Search Results (8,806)

Background/Objective: To externally validate our previously published machine learning model for identifying hospitalized patients with community-acquired pneumonia (CAP) at low risk of respiratory deterioration or death using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Methods: This is a retrospective cohort study of adult patients (≥18 years) who were admitted with CAP and acute hypoxemic respiratory failure using the publicly available MIMIC-IV critical care dataset (Beth Israel Deaconess Medical Center, Boston, MA). We conducted an external validation study of a previously developed gradient boosting machine (GBM) model without recalibration using data available within the first 6 h of hospital admission. Results: For the primary composite outcome (need for advanced respiratory support [high flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), invasive mechanical ventilation (IMV)] or in-hospital death), the gradient boosting model demonstrated comparable performance in the derivation and external validation cohorts. The area under the receiver operating characteristic curve (AUC) was 0.713 in the Mayo cohort (n = 4379) and 0.689 in the MIMIC-IV cohort. Accuracy was 0.612 (95% confidence interval [CI], 0.595–0.628) versus 0.606 (95% CI 0.600–0.611), specificity 0.574 versus 0.523, sensitivity 0.723 versus 0.754, NPV 0.860 versus 0.842, and PPV 0.364 versus 0.401, respectively. For secondary outcomes, model discrimination was comparable between cohorts. The AUC for in-hospital mortality was 0.727 in the Mayo Cohort versus 0.733 in MIMIC-IV; for IMV, 0.736 versus 0.724; and for NIMV, 0.732 versus 0.708. Conclusions: Our machine learning algorithm demonstrated good discrimination and a high negative predictive value for identifying low-risk hospitalized CAP patients for respiratory deterioration or death in the external MIMIC-IV dataset, supporting its potential utility for prognostic enrichment in pneumonia clinical trials. Full article

Background: Neuroblastoma is a common extracranial solid malignant tumor of early childhood; however, mandibular involvement is rare and may mimic odontogenic or inflammatory disease. Case Presentation: We report an 8-month-old girl with left paramandibular swelling initially suspected to represent parotitis or odontogenic inflammation. Imaging revealed a destructive mandibular lesion with sunburst periosteal reaction, and histology confirmed undifferentiated neuroblastoma. Staging identified a left primary adrenal tumor with extensive bone marrow infiltration and MYCN proto-oncogene amplification. The patient received multimodal high-risk neuroblastoma therapy, including chemotherapy, surgery, autologous stem cell transplantation, proton therapy, antibody therapy, and Lorlatinib. Despite radiological remission, she developed severe pulmonary complications and died shortly before the age of five years. Methods: A focused literature review was conducted to identify published pediatric cases of metastatic neuroblastoma involving the mandible. Results: Through our review, we identified 31 published pediatric cases of mandibular metastatic neuroblastoma. Reported cases most commonly described mandibular swelling, pain, tooth mobility, and facial asymmetry. Most mandibular lesions represented metastatic disease from an adrenal or abdominal primary tumor. Conclusions: Mandibular involvement of neuroblastoma is rare but clinically important. In infants and young children, persistent or atypical (para-/peri)mandibular swelling should not be assumed to be odontogenic or inflammatory. Early imaging, biopsy, and interdisciplinary referral are essential for timely diagnosis and treatment. Full article

