bluuebunny/crossref_metadata_2025_split huggingface dataset:
MELD 3.0 for adolescent liver transplant candidates
Authors: Kwong Allison J. , Zhang Ke-You , Ebel Noelle , Mannalithara Ajitha , Kim W. Ray 
Published: March 2023

Background and Aims:
Adolescents constitute a unique waitlist cohort that is distinct from younger children. Model for End-stage Liver Disease (MELD) 3.0, which was developed in an adult population of liver transplant candidates, is planned to replace MELD-Sodium in the current liver allocation system for both adults and adolescents aged 12–17. We evaluated the predictive performance of MELD-Sodium, MELD 3.0, and Pediatric End-stage Liver Disease for 90-day waitlist mortality risk among adolescent liver transplant registrants.

Approach and Results:
New waitlist registrations for primary liver transplants among individuals aged 12–17 and 18–25 for comparison were identified using Organ Procurement and Transplantation Network (OPTN) data from November 17, 2004, to December 31, 2021. The predictive performance of the current and proposed MELD and Pediatric End-stage Liver Disease scores was assessed using Harrell’s concordance (c) statistic. There were 1238 eligible listings for adolescents aged 12–17 and 1740 young adults aged 18–25. In the adolescent group, 90-day survival was 97.8%, compared with 95.9% in those aged 18–25 (log-rank p = 0.005), with no significant differences when stratified by sex or indication. Among adolescents, increasing MELD 3.0 was associated with an increased hazard of mortality (HR=1.27, 95% CI: 1.18–1.37), and the c-statistic for 90-day waitlist survival using MELD 3.0 was 0.893 compared with 0.871 using MELD-Sodium and 0.852 using Pediatric End-stage Liver Disease.

Conclusions:
The discriminative ability of MELD 3.0 to rank adolescents according to the risk of death within 90 days was robust. Although MELD 3.0 was initially developed and validated in adults, MELD 3.0 may also improve the prediction of waitlist mortality in adolescents and better represent their urgency for liver transplants.
Novel oral medications for retinal disease: an update on clinical development
Authors: DeBoer Charles Meno Theodore , Agrawal Rajat , Rahimy Ehsan 
Published: March 2023

Purpose of review
Intravitreal and periocular injections for retinal disease provide a targeted delivery of medication to the eye. However, given risks of injections, including endophthalmitis, pain and treatment burden for both patients and retina specialists, there has been significant interest and effort in developing oral medications for the management of retinal disease. This article provides clinical and preclinical details of new oral medications in the pipeline for management of retinal disease.

Recent findings
Several new oral medications show clinical and preclinical promise for the management of retinal disease, including macular degeneration, diabetic retinopathy and Stargardt disease.

Summary
Oral medications provide promise for treating retinal disease, possibly increasing compliance, and reducing side effects of intravitreal or periocular injections. However, difficulties in this approach include systemic side effects and efficacy targeting the eye. There are multiple medications that are currently under investigation with the potential to act as stand-alone treatment or as an adjunct treatment for management of retinal diseases such as diabetic retinopathy, macular degeneration and Stargardt disease.
Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement
Authors: Hohenschurz-Schmidt David J. , Cherkin Dan , Rice Andrew S.C. , Dworkin Robert H. , Turk Dennis C. , McDermott Michael P. , Bair Matthew J. , DeBar Lynn L. , Edwards Robert R. , Farrar John T. , Kerns Robert D. , Markman John D. , Rowbotham Michael C. , Sherman Karen J. , Wasan Ajay D. , Cowan Penney , Desjardins Paul , Ferguson McKenzie , Freeman Roy , Gewandter Jennifer S. , Gilron Ian , Grol-Prokopczyk Hanna , Hertz Sharon H. , Iyengar Smriti , Kamp Cornelia , Karp Barbara I. , Kleykamp Bethea A. , Loeser John D. , Mackey Sean , Malamut Richard , McNicol Ewan , Patel Kushang V. , Sandbrink Friedhelm , Schmader Kenneth , Simon Lee , Steiner Deborah J. , Veasley Christin , Vollert Jan 
Published: March 2023

Abstract
Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.
Metabolic and histomorphological changes of adipose tissue in cachexia
Authors: Molfino Alessio , Imbimbo Giovanni , Muscaritoli Maurizio 
Published: March 2023

Purpose of review
To describe the role of the main changes occurring in adipose tissue during cachexia and how these affects patient's outcomes, with a specific focus on cancer.

