A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements.

A covalent adduct of DFOB and DOTA separated by a l-lysine residue (DFOB-l-Lys-N 6-DOTA) exhibited remarkable regioselective metal binding, with {1H}-13C NMR spectral shifts supporting Zr(iv) coordinating to the DFOB unit, and Lu(iii) coordinating to the DOTA unit. This first-in-class, dual-chelator theranostic design could enable the use of imaging-therapy radiometal pairs of different elements, such as 89Zr for positron emission tomography (PET) imaging and 177Lu for low-energy ß--particle radiation therapy. DFOB-l-Lys-N 6-DOTA was elaborated with an amine-terminated polyethylene glycol extender unit (PEG4) to give DFOB-N 2-(PEG4)-l-Lys-N 6-DOTA (compound D2) to enable installation of a phenyl-isothiocyanate group (Ph-NCS) for subsequent monoclonal antibody (mAb) conjugation (mAb = HuJ591). D2-mAb was radiolabeled with 89Zr or 177Lu to produce [89Zr]Zr-D2-mAb or [177Lu]Lu-D2-mAb, respectively, and in vivo PET/CT imaging and in vivo/ex vivo biodistribution properties measured with the matched controls [89Zr]Zr-DFOB-mAb or [177Lu]Lu-DOTA-mAb in a murine LNCaP prostate tumour xenograft model. The 89Zr-immuno-PET imaging function of [89Zr]Zr-D2-mAb and [89Zr]Zr-DFOB-mAb showed no significant difference in tumour accumulation at 48 or 120 h post injection. [89Zr]Zr-D2-mAb and [177Lu]Lu-D2-mAb showed similar ex vivo biodistribution properties at 120 h post-injection. Tumour uptake of [177Lu]Lu-D2-mAb shown by SPECT/CT imaging at 48 h and 120 h post-injection supported the therapeutic function of D2, which was corroborated by similar therapeutic efficacy between [177Lu]Lu-D2-mAb and [177Lu]Lu-DOTA-mAb, both showing a sustained reduction in tumour volume (>80% over 65 d) compared to vehicle. The work identifies D2 as a trifunctional chelator that could expand capabilities in mixed-element radiometal theranostics to improve dosimetry and the clinical outcomes of molecularly targeted radiation.

Identification of Coupled Landau and Anomalous Resonances in Space Plasmas.

Wave-particle resonance, a ubiquitous process in the plasma universe, occurs when resonant particles observe a constant wave phase to enable sustained energy transfer. Here, we present spacecraft observations of simultaneous Landau and anomalous resonances between oblique whistler waves and the same group of protons, which are evidenced, respectively, by phase-space rings in parallel-velocity spectra and phase-bunched distributions in gyrophase spectra. Our results indicate the coupling between Landau and anomalous resonances via the overlapping of the resonance islands.

Real-time tracking of structural evolution in 2D MXenes using theory-enhanced machine learning.

In situ Electron Energy Loss Spectroscopy (EELS) combined with Transmission Electron Microscopy (TEM) has traditionally been pivotal for understanding how material processing choices affect local structure and composition. However, the ability to monitor and respond to ultrafast transient changes, now achievable with EELS and TEM, necessitates innovative analytical frameworks. Here, we introduce a machine learning (ML) framework tailored for the real-time assessment and characterization of in operando EELS Spectrum Images (EELS-SI). We focus on 2D MXenes as the sample material system, specifically targeting the understanding and control of their atomic-scale structural transformations that critically influence their electronic and optical properties. This approach requires fewer labeled training data points than typical deep learning classification methods. By integrating computationally generated structures of MXenes and experimental datasets into a unified latent space using Variational Autoencoders (VAE) in a unique training method, our framework accurately predicts structural evolutions at latencies pertinent to closed-loop processing within the TEM. This study presents a critical advancement in enabling automated, on-the-fly synthesis and characterization, significantly enhancing capabilities for materials discovery and the precision engineering of functional materials at the atomic scale.

PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, ß/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (ß/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

Guidelines for minimal information on cellular senescence experimentation in vivo.

Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called "minimum information for cellular senescence experimentation in vivo" (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.

Longitudinal Improvement in Public Speaking Skills Through Participation in a Resident Public Speaking Curriculum.

