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Abstract White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1’s function during differentiation. These findings underscore PATZ1’s regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.

Vaccine efficacy and its quantification is a crucial concept for the proper design of public health vaccination policies. In this work we proposed a mathematical model to estimate the efficacy of the influenza vaccine in a real-word scenario. In particular, our model is a SEIR-type epidemiological model, which distinguishes vaccinated and unvaccinated populations. Mathematically, its dynamics is governed by a nonlinear system of ordinary differential equations, where the non-linearity arises from the effective contacts between susceptible and infected individuals. Two key aspects of this study is that we use a vaccine distribution over time that is based on real data specific to the elderly people in the Valencian Community and the calibration process takes into account that over one influenza season a specific proportion of the population becomes infected with influenza. To consider the effectiveness of the vaccine, the model incorporates a parameter, the vaccine attenuation factor, which is related with the vaccine efficacy against the influenza virus. With this framework, in order to calibrate the model parameters and to obtain an influenza vaccine efficacy estimation, we considered the 2016–2017 influenza season in the Valencian Community, Spain, using the influenza reported cases of vaccinated and unvaccinated. In order to ensure the model identifiability, we choose to deterministically calibrate the parameters for different scenarios and we find the one with the minimum error in order to determine the vaccine efficacy. The calibration results suggest that the influenza vaccine developed for 2016–2017 influenza season has an efficacy of approximately 76.7%, and that the risk of becoming infected is five times higher for an unvaccinated individual in comparison with a vaccinated one. This estimation partially agrees with some previous studies related to the influenza vaccine. This study presents a new integrated mathematical approach to study the influenza vaccine efficacy and gives further insight into this important public health topic.

Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi (T. cruzi), represents a worldwide public health issue. To date, there is no efficient treatment to combat this pathology, and the only drugs available are usually toxic to the patient. Through the enzyme trans-salidase, the parasite invades, infects, and multiplies intracellularly in the host cell. This protein has been considered an attractive target for developing or searching for compounds with potential trypanocidal activity. In this study, an in silico analysis was performed using a Food and Drug Administration-approved computational drug repositioning approach to identify compounds with anti-Chagas potential against two trans-sialidase proteins. Those compounds with potential inhibition were analyzed and selected through a molecular docking-based virtual screening. Forty-nine compounds were identified, of which forty-five are available on the market, and the rest were evaluated in silico. Our predicted results follow that these compounds are safe for human use and could be potential anti-trans-sialidase agents.

IntroductionProblematic behavior and drug use are behaviors of social concern, especially in adolescence. There are school factors that can contribute to their development or prevent them. The objective was to establish explanatory models of the relationship between various school variables with the consumption of alcohol, tobacco and cannabis; determining its direct and/or indirect relationship with problematic behaviors.Materials and methodsThe study was cross-sectional with a sample of 346 students (Main Age=14.81; 54% women) from secondary education. Structural Equation Model (SEM) were carried to analyze the relationship between the dimensions of the Scale of perception of aspects of school life and alcohol, tobacco and cannabis consume with the presence of Problematic Behavior.ResultsProblem behavior was predicted by alcohol, tobacco and cannabis consume, and binge drinking. Different aspects of school life differentially predicted problem behavior and drug use. Sense of challenge was observed as having a reciprocal predictive relationship with problem behavior. Perception of oneself at school predicts both alcohol and tobacco use; while the value given to school predicts binge drinking.DiscussionThese findings suggests that, when addressing problem behavior and drug use that affect minors in school and have repercussions on class dynamics and academic outcomes, we should not focus exclusively on these problem areas, but rather take a more integrated approach that includes modifying different school-related aspects that act as risk factors for these types of problems.

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of β3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

Background: Glioblastoma is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification., Methods: We developed a highly reproducible, personalized prognostication and clinical subgrouping system using machine learning (ML) on routine clinical data, MRI, and molecular measures from 2,838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR])., Results: The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95%CI: 1.43-1.84, p<0.001) and 3.48 (95%CI: 2.94-4.11, p<0.001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort., Conclusions: Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach for personalized patient management and clinical trial stratification in glioblastoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Here, we report the draft genome sequences of Flagellimonas sp. MMG031 and Marinobacter sp. MMG032, isolated from coral-associated dinoflagellate Symbiodinium pilosum , assembled and analyzed by undergraduate students participating in a Marine Microbial Genomics (MMG) course. A genomic comparison suggests MMG031 and MMG032 are novel species and a resource for restoration and biotechnology.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space.The BraTS-METS 2023 challenge successfully curated well-annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied clinical environments and providing personalized volumetric reports to patients undergoing BM treatment.

