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Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
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Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacosRESUMO
Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).
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Fibrose Pulmonar Idiopática , Indóis , Piridonas , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Indóis/uso terapêutico , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Resultado do Tratamento , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.
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Pesquisa Biomédica , Fibrose Pulmonar Idiopática , Estados Unidos , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Lagos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/terapia , Fatores de RiscoRESUMO
Sensory hair cells (HCs) in the utricle are mechanoreceptors required to detect linear acceleration. After damage, the mammalian utricle partially restores the HC population and organ function, although regenerated HCs are primarily type II and immature. Whether native, surviving HCs can repair and contribute to this recovery is unclear. Here, we generated the Pou4f3DTR/+; Atoh1CreERTM/+; Rosa26RtdTomato/+ mouse to fate map HCs prior to ablation. After HC ablation, vestibular evoked potentials were abolished in all animals, with â¼57% later recovering responses. Relative to nonrecovery mice, recovery animals harbored more Atoh1-tdTomato+ surviving HCs. In both groups, surviving HCs displayed markers of both type I and type II subtypes and afferent synapses, despite distorted lamination and morphology. Surviving type II HCs remained innervated in both groups, whereas surviving type I HCs first lacked and later regained calyces in the recovery, but not the nonrecovery, group. Finally, surviving HCs initially displayed immature and subsequently mature-appearing bundles in the recovery group. These results demonstrate that surviving HCs are capable of self-repair and may contribute to the recovery of vestibular function.
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Células Ciliadas Vestibulares , Regeneração , Sáculo e Utrículo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sobrevivência Celular/genética , Células Ciliadas Vestibulares/fisiologia , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Mutantes , RNA não Traduzido/genética , Regeneração/genética , Sáculo e Utrículo/citologia , Sáculo e Utrículo/lesões , Sáculo e Utrículo/fisiologia , Fator de Transcrição Brn-3C/genéticaRESUMO
OBJECTIVE: To evaluate the feasibility of developing a computer vision algorithm that uses preoperative computed tomography (CT) scans to predict superior mesenteric artery (SMA) margin status in patients undergoing Whipple for pancreatic ductal adenocarcinoma (PDAC), and to compare algorithm performance to that of expert abdominal radiologists and surgical oncologists. SUMMARY BACKGROUND DATA: Complete surgical resection is the only chance to achieve a cure for PDAC; however, current modalities to predict vascular invasion have limited accuracy. METHODS: Adult patients with PDAC who underwent Whipple and had preoperative contrast-enhanced CT scans were included (2010-2022). The SMA was manually annotated on the CT scans, and we trained a U-Net algorithm for SMA segmentation and a ResNet50 algorithm for predicting SMA margin status. Radiologists and surgeons reviewed the scans in a blinded fashion. SMA margin status per pathology reports was the reference. RESULTS: Two hundred patients were included. Forty patients (20%) had a positive SMA margin. For the segmentation task, the U-Net model achieved a Dice Similarity Coefficient of 0.90. For the classification task, all readers demonstrated limited sensitivity, although the algorithm had the highest sensitivity at 0.43 (versus 0.23 and 0.36 for the radiologists and surgeons, respectively). Specificity was universally excellent, with the radiologist and algorithm demonstrating the highest specificity at 0.94. Finally, the accuracy of the algorithm was 0.85 versus 0.80 and 0.76 for the radiologists and surgeons, respectively. CONCLUSIONS: We demonstrated the feasibility of developing a computer vision algorithm to predict SMA margin status using preoperative CT scans, highlighting its potential to augment the prediction of vascular involvement.
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BACKGROUND: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.
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Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Irinotecano , Leucovorina , Terapia Neoadjuvante , Oxaliplatina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/tratamento farmacológico , Terapia Neoadjuvante/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Leucovorina/administração & dosagem , Irinotecano/administração & dosagem , Fluoruracila/administração & dosagem , Taxa de Sobrevida , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Idoso , Seguimentos , Prognóstico , Pancreatectomia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/tratamento farmacológico , AdultoRESUMO
The pathological evaluation of hepatic vascular lesions in children requires special consideration. Inconsistent terminology, rarity of pathology specimens and overlapping pathological features between various lesions may pose a serious diagnostic challenge. In this review, we highlight the importance of using the International Society for the Study of Vascular Anomalies (ISSVA) classification scheme to characterise these lesions. Selected entities are discussed, including hepatic vascular tumours exclusively seen in the paediatric age group, hepatic infantile haemangioma and hepatic congenital haemangioma. Vascular malformations, with emphasis on their syndromic associations (venous malformation in blue rubber bleb naevus syndrome) and complications (hepatocellular nodules in Abernethy malformation) are also covered.
