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1.
Cell ; 162(6): 1418-30, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26359992

RESUMO

Progressive depletion of midbrain dopamine neurons (PDD) is associated with deficits in the initiation, speed, and fluidity of voluntary movement. Models of basal ganglia function focus on initiation deficits; however, it is unclear how they account for deficits in the speed or amplitude of movement (vigor). Using an effort-based operant conditioning task for head-fixed mice, we discovered distinct functional classes of neurons in the dorsal striatum that represent movement vigor. Mice with PDD exhibited a progressive reduction in vigor, along with a selective impairment of its neural representation in striatum. Restoration of dopaminergic tone with a synthetic precursor ameliorated deficits in movement vigor and its neural representation, while suppression of striatal activity during movement was sufficient to reduce vigor. Thus, dopaminergic input to the dorsal striatum is indispensable for the emergence of striatal activity that mediates adaptive changes in movement vigor. These results suggest refined intervention strategies for Parkinson's disease.


Assuntos
Dopamina/metabolismo , Mesencéfalo/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Animais , Gânglios da Base/metabolismo , Modelos Animais de Doenças , Hipocinesia/metabolismo , Hipocinesia/fisiopatologia , Camundongos , Músculo Esquelético/fisiologia
2.
Nat Methods ; 20(6): 935-944, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37169928

RESUMO

Learning is thought to involve changes in glutamate receptors at synapses, submicron structures that mediate communication between neurons in the central nervous system. Due to their small size and high density, synapses are difficult to resolve in vivo, limiting our ability to directly relate receptor dynamics to animal behavior. Here we developed a combination of computational and biological methods to overcome these challenges. First, we trained a deep-learning image-restoration algorithm that combines the advantages of ex vivo super-resolution and in vivo imaging modalities to overcome limitations specific to each optical system. When applied to in vivo images from transgenic mice expressing fluorescently labeled glutamate receptors, this restoration algorithm super-resolved synapses, enabling the tracking of behavior-associated synaptic plasticity with high spatial resolution. This method demonstrates the capabilities of image enhancement to learn from ex vivo data and imaging techniques to improve in vivo imaging resolution.


Assuntos
Neurônios , Sinapses , Camundongos , Animais , Sinapses/fisiologia , Aumento da Imagem , Camundongos Transgênicos , Plasticidade Neuronal
3.
Proc Natl Acad Sci U S A ; 120(23): e2301118120, 2023 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-37252984

RESUMO

For organic photovoltaic (OPV) devices to achieve consistent performance and long operational lifetimes, organic semiconductors must be processed with precise control over their purity, composition, and structure. This is particularly important for high volume solar cell manufacturing where control of materials quality has a direct impact on yield and cost. Ternary-blend OPVs containing two acceptor-donor-acceptor (A-D-A)-type nonfullerene acceptors (NFAs) and a donor have proven to be an effective strategy to improve solar spectral coverage and reduce energy losses beyond that of binary-blend OPVs. Here, we show that the purity of such a ternary is compromised during blending to form a homogeneously mixed bulk heterojunction thin film. We find that the impurities originate from end-capping C=C/C=C exchange reactions of A-D-A-type NFAs, and that their presence influences both device reproducibility and long-term reliability. The end-capping exchange results in generation of up to four impurity constituents with strong dipolar character that interfere with the photoinduced charge transfer process, leading to reduced charge generation efficiency, morphological instabilities, and an increased vulnerability to photodegradation. As a consequence, the OPV efficiency falls to less than 65% of its initial value within 265 h when exposed to up to 10 suns intensity illumination. We propose potential molecular design strategies critical to enhancing the reproducibility as well as reliability of ternary OPVs by avoiding end-capping reactions.