Recent findings
In cachexia, the changes within the adipose tissue have been recently described as the presence of inflammatory infiltration (T-lymphocytes and macrophages), enhanced fibrosis, and the occurrence of beige adipocytes (i.e., browning). The latter one is a process driving cachexia enhancing thermogenesis, primarily via modulation of uncoupling protein 1. Also, increased lipolysis of white adipose tissue, especially in cancer, via higher expression of hormone sensible and adipose tissue triglyceride lipases, was detected in experimental models and in human adipose tissue. Other systemic metabolic alterations occur in association with changes in adiposity, including insulin resistance and increased inflammation, all conditions associated with a worse outcome. Moreover, these profound metabolic alterations were shown to be implicated in several consequences, including extreme and progressive unvoluntary body weight loss.

Summary
Alterations in adiposity occur early during cachexia. Adipose tissue atrophy, as well as metabolic changes of white adipose tissues were observed to be pivotal in cachexia, and to be implicated in several clinical complications and poor prognosis.
Further research is necessary to clarify the mechanisms underlying the loss of adiposity and therefore to identify novel therapeutic options to counteract this phenomenon in cachexia.
Updates in the management of pediatric dyslipidemia
Authors: Choudhari Pooja , Patni Nivedita 
Published: March 2023

Purpose of review
Pediatric dyslipidemias increase the risk of atherosclerosis and clinical cardiovascular disease and are the leading cause of morbidity and mortality. Lifestyle modifications and pharmacotherapies have measurably improved abnormal lipids and reduced cardiovascular events. The review will focus on current standards of care and investigative medications with the potential to improve cardiovascular health in children and adults.

Recent findings
Lifestyle interventions and statins remain cornerstones in the treatment of pediatric hyperlipidemias. Bile acid sequestrants and ezetimibe continue to be used in the pediatric population as well. In recent years, successful clinical trials have approved use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in children with familial hypercholesterolemia. Use of angiopoietin-like protein 3 (ANGPTL3) inhibitors is also promising as it causes marked improvement in low-density lipoprotein cholesterol with safe side effect profiles. Additional medications undergoing pediatric clinical trials include inclisiran, bempedoic acid, and lomitapide.

Summary
Recent advances in pharmacotherapy, especially for treatment of familial hypercholesterolemia, greatly impact treatment of dyslipidemias in children. Despite the overall progress in the development of these medications, therapies targeted towards treating hypertriglyceridemia have lagged behind. Continuing research for the treatment of pediatric dyslipidemias remains an important endeavor to reduce the risk of atherosclerosis and future cardiovascular events in children.
A Case of Spontaneous Coronary Artery Dissection in the Setting of Exogenous Testosterone
Authors: Gongolli Julita , Vanderschaegen Anna , Prahlow Joseph A. 
Published: March 2023

Abstract
Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome, occurring when there is separation of the coronary artery walls by intramural hemorrhage creating a false lumen. This compresses the arterial lumen, compromising the ability of the coronary artery to perfuse the myocardial tissue. Spontaneous coronary artery dissection is usually fatal, with risk factors including pregnancy, young age, and female sex, birth control, and other hormonal therapies.
In this case report, we describe the case of a 31-year-old biological female transitioning to male with exogenous testosterone who experienced a SCAD. Given the known risk factors for SCAD, such as pregnancy and exogenous hormone therapy, this case raises additional considerations regarding rare unintended consequences of testosterone therapy.
A New Source of Mutilating Hand Injuries: The Side-by-Side Utility-Terrain Vehicle
Authors: Mendenhall Shaun D. , Graham Emily M. , Memmott Stanley , Frederiksen Hunter , Rioux-Forker Dana , Wang Angela A. , Hutchinson Douglas T. 
Published: March 2023

Purpose:
Rates of mutilating hand injuries are increasing from accidents caused by all-terrain vehicles (ATVs) and the recently popularized side-by-side utility-terrain vehicles (UTVs). Increasing surgeon familiarity with upper extremity (UE) injury patterns, severity, and outcomes following ATV and UTV accidents may improve patient care and advocacy.