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BACKGROUND: Despite the importance of recognizing interstitial lung abnormalities, screening methods using computer-based quantitative analysis are not well developed, and studies on the subject with an Asian population are rare. We aimed to identify the prevalence and progression rate of interstitial lung abnormality evaluated by an automated quantification system in the Korean population. METHODS: A total of 2,890 healthy participants in a health screening program (mean age: 49 years, men: 79.5%) with serial chest computed tomography images obtained at least 5 years apart were included. Quantitative lung fibrosis scores were measured on the chest images by an automated quantification system. Interstitial lung abnormalities were defined as a score ≥ 3, and progression as any score increased above baseline. RESULTS: Interstitial lung abnormalities were identified in 251 participants (8.6%), who were older and had a higher body mass index. The prevalence increased with age. Quantification of the follow-up images (median interval: 6.5 years) showed that 23.5% (59/251) of participants initially diagnosed with interstitial lung abnormality exhibited progression, and 11% had developed abnormalities (290/2639). Older age, higher body mass index, and higher erythrocyte sedimentation rate were independent risk factors for progression or development. The interstitial lung abnormality group had worse survival on follow-up (5-year mortality: 3.4% vs. 1.5%; P = 0.010). CONCLUSIONS: Interstitial lung abnormality could be identified in one-tenth of the participants, and a quarter of them showed progression. Older age, higher body mass index and higher erythrocyte sedimentation rate increased the risk of development or progression of interstitial lung abnormality.
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Pulmão , Tomografia Computadorizada por Raios X , Masculino , Humanos , Pessoa de Meia-Idade , Prevalência , Tomografia Computadorizada por Raios X/métodos , Fatores de Risco , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: Manipulation of colorectal polyps by biopsy, incomplete resection, or tattoo placement under the lesion has been shown to cause submucosal fibrosis and associated inferior outcomes. The effect of delays between index manipulation and definitive resection on the incidence of fibrosis is unknown. METHODS: Patients undergoing EMR of previously manipulated colorectal polyps ≥10 mm from 2016 to 2021 at a tertiary referral center were included. Time from index manipulation to definitive resection and the presence of fibrosis were noted. The effects of fibrosis on EMR outcomes were assessed. RESULTS: Among 221 previously manipulated lesions (180 biopsy, 23 incomplete/failed resection, 1 tattoo under lesion, 17 multiple types of manipulation), 51 (23%) demonstrated fibrosis. Fibrotic lesions were found to have been resected significantly later than nonfibrotic lesions (76 vs 61 days; P = .014). In a multivariate analysis controlling for other predictors of fibrosis, each 2-week delay was associated with a 14% increase in the odds of fibrosis. Fibrotic lesions had inferior outcomes with a lower en-bloc resection rate (8% vs 24%; P = .014) and longer procedure time (71 vs 52 minutes; P < .001). Adverse event and recurrence rates were similar between groups. CONCLUSIONS: Delays in definitive resection of previously manipulated polyps are associated with an increased incidence of fibrosis with time and associated inferior outcomes. Manipulation should be discouraged, and if it occurs, prompt referral and scheduling for definitive resection should be prioritized.
