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BACKGROUND: Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. METHODS: Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. RESULTS: Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years. CONCLUSIONS: Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Idoso , Adulto , Fatores Etários , Fatores Sexuais , Mutação , Genômica/métodos , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Idoso de 80 Anos ou maisRESUMO
PURPOSE: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. EXPERIMENTAL DESIGN: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a "genomic cohort" [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional "clinical cohort" of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT). RESULTS: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. CONCLUSIONS: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.
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Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Mutação , Ductos Biliares Intra-Hepáticos/patologia , GenômicaRESUMO
BACKGROUND: There are ongoing efforts to eliminate juvenile detention in King County, WA. An essential element of this work is effectively addressing the health needs of youth who are currently detained to improve their wellbeing and reduce further contact with the criminal legal system. This formative study sought to inform adaptation and piloting of an evidence-based systems engineering strategy - the Systems Analysis and Improvement Approach (SAIA) - in a King County juvenile detention center clinic to improve quality and continuity of healthcare services. Our aims were to describe the priority health needs of young people who are involved in Washington's criminal legal system and the current system of healthcare for young people who are detained. METHODS: We conducted nine individual interviews with providers serving youth. We also obtained de-identified quantitative summary reports of quality improvement discussions held between clinic staff and 13 young people who were detained at the time of data collection. Interview transcripts were analyzed using deductive and inductive coding and quantitative data were used to triangulate emergent themes. RESULTS: Providers identified three priority healthcare cascades for detention-based health services-mental health, substance use, and primary healthcare-and reported that care for these concerns is often introduced for the first time in detention. Interviewees classified incarceration itself as a health hazard, highlighting the paradox of resourcing healthcare quality improvement interventions in an inherently harmful setting. Fractured communication and collaboration across detention- and community-based entities drives systems-level inefficiencies, obstructs access to health and social services for marginalized youth, and fragments the continuum of care for young people establishing care plans while detained in King County. 31% of youth self-reported receiving episodic healthcare prior to detention, 15% reported never having medical care prior to entering detention, and 46% had concerns about finding healthcare services upon release to the community. CONCLUSIONS: Systems engineering interventions such as the SAIA may be appropriate and feasible approaches to build systems thinking across and between services, remedy systemic challenges, and ensure necessary information sharing for care continuity. However, more information is needed directly from youth to draw conclusions about effective pathways for healthcare quality improvement.
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Instituições de Assistência Ambulatorial , Prisões Locais , Adolescente , Humanos , Washington , Recursos em Saúde , Melhoria de QualidadeRESUMO
Peripheral nerve and spinal cord injuries are potentially devastating traumatic conditions with major consequences for patients' lives. Severe cases of these conditions are currently incurable. In both the peripheral nerves and the spinal cord, disruption and degeneration of axons is the main cause of neurological deficits. Biomaterials offer experimental solutions to improve these conditions. They can be engineered as scaffolds that mimic the nerve tissue extracellular matrix and, upon implantation, encourage axonal regeneration. Furthermore, biomaterial scaffolds can be designed to deliver therapeutic agents to the lesion site. This article presents the principles and recent advances in the use of biomaterials for axonal regeneration and nervous system repair.
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Materiais Biocompatíveis/uso terapêutico , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos da Medula Espinal/terapia , Animais , Axônios/patologia , Axônios/fisiologia , Matriz Extracelular/patologia , Matriz Extracelular/fisiologia , Humanos , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Nervos Periféricos/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/reabilitação , Alicerces Teciduais/tendênciasRESUMO
OBJECTIVE: Current guidelines advocate prehospital endotracheal intubation (ETI) in patients with suspected severe head injury and impaired level of consciousness. However, the ability to identify patients with traumatic brain injury (TBI) in the prehospital setting is limited and prehospital ETI carries a high complication rate. We investigated the prevalence of significant TBI among patients intubated in the field for that reason. METHODS: Data were retrospectively collected from emergency medical services and hospital records of trauma patients for whom prehospital ETI was attempted and who were transferred to Rambam Health Care Campus, Israel. The indication for ETI was extracted. The primary outcome was significant TBI (clinical or radiographic) among patients intubated due to suspected severe head trauma. RESULTS: In 57.3% (379/662) of the trauma patients, ETI was attempted due to impaired consciousness. 349 patients were included in the final analysis: 82.8% were male, the median age was 34 years (IQR 23.0-57.3), and 95.7% suffered blunt trauma. 253 patients (72.5%) had significant TBI. In a multivariable analysis, Glasgow Coma Scale>8 and alcohol intoxication were associated with a lower risk of TBI with OR of 0.26 (95% CI 0.13-0.51, p < 0.001) and 0.16 (95% CI 0.06-0.46, p < 0.001), respectively. CONCLUSION: Altered mental status in the setting of trauma is a major reason for prehospital ETI. Although most of these patients had TBI, one in four of them did not suffer a significant TBI. Patients with a higher field GCS and those suffering from intoxication have a higher risk of misdiagnosis. Future studies should explore better tools for prehospital assessment of TBI and ways to better define and characterize patients who may benefit from early ETI.