Methods:
Retrospective comparisons of UE injury patterns, severity, hospital and intensive care unit (ICU) admission lengths, and number of surgeries were made between ATVs and UTVs. Findings were analyzed with Fisher’s exact tests, MANOVA, ANOVAs with post hoc analyses, and multiple linear regressions.

Results:
A total of 154 cases were identified for inclusion (ATV=87; UTV=67). Patient ages ranged from 4-89 years. The UTV group contained significantly more hand and finger injuries, and more of the fractures were open (p=0.005, p<0.001, p<0.001, respectively). Riders of UTVs had nearly three times as many mutilating hand injuries and a near ninefold increase in amputations compared to ATV riders (p<0.001 and p<0.001, respectively). On average, the UTV group spent 2.5 additional days in the hospital, 0.91 additional days in an ICU, and had 1.3 additional surgeries (p=0.001, p=0.007, p<0.001, respectively). Vehicle type was the only variable significantly correlated with days in the hospital, ICU, and number of UE surgeries (p=0.002, p=0.008, p<0.001, respectively).

Conclusions:
Hand surgeons are in a unique position to serve as forerunners for increasing public awareness of off-road vehicle risks and promoting rider safety. Collaborating with manufacturers, emergency care providers, and directing teaching initiatives may improve patient outcomes.
Diagnostic Efficacy of Renal 2-D Shear Wave Elastography in Familial Mediterranean Fever Disease
Authors: Albayrak Eda , Akbas Meral Gizem 
Published: March 2023

Abstract
The aims of this study were to evaluate the kidneys of patients with familial Mediterranean fever (FMF) noninvasively and quantitatively using 2-D shear wave elastography (SWE) and to reveal the diagnostic efficacy of SWE in FMF-induced renal involvement. Healthy controls, FMF patients, and FMF patients with proteinuria were included in the study, and differences in renal stiffness values between the groups were examined. In addition, a relationship between age, sex, height, weight, body mass index, serum erythrocyte sedimentation rate, C-reactive protein, glomerular filtration rate, and renal stiffness values was evaluated. A total of 120 subjects, including 60 controls, 41 FMF patients without proteinuria, and 19 FMF patients with proteinuria, were enrolled in the study. Renal stiffness values were found to be significantly higher in the group with FMF compared with the control group. In addition, the values in the proteinuria group were higher than both the control group and FMF patients without proteinuria (P < 0.001). A significant positive correlation was found between the renal stiffness value and C-reactive protein. According to receiver operating characteristic analysis, the mean renal stiffness value was 7.905 kPa or greater to determine FMF-induced proteinuria. The current study shows that renal stiffness values were higher in FMF patients compared with the normal population and the values showed further increase in the presence of proteinuria, which indicates a more advanced stage of renal involvement of the disease. These findings reveal that SWE can be used as a noninvasive diagnostic tool in the diagnosis, follow-up, and evaluating the severity of FMF.
Motor Evoked Potential—A Pilot Study Looking at Reliability and Clinical Correlations in Multiple Sclerosis
Authors: Jacques F.H. , Apedaile B.E. , Danis I , Sikati-Foko V , Lecompte M , Fortin J 
Published: March 2023

Purpose:
Multiple sclerosis (MS) is a clinically heterogeneous disease. Biomarkers that can assess pathological processes that are unseen with conventional imaging remain an unmet need in MS disease management. Motor evoked potentials (MEPs) could be such a biomarker. To determine and follow longitudinal MEP reliability and correlations with clinical measures in MS patients.

Methods:
This is a single-center study in alemtuzumab-treated MS patients to evaluate temporal reliability of MEPs, identify MEP minimum detectible differences, and explore correlations with existing clinical scales. Ten MS patients recently treated with alemtuzumab were evaluated every 6 months over 3 years. Clinical evaluations consisted of expanded disability status scale, timed 25-foot walk, 6-minute walk, and nine-hole peg test. MEPs were measured twice, 2 weeks apart, every 6 months.