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Pólipos do Colo , Ressecção Endoscópica de Mucosa , Fibrose , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pólipos do Colo/cirurgia , Pólipos do Colo/patologia , Ressecção Endoscópica de Mucosa/métodos , Idoso , Fatores de Risco , Tempo para o Tratamento , Colonoscopia/métodos , Estudos Retrospectivos , Duração da Cirurgia , Mucosa Intestinal/cirurgia , Mucosa Intestinal/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Resultado do Tratamento , Fatores de TempoRESUMO
BACKGROUND: Patients with IBD may require colectomy for severe disease unresponsive or refractory to pharmacological therapy. The question of the impact of biologic use on postoperative complications is a topic of active investigation. OBJECTIVE: A systematic literature review was performed to describe the current state of knowledge of the impact of perioperative biologic and tofacitinib use on postoperative complications in patients with IBD. DATA SOURCES: PubMed and Cochrane databases were searched. STUDY SELECTION: Studies between January 2000 and January 2023, in any language, were searched, followed by a snowball search identifying further studies in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Articles regarding pediatric or endoscopic management were excluded. INTERVENTIONS: Preoperative or perioperative exposure to biologics in IBD was included. MAIN OUTCOME MEASURES: Infectious and noninfectious complications, including anastomotic leaks, surgical site infections, urinary tract infections, pneumonia, sepsis, septic shock, postoperative length of stay, readmission, and reoperation, were the main outcomes measured. RESULTS: A total of 28 studies were included for analysis in this review, including 7 meta-analyses or systematic reviews and 5 randomized studies. Snowball search identified 11 additional studies providing topical information. Overall, tumor necrosis factor inhibitors likely do not increase the risk of postoperative adverse outcomes, while data on other biologics and small-molecule agents are emerging. LIMITATIONS: This is a qualitative review including all study types. The varied nature of study types precludes quantitative comparison. CONCLUSIONS: Although steroids increase postoperative infectious and noninfectious complications, tumor necrosis factor inhibitors do not appear to increase postoperative infectious and noninfectious complications. There is a need for further perioperative data for other agents. See video from symposium .
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Produtos Biológicos , Doenças Inflamatórias Intestinais , Complicações Pós-Operatórias , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Produtos Biológicos/uso terapêutico , Produtos Biológicos/efeitos adversos , Doenças Inflamatórias Intestinais/cirurgia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/complicações , Colectomia/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/etiologia , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Tempo de Internação/estatística & dados numéricos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Reoperação/estatística & dados numéricosRESUMO
BACKGROUND: Spatial normalization to a standardized brain template is a crucial step in magnetic resonance imaging (MRI) studies. Brain templates made from sufficient sample size have low brain variability, improving the accuracy of spatial normalization. Using population-specific template improves accuracy of spatial normalization because brain morphology varies according to ethnicity and age. METHODS: We constructed a brain template of normal Korean elderly (KNE200) using MRI scans 100 male and 100 female aged over 60 years old with normal cognition. We compared the deformation after spatial normalization of the KNE200 template to that of the KNE96, constructed from 96 cognitively normal elderly Koreans and to that of the brain template (OCF), constructed from 434 non-demented older Caucasians to examine the effect of sample size and ethnicity on the accuracy of brain template, respectively. We spatially normalized the MRI scans of elderly Koreans and quantified the amount of deformations associated with spatial normalization using the magnitude of displacement and volumetric changes of voxels. RESULTS: The KNE200 yielded significantly less displacement and volumetric change in the parahippocampal gyrus, medial and posterior orbital gyrus, fusiform gyrus, gyrus rectus, cerebellum and vermis than the KNE96. The KNE200 also yielded much less displacement in the cerebellum, vermis, hippocampus, parahippocampal gyrus and thalamus and much less volumetric change in the cerebellum, vermis, hippocampus and parahippocampal gyrus than the OCF. CONCLUSION: KNE200 had the better accuracy than the KNE96 due to the larger sample size and was far accurate than the template constructed from elderly Caucasians in elderly Koreans.
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Encéfalo , Imageamento por Ressonância Magnética , Humanos , Feminino , Imageamento por Ressonância Magnética/métodos , Masculino , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/anatomia & histologia , Pessoa de Meia-Idade , República da Coreia , Povo Asiático , Idoso de 80 Anos ou mais , Envelhecimento , Processamento de Imagem Assistida por Computador/métodos , População do Leste AsiáticoRESUMO
INTRODUCTION: There is a critical need for comprehensive surgical training in African countries given the unmet surgical burden of disease in this region. Collaborative and progressive initiatives in global surgical education will have the greatest impact on trainees. Little is known about surgical education needs from the perspective of practicing surgeons and trainees in low-middle-income countries (LMICs). Even less is known about the potential role for simulation to augment training. METHODS: A modified Delphi methodology with 2 rounds of responses was employed to survey program directors (PD) and associate program directors (APD) of Pan-African Association of Christian Surgeons (PAACS) general surgery residency programs across eight low-middle-income countries in Africa. 3 PD/APDs and 2 surgical residents participated in semi-structured interviews centered around the role of simulation in training. Descriptive analysis was performed to elicit key themes and illustrative examples. RESULTS: The survey of program directors revealed that teaching residents the psychomotor skills need to perform intracorporeal suturing was both high priority and desired in multiple training sites. Other high priority skills were laparoscopic camera driving and medial visceral rotation. The interviews revealed a specific desire to perform laparoscopic surgery and a need for a simulation curriculum to familiarize staff and trainees with laparoscopic techniques. Several barriers to laparoscopic surgery exist, such as lack of staff familiarity with the equipment, lack of public buy in, and lack of generalizable and adaptable educational modules. Trainees saw utility in the use of simulation to optimize time in the operating room and sought opportunities to improve their laparoscopic skills. CONCLUSION: Faculty and surgical trainees in LMICs have interest in learning advanced surgical techniques, such as laparoscopy. Developing a simulation curriculum tailored to the trainees' local context has the potential to fill this need.