4.
Artigo em Inglês | MEDLINE | ID: mdl-39212768

RESUMO

Systemic inflammation is reported in normal-weight obesity (NWO) and metabolically healthy obesity (MHO), which may be linked to their increased cardiovascular disease (CVD) risk. Yet, drivers of this inflammation remain unclear. We characterized factors known to influence inflammatory status (i.e., intestinal permeability, adipose tissue, diet quality, microbiota) - and their relationships with measured inflammation - in NWO and MHO, healthy controls (CON) and metabolically unhealthy obesity (MUO; N=80; n=20/group). Serum indicators of intestinal permeability and inflammation were assessed using ELISA and/or multiplex. Total, visceral, and percent body fat were measured with dual-energy X-ray absorptiometry (DXA). Fecal microbiota composition was assessed via 16S rRNA sequencing (n=9-10/group). For C-reactive protein (CRP), MUO > NWO > CON (p<0.0001). In MHO, CRP was intermediate - and similar to - both MUO and NWO. Lipopolysaccharide binding protein (LBP) and the ratio of LBP to soluble CD14 (sCD14) were higher in MHO and MUO versus CON/NWO (p's<0.0001). Across correlation and regression analyses, LBP consistently displayed the strongest relationships with CRP in the entire sample (r=0.78;ß = 0.57;p's<0.0001) and in MHO (r=0.74;p<0.01), but not NWO (r=0.37;p = 0.11). Shannon index was higher in CON compared to MUO (p<0.05) and inversely correlated with CRP in the full sample (r=-0.37;p<0.05). These data are consistent with the notion that intestinal permeability is associated with low-grade inflammation in MHO, which could be implicated in this population's reported CVD risk.

5.
Cancer Causes Control ; 35(6): 955-961, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38388859

RESUMO

PURPOSE: Metastatic breast cancer (MBC) patients often face substantial financial burden due to prolonged and expensive therapy. However, in-depth experiences of financial burden among MBC patients are not well understood. METHODS: Qualitative interviews were conducted to describe the experiences of financial burden for MBC patients, focusing on the drivers of financial burden, their experience using their health insurance, accessing financial assistance, and any resulting cost-coping behaviors. Interviews were transcribed and qualitatively analyzed using a descriptive phenomenological approach to thematic analysis. RESULTS: A total of n = 11 MBC patients or caregiver representatives participated in the study. MBC patients were on average 50.2 years of age (range: 28-65) and 72.7% non-Hispanic White. MBC patients were diagnosed as metastatic an average of 3.1 years (range: 1-9) before participating in the study. Qualitative analysis resulted in four themes including (1) causes of financial burden, (2) financial assistance mechanisms, (3) health insurance and financial burden, and (4) cost-coping behaviors. Both medical and non-medical costs drove financial burden among participants. All participants reported challenges navigating their health insurance and applying for financial assistance. Regardless of gaining access to assistance, financial burden persisted for nearly all patients and resulted in cost-coping behaviors. CONCLUSION: Our findings suggest that current systems for health insurance and financial assistance are complex and difficult to meet patient needs. Even when MBC patients accessed assistance, excess financial burden persisted necessitating use of financial coping-behaviors such as altering medication use, maintaining employment, and taking on debt.


Assuntos
Adaptação Psicológica , Neoplasias da Mama , Efeitos Psicossociais da Doença , Seguro Saúde , Pesquisa Qualitativa , Humanos , Feminino , Pessoa de Meia-Idade , Adulto , Neoplasias da Mama/economia , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Seguro Saúde/economia , Idoso , Metástase Neoplásica , Capacidades de Enfrentamento
6.
Cancer Causes Control ; 35(9): 1297-1309, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38796675

RESUMO

The National Comprehensive Cancer Control Program, a Centers for Disease Control and Prevention funded program, supports cancer coalitions across the United States (US) in efforts to prevent and control cancer including development of comprehensive cancer control (CCC) plans. CCC plans often focus health equity within their priorities, but it is unclear to what extent lesbian, gay, bisexual, transgender, queer/questioning, plus (LGBTQ+) populations are considered in CCC plans. We qualitatively examined to what extent LGBTQ+ populations were referenced in 64 U.S. state, jurisdiction, tribes, and tribal organization CCC plans. A total of 55% of CCC plans mentioned LGBTQ+ populations, however, only one in three CCC plans mentioned any kind of LGBTQ+ inequity or LGBTQ+ specific recommendations. Even fewer plans included mention of LGBTQ+ specific resources, organizations, or citations. At the same time almost three fourths of plans conflated sex and gender throughout their CCC plans. The findings of this study highlight the lack of prioritization of LGBTQ+ populations in CCC plans broadly while highlighting exemplar plans that can serve as a roadmap to more inclusive future CCC plans. Comprehensive cancer control plans can serve as a key policy and advocacy structure to promote a focus on LGBTQ+ cancer prevention and control.