Objective: To advance oral health policies (OHPs) in the World Health Organization (WHO) African region, barriers to and facilitators for creating, disseminating, implementing, monitoring and evaluating OHPs in the region were examined., Methods: Global Health, Embase, PubMed, Public Affairs Information Service Index, ABI/Inform, Web of Science, Academic Search Complete, Scopus, Dissertations Global, Google Scholar, WHO's Institutional Repository for Information Sharing (IRIS), the WHO Noncommunicable Diseases Document Repository and the Regional African Index Medicus and African Journals Online were searched. Technical officers at the WHO Regional Office for Africa were contacted. Research studies and policy documents reporting barriers to and facilitators for OHP in the 47 Member States in the WHO African region published between January 2002 and March 2024 in English, French or Portuguese were included. Frequencies were used to summarize quantitative data, and descriptive content analysis was used to code and classify barrier and facilitator statements., Results: Eighty-eight reports, including 55 research articles and 33 policy documents, were included. The vast majority of the research articles and policy documents were country-specific, but they were lacking for most countries. Frequently mentioned barriers across policy at all stages included financial constraints, a limited and poorly organized workforce, deprioritization of oral health, the absence of health information systems, inadequate integration of oral health services within the overarching health system and limited oral health literacy. Facilitators included a renewed commitment to establishing national OHPs, recognition of a need to diversify the oral health workforce, and an increased understanding of the influence of social determinants of health among oral health care providers., Conclusions: Most countries lack a country-specific body of evidence to assist policymakers in anticipating barriers to and facilitators for OHPs. The barriers and facilitators relevant to disparate subnational, national, and regional conditions and circumstances must be considered to advance the creation, dissemination, implementation, monitoring and evaluation of OHPs in the WHO African region., (© 2024 The Author(s). Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Background: In the current era of heart transplantation, machine perfusion strategies are emerging as potential additions to the armamentarium of a transplant unit. Donation after circulatory death (DCD) donor hearts assessed through normothermic machine perfusion (NMP) has helped expand the donor pool. Hypothermic machine perfusion (HMP) is emerging as an alternative strategy to traditional static cold storage (SCS) when a prolonged ischemic time is anticipated in brain dead (BD) donors, this is important in Australia where long distant procurement is vital. In this study we examine the outcomes in our unit where both forms of machine perfusion (NMP and HMP), as well as SCS is utilized for donor heart preservation, with a particular focus on severe primary graft dysfunction (sPGD) and mortality., Methods: The year 2021 represents the year when both forms of machine perfusion were available to our unit. Heart transplants in our unit from January 2021 to February 2024 were categorized into three groups for retrospective analysis: (I) DCD-NMP group (n=44); (II) BD-HMP group (n=38), and (III) BD-SCS group (n=78)., Results: There were no significant differences in the mean donor and recipient ages between the three groups. Donor preservation time in the BD-HMP group was significantly longer than the donor ischemic time in the BD-SCS group, and organ care system (OCS) run time in the DCD-NMP group (361±89 vs. 208±47 and 249±49 min respectively, P<0.001). For DCD-NMP, BD-HMP and BD-SCS groups respectively: 30-day survival was: 100%, 97% and 100%; 1-year survival was: 94%, 90% and 94%; 2-year survival was: 90%, 90% and 89% (P=0.9). There was no significant difference in the incidence of sPGD between the three groups (DCD-NMP: 7%, BD-HMP: 5%, and BD-SCS: 5%, P=0.9)., Conclusions: Machine perfusion strategies represent important additions to the modern transplant unit and can expand the donor pool. Results are encouraging with no differences in 2-year survival or incidence of sPGD across the preservation modalities: DCD-NMP, BD-HMP, and BD-SCS., Competing Interests: Conflicts of Interest: Y.J. is supported by a National Heart Foundation PhD scholarship. P.M.: modules in kind from XVIVO and Transmedics (unrelated to submitted work); Novartis and Amgen (grant paid to institution), Novartis, Boehringer-Ingelheim and Astra-Zeneca (Advisory board membership). The other authors have no conflicts of interest., (2024 AME Publishing Company. All rights reserved.)

The aim of this study was to assess the evidence gaps identified in a recent mapping review of orthognathic surgery by evaluating them through consultation with maxillofacial surgeons. Using the Delphi technique, a panel of surgeons who regularly perform orthognathic surgery was engaged. Potential participants were identified through articles included in the mapping review, peer nominations, and social media platforms . Two rounds of surveys, incorporating Likert-type and open-ended questions, were conducted to gauge the clinical relevance of evidence gaps. Questions were refined based on responses from the initial round, with a consensus threshold set at 60%. Seventy-four surgeons participated in the first round and 55 in the second round (retention rate of 74%) . The intra-class correlation analysis revealed 'almost perfect' agreement in each round. Participants in the first round proposed 11 new evidence gaps. A list of 15 potentially clinically relevant research questions was compiled to guide future investigations in orthognathic surgery. This collaborative Delphi study between researchers and clinicians has explored the existing understanding of the clinical relevance of potential evidence gaps in orthognathic surgery. The study findings offer others a pathway to address information gaps and guide future research endeavours., Competing Interests: Competing interests None., (Copyright © 2024 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Automated brain tumor segmentation methods have become well-established and reached performance levels offering clear clinical utility. These methods typically rely on four input magnetic resonance imaging (MRI) modalities: T1-weighted images with and without contrast enhancement, T2-weighted images, and FLAIR images. However, some sequences are often missing in clinical practice due to time constraints or image artifacts, such as patient motion. Consequently, the ability to substitute missing modalities and gain segmentation performance is highly desirable and necessary for the broader adoption of these algorithms in the clinical routine. In this work, we present the establishment of the Brain MR Image Synthesis Benchmark (BraSyn) in conjunction with the Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2023. The primary objective of this challenge is to evaluate image synthesis methods that can realistically generate missing MRI modalities when multiple available images are provided. The ultimate aim is to facilitate automated brain tumor segmentation pipelines. The image dataset used in the benchmark is diverse and multi-modal, created through collaboration with various hospitals and research institutions.