OBJECTIVE: To promote public speaking skills, a pediatrics residency program developed a longitudinal public speaking curriculum grounded in deliberate practice and reflective practice. METHODS: Residents delivered annual presentations and received formal feedback. Audience evaluation forms from 2005-2017 were included for analysis. The form used 5-point scales (5= best) for specific presentation elements (clarity, eye contact/body language, pace, succinct text, minimally distracting delivery, clear conclusion, appropriate learning objectives, achieving learning objectives, and answering questions) and for overall quality. Longitudinal changes in scores were analyzed with paired t tests. RESULTS: Overall, 5,771 evaluations of 276 presentations given by 97 residents were analyzed. Between post-graduate year (PGY)-1 and PGY-3 presentations, mean overall rating increased from 4.38 to 4.59 (P<.001, d=0.51). The median percentage of 5-point scores increased from 50.0% (IQR, 24.3%-65.4%) to 72.5% (IQR, 53.3%-81.2%). Eight of 9 specific elements showed significant increases (median effect size 0.55). Residents whose initial presentations ranked in the bottom quartile had larger improvements than residents initially ranked in the top quartile. CONCLUSIONS: After pediatric residents participated in a public speaking curriculum with targeted objectives, formal feedback, and repeated practice, their public speaking skills improved. Public speaking curricula can and should be adopted more broadly in graduate medical education.

DNA methylation correlates of chronological age in diverse human tissue types.

BACKGROUND: While the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types. RESULTS: Here, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project. We identified age-associated CpG sites (false discovery rate < 0.05) in 8 tissues (all except skeletal muscle, n = 47). This included 162,002 unique hypermethylated and 90,626 hypomethylated CpG sites across all tissue types, with 130,137 (80%) hypermethylated CpGs and 74,703 (82%) hypomethylated CpG sites observed in a single tissue type. While the majority of age-associated CpG sites appeared tissue-specific, the patterns of enrichment among genomic features, such as chromatin states and CpG islands, were similar across most tissues, suggesting common mechanisms underlying cellular aging. Consistent with previous findings, we observed that hypermethylated CpG sites are enriched in regions with repressed polycomb signatures and CpG islands, while hypomethylated CpG sites preferentially occurred in non-CpG islands and enhancers. To gain insights into the functional effects of age-related DNAm changes, we assessed the correlation between DNAm and local gene expression changes to identify age-related expression quantitative trait methylation (age-eQTMs). We identified several age-eQTMs present in multiple tissue-types, including in the CDKN2A, HENMT1, and VCWE regions. CONCLUSION: Overall, our findings will aid future efforts to develop biomarkers of aging and understand mechanisms of aging in diverse human tissue types.

TGF-ß neutralization attenuates tumor residency of activated T cells to enhance systemic immunity in mice.

A tissue resident-like phenotype in tumor infiltrating T cells can limit systemic anti-tumor immunity. Enhanced systemic anti-tumor immunity is observed in head and neck cancer patients after neoadjuvant PD-L1 immune checkpoint blockade (ICB) and transforming growth factor ß (TGF-ß) neutralization. Using T cell receptor (TCR) sequencing and functional immunity assays in a syngeneic model of oral cancer, we dissect the relative contribution of these treatments to enhanced systemic immunity. The addition of TGF-ß neutralization to ICB resulted in the egress of expanded and exhausted CD8+ tumor infiltrating lymphocytes (TILs) into circulation and greater systemic anti-tumor immunity. This enhanced egress associated with reduced expression of Itgae (CD103) and its upstream regulator Znf683. Circulating CD8+ T cells expressed higher Cxcr3 after treatment, an observation also made in samples from patients treated with dual TGF-ß neutralization and ICB. These findings provide the scientific rationale for the use of PD-L1 ICB and TGF-ß neutralization in newly diagnosed patients with carcinomas prior to definitive treatment of locoregional disease.

Extracting Pulmonary Nodules and Nodule Characteristics from Radiology Reports of Lung Cancer Screening Patients Using Transformer Models.