Assuntos
Neoplasias , Minorias Sexuais e de Gênero , Humanos , Estados Unidos/epidemiologia , Neoplasias/prevenção & controle , Neoplasias/epidemiologia , Masculino , Feminino , Pesquisa Qualitativa
7.
Oncology ; 102(7): 621-630, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38160661

RESUMO

INTRODUCTION: Grade 3 solitary fibrous tumor, previously known as anaplastic hemangiopericytoma, is a rare and highly malignant intracranial tumor with a limited understanding of its natural history and treatment outcomes. METHODS: We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database spanning 2000-2019 to evaluate the clinical characteristics and treatment modalities that influence overall survival in this tumor entity. A cohort of 249 patients with intracranial grade 3 solitary fibrous tumors was identified. Univariate and multivariable Cox proportional hazard models were employed to determine significant prognostic factors for overall survival. Kaplan-Meier models were used to visualize survival curves, and a nomogram was constructed to predict survival probabilities at 6- and 12-month following diagnosis. RESULTS: Our findings indicated that patient age (<65 years), localized or regional disease burden, surgical resection, and radiation therapy were significant predictors of better overall survival. Combination therapies showed improved survival, with surgery and radiation therapy having the most significant impact. However, chemotherapy alone or in combination did not demonstrate a significant survival benefit, likely due to the limited sample size. The nomogram provided personalized prognostic predictions based on significant clinical factors. CONCLUSIONS: These data emphasize the importance of surgical resection and radiation therapy in the management of grade 3 solitary fibrous tumors, supporting the use of combination therapies to improve overall survival in this rare and aggressive intracranial neoplasm.


Assuntos
Hemangiopericitoma , Programa de SEER , Tumores Fibrosos Solitários , Humanos , Estudos Retrospectivos , Masculino , Feminino , Tumores Fibrosos Solitários/terapia , Tumores Fibrosos Solitários/mortalidade , Tumores Fibrosos Solitários/patologia , Tumores Fibrosos Solitários/epidemiologia , Pessoa de Meia-Idade , Hemangiopericitoma/terapia , Hemangiopericitoma/mortalidade , Hemangiopericitoma/patologia , Hemangiopericitoma/epidemiologia , Idoso , Prognóstico , Adulto , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/epidemiologia , Nomogramas , Gradação de Tumores , Estimativa de Kaplan-Meier , Adulto Jovem , Idoso de 80 Anos ou mais , Terapia Combinada
8.
PLoS Comput Biol ; 19(6): e1010684, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37307282

RESUMO

The Ross-Macdonald model has exerted enormous influence over the study of malaria transmission dynamics and control, but it lacked features to describe parasite dispersal, travel, and other important aspects of heterogeneous transmission. Here, we present a patch-based differential equation modeling framework that extends the Ross-Macdonald model with sufficient skill and complexity to support planning, monitoring and evaluation for Plasmodium falciparum malaria control. We designed a generic interface for building structured, spatial models of malaria transmission based on a new algorithm for mosquito blood feeding. We developed new algorithms to simulate adult mosquito demography, dispersal, and egg laying in response to resource availability. The core dynamical components describing mosquito ecology and malaria transmission were decomposed, redesigned and reassembled into a modular framework. Structural elements in the framework-human population strata, patches, and aquatic habitats-interact through a flexible design that facilitates construction of ensembles of models with scalable complexity to support robust analytics for malaria policy and adaptive malaria control. We propose updated definitions for the human biting rate and entomological inoculation rates. We present new formulas to describe parasite dispersal and spatial dynamics under steady state conditions, including the human biting rates, parasite dispersal, the "vectorial capacity matrix," a human transmitting capacity distribution matrix, and threshold conditions. An [Formula: see text] package that implements the framework, solves the differential equations, and computes spatial metrics for models developed in this framework has been developed. Development of the model and metrics have focused on malaria, but since the framework is modular, the same ideas and software can be applied to other mosquito-borne pathogen systems.