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Lesões Encefálicas Traumáticas/epidemiologia , Estado de Consciência , Intubação Intratraqueal/estatística & dados numéricos , Adulto , Idoso , Lesões Encefálicas Traumáticas/diagnóstico , Serviços Médicos de Emergência/estatística & dados numéricos , Feminino , Escala de Coma de Glasgow , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Estudos RetrospectivosRESUMO
Microtia is a small, malformed external ear, which occurs at an incidence of 1-10 per 10 000 births. Autologous reconstruction using costal cartilage is the most widely accepted surgical microtia repair technique. Yet, the method involves donor-site pain and discomfort and relies on the artistic skill of the surgeon to create an aesthetic ear. This study employed novel tissue engineering techniques to overcome these limitations by developing a clinical-grade, 3D-printed biodegradable auricle scaffold that formed stable, custom-made neocartilage implants. The unique scaffold design combined strategically reinforced areas to maintain the complex topography of the outer ear and micropores to allow cell adhesion for the effective production of stable cartilage. The auricle construct was computed tomography (CT) scan-based composed of a 3D-printed clinical-grade polycaprolactone scaffold loaded with patient-derived chondrocytes produced from either auricular cartilage or costal cartilage biopsies combined with adipose-derived mesenchymal stem cells. Cartilage formation was measured within the constructin vitro, and cartilage maturation and stabilization were observed 12 weeks after its subcutaneous implantation into a murine model. The proposed technology is simple and effective and is expected to improve aesthetic outcomes and reduce patient discomfort.
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Microtia Congênita , Células-Tronco Mesenquimais , Animais , Condrócitos , Microtia Congênita/cirurgia , Cartilagem da Orelha , Humanos , Camundongos , Impressão Tridimensional , Engenharia Tecidual/métodos , Alicerces TeciduaisRESUMO
Engineering hierarchical vasculatures is critical for creating implantable functional thick tissues. Current approaches focus on fabricating mesoscale vessels for implantation or hierarchical microvascular in vitro models, but a combined approach is yet to be achieved to create engineered tissue flaps. Here, millimetric vessel-like scaffolds and 3D bioprinted vascularized tissues interconnect, creating fully engineered hierarchical vascular constructs for implantation. Endothelial and support cells spontaneously form microvascular networks in bioprinted tissues using a human collagen bioink. Sacrificial molds are used to create polymeric vessel-like scaffolds and endothelial cells seeded in their lumen form native-like endothelia. Assembling endothelialized scaffolds within vascularizing hydrogels incites the bioprinted vasculature and endothelium to cooperatively create vessels, enabling tissue perfusion through the scaffold lumen. Using a cuffing microsurgery approach, the engineered tissue is directly anastomosed with a rat femoral artery, promoting a rich host vasculature within the implanted tissue. After two weeks in vivo, contrast microcomputer tomography imaging and lectin perfusion of explanted engineered tissues verify the host ingrowth vasculature's functionality. Furthermore, the hierarchical vessel network (VesselNet) supports in vitro functionality of cardiomyocytes. Finally, the proposed approach is expanded to mimic complex structures with native-like millimetric vessels. This work presents a novel strategy aiming to create fully-engineered patient-specific thick tissue flaps.
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Materiais Biomiméticos/química , Bioimpressão/métodos , Engenharia Tecidual , Animais , Colágeno Tipo I/química , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Artéria Femoral/cirurgia , Humanos , Hidrogéis/química , Tinta , Masculino , Metacrilatos/química , Polímeros/química , Impressão Tridimensional , Próteses e Implantes , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/metabolismo , Alicerces Teciduais/químicaRESUMO
As I begin my 4th year of medical school amidst the coronavirus disease 2019 (COVID-19) pandemic, telehealth has allowed me to connect with many patients who previously struggled to access consistent primary care. In this essay, I describe 2 of my most formative experiences with telehealth: participating in my medical school's new "tele-hotspotting" elective, and providing virtual gender-affirming care through our student-run free clinic. These experiences demonstrate not only telehealth's utility during a viral pandemic, but also its potential as a powerful tool for expanding access to care and promoting health equity over the coming years. With this said, telehealth is not without limitations. Patients and clinicians alike have expressed concerns regarding the challenge of performing a physical exam and maintaining emotional connection across physical distance. A sustained expansion of telehealth is further challenged by inconsistent availability of broadband Internet, as well as a lack of standardized reimbursement procedures for telehealth visits. Strategies are available to help meet these challenges while maximizing health equity.