Results:
Eight patients completed all 3 years of study. The intraclass correlation coefficient for MEP parameters ranged from 0.76 to 0.98. TA latency and amplitude with facilitation significantly and strongly correlated with all clinical measures, whereas the MEP duration modestly correlated. Biceps latency with facilitation significantly and moderately correlated with 9-hole peg test. Longitudinal correlations demonstrated good predictive values for either clinical deterioration or improvement.

Conclusions:
MEPs have excellent intrapatient and intrarater reliability, and TA MEPs significantly and strongly correlated with expanded disability status scale, 6-minute walk, and timed 25-foot walk, whereas biceps MEPs significantly and moderately correlated with nine-hole peg test. Further studies using larger cohorts of MS patients are indicated.

Clinical trial registration:
ClinicalTrials.gov, Identifier: NCT02623946.
Rapid emergence and transmission of virulence-associated mutations in the oral poliovirus vaccine following vaccination campaigns
Authors: Walter Katharine S. , Altamirano Jonathan , Huang ChunHong , Carrington Yuan J. , Zhou Frank , Andrews Jason R. , Maldonado Yvonne 
Published: March 2023

AbstractThere is an increasing burden of circulating vaccine-derived polioviruses (cVDPVs) due to the continued use of oral poliovirus vaccine (OPV). However, the informativeness of routine OPV VP1 sequencing for the early identification of viruses carrying virulence-associated reversion mutations has not been directly evaluated in a controlled setting. We prospectively collected 15,331 stool samples to track OPV shedding from vaccinated children and their contacts for ten weeks following an immunization campaign in Veracruz State, Mexico and sequenced VP1 genes from 358 samples. We found that OPV was genetically unstable and evolves at an approximately clocklike rate that varies across serotypes and by vaccination status. Alarmingly, 28% (13/47) of OPV-1, 12% (14/117) OPV-2, and 91% (157/173) OPV-3 of Sabin-like viruses had ≥1 known reversion mutation. Our results suggest that current definitions of cVDPVs may exclude circulating virulent viruses that pose a public health risk and underscore the need for intensive surveillance following OPV use.
MultiomicsTracks96: A high throughput PIXUL-Matrix-based toolbox to profile frozen and FFPE tissues multiomes
Authors: Mar Daniel , Babenko Ilona M. , Zhang Ran , Noble William Stafford , Denisenko Oleg , Vaisar Tomas , Bomsztyk Karol 
Published: March 2023

BackgroundThe multiome is an integrated assembly of distinct classes of molecules and molecular properties, or “omes,” measured in the same biospecimen. Freezing and formalin-fixed paraffin-embedding (FFPE) are two common ways to store tissues, and these practices have generated vast biospecimen repositories. However, these biospecimens have been underutilized for multi-omic analysis due to the low throughput of current analytical technologies that impede large-scale studies.MethodsTissue sampling, preparation, and downstream analysis were integrated into a 96-well format multi-omics workflow, MultiomicsTracks96. Frozen mouse organs were sampled using the CryoGrid system, and matched FFPE samples were processed using a microtome. The 96-well format sonicator, PIXUL, was adapted to extract DNA, RNA, chromatin, and protein from tissues. The 96-well format analytical platform, Matrix, was used for chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP), methylated RNA immunoprecipitation (MeRIP), and RNA reverse transcription (RT) assays followed by qPCR and sequencing. LC-MS/MS was used for protein analysis. The Segway genome segmentation algorithm was used to identify functional genomic regions, and linear regressors based on the multi-omics data were trained to predict protein expression.ResultsMultiomicsTracks96 was used to generate 8-dimensional datasets including RNA-seq measurements of mRNA expression; MeRIP-seq measurements of m6A and m5C; ChIP-seq measurements of H3K27Ac, H3K4m3, and Pol II; MeDIP-seq measurements of 5mC; and LC-MS/MS measurements of proteins. We observed high correlation between data from matched frozen and FFPE organs. The Segway genome segmentation algorithm applied to epigenomic profiles (ChIP-seq: H3K27Ac, H3K4m3, Pol II; MeDIP-seq: 5mC) was able to recapitulate and predict organ-specific super-enhancers in both FFPE and frozen samples. Linear regression analysis showed that proteomic expression profiles can be more accurately predicted by the full suite of multi-omics data, compared to using epigenomic, transcriptomic, or epitranscriptomic measurements individually.ConclusionsThe MultiomicsTracks96 workflow is well suited for high dimensional multi-omics studies – for instance, multiorgan animal models of disease, drug toxicities, environmental exposure, and aging as well as large-scale clinical investigations involving the use of biospecimens from existing tissue repositories.
Reduction of human Alzheimer’s disease risk and reversal of mouse model cognitive deficit with nucleoside analog use
Authors: Magagnoli Joseph , Yerramothu Praveen , Ambati Kameshwari , Cummings Tammy , Nguyen Joseph , Thomas Claire C. , Wang Shao-bin , Cheng Kaitlyn , Juraev Maksud , Dholkawala Roshni , Nagasaka Ayami , Ambati Meenakshi , Nagasaka Yosuke , Ban Ashley , Ambati Vidya L. , Sutton S. Scott , Gelfand Bradley D. , Ambati Jayakrishna 
Published: March 2023