Assuntos
Culicidae , Malária Falciparum , Malária , Adulto , Animais , Humanos , Malária/epidemiologia , Culicidae/fisiologia , Ecologia , Ecossistema
9.
Analyst ; 149(13): 3564-3574, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38717518

RESUMO

Field-forward analytical technologies, such as portable mass spectrometry (MS), enable essential capabilities for real-time monitoring and point-of-care diagnostic applications. Significant and recent investments improving the features of miniaturized mass spectrometers enable various new applications outside of small molecule detection. Most notably, the addition of tandem mass spectrometry scans (MS/MS) allows the instrument to isolate and fragment ions and increase the analytical specificity by measuring unique chemical signatures for ions of interest. Notwithstanding these technological advancements, low-cost, portable systems still struggle to confidently identify clinically significant organisms of interest, such as bacteria, viruses, and proteinaceous toxins, due to the limitations in resolving power. To overcome these limitations, we developed a novel multidimensional mass fingerprinting technique that uses tandem mass spectrometry to increase the chemical specificity for low-resolution mass spectral profiles. We demonstrated the method's capabilities for differentiating four different bacteria, including attentuated strains of Yersinia pestis. This approach allowed for the accurate (>92%) identification of each organism at the strain level using de-resolved matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) data to mimic the performance characteristics of miniaturized mass spectrometers. This work demonstrates that low-resolution mass spectrometers, equipped with tandem MS acquisition modes, can accurately identify clinically relevant bacteria. These findings support the future application of these technologies for field-forward and point-of-care applications where high-performance mass spectrometers would be cost-prohibitive or otherwise impractical.


Assuntos
Espectrometria de Massas em Tandem , Yersinia pestis , Yersinia pestis/isolamento & purificação , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação , Bactérias/isolamento & purificação
10.
Pediatr Blood Cancer ; 71(2): e30790, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38053241

RESUMO

It is unknown how common job lock (i.e., staying at job to maintain health insurance) remains among childhood cancer survivors after Affordable Care Act (ACA) implementation in 2010. We examined prevalence of and factors associated with job lock using a cross-sectional survey from the Childhood Cancer Survivor Study (3503 survivors; 942 siblings). Survivor, spousal, and any survivor/spouse job lock were more frequently reported by survivors than siblings. Survivor job lock/any job lock was associated with older age, low income, severe chronic conditions, and debt/inability to pay debt. Job lock remains more common among survivors than siblings after ACA implementation.


Assuntos
Sobreviventes de Câncer , Neoplasias , Estados Unidos/epidemiologia , Humanos , Criança , Neoplasias/epidemiologia , Patient Protection and Affordable Care Act , Estudos Transversais , Cônjuges , Sobreviventes , Irmãos
11.
AJR Am J Roentgenol ; : 1-11, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-38117098

RESUMO

PET/CT using 16α-[18F]-fluoro-17ß-estradiol (FES) noninvasively images tissues expressing estrogen receptors (ERs). FES has undergone extensive clinicopathologic validation for ER-positive breast cancer and in 2020 received FDA approval for clinical use as an adjunct to biopsy in patients with recurrent or metastatic ER-positive breast cancer. Clinical use of FES PET/CT is increasing but is not widespread in the United States. This AJR Expert Panel Narrative Review explores the present status and future directions of FES PET/CT, including image interpretation, existing and emerging uses, knowledge gaps, and current controversies. Specific controversies discussed include whether both FES PET/CT and FDG PET/CT are warranted in certain scenarios, whether further workup is required after negative FES PET/CT results, whether FES PET/CT findings should inform endocrine therapy selection, and whether immunohistochemistry should remain the stand-alone reference standard for determining ER status for all breast cancers. Consensus opinions from the panel include agreement with the appropriate clinical uses of FES PET/CT published by a multidisciplinary expert work group in 2023, anticipated expanded clinical use of FES PET/CT for staging ER-positive invasive lobular carcinomas and low-grade invasive ductal carcinomas pending ongoing clinical trial results, and the need for further research regarding the use of FES PET/CT for nonbreast malignancies expressing ER.