Background: Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is a progressive metabolic, genetic disease with wide clinical heterogeneity, ranging from perinatal lethality to mild or moderate localized symptoms. This study aims to analyze the perception of pain, quality of life, and access barriers to healthcare among patients diagnosed with hypophosphatasia in Colombia. In this document we present pain and quality of life results., Methods: This study is an observational cohort of 18 HPP patients registered in the Colombian Association of Patients with Lysosomal Storage Diseases and Other Orphan Diseases (ACOPEL) database. We conducted a descriptive analysis using data from three questionnaires (SF-36, Brief Pain Questionnaire (BPQ), and Hypophosphatasia Impact Patient Survey (HIPS); the latter was translated into Spanish and validated for this study., Results: The most affected features, according to the SF-36 questionnaire, were overall health, vitality, and pain, with a median score above 67%. Patients' perception of their health status (HIPS questionnaire) was favorable, with 38.9% of cases reporting excellent health. On average, results from the BPQ indicated mild to moderate intensity of current pain experienced by patients. Consistency was observed in the reports of either the absence of pain or the presence of mild to moderate intensity when analyzing the results of the three questionnaires., Conclusions: Colombian patients with HPP experience mild to moderate impairment in quality of life and pain that interfere with their daily activities. However, there is wide variability in the results obtained., (© 2024. The Author(s).)

This report illustrates the Food and Drug Administration (FDA) approval of first-in-its-class activin A receptor IIA inhibitor, sotatercept (Winrevair™), for the treatment of pulmonary arterial hypertension (PAH). Sotatercept is used to increase exercise capacity, improve WHO functional class, and decrease the risk of clinical worsening events in adults with PAH. One phase 2 trial, one phase 3 trial, and an ongoing open-label extension study is described in detail within the current text. Sotatercept significantly improved the 6-min walk distance in patients with PAH after 24 weeks with a mean change increase of 40.1 meters in the experimental group versus 1.4 meters decrease in the placebo group. Epistaxis, telangiectasia, increased hemoglobin, hematocrit, red blood cell levels, and dizziness were adverse events more frequently observed in the sotatercept group than in the placebo group. Sotatercept has shown significant benefits in the reduction of pulmonary vascular resistance and N-terminal pro b-type natriuretic peptide in patients with PAH. However, more studies are needed to evaluate the reduction in mortality. Limitations in practice include high cost and unknown long-term effects., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Patients presenting with ureteral stones and concurrent urinary tract infections require prompt kidney drainage as per standard care guidelines. However, even in patients who are promptly drained and treated with appropriate antibiotics, the mortality rate due to urosepsis has been reported to be nearly 9%. Therefore, Predictive tools for early sepsis detection have become essential. The Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) are potential biomarkers for predicting infection risk in these patients., Methods: A retrospective cohort analysis involving patients diagnosed with obstructing ureteral stones who underwent urgent stent placement due to suspected urinary tract infection (UTI) in the emergency room (ER) was conducted. The baseline characteristics of patients were age, sex, comorbidities, and urological history. Laboratory data collected during hospitalization included total leukocyte and platelet counts and blood cultures. Ratios were calculated from the serum studies obtained upon admission to the ER. A logistic regression model was utilized to predict the incidence of positive qSOFA score (sepsis prediction score), the need for vasopressors, intensive care unit (ICU) admission, and sepsis, using NLR and PLR as independent variables., Results: Between January 2016 and December 2020, 143 patients with a diagnosis of obstructing ureteral stone were admitted to the ER with a suspected UTI. 11.9% showed a positive qSOFA score, 20.3% required vasopressor support for > 1 h after ureteral stent placement, 28.7% required ICU admission, and 16.8% met sepsis criteria. Sepsis was defined as patients who were qSOFA positive and vasopressors needed for more than 1 h following stent placement. Logistic regression analysis revealed that PLR and positive blood cultures correlated significantly with positive qSOFA scores. Using logistic regression analysis, PLR, NLR, and positive blood culture were each independent predictors of vasopressor requirements, ICU admission, and urosepsis., Conclusions: NLR and PLR may be valuable prognostic markers for predicting urosepsis risk in urolithiasis patients who present with obstructing stones and concern for systemic infection. Their utility may be in helping clinicians in early risk stratification, prompt intervention, and resource allocation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Context: The first case of mpox was detected in the United States in a Laboratory Response Network (LRN) laboratory at the Massachusetts Department of Public Health on May 17, 2022. Through previous years of smallpox preparedness efforts by the United States government, testing capacity in LRN laboratories across the United States utilizing the FDA-cleared Centers for Disease Control and Prevention (CDC) Non-variola orthopoxvirus (NVO) test was approximately 6000 tests weekly across the nation prior to the mpox outbreak. By early June 2022, the LRN laboratories had capacity to perform up to 8000 tests per week. As the outbreak expanded, cases were identified in every United States state, peaking at ~3000 cases per week nationally in August 2022., Objective: Although NVO testing capacity in LRN laboratories exceeded national mpox testing demand overall, LRN testing access in some areas was challenged and test expansion was necessary., Participants: CDC engaged with partners and select commercial laboratories early to increase diagnostic testing access by allowing these commercial laboratories to utilize the NVO test., Setting: The expansion of testing to commercial laboratories increased testing availability, capacity, and volume nationwide. This was the first time that CDC shared an FDA 510k-cleared molecular test with commercial laboratories to support a public health emergency., Design: Extensive efforts were made to ensure the CDC NVO test was used appropriately in the private sector and that the transfer process met regulatory requirements., Main Outcome Measures, Results, Conclusions: These novel methods to expand NVO testing to commercial laboratories increased national testing capacity to 80 000 mpox tests/week. Test volumes among these laboratories never exceeded this expanded capacity. The rapid increase in the nation's testing capacity, in conjunction and coordination with other public and private health efforts, helped to detect cases rapidly. These actions demonstrated the importance of highly functional and efficient public health and private sector partnerships for responding to public health emergencies., Competing Interests: The authors declare no conflicts of interest.