 Pulmonary nodules and nodule characteristics are important indicators of lung nodule malignancy. However, nodule information is often documented as free text in clinical narratives such as radiology reports in electronic health record systems. Natural language processing (NLP) is the key technology to extract and standardize patient information from radiology reports into structured data elements. This study aimed to develop an NLP system using state-of-the-art transformer models to extract pulmonary nodules and associated nodule characteristics from radiology reports. We identified a cohort of 3080 patients who underwent LDCT at the University of Florida health system and collected their radiology reports. We manually annotated 394 reports as the gold standard. We explored eight pretrained transformer models from three transformer architectures including bidirectional encoder representations from transformers (BERT), robustly optimized BERT approach (RoBERTa), and A Lite BERT (ALBERT), for clinical concept extraction, relation identification, and negation detection. We examined general transformer models pretrained using general English corpora, transformer models fine-tuned using a clinical corpus, and a large clinical transformer model, GatorTron, which was trained from scratch using 90 billion words of clinical text. We compared transformer models with two baseline models including a recurrent neural network implemented using bidirectional long short-term memory with a conditional random fields layer and support vector machines. RoBERTa-mimic achieved the best F1-score of 0.9279 for nodule concept and nodule characteristics extraction. ALBERT-base and GatorTron achieved the best F1-score of 0.9737 in linking nodule characteristics to pulmonary nodules. Seven out of eight transformers achieved the best F1-score of 1.0000 for negation detection. Our end-to-end system achieved an overall F1-score of 0.8869. This study demonstrated the advantage of state-of-the-art transformer models for pulmonary nodule information extraction from radiology reports. Supplementary Information: The online version contains supplementary material available at 10.1007/s41666-024-00166-5.

Concurrent Care and use of Advanced Cardiac Therapies for Hospitalized Veterans with Heart Failure.

CONTEXT: Concurrent care allows patients to receive hospice while continuing disease-directed therapies. This treatment model is available in the Veterans Administration (VA) medical system, but its use in Veterans with heart failure (HF) is unexplored. OBJECTIVE: To compare use of advanced HF therapies 30 days post-hospitalization in Veterans on hospice versus not on hospice following admission for HF exacerbation. METHODS: We evaluated Veterans admitted for HF exacerbation to VA hospitals between Jan 2011 and June 2019 who received advanced HF therapies, hospice services, or both post-discharge. Concurrent care was defined as receiving both hospice services and advanced HF therapies. Demographics, comorbidities, and prior healthcare utilization were compared. Secondary outcomes included burdensome transitions and mortality. RESULTS: Among 317,967 HF Veterans, 18,350 (5.8%) chose hospice post-hospitalization. Only 58 hospice-enrolled Veterans (0.3%) received advanced HF therapies (i.e. concurrent care) within 30 days post-discharge. Of 299,617 Veterans not on hospice, 6,083 (2.0%) received advanced HF therapies (0.3% vs 2.0%; p<0.001). Veterans receiving concurrent care had higher six-month mortality than those receiving advanced HF therapies alone (77.6% vs. 14.9%, SMD 1.61). Hazard of burdensome transitions was similar (adjusted HR 1.44, 95% CI 0.95-2.17). CONCLUSION: Veterans with HF receiving concurrent care were few and experienced higher mortality. Rate of burdensome transitions was similar between Veterans receiving concurrent care and those not on hospice. Further research may explore why Veterans infrequently utilize concurrent care at the end of life.

Emergency department clinical performance of ADVIA Centaur n-terminal prohormone of B-type natriuretic peptide assay.

BACKGROUND: Natriuretic peptide testing is guideline recommended as an aid to the diagnosis of heart failure (HF). We sought to evaluate the performance of the ADVIA Centaur (Siemens Healthcare Diagnostics, Tarrytown, NY) NT-proBNPII assay (PBNPII) in emergency department (ED) dyspneic patients. METHODS: Eligible patients presented to the ED with dyspnea, with their gold standard diagnosis determined by up to 3 cardiologists blinded to the PBNPII results. Patients were stratified into 3 groups based on PBNPII resultsa rule out group of NT-proBNP<300  pg/mL, an age-specific rule in group using cutoffs of 450, 900, and 1800 pg/mL, for <50, 50-75, and > 75 years respectively, and an intermediate cohort for results between the rule out and rule in groups. RESULTS: Of 3128 eligible patients, 1148 (36.7 %) were adjudicated as acute heart failure (AHF). The gold standard AHF diagnosis rate was 3.7, 24.3, and 67.2 % for patients with NTproBNPII in the negative, indeterminate, and positive groups, respectively. Overall likelihood ratios (LR) were 0.07 (95 % CI: 0.05,0.09), 0.55 (0.45,0.67), and 3.53 (3.26,3.83) for the same groups, respectively. Individual LR+for age dependent cutoffs were 5.01 (4.25,5.91), 3.71 (3.25,4.24), and 2.38 (2.10,2.69), respectively. NTproBNPII increased with increasing severity of HF when stratified by NYHA classification. CONCLUSIONS: The ADVIA Centaur PBNPII assay demonstrates acceptable clinical performance using the recommended single rule out and age dependent rule in cutoffs for an AHF diagnosis in dyspneic ED patients.

