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Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. Here, we used single nucleus RNA sequencing and bulk whole genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape including suppression of MYCN activity and activation of NF-κB signaling, the latter is further enhanced by cell-cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse.
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INTRODUCTION: In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. METHODS: The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. RESULTS: Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). DISCUSSION: AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.
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INTRODUCTION: We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care. METHODS: IMPACT-AD BC is an observational study of clinic patients who underwent AD CSF biomarker testing as part of their routine medical care (n = 142). In the personal utility arm of the study, semi-structured phone interviews were conducted with a subset of patients (n = 34), and separately with their care partners (n = 31). Post-disclosure interviews were conducted â¼1 month and â¼6 months after biomarker result disclosure and investigated the patients' decision-making process around testing, impact of receiving results, wellness and lifestyle changes, and future planning. RESULTS: A majority of patients (90%) rated their decision to undergo testing as "easy." Post-disclosure, the majority (82%) reported overall positive feelings from having greater certainty and the ability to plan ahead, and results spurred them to adopt/continue healthy behaviors such as exercise (84%) and cognitive activities (54%). Care partners expressed relief from having more diagnostic certainty, increased appreciation of future caregiving responsibilities, and a desire to connect with support resources. DISCUSSION: Perspectives of persons with lived experience in dementia provide new insight into the value of biomarker testing and should be included as part of evidence-guided considerations for pre-test counseling and result disclosure. Moreover, study findings identify an interval when patients and care partners are highly receptive to positive lifestyle and medical interventions.
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Virtual reality (VR) displays are being used in an increasingly wide range of applications. However, previous work shows that viewers often perceive scene properties very differently in real and virtual environments and so realistic perception of virtual stimuli should always be a carefully tested conclusion, not an assumption. One important property for realistic scene perception is surface color. To evaluate how well virtual platforms support realistic perception of achromatic surface color, we assessed lightness constancy in a physical apparatus with real lights and surfaces, in a commercial VR headset, and on a traditional flat-panel display. We found that lightness constancy was good in all three environments, though significantly better in the real environment than on the flat-panel display. We also found that variability across observers was significantly greater in VR and on the flat-panel display than in the physical environment. We conclude that these discrepancies should be taken into account in applications where realistic perception is critical but also that in many cases VR can be used as a flexible alternative to flat-panel displays and a reasonable proxy for real environments.
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The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of one Bptf allele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). High BPTF levels are associated with high-risk features and decreased survival. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation of BPTF and CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.
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Physical, social, and psychological outcomes have been identified as relevant to the rehabilitation process of children with burn injuries. Existing legacy measures are limited in item content and only cover a few constructs. Condition-specific outcomes are highly relevant to gauge early growth and development. Computerized adaptive tests (CATs) leveraging advanced psychometric technologies minimize respondent burden. This project developed PS-LIBRE1-5 Profile CAT (Preschool Life Impact Burn Recovery Evaluation) to measure relevant postburn outcomes in children aged one to five. Responses to the field-tested PS-LIBRE1-5 Profile (188 items) were measured on a scale of frequency or ability. Scores were coded from 0 to 4 where higher scores reflected better functioning. Factor analysis identified the items retained in the final item bank of each scale. CAT simulations were conducted to estimate the mean score of each scale. The simulated CAT score and full item bank scores were compared based upon the score range, ceiling and floor effects, and marginal reliabilities. The child mean age was 3.0 ± 1.5 years (n = 500). Average burn size and time since burn injury were 4.2% TBSA and 1.1 years, respectively. Psychometric analysis resulted in eight scales: Physical, Communication and Language, Emotional Wellbeing, Mood, Anxiety, Peer Acceptance, Play, and Peer Relations. Ceiling effects were acceptable at <13% for all scales. Marginal reliabilities of the CATs were credible. The PS-LIBRE1-5 Profile CAT contains 111 items, and is a comprehensive measure that captures physical, communication and language, psychological, and social functioning of preschool burn survivors.
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Queimaduras , Criança , Humanos , Pré-Escolar , Lactente , Queimaduras/psicologia , Relações Interpessoais , Comportamento Social , Escolaridade , Sobreviventes/psicologia , Psicometria , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target. Highlights: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer DLK1 silencing in neuroblastoma cells results in cellular differentiation ADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models.