Natural products featuring a direct σ-bond between a cyclic monoterpene and an aromatic moiety provide a vast source of biological activities, such as antimicrobial, anticancer, antiviral, anticoagulant and cannabinoid regulatory, among others. Only few methods exist for synthetically accessing such hybrid structures and their analogs, all of which are prone to limitations, most notably the reliance on sensitive organometallic intermediates and the difficulty in furnishing certain stereoisomers. An efficient, three-stage synthetic methodology is described herein, that enables the production of hybrid structures featuring a C(sp³)-C(sp²) bond between six-membered cyclic monoterpenes and aromatic moieties. This process combines: enol triflate formation from a terpenoid ketone precursor, that introduces most of the stereochemical information; Suzuki–Miyaura C-C cross-coupling of the enol triflate with a pool of (hetero)arylboronic acids, to establish the terpene–aromatic link, initially in the form of a C(sp²)-C(sp²) bond; and a stereoselective hydrogenation of the resulting adducts to afford the target compounds, establishing the stereoconfiguration of the last chiral center. Enantiomeric terpenoid scaffolds derived from menthone and trans-tetrahydrocarvone have been combined with six (6) (hetero)arylboronic acids, including medicinally relevant moieties, such as methoxyphenyl, pyridine, quinoline and benzofuran. The power of this method, apart from circumventing the need for in situ-formed sensitive organometallic intermediates, resides in providing access, for the first time, to menthyl- and trans-tetrahydrocarvoneyl-type stereoisomers, that were unattainable by any previously described method. The resulting compound library members exhibit drug-like features, based on the computational assessment of 11 selected physicochemical parameters (molecular weight, polarity, aqueous solubility, degree of unsaturation, conformational flexibility, lipophilicity, BBB permeability, skin permeability, gastrointestinal absorption, P-glycoprotein substrate behavior and Lipinski compatibility), using the platforms SwissADME, ADMETLab 3.0 and pkCSM. A computational docking study employing AutoDock Vina further identified promising candidates for targeting the known binding sites of human cannabinoid receptors CB1 and CB2, with calculated binding affinities comparable to those of established ligands. Full article

Lymphomas are a heterogeneous group of aggressive lymphoid malignancies characterized by frequent extranodal involvement. Musculoskeletal manifestations, although uncommon, represent a clinically significant and under-recognized presentation that often mimics primary bone tumors, soft tissue sarcomas, and infectious conditions, leading to diagnostic delays and inappropriate initial management. This narrative review synthesizes current evidence on the clinical presentation, imaging characteristics, pathology, and biological basis of musculoskeletal T-cell lymphomas, with particular emphasis on implications for orthopedic practice. A structured literature search was conducted across major databases from 2000 to the present, and evidence was integrated across clinical, radiologic, pathologic, and therapeutic domains. Musculoskeletal involvement most commonly presents with localized bone pain, soft tissue masses, or pathological fractures, with imaging features such as diffuse marrow infiltration, soft tissue extension, and relatively preserved cortical bone serving as important diagnostic clues. Definitive diagnosis relies on tissue biopsy with comprehensive immunophenotypic and molecular characterization. Emerging insights into the tumor microenvironment highlight its role in disease progression and therapeutic response, offering potential avenues for targeted treatment strategies. Management is subtype-specific and centers on systemic therapy, with selective roles for radiotherapy and orthopedic intervention in cases of structural compromise. Early recognition through integrated clinical, imaging, and pathological assessment, combined with multidisciplinary collaboration, is essential to optimize outcomes in this rare but challenging disease entity. Full article

Brain metastases have traditionally been investigated primarily with regard to interactions between tumor cells, the surrounding brain microenvironment, and associated inflammatory responses. By contrast, the presence of a true intratumoral stromal compartment in brain metastases has received much less attention, partly because the normal brain parenchyma lacks classical interstitial fibroblasts. However, recent histological, transcriptomic, and spatial studies suggest that at least a subset of carcinoma brain metastases contains fibroblast-like or cancer-associated fibroblast-like cells associated with collagen-rich extracellular matrix deposition. This raises a fundamental biological question: where do these cells come from? In this review, we discuss seven non-mutually exclusive hypotheses for the origin of cancer-associated fibroblast (CAF)-like cells in brain metastases, including pseudostromal mimics, meningeal or perivascular fibroblast-related cells, vascular mural cells, glial cells, cancer stem cell plasticity, tumor–stroma clusters, and circulating mesenchymal precursors. We compare the current findings for each hypothesis and highlight their major limitations. Overall, the available data support a heterogeneous and context-dependent model rather than a single universal origin. A better understanding of these stromal cell states may help refine the biological classification of brain metastases and support the future development of more targeted stromal therapies. Full article