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Internato e Residência , Laparoscopia , Treinamento por Simulação , Cirurgiões , Humanos , Avaliação das Necessidades , Currículo , Escolaridade , Laparoscopia/educação , Competência Clínica , Simulação por Computador , Educação de Pós-Graduação em Medicina/métodosRESUMO
OBJECTIVE: Increased subcutaneous and visceral adipose tissue (SAT/VAT) volume is associated with risk for cardiometabolic diseases. This work aimed to develop and evaluate automated abdominal SAT/VAT segmentation on longitudinal MRI in adults with overweight/obesity using attention-based competitive dense (ACD) 3D U-Net and 3D nnU-Net with full field-of-view volumetric multi-contrast inputs. MATERIALS AND METHODS: 920 adults with overweight/obesity were scanned twice at multiple 3 T MRI scanners and institutions. The first scan was divided into training/validation/testing sets (n = 646/92/182). The second scan from the subjects in the testing set was used to evaluate the generalizability for longitudinal analysis. Segmentation performance was assessed by measuring Dice scores (DICE-SAT, DICE-VAT), false negatives (FN), and false positives (FP). Volume agreement was assessed using the intraclass correlation coefficient (ICC). RESULTS: ACD 3D U-Net achieved rapid (< 4.8 s/subject) segmentation with high DICE-SAT (median ≥ 0.994) and DICE-VAT (median ≥ 0.976), small FN (median ≤ 0.7%), and FP (median ≤ 1.1%). 3D nnU-Net yielded rapid (< 2.5 s/subject) segmentation with similar DICE-SAT (median ≥ 0.992), DICE-VAT (median ≥ 0.979), FN (median ≤ 1.1%) and FP (median ≤ 1.2%). Both models yielded excellent agreement in SAT/VAT volume versus reference measurements (ICC > 0.997) in longitudinal analysis. DISCUSSION: ACD 3D U-Net and 3D nnU-Net can be automated tools to quantify abdominal SAT/VAT volume rapidly, accurately, and longitudinally in adults with overweight/obesity.
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Gordura Abdominal , Imageamento Tridimensional , Gordura Intra-Abdominal , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Obesidade , Humanos , Imageamento por Ressonância Magnética/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Imageamento Tridimensional/métodos , Gordura Abdominal/diagnóstico por imagem , Obesidade/diagnóstico por imagem , Gordura Intra-Abdominal/diagnóstico por imagem , Estudos Longitudinais , Sobrepeso/diagnóstico por imagem , Reprodutibilidade dos Testes , Idoso , Meios de Contraste , Algoritmos , Interpretação de Imagem Assistida por Computador/métodosRESUMO
BACKGROUND: Older adults are at a higher risk of severe adverse drug events (ADEs) because of multimorbidity, polypharmacy, and lower physiological function. This study aimed to determine whether polypharmacy, defined as the use of ≥ 5 active drug ingredients, was associated with severe ADEs in this population. METHODS: We used ADE reports from the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System Database, a national spontaneous ADE report system, from 2012 to 2021 to examine and compare the strength of association between polypharmacy and severe ADEs in older adults (≥ 65 years) and younger adults (20-64 years) using disproportionality analysis. RESULTS: We found a significant association between severe ADEs of cardiac and renal/urinary Medical Dictionary for Regulatory Activities System Organ Classes (MedDRA SOC) with polypharmacy in older adults. Regarding individual-level ADEs included in these MedDRA SOCs, acute cardiac arrest and renal failure were more significantly associated with polypharmacy in older adults compared with younger adults. CONCLUSION: The addition of new drugs to the regimens of older adults warrants close monitoring of renal and cardiac symptoms.