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While CT lung cancer screening reduces lung cancer-specific mortality, there are remaining challenges. Radiomic tools promiss to address these challenges, however, they are subject to interobserver variability if semi-automated segmentation techniques are used. Herein we report interobserver variability for two validated radiomic tools, BRODERS (Benign versus aggRessive nODule Evaluation using Radiomic Stratification) and CANARY (Computer-Aided Nodule Assessment and Risk Yield). We retrospectively analyzed the CT images of 95 malignant lung nodules of the adenocarcinoma spectrum using BRODERS and CANARY. Cases were identified at Mayo Clinic (n = 45) and Vanderbilt University Medical Center and Nashville/Veteran Administration Tennessee Valley Health Care System (n = 50). Three observers with different training levels (medical student, internal medicine resident and thoracic radiology fellow) each performed lung nodule segmentation. All methods were carried out in accordance with relevant guidelines and regulations. Interclass correlation coefficients (ICC) of 0.77, 0.98 and 0.97 for the average nodule volume, BRODERS cancer probability and Score Indicative of Lesion Aggression (SILA) which summarizes the distribution of the CANARY exemplars indicated good to excellent reliability, respectively. The dice similarity coefficient was 0.79 and 0.81 for the data sets from the two institutions. BRODERS and CANARY are robust radiomics tools with excellent interobserver variability. These tools are simple and reliable regardless the observer/operator's level of training.
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Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Detecção Precoce de Câncer , Agressão , Reprodutibilidade dos Testes , Pulmão/diagnóstico por imagem , Pulmão/patologiaRESUMO
Survivors of out-of-hospital cardiac arrest (OHCA) experience significant mortality rates and neurological impairment, potentially attributed to the hypoxic-ischemic injury sustained amid the cardiac arrest episode. Post-resuscitation care plays a crucial role in determining outcomes for survivors of OHCA. Supportive therapies have proven to be influential in shaping these outcomes. However, targeting higher blood pressure or oxygen levels during the post-resuscitative phase has not been shown to offer any mortality or neurological benefits. In terms of maintaining hemodynamic instability after resuscitation, it is recommended to use norepinephrine rather than epinephrine. While extracorporeal cardiopulmonary resuscitation has shown promising results, targeted temperature management has been found ineffective in improving outcomes despite its previous potential. This review also investigates various challenges and barriers associated with the practical implementation of these supportive therapies in clinical settings. The review also highlights areas ripe for future research and proposes potential directions to further enhance post-resuscitation supportive care for OHCA survivors.
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OBJECTIVES: To evaluate the reliability of a novel segmentation-based volume rendering approach for quantification of benign central airway obstruction (BCAO). DESIGN: A retrospective single-center cohort study. SETTING: Data were ascertained using electronic health records at a tertiary academic medical center in the United States. PARTICIPANTS AND INCLUSION: Patients with airway stenosis located within the trachea on two-dimensional (2D) computed tomography (CT) imaging and documentation of suspected benign etiology were included. Four readers with varying expertise in quantifying tracheal stenosis severity were selected to manually segment each CT using a volume rendering approach with the available free tools in the medical imaging viewing software OsiriX (Bernex, Switzerland). Three expert thoracic radiologists were recruited to quantify the same CTs using traditional subjective methods on a continuous and categorical scale. OUTCOME MEASURES: The interrater reliability for continuous variables was calculated by the intraclass correlation coefficient (ICC) using a two-way mixed model with 95% confidence intervals (CI). RESULTS: Thirty-eight patients met the inclusion criteria, and fifty CT scans were selected for measurement. The most common etiology of BCAO was iatrogenic in 22 patients (58%). There was an even distribution of chest and neck CT imaging within our cohort. The average ICC across all four readers for the volume rendering approach was 0.88 (95% CI, 0.84 to 0.93), suggesting good to excellent agreement. The average ICC for thoracic radiologists for subjective methods on the continuous scale was 0.38 (95% CI, 0.20 to 0.55), suggesting poor to fair agreement. The kappa for the categorical approach was 0.26, suggesting a slight to fair agreement amongst the raters. CONCLUSION: In this retrospective cohort study, agreement was good to excellent for raters with varying expertise in airway cross-sectional imaging using a novel segmentation-based volume rendering approach to quantify BCAO. This proposed measurement outperformed our expert thoracic radiologists using conventional subjective grading methods.