Background: Neonatal encephalopathy (NE) is a major cause of neonatal mortality and long-term neurological disability. Although hypoxic–ischaemic encephalopathy (HIE) is the most common cause, several genetic disorders may mimic or coexist with hypoxic–ischaemic injury. Next-generation sequencing has emerged as a promising diagnostic tool in this setting. This systematic review evaluated the current evidence on genomic sequencing in NE. Material and methods: A systematic review was conducted according to PRISMA 2020 guidelines and prospectively registered in PROSPERO. PubMed/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included neonates (≤28 days) with NE, suspected or confirmed HIE, HIE mimics, or unexplained NE who underwent genomic sequencing. Whole-exome sequencing (WES), whole-genome sequencing (WGS), clinical exome sequencing (CES), rapid genomic sequencing, and targeted next-generation sequencing panels were considered. Study quality was assessed using the Newcastle–Ottawa Scale. Results: Seven studies met the inclusion criteria. Considerable heterogeneity was observed regarding patient selection, sequencing strategies, and reported outcomes. Among diagnostic sequencing studies, diagnostic yield ranged from 23.5% to 53.1%. Pathogenic and likely pathogenic variants were identified in genes associated with developmental and epileptic encephalopathies, metabolic disorders, mitochondrial diseases, and neurodevelopmental syndromes, including SCN2A, KCNQ2, CACNA1A, STXBP1, PTPN11, BCOR, MMUT, COQ2, and GBE1. Genomic sequencing frequently refined or changed the initial diagnosis, improved prognostic assessment and genetic counselling, and, in selected cases, guided disease-specific treatment. One study investigated genetic susceptibility to hypoxic–ischaemic injury rather than diagnostic sequencing. Conclusions: Genomic sequencing provides clinically meaningful diagnoses in a substantial proportion of neonates with unexplained NE or atypical HIE presentations. Current evidence supports integrating genomic sequencing into the diagnostic evaluation of selected infants, although larger prospective studies are needed to define its optimal timing, clinical utility, and cost-effectiveness. Full article

In spite of at least six discrete classes of drugs available for cancer treatment, the quest for more biologic drugs continues. One type of biologic molecule that occurs naturally in the body is microRNA. MicroRNAs regulate post-transcriptional gene expression and can be under expressed in cancer (tumor suppressor microRNAs) or over expressed (oncogenic microRNAs). Strand-specific mimics of microRNAs have been developed and used successfully in vitro, in vivo, and in clinical trials, to control multiple aspects of cancer including metastasis, apoptosis and proliferation. Each microRNA is capable of binding a specific target mRNA or mRNAs, sometimes simultaneously interfering with multiple genes in a single pathway, or binding with a single nodal mRNA. Some microRNAs can facilitate chemotherapy that has stopped working, addressing the issue of drug resistance. Without chemical modification, microRNAs are too vulnerable to have lasting therapeutic value. Chemical modifications to microRNAs have provided nuclease resistance and greater stability and are the basis for microRNA mimics that can be used therapeutically. However, without a vehicle, microRNA mimics do not cross cell membranes. These nanoparticles can cause inflammatory reactions in patients. Additional modifications that enabled microRNA mimics to cross cell membranes include substituting uracil with 5-fluorouracil. Lessons from an siRNA therapeutic called Patisiran offer a roadmap for future success for microRNAs in cancer. This review provides a historical perspective of the continuing evolution of microRNA mimics for cancer treatment. Full article