12.
Org Biomol Chem ; 22(33): 6791-6798, 2024 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-39105610

RESUMO

The development of sustainable routes to organic building blocks is a critical endeavor for reducing the environmental impact of chemical synthesis. Biocatalysts are poised to play an important role in sustainable synthesis, as they perform highly selective reactions under mild conditions. The application of enzymes to organic synthesis requires an approach which is operationally simple, inexpensive to prepare, and reasonably scalable. In this work, we demonstrated the utility of a Type I ring-cleaving dioxygenase CatA (P. putida KT2440) for preparative-scale synthesis of muconic acid derivatives. Muconic acids are important precursors in the synthesis of polymers and commodity chemicals. In this work, we optimized the performance of CatA under millimolar substrate concentrations and characterized the activity of the enzyme with an array of catechol substrates. Furthermore, we developed a scalable platform using cellular lysates to produce diverse muconic acids, generating up to a gram of the desired product. A simple trituration procedure was utilized for the purification of these muconic acids that obviated the need for chromatographic purification and reduced overall solvent waste.


Assuntos
Biocatálise , Ácido Sórbico , Ácido Sórbico/análogos & derivados , Ácido Sórbico/metabolismo , Ácido Sórbico/química , Ácido Sórbico/síntese química , Pseudomonas putida/enzimologia , Pseudomonas putida/metabolismo , Dioxigenases/metabolismo , Estrutura Molecular
13.
Ann Pharmacother ; 58(1): 54-64, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37119212

RESUMO

OBJECTIVE: The objective of this study was to review the available literature for dexmedetomidine sublingual film use in the treatment of acute agitation associated with schizophrenia and bipolar disorders. DATA SOURCES: A literature search of PubMed (January 2017-March 2023) and EMBASE (January 2017-March 2023) was performed using the terms: Igalmi, dexmedetomidine, schizophrenia, bipolar disorder, and agitation. Additional information sources include ClinicalTrials.gov, scientific posters, and articles identified through review of references from clinical trials publications. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language articles conducted in humans were considered, with a preference for phase 3 clinical trials. Trial analyses and articles discussing pharmacology, pharmacokinetics, efficacy, and safety were also evaluated. DATA SYNTHESIS: Dexmedetomidine sublingual film was evaluated for use in schizophrenia in the SERENITY 1 pivotal trial and for bipolar disorders in the SERENITY 2 pivotal trial. Both studies found treatment of mild to moderate agitation with dexmedetomidine sublingual film 180 and 120 µg to be superior to placebo in reducing the severity of agitation. Treatment effect was seen as early as 20 minutes. Somnolence was the most common adverse effect in both studies. Cardiovascular adverse effects were mild and transient in most cases. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Dexmedetomidine sublingual film is a new and novel treatment for agitation and gives clinicians an alternative to antipsychotic and benzodiazepine use. It has advantageous properties including its noninvasive route of administration, fast absorption, and rapid onset of effect. Cost may limit its use. CONCLUSION: Dexmedetomidine sublingual film provides an alternative approach to treatment of acute agitation in adults with schizophrenia and bipolar disorders based on both mechanism of action and route of administration.


Assuntos
Antipsicóticos , Transtorno Bipolar , Dexmedetomidina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Esquizofrenia , Adulto , Humanos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Transtorno Bipolar/complicações , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/induzido quimicamente , Dexmedetomidina/efeitos adversos , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/etiologia , Antipsicóticos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações
14.
Nutr Metab Cardiovasc Dis ; 34(1): 121-125, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37788958