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Tomografia Computadorizada por Raios X , Humanos , Estudos Retrospectivos , Reprodutibilidade dos Testes , Estudos de Coortes , Constrição Patológica , Tomografia Computadorizada por Raios X/métodos , Variações Dependentes do ObservadorRESUMO
MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) and predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to MNA+ NB remains poorly understood. Here, we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently coexpressed with MYCN and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN, among which we uncover myosin 1B (MYO1B) as being highly expressed in MNA+ NB and, using a chick chorioallantoic membrane (CAM) model, as a crucial regulator of invasion and metastasis. Global secretome and proteome profiling further delineates MYO1B in regulating secretome reprogramming in MNA+ NB cells, and the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism promoting aggressive behavior in MNA+ NB and independently of MYCN.
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Neuroblastoma , Secretoma , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Agressão , Sobrevivência CelularRESUMO
The use of triplet excitons harvesting and short exciton lifetime organic emitters is important to improve the exciton utilization in organic semiconductor laser diodes. In this study, a hybridized local and charge-transfer (HLCT)-type molecule, 11-(3-(10-(4-(1-phenyl-1H-phenanthro[9,10-d]imidazol-2-yl)phenyl)anthracen-9-yl)phenyl)-11H-benzofuro[3,2-b]carbazole (PhAnMBf), is used as an emitter for blue-emitting organic solid-state lasers (OSSLs). The short exciton lifetime and high photoluminescence quantum yield of the PhAnMBf emitter allowed the fabrication of an organic laser with an emission wavelength of 453 nm, a small full width at half-maximum of 1.2 nm, and a threshold of 105 nJ/pulse, corresponding to 44 µJ/cm2, on the distributed feedback substrate. The anthracene-based PhAnMBf material showed the potential of the HLCT emitter as an OSSL.
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Lung adenocarcinoma (LUAD) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate the biological determinants of early LUAD indolence or aggressiveness using radiomics as a surrogate of behavior. We present a set of 92 patients with LUAD with data collected across different methodologies. Patients were risk-stratified using the CT-based Score Indicative of Lung cancer Aggression (SILA) tool (0 = least aggressive, 1 = most aggressive). We grouped the patients as indolent (x ≤ 0.4, n = 14), intermediate (0.4 > x ≤ 0.6, n = 27), and aggressive (0.6 > x ≤ 1, n = 52). Using Cytometry by time of flight (CyTOF), we identified subpopulations with high HLA-DR expression that were associated with indolent behavior. In the RNA sequencing (RNA-seq) dataset, pathways related to immune response were associated with indolent behavior, while pathways associated with cell cycle and proliferation were associated with aggressive behavior. We extracted quantitative radiomics features from the CT scans of the patients. Integrating these datasets, we identified four feature signatures and four patient clusters that were associated with survival. Using single-cell RNA-seq, we found that indolent tumors had significantly more T cells and less B cells than aggressive tumors, and that the latter had a higher abundance of regulatory T cells and Th cells. In conclusion, we were able to uncover a correspondence between radiomics and tumor biology, which could improve the discrimination between indolent and aggressive LUAD tumors, enhance our knowledge in the biology of these tumors, and offer novel and personalized avenues for intervention. Significance: This study provides a comprehensive profiling of LUAD indolence and aggressiveness at the biological bulk and single-cell levels, as well as at the clinical and radiomics levels. This hypothesis generating study uncovers several potential future research avenues. It also highlights the importance and power of data integration to improve our systemic understanding of LUAD and to help reduce the gap between basic science research and clinical practice.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Multiômica , Adenocarcinoma de Pulmão/diagnóstico por imagem , Agressão , Adenocarcinoma/genética , Neoplasias Pulmonares/genéticaRESUMO
BACKGROUND: The growing power and ever decreasing cost of RNA sequencing (RNA-Seq) technologies have resulted in an explosion of RNA-Seq data production. Comparing gene expression values within RNA-Seq datasets is relatively easy for many interdisciplinary biomedical researchers; however, user-friendly software applications increase the ability of biologists to efficiently explore available datasets. RESULTS: Here, we describe ROGUE (RNA-Seq Ontology Graphic User Environment, https://marisshiny. RESEARCH: chop.edu/ROGUE/ ), a user-friendly R Shiny application that allows a biologist to perform differentially expressed gene analysis, gene ontology and pathway enrichment analysis, potential biomarker identification, and advanced statistical analyses. We use ROGUE to identify potential biomarkers and show unique enriched pathways between various immune cells. CONCLUSIONS: User-friendly tools for the analysis of next generation sequencing data, such as ROGUE, will allow biologists to efficiently explore their datasets, discover expression patterns, and advance their research by allowing them to develop and test hypotheses.