Background: Antimicrobial combination therapies outperform traditional monotherapies by offering additive or synergetic effects, a broader spectrum of activity, enhanced efficacy against polymicrobial infections, and a reduced risk of resistance development and infection relapse. Methods: Herein, we have combined the chemotherapeutic antibiotic alkylating agent mitomycin C (MMC) with the wide-spectrum antiseptic octenidine hydrochloride (OCT). The non-specific mode of action via membrane disruption of the latter, together with the DNA-alkylating ability of the former, is here combined to produce bactericidal antibiotic-like mixtures against clinical isolates of Methicillin-resistant Staphylococcus aureus and uropathogenic Escherichia coli. The concentrations required for both antimicrobials to inhibit or eradicate bacterial biofilms as well as intracellular persisters are also determined here. The cytotoxicity of the selected combinations on eukaryotic cells was also evaluated in traditional 2D cultures and in 3D-fibroblast spheroids to mimic a physiologically relevant microenvironment present in topical infections. Finally, the ecotoxicity of the studied compounds was also evaluated through standardized bioassays using representative microorganisms commonly employed in environmental toxicity assessments such as Daphnia magna (D. magna) and Aliivibrio fischeri (A. fischeri). Results: Compared to monotherapy, these environmentally friendly antibiotic-like combinations at specific concentrations may achieve additive antimicrobial effects against planktonic, sessile, and intracellular pathogenic strains. However, the ecotoxicological response was bioindicator-dependent: the OCT–MMC combination reduced toxicity in A. fischeri, but not in D. magna, where toxicity was comparable to OCT alone, indicating OCT as the main driver. Thus, any reduction in ecotoxicity appears species-specific. Nonetheless, the use of lower doses may help minimize selective pressure for resistance. Conclusions: Collectively, these findings demonstrate that selected MMC–OCT combinations achieve antibacterial efficacy against planktonic, sessile, and intracellular pathogenic bacteria while preserving the viability of eukaryotic cells and exhibiting minimal toxicity toward standard ecotoxicological model organisms. Further studies are needed to guarantee the safe use of this combination at selected doses and to guarantee its non-systemic absorption after topical administration. Full article

Whipple disease is a rare systemic infection caused by Tropheryma whipplei that often presents with nonspecific gastrointestinal symptoms and may mimic other disorders. We report the case of a 75-year-old woman with type 2 diabetes mellitus who presented with chronic diarrhoea and a 15 kg unintentional weight loss over 6 months despite preserved appetite. Laboratory investigations revealed iron-deficiency anaemia, hypoproteinaemia, mild inflammatory and liver function abnormalities, and peripheral eosinophilia. Extensive infectious, autoimmune, and gastrointestinal investigations were unrevealing. Abdominal computed tomography demonstrated mesenteric lymphadenopathy, raising suspicion for lymphoma. Histopathological examination of duodenal biopsies revealed numerous foamy macrophages containing periodic acid–Schiff-positive, diastase-resistant granular material, consistent with Whipple disease. Ziehl–Neelsen staining additionally demonstrated acid-fast bacilli, and subsequent investigations confirmed concomitant Mycobacterium szulgai infection. The significance of this finding remains uncertain, as it may represent either true coinfection or incidental colonisation. A potential explanation is that T. whipplei-induced macrophage dysfunction creates a permissive intracellular niche for nontuberculous mycobacteria, although supporting evidence is lacking. Following antimicrobial therapy, the patient experienced marked clinical improvement with resolution of symptoms and an 8 kg weight gain. This case highlights the diagnostic challenges of Whipple disease and the need to consider concomitant mycobacterial infection when acid-fast organisms are identified. Full article