Purpose of Review: To summarise current international clinical outcomes from donation after circulatory death heart transplantation (DCD-HT); discuss procurement strategies, their impact on outcomes and overall organ procurement; and identify novel approaches and future areas for research in DCD-HT., Recent Findings: Globally, DCD-HT survival outcomes (regardless of procurement strategy) are comparable to heart transplantation from brain dead donors (BDD). Experience with normothermic machine perfusion sees improvement in rates of primary graft dysfunction. Techniques have evolved to reduce cold ischaemic exposure to directly procured DCD hearts, though controlled periods of cold ischaemia can likely be tolerated. There is interest in hypothermic machine perfusion (HMP) for directly procured DCD hearts, with promising early results. Survival outcomes are firmly established to be equivalent between BDD and DCD-HT. Procurement strategy (direct procurement vs. regional perfusion) remains a source of debate. Methods to improve allograft warm ischaemic tolerance are of interest and will be key to the uptake of HMP for directly procured DCD hearts., (© 2024. The Author(s).)

Parasitic infections are among the most important causes of morbidity and mortality in horses worldwide. In the Andean mountainous regions of Chile, horses are a highly valued specie, playing a key role as working animals also providing support in cattle transhumance grazing into high mountainous areas during dry season. The breeding and maintenance of horses in the mountainous region of La Araucanía in Chile is a key issue allowing to the subsistence economy of communities with a strong ethnic component represented by Mapuche-Pehuenche origin families. However, the health status of these animals is unknown. Therefore, the objective of this study was to determine endoparasitic infections in horses from this area and the main factors that may influence parasitism. Thus, a cross-sectional study performed in 126 working horses from Andean region was achieved by using different coproparasitologycal analyses, resulting in a 97,6% of prevalence of endoparasitism with the strongyle eggs showing the highest prevalence of infection in analysed horses (96%) followed by Oxyuris equi (27%), Parascaris equorum (17,5%) and protozoans including ciliates (11,1%), Blastocystis spp (5,6%), Giardia spp (2,4%) and Cryptosporidium spp (1,6%) highlighting zoonotic relevance of some of these species. Concerning risk factors, the high prevalence suggests that exposure was high regardless of age or sex. The higher proportion of infected horses were grazing compared to those stabled, likewise drinking non-potable water, being these the main risks factors linked to the high prevalence of horse infections in Andean communities here studied., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Macroautophagy/autophagy-lysosome function promotes growth and survival of cancer cells, making them attractive targets for cancer therapy. One intriguing lysosomal target is PPT1 (palmitoyl-protein thioesterase 1). PPT1 inhibitors derived from chloroquine block autophagy, have significant antitumor activity in preclinical models and are being developed for clinical trials. However, the role of PPT1 in tumorigenesis remains poorly understood. Here we report that in melanoma cells, acute siRNA or pharmacological PPT1 inhibition led to increased ferroptosis sensitivity and significant loss of viability, whereas chronic PPT1 knockout using CRISPR-Cas9 produced blunted ferroptosis that led to sustained viability and growth. Each mode of PPT1 inhibition produced lysosome-autophagy inhibition but distinct proteomic changes, demonstrating the complexity of cellular adaptation mechanisms. To determine whether total genetic loss of Ppt1 would affect tumorigenesis in vivo, we developed a Ppt1 conditional knockout mouse model. We then crossed it into the BrafCA, PtenloxP, Tyr:CreERT2 melanoma mouse model to investigate the impact of Ppt1 loss on tumorigenesis. Loss of Ppt1 had no impact on melanoma histology, time to tumor initiation, or survival of tumor-bearing mice. These results suggest that chemical PPT1 inhibitors produce different adaptations than genetic PPT1 inhibition, and additional studies are warranted to fully understand the mechanism of chloroquine derivatives that target PPT1 in cancer. Abbreviations : 4-HT: 4-hydroxytamoxifen; BRAF: B-Raf proto-oncogene, serine/threonine kinase; cKO: conditional knockout; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9; DC661: A specific PPT1 inhibitor; DMSO: dimethyl sulfoxide; Dox; doxycycline hyclate; Easi-CRISPR: efficient additions with ssDNA inserts-CRISPR; GNS561/ezurpimtrostat: A PPT1 inhibitor; Hug: human guide; iCas: inducible CRISPR-Cas9; KO: knockout; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; LDLR: low density lipoprotein receptor; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NT: non-target; PTEN: phosphatase and tensin homolog; PPT1: palmitoyl-protein thioesterase 1; RSL3: RAS-selective lethal small molecule 3; SCRIB/SCRB1: scribble planar cell polarity protein; Tyr:CreERT2 : tyrosinase-driven Cre recombinase fused with the tamoxifen-inducible mutant ligand binding domain of the human estrogen receptor; UGCG: UDP-glucose ceramide glucosyltransferase; WT: wild-type.

