MRI having increased sensitivity over PET/CT.
Human leucocytes processed by fast-rate inertial microfluidics retain conventional functional characteristics
Authors: Carvell Tom , Burgoyne Paul , Milne Laura , Campbell John D. M. , Fraser Alasdair R. , Bridle Helen
Published: March 2024

The manufacturing of clinical cellular therapies is a complex process frequently requiring manipulation of cells, exchange of buffers and volume reduction. Current manufacturing processes rely on either low throughput open centrifugation-based devices, or expensive closed-process alternatives. Inertial focusing (IF) microfluidic devices offer the potential for high-throughput, inexpensive equipment which can be integrated into a closed system, but to date no IF devices have been approved for use in cell therapy manufacturing, and there is limited evidence for the effects that IF processing has on human cells. The IF device described in this study was designed to simultaneously separate leucocytes, perform buffer exchange and provide a volume reduction to the cell suspension, using high flow rates with high Reynolds numbers. The performance and effects of the IF device were characterized using peripheral blood mononuclear cells and isolated monocytes. Post-processing cell effects were investigated using multi-parameter flow cytometry to track cell viability, functional changes and fate. The IF device was highly efficient at separating CD14+ monocytes (approx. 97% to one outlet, approx. 60% buffer exchange, 15 ml min−1) and leucocyte processing was well tolerated with no significant differences in downstream viability, immunophenotype or metabolic activity when compared with leucocytes processed with conventional processing techniques. This detailed approach provides robust evidence that IF devices could offer significant benefits to clinical cell therapy manufacture.
Parameter identifiability and model selection for partial differential equation models of cell invasion
Authors: Liu Yue , Suh Kevin , Maini Philip K. , Cohen Daniel J. , Baker Ruth E.
Published: March 2024

When employing mechanistic models to study biological phenomena, practical parameter identifiability is important for making accurate predictions across wide ranges of unseen scenarios, as well as for understanding the underlying mechanisms. In this work, we use a profile-likelihood approach to investigate parameter identifiability for four extensions of the Fisher–Kolmogorov–Petrovsky–Piskunov (Fisher–KPP) model, given experimental data from a cell invasion assay. We show that more complicated models tend to be less identifiable, with parameter estimates being more sensitive to subtle differences in experimental procedures, and that they require more data to be practically identifiable. As a result, we suggest that parameter identifiability should be considered alongside goodness-of-fit and model complexity as criteria for model selection.
Connecting continuum poroelasticity with discrete synthetic vascular trees for modelling liver tissue
Authors: Ebrahem Adnan , Jessen Etienne , ten Eikelder Marco F. P. , Gangwar Tarun , Mika Michał , Schillinger Dominik
Published: March 2024

The modelling of liver tissue across multiple length scales constitutes a significant challenge, primarily due to the multiphysics coupling of mechanical response and perfusion within the complex multiscale vascularization of the organ. In this paper, we present a modelling framework that connects continuum poroelasticity and discrete vascular tree structures to model liver tissue across disparate levels of the perfusion hierarchy. The connection is achieved through a series of modelling decisions, which include source terms in the pressure equation to model inflow from the supplying tree, pressure boundary conditions to model outflow into the draining tree, and contact conditions to model surrounding tissue. We investigate the numerical behaviour of our framework and apply it to a patient-specific full-scale liver problem that demonstrates its potential to help assess surgical liver resection procedures.
Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease
Authors: Weiss Lan , Carrer Michele , Shmara Alyaa , Cheng Cheng , Yin Hong , Ta Lac , Boock Victoria , Fazeli Yasamin , Chang Mindy , Paguio Marvin , Lee Jonathan , Yu Howard , Martin Angela , Raben Nina , Weiss John , Grossman Tamar , Jafar-nejad Paymaan , Kimonis Virginia
Published: March 2024

Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridize to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa-/-mouse model of PD led to a robust reduction in glycogen accumulation in skeletal and cardiac muscle. In addition, combining Gys1 ASO with ERT further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa-/-mice. Our results provide a strong foundation for further validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD.
Identifying High and Low Performing Emergency General Surgery Hospitals Using Direct Standardization
Authors: Goldberg Drew , Keele Luke , Wirtalla Chris , Syvyk Solomiya , Kelz Rachel R.
Published: March 2024

Importance

Variation in outcomes for emergency general surgery conditions has been shown at the hospital level. Few have examined difference across hospitals for older adults who often present with the greatest risk. To date, no one has examined differences in the outcome for those undergoing operative and nonoperative treatment.

Objective

Identify high and low performing emergency general surgery (EGS) hospitals with risk-standardization to determine clinical performance differences as well as correlation between patients treated operatively and non-operatively.

Design

A retrospective cohort study with 30-day outcomes.

Setting

Nationwide study of acute care hospitals.

Participants

Medicare beneficiaries > 65.5 years old hospitalized for an emergency general surgery condition admitted from July 1, 2015 to June 30, 2018.

Exposure

Unique hospital identification.

Main outcome

A composite metric of 30-day mortality, adverse events, prolonged length of stay, and readmission.

Results

There were 536,284 total patients with a mean age of 74.4 ± 12.2 years, 55% female, 84% white with average claims-based frailty index of 0.16 ± 0.06 and mean comorbidity count of 3.57 ± 2.46. Amongst the 1866 hospitals identified, there were 3 best performing and 11 worst performing hospitals. There were weak correlations between operative and non-operative for mortality (0.10), adverse events rates (0.21), prolonged length of stay (0.32), and readmissions (0.18) at the hospital level (all p<0.001).

Conclusions and Relevance

Significant variation exists in EGS hospital performance with best ranked hospitals out-performing worst ranked hospitals on adverse event, mortality, prolonged length of stay and readmission. There is little association between patient outcomes for those treated with operative and non-operative care.