Background/Objectives: Background parenchymal enhancement (BPE) on contrast-enhanced mammography (CEM) represents enhancement of otherwise normal fibroglandular tissue. Although BPE is well established in breast MRI interpretation, its determinants, technical variability, diagnostic implications, and potential value as a breast cancer risk biomarker on CEM remain incompletely defined. This review summarizes the current evidence and outlines the steps required for responsible clinical translation. Methods: PubMed/MEDLINE was searched from database inception through April 2026 using terms related to CEM and BPE. Reference lists of eligible studies and relevant reviews were also screened. Human studies evaluating CEM-specific BPE in relation to biologic or hormonal determinants, breast density, technical factors, measurement methods, reproducibility, diagnostic performance, temporal variability, asymmetry, or breast cancer outcomes were synthesized narratively. Results: CEM BPE is influenced by age, menopausal status, menstrual and hormonal factors, lactation, endocrine therapy, breast density, contrast timing, view order, compression, positioning, imaging system, and post-processing. Because CEM is a projection-based technique acquired over several minutes, its BPE should not be considered physiologically interchangeable with MRI BPE. Moderate or marked BPE may reduce lesion conspicuity or mimic abnormal enhancement, particularly when asymmetric. Early studies suggest that higher CEM BPE may be associated with prevalent or subsequent breast cancer after adjustment for established risk factors, but findings remain heterogeneous and derive predominantly from retrospective, single-center cohorts. Quantitative and artificial-intelligence approaches are promising but require technical normalization, reproducibility testing, multicenter validation, and linkage to clinically meaningful outcomes. Conclusions: CEM BPE is a functional imaging feature shaped by patient biology, tissue composition, acquisition technique, and reader assessment. It should currently be reported and interpreted in context but should not independently alter screening, biopsy, or risk-management decisions. Translation into a clinically useful biomarker will require standardized measurement, longitudinal prognostic validation, demonstration of added value beyond established risk models, and prospective evidence that BPE-informed care improves outcomes without producing excessive harms or costs. Full article

Large language models are increasingly deployed as natural-language interfaces to clinical databases, yet their evaluation has focused almost exclusively on query correctness rather than access minimality. Data-protection frameworks such as HIPAA §164.502(b) and the GDPR data-minimisation principle require that personal data be accessed only to the extent necessary for the immediate purpose. This paper presents the first empirical audit of open-weight LLMs on this access-scope dimension, using the EHRSQL 2024 benchmark over MIMIC-IV. We measure deviations from minimum-necessary access via three static metrics computable without executing queries: Sensitive Column Exposure (SCE), Table Over-Join Rate (TOJ), and Aggregate Identifier Exposure (AIE). Unlike prior work on adversarial attacks, we study default model behaviour under ordinary, benign queries—the over-reach we document requires no attacker and is present from the first interaction. Among twelve open-weight models, a non-trivial fraction fail a basic SQL-generation viability threshold; among nine viable models, SQL-specialised training paradoxically increases over-reach while domain-adapted medical variants achieve the lowest exposure. Schema redaction largely eliminates column-level exposure but increases table-level over-reach for most models. Random in-context demonstrations produce statistically significant over-reach regressions in specific models; BM25-based retrieval resolves most of these failures, though a residual aggregate-identifier exposure risk persists for one model family. Full article

To address the persistent challenge of membrane wetting during oil-gas separation in transformer condition monitoring, an omniphobic composite membrane was developed to facilitate the reliable online detection of dissolved gases. An F-CNTs/Teflon AF/PVDF composite membrane, featuring a loofah-like hierarchical structure and omniphobic properties, was fabricated via spraying-deposition strategy on the polyvinylidene fluoride (PVDF) substrate. The morphology, surface chemical composition, wettability and stability of the F-CNTs/Teflon AF/PVDF composite membrane were systematically characterized. Subsequently, the oil-gas separation performance of the composite membrane was evaluated using standard transformer oil containing dissolved gases as the feed solution. The results indicated that fluorinated carbon nanotubes (F-CNTs) were successfully modified onto the membrane surface, creating a re-entrant morphology composed of an intersecting nanotube network that mimics the hierarchical architecture of a loofah. The F-CNTs/Teflon AF/PVDF composite membrane exhibited exceptional omniphobicity, achieving contact angles of 168.2 ± 1.5° and 127.5 ± 1.0° towards DI water and mineral insulating oil, respectively. Additionally, the loofah-inspired composite membrane demonstrated robust thermal and ultrasonic stability. In oil-gas separation tests, the omniphobic membrane displayed a rapid response and high efficiency for dissolved gas extraction, achieving dynamic equilibrium within 64 min. Furthermore, the modification improved permeation efficiency by 25.6%. These results suggest that the developed omniphobic membrane is a promising alternative for oil-gas separation in the condition monitoring of oil-filled electrical equipment. Full article