This case report follows a 63-year-old female patient with a history of a gastroenteropancreatic (GEP) neuroendocrine tumor of the terminal ileum who developed ovarian metastasis and later progressed to peritoneal carcinomatosis. The patient was found to have worsening metastasis on CT that was subsequently confirmed with ( 68 Ga)-DOTATATE PET/CT imaging. This case outlines the rare metastatic nature of a primary ileal neuroendocrine tumor and emphasizes the efficacy of ( 68 Ga)-DOTATATE PET/CT imaging in the localization, progression, and treatment of neuroendocrine metastatic disease., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

The objective of the present study was to analyze the psychometric properties of a life satisfaction scale in older Peruvian adults using an exploratory graph analysis (EGA) approach. A total of 407 older adults aged between 60 and 95 years (M = 69.5; SD = 6.7) from three comprehensive elderly care centers (CIAMs) in Lima, Peru, were recruited. A non-probabilistic convenience sampling was used. The Satisfaction with Life Scale (SWLS) was analyzed using EGA with the Gaussian GLASSO model to assess its dimensionality and structural consistency. The relationship with other variables was analyzed using scales such as the GAD-7 and PHQ-9. The network structure of the SWLS indicates a single dimension. Additionally, network loadings (nodes) were examined, showing high values (>0.35) for most items except item 1, which had a moderate loading (>0.25). Structural reliability showed that a single dimension was identified 100% of the time. The post hoc CFA considering the unidimensional network structure obtained through EGA showed satisfactory fit (χ2/df = 3.48, CFI = 0.96, TLI = 0.92, SRMR = 0.02, RMSEA = 0.07 [90% CI 0.05, 0.08]). Finally, internal consistency reliability was acceptable (ω = 0.92). The SWLS measure is robust and consistent. These findings are a valuable reference for advancing research on aging in Peru, as they provide a practical, valid, and reliable measure.

Introduction: Percutaneous nephrolithotomy (PCNL) is the gold-standard treatment for large renal stones. One potentially significant complication of PCNL is blood loss, which can result in transfusion requirement and poorer stone-free outcomes. Tranexamic acid (TXA) has emerged as a promising intervention, administered systemically (TXA-S) or as part of irrigation fluid (TXA-I) in endourology. This study aimed to comprehensively analyze existing evidence regarding the applications of TXA in PCNL through a Bayesian network meta-analysis, offering insights into its efficacy and comparative effectiveness., Methods: In February 2022, a PRISMA-compliant systematic review (PROSPERO registration number CRD 42021270593) was performed to identify randomized controlled clinical trials (RCT) on TXA as either systemic therapy or in irrigation fluid. Studies in languages other than English and Spanish were not considered. A Bayesian network was built using results from identified studies to create models that were later run through Markov Chain Monte Carlo sampling through 200 000 iterations., Results: Eight RCTs compared TXA-S vs. placebo, one TXA-I vs. placebo, and one TXA-I vs. TXA-S. TXA-I had lower risk of transfusion (relative risk [RR] 0.63 [0.47,0.84], SUCRA 0.950) than TXA-S (RR 0.79 [0.65,0.95], SUCRA 0.545). TXA-I had a lower risk of complications (RR 0.38 [0.21,0.67], SUCRA=0.957) compared to TXA-S (RR 0.55 [0.39, 0.78], SUCRA 0.539). TXA-I had a lower postoperative decrease in hemoglobin (mean difference [MD] -1.2 [1.3, 1.0], SUCRA 0.849) compared to TXA-S (MD -0.97 [-1.0, -0.93], SUCRA 0.646])., Conclusions: TXA, regardless of the route of administration, is an effective intervention in decreasing bleeding, postoperative complications, and risk of transfusion when compared with placebo. Further studies directly comparing TXA-S to TXA-I would be useful to determine the optimal route of delivery.

Background/objective: Meningioma calcification is thought to predict reduced growth potential and aggression. However, historical studies have primarily focused on correlating calcification in small meningiomas (diameter less than 2.5 cm) rather than analyzing characteristics of calcified meningiomas across all sizes. In this study, we investigate the pathologic and clinical implications of meningioma calcification., Methods: We utilized a historical database of 342 consecutive newly diagnosed intracranial meningiomas with preoperative computed tomography and magnetic resonance imaging scans treated at a single institution from 2005 to 2019. We correlated the presence of calcification with patient demographics, grade, Mindbomb Homolog-1 index, location, volume, Simpson grade, and recurrence using both univariate and multivariate generalized linear models., Results: On univariate analysis, no single variable correlated with tumor calcification. Notably, neither tumor 2021 World Health Organization grade (P = 0.91) nor Mindbomb Homolog-1 index (P = 0.62) predicted calcification. After accounting for demographic characteristics and tumor volume and location, there was no significant association between 2021 World Health Organization grade (P = 0.52) and Mindbomb Homolog-1 index (P = 0.54) and calcification. Calcification had no influence on resection grade (P = 0.59) or recurrence (P = 0.80)., Conclusions: In this series, calcified meningiomas exhibited similar 2021 World Health Organization tumor grading distribution, proliferation indexes, and immediate surgical outcomes compared to their noncalcified counterparts. These findings question the historical role of using meningioma calcification as an independent guide to their management., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preliminary evidence suggests that Qigong (QG), a mind-body therapy, may help address symptoms of multiple sclerosis (MS), but the heterogeneity of QG content and delivery may affect its feasibility, acceptability, and efficacy., Objective: To survey researchers, clinicians, and QG instructors with experience working with people with MS to identify key components of MS-specific QG guidelines and protocols., Methods: We conducted an online survey to identify QG forms and movements considered helpful for MS, reasons for selection, characteristics of effective learning environments, and recommended dosage and frequency of practice. Quantitative data were analyzed using summary statistics. Qualitative data were analyzed using reflexive thematic analysis., Results: Forty-seven experts, including QG instructors, clinicians, and QG and MS researchers, completed the survey. Respondents had a mean (SD) of 20 (11) years of QG teaching experience, 26 (12) years of clinical practice, 24 (9) years of QG research experience, 13 (5) years of MS research experience, and worked with at least 3 (2) people with MS. Approximately 125 QG forms/movements were recommended. Some forms were specifically recommended to address MS symptoms (e.g., emotional regulation, balance and coordination, muscle strength and flexibility, immune regulation, and circulation). Some respondents felt that any QG form could be beneficial if basic principles were met (e.g., intentional movement, posture, focused awareness, rhythmic breathing/movement, and a relaxed mind and body). Instructor qualities included the ability to convey information clearly, being caring and compassionate, proficient in QG, and having basic knowledge of MS. To promote confidence in learning QG, recommendations included having simple, easy-to-learn movements with modifications based on physical ability. We provide a sample protocol based on these recommendations., Conclusions: This study provides expert guidance for developing a QG protocol for an MS population, including content and delivery recommendations., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LB has received payment for teaching QG since 2005. The other authors declare no conflicts of interest., (© The Author(s) 2024.)

