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1.
J Cutan Pathol ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33576022

RESUMO

BACKGROUND: Novel solutions are needed for expediting margin assessment to guide BCC surgeries. Ex-vivo fluorescence confocal microscopy (FCM) is starting to be used in freshly-excised surgical specimens to examine BCC margins in real-time. Training and educational process are needed for this novel technology to be implemented into clinic. OBJECTIVE: To test a training and reading process, and measure diagnostic accuracy of clinicians with varying expertise level in reading ex-vivo FCM images. METHODS: An international 3-center study was designed for training and reading to assess BCC surgical margins and residual subtypes. Each center included a lead dermatologic/Mohs surgeon (clinical developer of FCM), and 3 additional readers (dermatologist, dermatopathologist, dermatologic/Mohs surgeon), who use confocal in clinical practice. Testing was conducted on 30 samples. RESULTS: Overall, the readers achieved 90% average sensitivity, 78% average specificity in detecting residual BCC margins, showing high and consistent diagnostic reading accuracy. Those with expertise in dermatologic surgery and dermatopathology showed the strongest potential for learning to assess FCM images. LIMITATIONS: Small dataset, variability in mosaic quality between centers. CONCLUSION: Suggested process is feasible and effective. This process is proposed for wider implementation, to facilitate wider adoption of FCM to potentially expedite BCC margin assessment to guide surgery in real-time. This article is protected by copyright. All rights reserved.

2.
Lancet Respir Med ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33581080

RESUMO

BACKGROUND: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. METHODS: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and 'tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). FINDINGS: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls. INTERPRETATION: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. FUNDING: Vertex Pharmaceuticals Incorporated.

3.
J Cyst Fibros ; 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33495079

RESUMO

BACKGROUND: CF patients demonstrate clinical heterogeneity and much remains unknown about how to risk stratify individuals for disease progression.  The most common cystic fibrosis mutation, F508del, is a protein folding mutation that has been shown in vitro to negatively affect proteostasis and CFTR transcription. Since CFTR is expressed in the nasal epithelium, we hypothesized that by using unbiased transcriptomics we could gain clinically relevant insights about differential gene expression and heterogeneity in CF patients as well as assess proteostatic dysfunction in the nasal epithelium. METHODS: Using nasal curettage and RNA-seq we assessed differential gene expression in F508del homozygotes compared to healthy volunteers. Gene set enrichment analysis was performed using a list of known chaperones. Pilot and validation cohorts were studied. RESULTS: PCA analysis and gene expression heatmaps exhibited greater heterogeneity among CF than healthy volunteers. Differentially expressed genes were enriched for the downregulation of ciliary/microtubular genes and the upregulation of inflammatory/immune response genes in F508del homozygotes compared to healthy volunteers. Gene set analysis identified negative enrichment for chaperone genes and decreased CFTR transcription in the F508del homozygotes. We also found preliminary evidence for the recently identified ionocyte in the nasal specimens. CONCLUSION: CF patients homozygous for F508del demonstrate heterogeneous gene expression profiles, proteostatic dysregulation, and reduced CFTR transcription. Larger studies are needed to determine whether nasal epithelial gene transcription profiles can be leveraged for insights into disease heterogeneity.

4.
J Am Acad Dermatol ; 84(1): 102-119, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32454102

RESUMO

BACKGROUND: There is lack of uniformity in the reflectance confocal microscopy (RCM) terminology for melanocytic lesions. OBJECTIVE: To review published RCM terms for melanocytic lesions and identify redundant, synonymous terms. METHODS: A systematic review of original research articles adhering to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was conducted until August 15, 2018. Two investigators gathered all published RCM terms used to describe melanoma and melanocytic nevi. Synonymous terms were grouped based on similarity in definition and in histopathologic correlation. RESULTS: Out of 156 full-text screened articles, 59 studies met the inclusion criteria. We identified 209 terms; 191 (91.4%) corresponding to high-magnification/cellular-level terms and 18 (8.6%) corresponding to low-magnification/architectural patterns terms. The overall average use frequency of RCM terms was 3.1 times (range, 1-31). By grouping of individual RCM terms based on likely synonymous definitions and by eliminating terms lacking clear definition, the total number of RCM terms could be potentially reduced from 209 to 40 terms (80.8% reduction). LIMITATIONS: Non-English and non-peer-reviewed articles were excluded. CONCLUSIONS: This systematic review of published RCM terms identified significant terminology redundancy. It provides the basis for subsequent terminology consensus on melanocytic neoplasms.

5.
Pediatr Pulmonol ; 2020 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-33369260

RESUMO

INTRODUCTION: The 2017-2018 National Survey of Children's Health estimates that 30 million (42%) US children have experienced at least one adverse childhood experience (ACE), including abuse, neglect, and household dysfunction. ACEs negatively impact long-term health, and there has been no study of ACEs in cystic fibrosis (CF). We assessed willingness to disclose ACEs experienced by children with CF by surveying their parents and adults with CF. METHODS: We anonymously surveyed parents of children with CF and adults with CF at the Northwestern University/Lurie Children's CF Center to determine their willingness to disclose ACEs. RESULTS: The survey was completed by 46/157 (29%) parents and 36/105 (34%) adults with CF. Few parents (22%) and adults (17%) were willing to discuss most or all specific ACEs, more were willing to disclose the number of ACEs experienced in a category (57% parents, 47% adults), and the majority were willing to participate in anonymous research about ACEs (76% parents, 67% adults). Most parents (63%) and adults (50%) would prefer to have ACEs screened separately from their CF appointment, and most parents (63%) and adults (56%) wanted to learn more about ACEs from a member of their care team. CONCLUSIONS: Participants preferred to disclose the number of categorical ACEs rather than specific ACEs and most were open to participating in anonymous ACEs research. More research is needed before implementing screening. Educating patients, parents, and providers about ACEs and appropriate interventions when ACES are identified is needed for both research and clinical applications of ACEs screening.