RESUMO

BACKGROUND & AIMS: Elevated postprandial triglycerides are an independent cardiovascular disease risk factor and observed in older adults. However, differences in postprandial triglycerides across the spectrum of adulthood remain unclear. METHODS AND RESULTS: We performed a secondary analysis of six studies where adults (aged 18-84 years; N = 155) completed an abbreviated fat tolerance test (9 kcal/kg; 70% fat). Differences in postprandial triglycerides were compared in those ≥50 and <50 years and by decade of life, adjusting for sex and BMI. Compared to those <50 years, participants ≥50 years had higher fasting, 4 h, and Δ triglycerides from baseline (p's < 0.05). When examining triglyceride parameters by decade, no differences were observed for fasting triglycerides, but 50 s, 60 s, and 70s-80 s displayed greater 4 h and Δ triglycerides versus 20 s (p's ≤ 0.001). The frequency of adverse postprandial triglyceride responses (i.e., ≥220 mg/dL) was higher in participants ≥50 versus <50 years (p < 0.01), and in 60 s compared to all other decades (p = 0.01). CONCLUSION: Older age was generally associated with higher postprandial triglycerides, with no divergence across the spectrum of older adulthood. In our sample, postprandial triglyceride differences in older and younger adults were driven by those >50 years relative to young adults in their 20 s. REGISTRATION: N/A (secondary analysis).


Assuntos
Hipertrigliceridemia , Adulto , Idoso , Humanos , Adulto Jovem , Envelhecimento , Jejum , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/epidemiologia , Período Pós-Prandial/fisiologia , Triglicerídeos , Pessoa de Meia-Idade
15.
Mol Ther ; 31(7): 1979-1993, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37012705

RESUMO

Success in the treatment of infants with spinal muscular atrophy (SMA) underscores the potential of vectors based on adeno-associated virus (AAV). However, a major obstacle to the full realization of this potential is pre-existing natural and therapy-induced anti-capsid humoral immunity. Structure-guided capsid engineering is one possible approach to surmounting this challenge but necessitates an understanding of capsid-antibody interactions at high molecular resolution. Currently, only mouse-derived monoclonal antibodies (mAbs) are available to structurally map these interactions, which presupposes that mouse and human-derived antibodies are functionally equivalent. In this study, we have characterized the polyclonal antibody responses of infants following AAV9-mediated gene therapy for SMA and recovered 35 anti-capsid mAbs from the abundance of switched-memory B (smB) cells present in these infants. For 21 of these mAbs, seven from each of three infants, we have undertaken functional and structural analysis measuring neutralization, affinities, and binding patterns by cryoelectron microscopy (cryo-EM). Four distinct patterns were observed akin to those reported for mouse-derived mAbs, but with early evidence of differing binding pattern preference and underlying molecular interactions. This is the first human and largest series of anti-capsid mAbs to have been comprehensively characterized and will prove to be powerful tools for basic discovery and applied purposes.


Assuntos
Anticorpos Monoclonais , Capsídeo , Lactente , Humanos , Animais , Camundongos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/genética , Microscopia Crioeletrônica , Capsídeo/química , Proteínas do Capsídeo/química , Dependovirus , Terapia Genética , Vetores Genéticos/genética
16.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34620713

RESUMO

In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive, in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to skin injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to reveal potential mechanisms controlling fibroblast fate during migration, proliferation, and differentiation following skin injury, and thereby reexamine the canonical phases of wound healing. These findings have broad implications for the study of tissue repair in complex organ systems.


Assuntos
Cicatriz/patologia , Fibroblastos/metabolismo , Fibrose/patologia , Pele/lesões , Cicatrização/fisiologia , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Matriz Extracelular/metabolismo , Feminino , Mecanotransdução Celular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/metabolismo
17.
J Med Internet Res ; 26: e50205, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38780994