Objective. We aim to develop a Multi-modal Fusion and Feature Enhancement U-Net (MFFE U-Net) coupling with stem cell niche proximity estimation to improve voxel-wise Glioblastoma (GBM) recurrence prediction. Approach. 57 patients with pre- and post-surgery magnetic resonance (MR) scans were retrospectively solicited from 4 databases. Post-surgery MR scans included two months before the clinical diagnosis of recurrence and the day of the radiologicaly confirmed recurrence. The recurrences were manually annotated on the T1ce. The high-risk recurrence region was first determined. Then, a sparse multi-modal feature fusion U-Net was developed. The 50 patients from 3 databases were divided into 70% training, 10% validation, and 20% testing. 7 patients from the 4th institution were used as external testing with transfer learning. Model performance was evaluated by recall, precision, F1-score, and Hausdorff Distance at the 95% percentile (HD95). The proposed MFFE U-Net was compared to the support vector machine (SVM) model and two state-of-the-art neural networks. An ablation study was performed. Main results. The MFFE U-Net achieved a precision of 0.79 ± 0.08, a recall of 0.85 ± 0.11, and an F1-score of 0.82 ± 0.09. Statistically significant improvement was observed when comparing MFFE U-Net with proximity estimation couple SVM (SVM PE ), mU-Net, and Deeplabv3. The HD95 was 2.75 ± 0.44 mm and 3.91 ± 0.83 mm for the 10 patients used in the model construction and 7 patients used for external testing, respectively. The ablation test showed that all five MR sequences contributed to the performance of the final model, with T1ce contributing the most. Convergence analysis, time efficiency analysis, and visualization of the intermediate results further discovered the characteristics of the proposed method. Significance . We present an advanced MFFE learning framework, MFFE U-Net, for effective voxel-wise GBM recurrence prediction. MFFE U-Net performs significantly better than the state-of-the-art networks and can potentially guide early RT intervention of the disease recurrence., (© 2024 Institute of Physics and Engineering in Medicine.)

This study aims to investigate the development of pitch-matching, rhythmic entrainment, and socioemotional skills in children who received formal music instruction and other non-music based after school programs. Eighty-three children, averaging 6.81 years old at baseline, were enrolled in either a music, sports, or no after-school program and followed over four years. The music program involved formal and systematic instruction in music theory, instrumental technique, and performance. Most control participants had no music education; however, in some instances, participants received minimal music education at school or at church. Musical development was measured using a pitch-matching and drumming-based rhythmic entrainment task. Sharing behavior was measured using a variation of the dictator game, and empathy was assessed using three different assessments: the Index of Empathy for Children and Adolescence (trait empathy), the Reading the Mind in the Eyes Test (theory of mind), and a Fiction Emotion-Matching task (state empathy). Results revealed no time-related associations in pitch-matching ability; however, formal music instruction improved pitch-matching relative to controls. On the contrary, improvements in rhythmic entrainment were best explained by age-related changes rather than music instruction. This study also found limited support for a positive association between formal music instruction and socioemotional skills. That is, individuals with formal music instruction exhibited improved emotion-matching relative to those with sports training. In terms of general socioemotional development, children's trait-level affective empathy did not improve over time, while sharing, theory of mind, and state empathy did. Additionally, pitch-matching and rhythmic entrainment did not reliably predict any socioemotional measures, with associations being trivial to small. While formal music instruction benefitted pitch-matching ability and emotion-matching to an audiovisual stimulus, it was not a significant predictor of rhythmic entrainment or broader socioemotional development. These findings suggest that the transfer of music training may be most evident in near or similar domains., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Villanueva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Risk scores (RS) evaluate the likelihood of short-term mortality in patients diagnosed with community-acquired pneumonia (CAP). However, there is a scarcity of evidence to determine the risk of long-term mortality. This article aims to compare the effectiveness of 16 scores in predicting mortality at three, six, and twelve months in adult patients with CAP., Methods: A retrospective cohort study on individuals diagnosed with CAP was conducted across two hospitals in Colombia. Receiver Operating Characteristic (ROC) curves were constructed at 3, 6, and 12 months to assess the predictive ability of death for the following scoring systems: CURB-65, CRB-65, SCAP, CORB, ADROP, NEWS, Pneumonia Shock, REA-ICU, PSI, SMART-COP, SMRT-CO, SOAR, qSOFA, SIRS, CAPSI, and Charlson Comorbidity Index (CCI)., Results: A total of 3688 patients were included in the final analysis. Mortality at 3, 6, and 12 months was 5.2%, 8.3%, and 16.3% respectively. At 3 months, PSI, CCI, and CRB-65 scores showed ROC curves of 0.74 (95% CI: 0.71-0.77), 0.71 (95% CI: 0.67-0.74), and 0.70 (95% CI: 0.66-0.74). At 6 months, PSI and CCI scores showed performances of 0.74 (95% CI: 0.72-0.77) and 0.72 (95% CI: 0.69-0.74), respectively. Finally at 12 months, all evaluated scores showed poor discriminatory capacity, including PSI, which decreased from acceptable to poor with an ROC curve of 0.64 (95% CI: 0.61-0.66)., Conclusion: When predicting mortality in patients with CAP, at 3 months, PSI, CCI, and CRB-65 showed acceptable predictive performances. At 6 months, only PSI and CCI maintained acceptable levels of accuracy. For the 12-month period, all evaluated scores exhibited very limited discriminatory ability, ranging from poor to almost negligible., (© 2024. The Author(s).)

Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase homolog 2 (LOXL2). This histone modification is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here, we show that LOXL2 interacts with RuvB-Like 1 (RUVBL1), RuvB-Like 2 (RUVBL2), Actin-like protein 6A (ACTL6A), and DNA methyltransferase 1associated protein 1 (DMAP1), a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2-dependent chromatin compaction. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC-seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA-MB-231)., (© 2024 Federation of European Biochemical Societies.)

When speech is presented in noise, listeners must recruit cognitive resources to resolve the mismatch between the noisy input and representations in memory. A consequence of this effortful listening is impaired memory for content presented earlier. In the first study on effortful listening, Rabbitt, The Quarterly Journal of Experimental Psychology, 20, 241-248 (1968; Experiment 2) found that recall for a list of digits was poorer when subsequent digits were presented with masking noise than without. Experiment 3 of that study extended this effect to more naturalistic, passage-length materials. Although the findings of Rabbitt's Experiment 2 have been replicated multiple times, no work has assessed the robustness of Experiment 3. We conducted a replication attempt of Rabbitt's Experiment 3 at three signal-to-noise ratios (SNRs). Results at one of the SNRs (Experiment 1a of the current study) were in the opposite direction from what Rabbitt, The Quarterly Journal of Experimental Psychology, 20, 241-248, (1968) reported - that is, speech was recalled more accurately when it was followed by speech presented in noise rather than in the clear - and results at the other two SNRs showed no effect of noise (Experiments 1b and 1c). In addition, reanalysis of a replication of Rabbitt's seminal finding in his second experiment showed that the effect of effortful listening on previously presented information is transient. Thus, effortful listening caused by noise appears to only impair memory for information presented immediately before the noise, which may account for our finding that noise in the second-half of a long passage did not impair recall of information presented in the first half of the passage., (© 2024. The Psychonomic Society, Inc.)

Meningiomas are the most common primary intracranial tumors and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on brain MRI for diagnosis, treatment planning, and longitudinal treatment monitoring. However, automated, objective, and quantitative tools for non-invasive assessment of meningiomas on multi-sequence MR images are not available. Here we present the BraTS Pre-operative Meningioma Dataset, as the largest multi-institutional expert annotated multilabel meningioma multi-sequence MR image dataset to date. This dataset includes 1,141 multi-sequence MR images from six sites, each with four structural MRI sequences (T2-, T2/FLAIR-, pre-contrast T1-, and post-contrast T1-weighted) accompanied by expert manually refined segmentations of three distinct meningioma sub-compartments: enhancing tumor, non-enhancing tumor, and surrounding non-enhancing T2/FLAIR hyperintensity. Basic demographic data are provided including age at time of initial imaging, sex, and CNS WHO grade. The goal of releasing this dataset is to facilitate the development of automated computational methods for meningioma segmentation and expedite their incorporation into clinical practice, ultimately targeting improvement in the care of meningioma patients., (© 2024. The Author(s).)

Introduction: Renal colic is frequently treated with opioids; however, narcotic analgesic use can lead to dependence and abuse. We evaluated use trends of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management of kidney stones in United States emergency departments (EDs) from 2015 to 2021. Methods: Kidney stone encounters were identified using National Hospital Ambulatory Medical Care Survey data. We applied a multistage survey weighting procedure to account for selection probability, nonresponse, and population weights. Medication use trends were estimated through logistic regressions on the timing of the encounter, adjusted for selected demographic and clinical characteristics. Results: Between 2015 and 2021, there were an estimated 9,433,291 kidney stone encounters in United States EDs. Opioid use decreased significantly (annual odds ratio [OR]: 0.87, p  = 0.003), and there was no significant trend in NSAID use. At discharge, male patients were more likely than females (OR: 1.93, p  = 0.001) to receive opioids, and Black patients were less likely than White patients (OR: 0.34, p  = 0.010) to receive opioids. Regional variation was also observed, with higher odds of discharge prescriptions in the West (OR: 3.15, p  = 0.003) and Midwest (OR: 2.49, p  = 0.010), compared with the Northeast. Thirty-five percent of patients received opioids that were stronger than morphine. Conclusion: These results suggest improved opioid stewardship from ED physicians in response to the national opioid epidemic. However, regional variation as well as disparities in discharge prescriptions for Black and female patients underscore opportunities for continued efforts.