AbstractInnate immune signaling through the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer’s disease (AD), the most prevalent form of dementia. We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat HIV and hepatitis B infections, also inhibit inflammasome activation. Here we report that in humans, NRTI exposure was associated with a significantly lower incidence of AD in two of the largest health insurance databases in the United States. Treatment of aged 5xFAD mice (a mouse model of amyloid-β deposition that expresses five mutations found in familial AD) with Kamuvudine-9 (K-9), an NRTI-derivative with enhanced safety profile, reduced Aβ deposition and reversed their cognitive deficit by improving their spatial memory and learning performance to that of young wild-type mice. These findings support the concept that inflammasome inhibition could benefit AD and provide a rationale for prospective clinical testing of NRTIs or K-9 in AD.
MicroRNA-29 Differentially Mediates Preeclampsia-Dysregulated Cellular Responses to Cytokines in Female and Male Fetal Endothelial Cells
Authors: Zhou Chi , Freel Colman , Mills Olivia , Yang Xin-Ran , Yan Qin , Zheng Jing 
Published: March 2023

AbstractIntroductionPreeclampsia (PE) differentially impairs female and male fetal endothelial cell function which is associated with the increased risks of adult-onset cardiovascular disorders in children born to mothers with PE. However, the underlying mechanisms are poorly defined. Wehypothesizethat dysregulation of microRNA-29a-3p and 29c-3p (miR-29a/c-3p) in PE disturbs gene expression and cellular responses to cytokines in fetal endothelial cells in a fetal sex-dependent manner.MethodsRT-qPCR analysis of miR-29a/c-3p was performed on female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive (NT) and PE pregnancies. Bioinformatic analysis of an RNAseq dataset was performed to identify PE-dysregulated miR-29a/c-3p target genes in female and male P0-HUVECs. Gain- and loss-of-function assays were conducted to determine the effects of miR-29a/c-3p on endothelial monolayer integrity and proliferation in response to TGFβ1 and TNFα in NT and PE HUVECs at passage 1.ResultsPE downregulated miR-29a/c-3p in male, but not female P0-HUVECs. PE dysregulated significantly more miR-29a/c-3p target genes in female vs. male P0-HUVECs. Many of these PE-differentially dysregulated miR-29a/c-3p target genes are associated with critical cardiovascular diseases and endothelial functions. We further demonstrated that miR-29a/c-3p knockdown specifically recovered the PE-abolished TGFβ1-induced strengthening of endothelial monolayer integrity in female HUVECs, while miR-29a/c-3p overexpression specifically enhanced the TNFα-promoted cell proliferation in male PE HUVECs.ConclusionsPE differentially dysregulates miR-29a/c-3p and their target genes associated with cardiovascular diseases- and endothelial function in female and male fetal endothelial cells, possibly contributing to the fetal sex-specific endothelial dysfunction observed in PE.