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Sistemas de Notificação de Reações Adversas a Medicamentos , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Polimedicação , Humanos , Idoso , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Masculino , Adulto Jovem , Idoso de 80 Anos ou mais , Fatores de Risco , Fatores EtáriosRESUMO
Not meeting recommended A1C targets may be associated with postoperative complications in adults, but there are no studies reporting on the relationship between preoperative A1C and postoperative complications in children with type 1 or type 2 diabetes. The objective of this study was to determine whether elevated A1C levels were associated with an increased incidence of postoperative complications in children with diabetes presenting for elective noncardiac surgery or diagnostic procedures. It found no such association, suggesting no need to delay elective surgery in children with diabetes until A1C is optimized.
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OBJECTIVE: Telehealth is an essential tool to provide access to care while reducing infection exposure for high-risk populations during the COVID-19 pandemic. Our study aims to examine factors associated with telehealth availability and usage among Medicare and dual-eligible recipients 1 year after implementation of the Medicare's temporary telehealth waiver. DESIGN, SETTING, AND PARTICIPANT: A cross-sectional, phone survey with a national representative sample of Medicare recipients. We obtained a final study sample from the Winter 2021 COVID-19 Supplement of Medicare Current Beneficiary Survey dataset (N = 10 586). We examined associations for being offered and having had telehealth visits or any video telehealth visits during the pandemic since November 1, 2020. MAIN OUTCOME MEASURES: Our primary outcomes were being offered any telehealth, being offered any video telehealth, having had any telehealth visit, and having had any video telehealth. RESULTS: Although dual eligibility was not significantly associated with being offered or having had any telehealth services during the pandemic, those who were dual eligible were more likely to have had video telehealth visits (adjusted odds ratio = 1.39, 95% confidence interval 1.04-1.86, P = .03) compared with those with non-dual eligibility. Recipients with disability eligibility, technology access, and severe chronic conditions were more likely to have been offered or have had telehealth. At the same time, those who lived in the nonmetropolitan area were less likely to have been offered or have had telehealth, including video telehealth. CONCLUSIONS: Our findings suggest that the federal waivers to expand telehealth services were successful in continuing care for vulnerable Medicare recipients. The providers' specific outreach and intervention efforts to offer telehealth visits are crucial for dual-eligible recipients. To increase video telehealth uptake, technology access and services to rural areas should be prioritized.
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COVID-19 , Telemedicina , Idoso , Estados Unidos/epidemiologia , Humanos , COVID-19/epidemiologia , Estudos Transversais , Medicare , PandemiasRESUMO
Background The recent release of large language models (LLMs) for public use, such as ChatGPT and Google Bard, has opened up a multitude of potential benefits as well as challenges. Purpose To evaluate and compare the accuracy and consistency of responses generated by publicly available ChatGPT-3.5 and Google Bard to non-expert questions related to lung cancer prevention, screening, and terminology commonly used in radiology reports based on the recommendation of Lung Imaging Reporting and Data System (Lung-RADS) v2022 from American College of Radiology and Fleischner society. Materials and Methods Forty of the exact same questions were created and presented to ChatGPT-3.5 and Google Bard experimental version as well as Bing and Google search engines by three different authors of this paper. Each answer was reviewed by two radiologists for accuracy. Responses were scored as correct, partially correct, incorrect, or unanswered. Consistency was also evaluated among the answers. Here, consistency was defined as the agreement between the three answers provided by ChatGPT-3.5, Google Bard experimental version, Bing, and Google search engines regardless of whether the concept conveyed was correct or incorrect. The accuracy among different tools were evaluated using Stata. Results ChatGPT-3.5 answered 120 questions with 85 (70.8%) correct, 14 (11.7%) partially correct, and 21 (17.5%) incorrect. Google Bard did not answer 23 (19.1%) questions. Among the 97 questions answered by Google Bard, 62 (51.7%) were correct, 11 (9.2%) were partially correct, and 24 (20%) were incorrect. Bing answered 120 questions with 74 (61.7%) correct, 13 (10.8%) partially correct, and 33 (27.5%) incorrect. Google search engine answered 120 questions with 66 (55%) correct, 27 (22.5%) partially correct, and 27 (22.5%) incorrect. The ChatGPT-3.5 is more likely to provide correct or partially answer than Google Bard, approximately by 1.5 folds (OR = 1.55, P = 0.004). ChatGPT-3.5 and Google search engine were more likely to be consistent than Google Bard by approximately 7 and 29 folds (OR = 6.65, P = 0.002 for ChatGPT and OR = 28.83, P = 0.002 for Google search engine, respectively). Conclusion Although ChatGPT-3.5 had a higher accuracy in comparison with the other tools, neither ChatGPT nor Google Bard, Bing and Google search engines answered all questions correctly and with 100% consistency.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Ferramenta de Busca , Tomografia Computadorizada por Raios X , Idioma , Inteligência ArtificialRESUMO
Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Although current recommendations suggest that immunohistochemistry for p53, Rb, ATRX, and DAXX can distinguish most cases, some cases remain difficult to classify using this approach. In this study, we reviewed 47 high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains, we performed capture-based sequencing of approximately 500 cancer genes and immunohistochemistry for p16 and trypsin or chymotrypsin. Using an integrated molecular and clinicopathologic approach, 42 (89%) of 47 cases had a clear final diagnosis of either G3 PanNET (n = 17), PanNEC (n = 17), or mixed acinar-NEC (n = 8). The 17 G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. The 17 PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was coaltered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. The 8 acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Five cases remained difficult to classify, 3 of which exhibited overlapping molecular features with alterations in MEN1 with or without ATRX, and RB1 with or without TP53, making it unclear whether to classify as PanNET or PanNEC. Our data demonstrate that molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC.
Assuntos
Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , GenômicaRESUMO
OBJECTIVES: To investigate computer-aided quantitative scores from high-resolution CT (HRCT) images and determine their longitudinal changes and clinical significance in patients with idiopathic inflammatory myopathies (IIMs)-related interstitial lung disease (IIMs-ILD). METHODS: The clinical data and HRCT images of 80 patients with IIMs who underwent serial HRCT scans at least twice were retrospectively analysed. Quantitative ILD (QILD) scores (%) were calculated as the sum of the extent of lung fibrosis, ground-glass opacity, and honeycombing. The individual time-estimated ΔQILD between two consecutive scans was derived using a linear approximation of yearly changes. RESULTS: The baseline median QILD (interquartile range) scores in the whole lung were 28.1% (19.1-43.8). The QILD was significantly correlated with forced vital capacity (r = -0.349, P = 0.002) and diffusing capacity for carbon monoxide (r = -0.381, P = 0.001). For ΔQILD between the first two scans, according to the visual ILD subtype, QILD aggravation was more frequent in patients with usual interstitial pneumonia (UIP) than non-UIP (80.0% vs 44.4%, P = 0.013). Multivariable logistic regression analyses identified UIP was significantly related to radiographic ILD progression (ΔQILD >2%, P = 0.015). Patients with higher baseline QILD scores (>28.1%) had a higher risk of lung transplantation or death (P = 0.015). In the analysis of three serial HRCT scans (n = 41), dynamic ΔQILD with four distinct patterns (improving, worsening, convex and concave) was observed. CONCLUSION: QILD changes in IIMs-ILD were dynamic, and baseline UIP patterns seemed to be related to a longitudinal progression in QILD. These may be potential imaging biomarkers for lung function, changes in ILD severity and prognosis in IIMs-ILD.
Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Miosite , Humanos , Estudos Retrospectivos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Miosite/diagnóstico por imagemRESUMO
Sequence-specific fluorescent probes for RNA are widely used in microscopy applications such as fluorescence in situ hybridization and a growing number of newer approaches to live-cell RNA imaging. The sequence specificity of most of these approaches relies on differential hybridization of the probe to the correct target. Competing sequences with only one or two base mismatches are prone to causing off-target recognition. Here, we report the sequence-specific fluorescent detection of model RNA targets using a tricyclic cytidine analogue DEAtC that is included as a surrogate for natural cytidine in DNA probe strands and that reports directly on Watson-Crick base pairing. The DEAtC-containing DNA oligonucleotide probes exhibit an average 8-fold increase in fluorescence intensity when hybridized to matched RNA with DEAtC base paired with G and little fluorescence turn-on when DEAtC is base paired with A. Duplex structure determination by NMR, time-resolved fluorescence studies, and Stern-Volmer quenching experiments suggest that the combination of greater π stacking and narrower grooves in the A-form DNA-RNA heteroduplex provides additional shielding and favorable electronic interactions between bases, explaining why DEAtC's fluorescence turn-on response to RNA targets is typically 3-fold greater than for DNA targets.