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Pesquisa Biomédica , Aplicativos Móveis , Sequenciamento de Nucleotídeos em Larga Escala , Ontologia Genética , Análise de Sequência de RNARESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti-inflammatory, antipyretic, and analgesic properties. However, their use is often associated with gastrointestinal tract (GIT) side effects due to the inhibition of both cyclooxygenase (COX)-1 and COX-2 enzymes, leading to a decrease in gastroprotective prostaglandins (PG). To minimize these adverse effects, various approaches have been explored, including selective COX-2 inhibitors, NO-NSAIDs (nitric oxide-releasing NSAIDs), and dual COX/LOX (lipoxygenase) NSAIDs. However, the effects of these gastroprotective NSAIDs on the GIT and their efficacy remains uncertain. This review aims to provide an overview of the current understanding of the effects of traditional NSAIDs and gastroprotective NSAIDs on GIT. We discuss the underlying mechanisms of GIT damage caused by NSAIDs, including mucosal injury, ulceration, and bleeding, and the potential of gastroprotective NSAIDs to mitigate these effects. We also summarize recent studies on the efficacy and safety of various gastroprotective NSAIDs and highlight the limitations and challenges of these approaches. The review concludes with recommendations for future research in this field.
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A timely understanding of the biological secrets of complex diseases will ultimately benefit millions of individuals by reducing the high risks for mortality and improving the quality of life with personalized diagnoses and treatments. Due to the advancements in sequencing technologies and reduced cost, genomics data are developing at an unmatched pace and levels to foster translational research and precision medicine. Over 10 million genomics datasets have been produced and publicly shared in 2022. Diverse and high-volume genomics and clinical data have the potential to broaden the scope of biological discoveries and insights by extracting, analyzing and interpreting the hidden information. However, the current and still unresolved challenges include the integration of genomic profiles of the patients with their medical records. The definition of disease in genomics medicine is simplified, whereas in the clinical world, diseases are classified, identified and adopted with their International Classification of Diseases (ICD) codes, which are maintained by the World Health Organization. Several biological databases have been produced, which include information about human genes and related diseases. However, still, there is no database that exists, which can precisely link clinical codes with relevant genes and variants to support genomic and clinical data integration for clinical and translational medicine. In this project, we focused on the development of an annotated gene-disease-code database, which is accessible through an online, cross-platform and user-friendly application, i.e. PROMIS-APP-SUITE-Gene-Disease-Code. However, our scope is limited to the integration of ICD-9 and ICD-10 codes with the list of genes approved by the American College of Medical Genetics and Genomics. The results include over 17 000 diseases and 4000 ICD codes, and over 11 000 gene-disease-code combinations. Database URL https://promis.rutgers.edu/pas/.
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Classificação Internacional de Doenças , Medicina de Precisão , Humanos , Estados Unidos , Qualidade de Vida , Pesquisa Translacional Biomédica , Ciência Translacional BiomédicaRESUMO
BACKGROUND: Procalcitonin (PCT), a peptide precursor of the hormone calcitonin, is a biomarker whose serum concentrations are elevated in response to systemic inflammation caused by bacterial infection and sepsis. Clinical adoption of PCT in the United States has only recently gained traction with an increasing number of Food and Drug Administration-approved assays and expanded indications for use. There is interest in the use of PCT as an outcomes predictor as well as an antibiotic stewardship tool. However, PCT has limitations in specificity, and conclusions surrounding its utility have been mixed. Further, there is a lack of consensus regarding appropriate timing of measurements and interpretation of results. There is also a lack of method harmonization for PCT assays, and questions remain regarding whether the same clinical decision points may be used across different methods. CONTENT: This guidance document aims to address key questions related to the use of PCT to manage adult, pediatric, and neonatal patients with suspected sepsis and/or bacterial infections, particularly respiratory infections. The document explores the evidence for PCT utility for antimicrobial therapy decisions and outcomes prediction. Additionally, the document discusses analytical and preanalytical considerations for PCT analysis and confounding factors that may affect the interpretation of PCT results. SUMMARY: While PCT has been studied widely in various clinical settings, there is considerable variability in study designs and study populations. Evidence to support the use of PCT to guide antibiotic cessation is compelling in the critically ill and in some lower respiratory tract infections but is lacking in other clinical scenarios, and evidence is also limited in the pediatric and neonatal populations. Interpretation of PCT results requires guidance from multidisciplinary care teams of clinicians, pharmacists, and clinical laboratorians.