Historical Perspectives on the Use Plastic-Based Cements in Endodontics and Prosthodontics: Part 1 - Oxychlorides.

Oxychloride of zinc was used for years to treat teeth by different approaches and procedures. The success of material usage depended on how well the procedures were conducted and largely on the mix of the material. This article aims to review the evolutionary history of this material with a view to its clinical uses, properties, procedures, applications, and successes when used in the management of decayed tooth structure. Perspectives proffered within focus cover 110 years from 1850 to 1960."Who has not mentally asked the question, as he has taxed himself and his patient to almost complete exhaustion in some dental operation of unusual magnitude or length, Is there not some way either to prevent this destruction of tissue or to restore these organs when attacked, unattended by the severe mental and physical strain upon the operator, and the shrinking, dread, and suffering to the patient which the present general practice and teaching involve?…If the profession would avert this evil, observation must be extended and accurate; new remedies must be sought and applied; investigation by experiment made popular, and the employment of other than mere mechanical remedies encouraged."

Editorial - Venturing into the Depths of Historical Perspectives in Dentistry & Medicine.

With this volume of the Journal of the History of Dentistry we are proud to introduce to our readers and our healing professions, in-depth Essays that focuses on our historical evolution. One might ask, "What is an Essay and Why is This Unique?" The simplest definition of an essay is a non-fictional written work that focuses on a particular subject, sometimes in general terms and sometimes in depth. The word "essay" is derived from the French word "essai," (or as a collection "Essais) meaning trial or attempt. The first use of this approach to address a particular issue has often been attributed to the Frenchman Michel de Montaigne, born in 1533 (Fig. 1).

Trichloroacetic Acid - Historical Origins and Dental Applications.

The use of trichloroacetic acid in dentistry has been advocated by several authors in the last 50 years due to its action on invasive gingival tissues that are seen in the presence of cervical resorption or proximal cavities. Publications addressing this substance and its applications are completely silent regarding its historical evolution or make general claims regarding its original source without substantiation. This perspective will attempt to provide the missing links to this substance and its contemporary use in dentistry, specifically in Endodontics.

Historical Perspectives and Comparisons on the Use Plastic-Based Cements in Endodontics and Prosthodontics: Part 2 - Oxyphosphates.

Oxyphosphate of zinc was used for years to treat teeth by different approaches and procedures. Like oxychloride of zinc, success of the material depended on how well the procedures were conducted and largely on the mix of the material. This article aims to review the evolutionary history of this material with a view to its clinical uses, properties, procedures, applications, and successes when used in the management of decayed tooth structure and rebuilding of teeth. Perspectives proffered within focus cover 110 years from 1850 to 1960.

Assessing the immunogenicity risk of salmon calcitonin peptide impurities using in silico and in vitro methods.

Advances in synthetic peptide synthesis have enabled rapid and cost-effective peptide drug manufacturing. For this reason, peptide drugs that were first produced using recombinant DNA (rDNA) technology are now being produced using solid- and liquid-phase peptide synthesis. While peptide synthesis has some advantages over rDNA expression methods, new peptide-related impurities that differ from the active pharmaceutical ingredient (API) may be generated during synthesis. These impurity byproducts of the original peptide sequence feature amino acid insertions, deletions, and side-chain modifications that may alter the immunogenicity risk profile of the drug product. Impurities resulting from synthesis have become the special focus of regulatory review and approval for human use, as outlined in the FDA's Center for Drug Evaluation and Research guidance document, "ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin," published in 2021. This case study illustrates how in silico and in vitro methods can be applied to assess the immunogenicity risk of impurities that may be present in synthetic generic versions of the salmon calcitonin (SCT) drug product. Sponsors of generic drug abbreviated new drug applications (ANDAs) should consider careful control of these impurities (for example, keeping the concentration of the immunogenic impurities below the cut-off recommended by FDA regulators). Twenty example SCT impurities were analyzed using in silico tools and assessed as having slightly more or less immunogenic risk potential relative to the SCT API peptide. Class II human leukocyte antigen (HLA)-binding assays provided independent confirmation that a 9-mer sequence present in the C-terminus of SCT binds promiscuously to multiple HLA DR alleles, while T-cell assays confirmed the expected T-cell responses to SCT and selected impurities. In silico analysis combined with in vitro assays that directly compare the API to each individual impurity peptide may be a useful approach for assessing the potential immunogenic risk posed by peptide impurities that are present in generic drug products.