6.
10.
Pharmacotherapy ; 40(6): 584-591, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32259317

RESUMO

OBJECTIVE: Systemic aminoglycosides remain a cornerstone of treatment for cystic fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides. METHODS: We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and forced expiratory volume over 1 second (FEV1 ) data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain area under the curve (AUC)0-24 hr , maximum concentration (Cmax0-24 hr ), and minimum concentration (Cmin0-24 hr ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV1 by 30 days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis. RESULTS: The study included 51 patients who contributed 188 FEV1 observations. There were 3.0 ± 1.7 (mean ± SD) aminoglycoside concentrations per patient. The mean AUC0-24 hr , Cmax0-24 hr , and Cmin0-24 hr across all agents and patients were 156 ± 96 mg*hr/L, 29.9 ± 12.7 mg/L, and 0.35 ± 0.66 mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery posttreatment. Of the 51 included patients, 6 (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24 hr nor Cmax0-24 hr was associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 . CONCLUSIONS: Increasing aminoglycoside AUC0-24 hr and Cmax0-24 hr were not associated with FEV1 during PEx treatment. Although individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population.

12.
Eur Respir J ; 55(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31601718

RESUMO

Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms.We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis.We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis.Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.

13.
J Am Acad Dermatol ; 83(4): 1057-1063, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31202873

RESUMO

BACKGROUND: Reflectance confocal microscopy (RCM) allows accurate, noninvasive, in vivo diagnosis for skin cancer. However, its impact on physicians' diagnostic confidence and management is unknown. OBJECTIVES: We sought to assess the physicians' diagnostic confidence and management before and after RCM of equivocal skin lesions. METHODS: Prospective, 2-center, observational study. During clinical practice, 7 dermatologists recorded their diagnostic confidence level (measured in a scale from 0 to 10), diagnosis, and management before and after RCM of clinically/dermoscopically equivocal lesions that raised concern for skin cancer. We also evaluated the diagnostic accuracy before and after RCM. RESULTS: We included 272 consecutive lesions from 226 individuals (mean age, 53.5 years). Diagnostic confidence increased from 6.2 to 8.1 after RCM (P < .001) when RCM confirmed or changed the diagnosis. Lesion management changed in 33.5% cases after RCM (to observation in 51 cases and to biopsy/excision in 31 cases). After RCM, the number needed to excise was 1.2. Sensitivity for malignancy before and after RCM was 78.2% and 85.1%, respectively. Specificity before and after RCM was 78.8% and 80%, respectively. LIMITATIONS: Small sample size, real-life environment, and different levels of expertise among RCM users. CONCLUSION: Physicians' diagnostic confidence and accuracy increased after RCM when evaluating equivocal tumors, frequently resulting in management changes while maintaining high diagnostic accuracy.

18.
J Am Acad Dermatol ; 80(5): 1414-1427.e3, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30529706

RESUMO

BACKGROUND: There is lack of uniformity in reflectance confocal microscopy (RCM) terminology for nonmelanocytic lesions (NMLs). OBJECTIVE: To review published RCM terms for NMLs and identify likely synonymous terms. METHODS: We conducted a systematic review of original research articles published up to August 19, 2017, adhering to Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines. Two investigators gathered all published RCM terms used to describe basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and seborrheic keratosis/solar lentigo/lichen planus-like keratosis (SK/SL/LPLK). Synonymous terms were grouped on the basis of similarity in definition and histopathologic correlates. RESULTS: The inclusion criteria was met by 31 studies. Average frequency of use per term was 1.6 (range 1-8). By grouping synonymous terms, the number of terms could be reduced from 58 to 18 for BCC, 58 to 36 for SCC, 23 to 12 for SK/SL/LPLK, and from 139 to 66 terms (52.5% reduction) in total. The frequency of term usage stratified by anatomic layer (suprabasal epidermis vs epidermal basal layer, dermoepidermal junction, and superficial dermis) was 27 (25.7%) versus 78 (74.2%) for BCC; 60 (64.5%) versus 33 (34.5%) for SCC, and 15 (45.4%) versus 18 (54.5%) for SK/SL/LPLK, respectively. LIMITATIONS: Articles that were not peer reviewed were excluded. CONCLUSION: Systematic review of published RCM terms provides the basis for future NMLs terminology consensus.


Assuntos
Carcinoma Basocelular/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Terminologia como Assunto , Humanos , Ceratose Seborreica/diagnóstico por imagem , Lentigo/diagnóstico por imagem , Microscopia Confocal
19.
Cell Metab ; 29(2): 335-347.e5, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30318339

RESUMO

Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6. Targeted genetic deletion of electron transport or CRAC channels in alveolar macrophages in mice prevented particulate matter-induced acceleration of arterial thrombosis. These findings suggest metformin as a potential therapy to prevent some of the premature deaths attributable to air pollution exposure worldwide.


Assuntos
Poluição do Ar/efeitos adversos , Pneumopatias/tratamento farmacológico , Macrófagos Alveolares/metabolismo , Metformina/farmacologia , Mitocôndrias/metabolismo , Material Particulado/toxicidade , Trombose/tratamento farmacológico , Animais , Linhagem Celular , Citocinas/metabolismo , Transporte de Elétrons , Humanos , Interleucina-6/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
20.
Am J Respir Crit Care Med ; 199(12): 1517-1536, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30554520

RESUMO

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.


Assuntos
Células Cultivadas/patologia , Células Epiteliais/patologia , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Análise de Sequência de RNA , Células-Tronco/patologia , Transcriptoma , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino
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