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Anti-Infecciosos , Infecções Bacterianas , Sepse , Adulto , Recém-Nascido , Humanos , Criança , Pró-Calcitonina , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Sepse/diagnóstico , Sepse/tratamento farmacológico , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêuticoRESUMO
Objective: To determine if there was a significant increase in cessation rates over a 6-month time frame with a pharmacist-managed smoking cessation clinic.Methods: This single-center, prospective study recruited veterans via ICD-10 diagnosis codes for nicotine/tobacco dependence to participate in a clinical pharmacy practitioner (CPP)-run smoking cessation clinic. To aid cessation efforts, participants were offered pharmacotherapy, behavioral modifications, and frequent follow-up appointments. Once a participant demonstrated tobacco-free success for 6 months, the veteran was eligible for discharge from the clinic. Patient visits were conducted between December 2020 and October 2021. Data were analyzed using intention-to-treat principle.Results: A total of 54 participants were screened, of which 29 met the inclusion criteria. Eleven participants withdrew from the study, as they were no longer willing to quit smoking. Thirty-eight percent (n = 11) of the enrolled participants achieved complete tobacco cessation by the end of the study, with 31% (n = 9) achieving the primary endpoint of tobacco cessation for 6 months. Seventeen percent (n = 5) of participants maintained ≥ 50% reduction in tobacco use. One participant increased the amount of tobacco used since the initial visit.Conclusions: Providing pharmacotherapy, behavioral counseling, and frequent follow-up visits may result in higher numbers of tobacco-free patients. Expanding pharmacist-run smoking cessation clinics may result in an increase in cessation rates in the veteran population.
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Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Tabagismo , Veteranos , Humanos , Farmacêuticos , Estudos Prospectivos , Dispositivos para o Abandono do Uso de Tabaco , AconselhamentoRESUMO
OBJECTIVE: Indeterminate pulmonary nodules (IPNs) represent a significant diagnostic burden in health care. We aimed to compare a combination clinical prediction model (Mayo Clinic model), fungal (histoplasmosis serology), imaging (computed tomography [CT] radiomics), and cancer (high-sensitivity cytokeratin fraction 21; hsCYFRA 21-1) biomarker approach to a validated prediction model in diagnosing lung cancer. METHODS: A prospective specimen collection, retrospective blinded evaluation study was performed in 3 independent cohorts with 6- to 30-mm IPNs (n = 281). Serum histoplasmosis immunoglobulin G and immunoglobulin M antibodies and hsCYFRA 21-1 levels were measured and a validated CT radiomic score was calculated. Multivariable logistic regression models were estimated with Mayo Clinic model variables, histoplasmosis antibody levels, CT radiomic score, and hsCYFRA 21-1. Diagnostic performance of the combination model was compared with that of the Mayo Clinic model. Bias-corrected clinical net reclassification index (cNRI) was used to estimate the clinical utility of a combination biomarker approach. RESULTS: A total of 281 patients were included (111 from a histoplasmosis-endemic region). The combination biomarker model including the Mayo Clinic model score, histoplasmosis antibody levels, radiomics, and hsCYFRA 21-1 level showed improved diagnostic accuracy for IPNs compared with the Mayo Clinic model alone with an area under the receiver operating characteristics curve of 0.80 (95% CI, 0.76-0.84) versus 0.72 (95% CI, 0.66-0.78). Use of this combination model correctly reclassified intermediate risk IPNs into low- or high-risk category (cNRI benign = 0.11 and cNRI malignant = 0.16). CONCLUSIONS: The addition of cancer, fungal, and imaging biomarkers improves the diagnostic accuracy for IPNs. Integrating a combination biomarker approach into the diagnostic algorithm of IPNs might decrease unnecessary invasive testing of benign nodules and reduce time to diagnosis for cancer.