Student mental health outcomes of a clustered SMART for developing an adaptive implementation strategy to support school-based CBT delivery.

PURPOSE: Most youth experiencing anxiety/depression lack access to evidence-based mental health practices (EBPs). School-delivered care improves access, and various support can help school professionals (SPs; school social workers, counselors) deliver EBPs, like Cognitive Behavioral Therapy (CBT). Understanding implementation strategies' impact on downstream mental health outcomes is crucial to scaling up EBPs to address the treatment gap, but it has rarely been assessed. METHODS: This paper compares implementation strategies' impact on change in student outcomes, collected as exploratory outcomes from a type III hybrid implementation-effectiveness trial. A clustered, sequential, multiple-assignment randomized trial design was used, which embedded four implementation supports that differentially sequence three implementation strategies, Replicating Effective Programs (REP), Coaching, and Facilitation. Prior to the first randomization, N = 169 SPs from 94 Michigan high schools each identified up to 10 students whom they believed could benefit from CBT and facilitated student survey completion. Changes in students' depression (Patient Health Questionnaire-9, modified for teens) and anxiety symptoms (Generalized Anxiety Disorder-7) over 10 months were compared across the four sequences of implementation support using a generalization of a marginal, weighted least squares approach developed for a clustered SMARTs. RESULTS: Small, non-clinically significant reductions in symptoms over the study period were found. Pairwise comparisons found no significant differences in symptom change across the four implementation strategies. The difference in the estimated mean PHQ-9 T/GAD-7 scores between the least and the most intensive strategies (REP vs. REP+Coaching+Facilitation) was 1.04 (95%CI = -0.95, 3.04) for depression and 0.82 (95%CI = -0.89, 2.52) for anxiety. DISCUSSION: No difference in symptom change was found across the four implementation strategies. Multiple forms of implementation support may be useful for improving student mental health outcomes. TRIAL REGISTRATION: NCT03541317-Registered on 29 May 2018 on ClinicalTrials.gov PRS.

Initial Outcomes following Fresh Meniscus Allograft Transplantation in the Knee.

Based on recent evidence-based advances in meniscus allograft transplantation (MAT), fresh (viable) meniscus allografts have a potential for mitigating key risk factors associated with MAT failure, and preclinical and clinical data have verified the safety of fresh meniscus allografts as well as possible efficacy advantages compared to fresh-frozen meniscus allografts. The objective of this study was to prospectively assess clinical outcomes for the initial cohort of patients undergoing MAT using fresh meniscus allografts at our center. Patients who were prospectively enrolled in a dedicated registry were included for analyses when they had undergone primary MAT using a fresh meniscus allograft for treatment of medial and/or lateral meniscus deficiency with at least 1-year follow-up data recorded. Forty-five patients with a mean final follow-up of 47.8 months (range = 12-90) were analyzed. Mean patient age was 30.7 years (range = 15-60), mean BMI was 29.7 kg/m2 (range = 19-48), and 14 patients (31%) were female. In total, 28 medial, 13 lateral, and 4 combined medial and lateral MATs with 23 concurrent ligament reconstructions and 2 concurrent osteotomies were included. No local or systemic adverse events or complications related to MAT were reported for any patient in the study. Treatment success rate for all patients combined was 91.1% with 3 patients requiring MAT revision and 1 patient requiring arthroplasty. Treatment failures occurred 8 to 34 months after MAT and all involved the medial meniscus. None of the variables assessed were significantly different between treatment success versus treatment failure cohorts. Taken together, the data suggest that the use of fresh (viable) meniscus allografts can be considered a safe and effective option for medial and lateral meniscus allograft transplantation. When transplanted using double bone plug suspensory fixation with meniscotibial ligament reconstruction, fresh MATs were associated with a 91% success rate, absence of local or systemic adverse events or complications, and statistically significant and clinically meaningful improvements in patient-reported measures of pain and function at a mean of 4 years postoperatively.