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COVID-19 , Previsões , Acessibilidade aos Serviços de Saúde/tendências , Atenção Primária à Saúde/tendências , Telemedicina/tendências , Humanos , Atenção Primária à Saúde/métodos , SARS-CoV-2RESUMO
Biodegradable polyesters have been extensively used for preparation of nerve guidance scaffolds, due to their high biocompatibility and defined degradation periods. However, conventional methods for fabrication of porous polyester scaffolds provide limited control over shape and micro-architecture. Here, a fabrication procedure based on 3D printing was developed to generate highly ordered and anatomically personalized, polyester scaffolds for soft tissue regeneration. Scaffolds composed of Poly-lactic-glycolic acid (PLGA) and poly-L-lactic acid (PLLA) were specifically customized for nerve injuries. This was obtained by using an oriented multi-layer printing pattern which established a linear structure in the fabricated scaffolds to match the aligned topography of nerve tissues. The oriented scaffold was shown to guide regenerating axons to linear conformations and support growth of induced pluripotent stem cell-derived neurons in vitro and in vivo in a model of spinal cord injury. The described scaffolds may advance the field of nerve regeneration. Furthermore, modifications could be integrated to generate soft implants for various types of tissues.
RESUMO
The key to understanding, harnessing, and manipulating natural biological processes for the benefit of tissue engineering lies in providing a controllable dynamic environment for tissue development in vitro while being able to track cell activity in real time. This work presents a multi-channel bioreactor specifically designed to enable on-line imaging of fluorescently labeled cells embedded in replicated 3D engineered constructs subjected to different flow conditions. The images are acquired in 3D using a standard upright confocal microscope and further analyzed and quantified by computer vision. The platform is used to characterize and quantify the pace and directionality of angiogenic processes induced by flow. The presented apparatus bears considerable potential to advance scientific research, from basic research pursuing the effect of flow versus static conditions on 3D scaffolds and cell types, to clinically oriented modeling in drug screening and cytotoxicity assays.
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Reatores Biológicos , Técnicas de Cultura de Células/métodos , Células Endoteliais/citologia , Engenharia Tecidual/métodos , Alicerces Teciduais , Técnicas de Cultura de Células/instrumentação , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Humanos , Imageamento Tridimensional/instrumentação , Imageamento Tridimensional/métodos , Microscopia Confocal , Neovascularização Fisiológica , Perfusão , Reologia , Engenharia Tecidual/instrumentação , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Autologous muscle flaps are commonly used to reconstruct defects that involve muscle impairment. To maintain viability and functionality of these flaps, they must be properly vascularized and innervated. Tissue-engineered muscles could potentially replace autologous muscle tissue, but still require establishment of sufficient innervation to ensure functionality. In this study, we explored the possibility of innervating engineered muscle grafts transplanted to an abdominal wall defect in mice, by transferring the native femoral nerve to the graft. Six weeks posttransplantation, nerve conduction studies and electromyography demonstrated increased innervation in engineered grafts neurotized with the femoral nerve, as compared to non-neurotized grafts. Histologic assessments revealed axonal penetration and formation of neuromuscular junctions within the grafts. The innervation process described here may advance the fabrication of a fully functional engineered muscle graft that will be of utility in clinical settings.
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Músculo Esquelético/inervação , Músculo Esquelético/transplante , Doenças Musculares/cirurgia , Regeneração Nervosa , Engenharia Tecidual/métodos , Alicerces Teciduais , Animais , Axônios/fisiologia , Linhagem Celular , Eletromiografia , Fibroblastos/citologia , Proteínas de Fluorescência Verde/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Nus , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
BACKGROUND: Low heart rate variability (HRV) was found in various medical conditions including heart failure and acute myocardial infarction. Decreased HRV in these conditions predicted poor prognosis. METHODS: HRV was estimated in 133 unselected inpatients with relevant clinical bedside conditions by non-linear analysis derived from chaos theory, which calculates the correlation dimension (CD) of the cardiac electrophysiologic system (HRV-CD). RESULTS: Mean HRV-CD in the entire group was 3.75+/-0.45. Heart failure, coronary artery disease, cardiac arrhythmia, low serum potassium, renal dysfunction, and diabetes mellitus were significantly associated with reduced HRV-CD compared to their counterparts [3.6 vs. 3.9 (P<.001), 3.65 vs. 3.87 (P=.005), 3.58 vs. 3.8 (P=.01), 3.38 vs. 3.81 (P=.02), 3.59 vs. 3.8 (P=.04), and 3.66 vs. 3.82 (P=.04), respectively]. Stepwise logistic regression showed heart failure to be the condition most significantly associated with low HRV-CD (odds ratio 4.2, 95% confidence interval 1.90-9.28, P<.001). In the entire group, decreased HRV-CD (< or =3.75 vs. >3.75) was associated with lower survival (P=.01). Mortality of diabetic patients with HRV-CD < or =3.75 exceeded the mortality in patients with HRV-CD >3.75 (P=.02). Heart failure, renal dysfunction or age over 70 combined with HRV-CD < or =3.75 also appeared to be associated with augmented mortality. CONCLUSIONS: Diminished HRV-CD is associated with heart failure, coronary artery disease, cardiac arrhythmia, renal dysfunction, diabetes mellitus and low serum potassium. Among the latter, heart failure is most significantly associated with decreased HRV-CD. Decreased HRV-CD values, especially in diabetics, are also associated with lower survival.