Right ventricular (RV) failure secondary to pulmonary hypertension manifests in significant biomechanical alterations of myocardial tissue, including capillary rarefaction and enhanced stiffness and anisotropy. However, how the changes in mechanical cues affect the angiogenic potential of endothelial cells (ECs)—and thereby impact the RV failure progression—remains unclear. The aim of this study is to investigate the effects of RV-relevant substrate stiffness and anisotropy on different EC types using polyurethane urea scaffolds engineered to mimic RV tissues. We find that substrate anisotropy increased EC number but reduced metabolic activity in both cell types. In contrast, the two cell types exhibit divergent responses in their angiogenic potential and angiogenic protein secretome. For HUVECs, neovessel formation is suppressed by substrate stiffening and anisotropy, whereas for HCMECs, it is increased by stiffening and suppressed by anisotropy. Our results highlight the mechanobiological regulation of ECs in a tissue- and cell-type-dependent manner, which is critical for new biomaterial or in vitro model development for cardiac diseases. Full article

The oxygen-evolving center (OEC) in photosynthesis is a unique biological Mn₄CaO₅-cluster that splits water into electrons, protons, and dioxygen. It is a great challenge for chemists to develop a robust and precise mimic of the OEC in the laboratory. Herein, we report the formation of a rare-earth-element-containing Mn₄YO₄-cluster that represents an excellent and robust model of the OEC. The key synthetic precursor, the Mn₃YO₂-cluster, is reported for the first time, which possesses an identical mixed-valence Mn^III₂Mn^IV metal core and a hydrogen-bonding network coordination sphere. This precursor is very reactive and can convert into various compounds in solution. Importantly, it has been found that the presence of organic bases significantly influences the distribution of intermediates and promotes the formation of the Mn₄YO₄-cluster. Meanwhile, two Mn₄YO₄-clusters are described, which closely mimic the main metal-oxide core and peripheral ligands, as well as the oxidation states of the four Mn ions in the OEC, revealing that both the terminal ligands and a bridging carboxylate are variable. This new Mn₄YO₄-cluster displays a remarkable stability in the presence of water in acetonitrile solution. These findings shed new light on the synthesis of rare-earth-element-containing clusters and the rational design of robust artificial water-splitting catalysts, and provide chemical insights into the dynamic structural changes of both biological and artificial clusters. Full article

Dural-based lymphomas are rare extranodal non-Hodgkin lymphomas that span from indolent primary dural entities, most commonly the extranodal marginal zone (mucosa-associated lymphoid tissue) lymphoma, to aggressive variants that are primary or represent secondary involvement from systemic lymphoma. They overlap radiologically with benign meningiomas, dural metastases, and immune-mediated pachymeningitis, creating a risk of anchoring bias, delayed diagnosis, and unnecessarily extensive resections when limited tissue sampling would be sufficient for diagnosis. We conducted a structured narrative review to synthesize the epidemiology, clinico-pathological classification, imaging phenotypes, and management principles of dural lymphomatous disease. This study will especially focus on primary dural lymphoma (PDL) with additional discussion of secondary dural involvement. Emphasis is placed on the clinical value of a multiparametric diagnostic approach that integrates computed tomography contrast-enhanced magnetic resonance imaging with functional techniques, and fluorodeoxyglucose positron emission tomography/computed tomography for systemic staging and for distinguishing truly localized primary dural lymphoma from secondary involvement. Potential diagnostic pitfalls related to somatostatin receptor–based tracer uptake will also be discussed. We introduced a pragmatic operational framework based on four clinico-biological clusters, translated into a step-by-step decision algorithm that prioritizes timely biopsy and comprehensive hematologic staging to guide surgical strategy. Given the absence of dedicated, multidisciplinary guidance for dural-based lymphomas, this algorithm is intended as a reproducible foundation for consensus recommendations and future multicenter validation. Full article