Oral bone defects occur as a result of trauma, cancer, infections, periodontal diseases, and caries. Autogenic and allogenic grafts are the gold standard used to treat and regenerate damaged or defective bone segments. However, these materials do not possess the antimicrobial properties necessary to inhibit the invasion of the numerous deleterious pathogens present in the oral microbiota. In the present study, poly(ε-caprolactone) (PCL), nano-hydroxyapatite (nHAp), and a commercial extract of Humulus lupulus L. (hops) were electrospun into polymeric matrices to assess their potential for drug delivery and bone regeneration. The fabricated matrices were analyzed using scanning electron microscopy (SEM), tensile analysis, thermogravimetric analysis (TGA), FTIR assay, and in vitro hydrolytic degradation. The antimicrobial properties were evaluated against the oral pathogens Streptococcus mutans , Porphyromonas gingivalis , and Aggregatibacter actinomycetemcomitans . The cytocompatibility was proved using the MTT assay. SEM analysis established the nanostructured matrices present in the three-dimensional interconnected network. The present research provides new information about the interaction of natural compounds with ceramic and polymeric biomaterials. The hop extract and other natural or synthetic medicinal agents can be effectively loaded into PCL fibers and have the potential to be used in oral applications.

Objective: Patients suffering from psychological disorders report decreased quality of life and low mood. The relationship of these symptoms to daily upsetting events or environments, and in the context of active coping mechanisms is poorly understood. The present study thus investigates the association between mood, psychological flexibility, upsetting events, and environment in the daily life of outpatients., Method: We investigated 80 outpatients at the beginning of treatment, using event sampling methodology (ESM). Patients' mood, occurrence of upsetting events, current environment, and psychological flexibility were sampled six times per day during a one-week intensive longitudinal examination. Data were analyzed using linear mixed models (LMMs)., Results: Participants reported worse mood the more upsetting events they experienced. Further, participants reported better mood when in private environments (e.g., with friends), and worse mood when at the hospital, compared to being at home. Higher levels of psychological flexibility, however, were associated with better mood, irrespective of the occurrence of upsetting events or current environment., Conclusion: Results suggest that mood is positively associated with psychological flexibility, not despite, but especially during the dynamic and context-specific challenges of daily life. Psychological flexibility may thus potentially act as a buffer against distress-provoking situations as patients go about their daily lives., Trial Registration: ISRCTN.org identifier: ISRCTN11209732.

Chromaffin cells have been used as a physiological model to understand neurosecretion in mammals for many years. Nicotinic receptors located in the cells' membrane are stimulated by acetylcholine, and they participate in the exocytosis of chromaffin granules, releasing catecholamines in response to stress. In this work, we discuss how the participation of nicotinic receptors and the localization of active zones in the borders of the cytoskeleton can generate local calcium signals leading to secretion. We use a computational model of a cytoskeleton cage to simulate Ca 2+ levels in response to voltage and acetylcholine pulses. We find that nicotinic receptors are able to enhance the differences between local and average calcium values, as well as the heterogeneous distributions around the active zones, producing a non-linear, highly localized Ca 2+ entry that, although consisting of a few ions, is able to improve secretion responses in chromaffin cells. Our findings emphasize the intricate interplay among nicotinic receptors, the cytoskeleton, and active zones within chromaffin cells as an example of Ca 2+ -dependent neurosecretion in mammals.

Background: Clinical data are usually analyzed with the assumption that knowledge gathered from group averages applies to the individual. Doing so potentially obscures patients with meaningfully different trajectories of therapeutic change. Needed are "idionomic" methods that first examine idiographic patterns before nomothetic generalizations are made. The objective of this paper is to test whether such an idionomic method leads to different clinical conclusions., Methods: 51 patients completed weekly process measures and symptom severity over a period of eight weeks. Change trajectories were analyzed using a nomothetic approach and an idiographic approach with bottom-up clustering of similar individuals. The outcome was patients' well-being at post-treatment., Results: Individuals differed in the extent that underlying processes were linked to symptoms. Average trend lines did not represent the intraindividual changes well. The idionomic approach readily identified subgroups of patients that differentially predicted distal outcomes (well-being)., Conclusions: Relying exclusively on average results may lead to an oversight of intraindividual pathways. Characterizing data first using idiographic approaches led to more refined conclusions, which is clinically useful, scientifically rigorous, and may help advance individualized psychotherapy approaches., Supplementary Information: The online version contains supplementary material available at 10.1007/s10608-023-10453-x., Competing Interests: Conflict of InterestDr. Gloster receives royalties and payments for his work from workshops and with various publishers. Dr. Hayes receives royalties for his books, online courses, webinars, workshops, apps, and other media from a variety of publishers. Dr. Hofmann receives financial support by the Alexander von Humboldt Foundation (as part of the Alexander von Humboldt Professur), the Hessische Ministerium für Wissenschaft und Kunst (as part of the LOEWE Spitzenprofessur), NIH/NIMH R01MH128377, NIH/NIMHU01MH108168, Broderick Foundation/MIT, and the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition—Special Initiative. He receives compensation for his work as editor from SpringerNature. He also receives royalties and payments for his work from various publishers. All other authors declare that they have no conflict of interest., (© The Author(s) 2024.)