RESUMO

BACKGROUND: Telehealth (telemedicine and telepharmacy) services increase access to patient services and ensure continuity of care. However, few studies have assessed factors that influence patients' willingness to use telehealth services, and we sought to investigate this. OBJECTIVE: This study aims to examine respondents' (aged between 45 and 75 years) willingness to use telehealth services (telepharmacy and telemedicine) and the correlates of the willingness to use telehealth services. METHODS: We administered a cross-sectional national survey of 1045 noninstitutionalized US adults aged between 45 and 75 years in March and April 2021. Multiple logistic regression analyses were used to identify demographic and health service use correlates of self-reported willingness to use telehealth services. RESULTS: Overall willingness to use telemedicine was high (674/1045, 64.5%). Adults aged 55 years and older were less willing to use telemedicine (aged between 55 and 64 years: odds ratio [OR] 0.61, 95% CI 0.42-0.86; aged 65 years or older: OR 0.33, 95% CI 0.22-0.49) than those younger than 55 years. Those with a regular provider (OR 1.01, 95% CI 1-1.02) and long travel times (OR 1.75, 95% CI 1.03-2.98) were more willing to use telemedicine compared to those without a regular provider and had shorter travel times, respectively. Willingness to use telemedicine services increased from 64.5% (674/1045) to 83% (867/1045) if the service was low-cost or insurance-covered, was with their existing health care provider, or was easy-to-use. Overall willingness to use telepharmacy was 76.7% (801/1045). Adults aged older than 55 years were less willing to use telepharmacy (aged between 55 and 64 years: OR 0.57, 95% CI 0.38-0.86; aged 65 years or older: OR 0.24, 95% CI 0.15-0.37) than those younger than 55 years. Those who rated pharmacy service quality higher were more willing to use telepharmacy (OR 1.06, 95% CI 1.03-1.09) than those who did not. CONCLUSIONS: Respondents were generally willing to use telehealth (telemedicine and telepharmacy) services, but the likelihood of their being willing to use telehealth decreased as they were older. For those initially unwilling (aged 55 years or older) to use telemedicine services, inexpensive or insurance-covered services were acceptable.


Assuntos
Telemedicina , Humanos , Telemedicina/estatística & dados numéricos , Estudos Transversais , Pessoa de Meia-Idade , Idoso , Masculino , Feminino , Estados Unidos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Inquéritos e Questionários
18.
J Am Pharm Assoc (2003) ; : 102130, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38796158

RESUMO

BACKGROUND: Colorectal cancer (CRC) screening can reduce CRC morbidity and mortality. Community pharmacies could be a viable option for delivering home-based CRC screening tests such as fecal immunochemical tests (FITs). However, little is known about community pharmacists' knowledge about CRC screening guidelines. OBJECTIVE: We assessed community pharmacists' knowledge about CRC screening to identify education and training needs for a pharmacy-based CRC screening program. METHODS: Between September 2022 and January 2023, we conducted an online national survey of community pharmacists practicing in the United States. Responders were eligible if they were currently-licensed community pharmacists and currently practiced in the United States. The survey assessed knowledge of national CRC screening guidelines, including recommended starting age, frequency of screening, different screening modalities, and follow-up care. Using multiple linear regression, we evaluated correlates of community pharmacists' level of CRC screening knowledge, defined as the total number of knowledge questions answered correctly from "0" (no questions correct) to "5" (all questions correct). RESULTS: A total of 578 eligible community pharmacists completed the survey, with a response rate of 59%. Most community pharmacists correctly answered the question about the next steps following a positive FIT (87%) and the question about where a FIT can be done (84%). A minority of community pharmacists responded correctly to questions about the age to start screening with FIT (34%) and how often a FIT should be repeated (28%). Only 5% of pharmacists answered all knowledge questions correctly. Community pharmacists answered more CRC screening knowledge questions correctly as their years in practice increased. Board-certified community pharmacists answered more CRC screening knowledge questions correctly compared to those who were not board-certified. CONCLUSION: To ensure the successful implementation of a pharmacy-based CRC screening program, community pharmacists need to be educated about CRC screening and trained to ensure comprehensive patient counseling and preventive service delivery.

19.
Artigo em Inglês | MEDLINE | ID: mdl-38695818

RESUMO

OBJECTIVES: The proliferation of social media has resulted in negative consequences such as fear of missing out (FoMO), the anxious feelings one has when others are having rewarding experiences. Few studies have assessed FoMO in Latinx emerging adult college students, none utilizing the socioecological framework. This study assessed the relationships between FoMO and psychological and sociocultural risk and protective factors. METHOD: Latinx college students (n = 452; Mage = 19.97 years, SD = 1.89; 77.2% female) completed an online survey assessing demographics, FoMO, social media addiction, depression, anxiety, stress, Machiavellianism, narcissism, psychopathy, familism, and acculturation. Two multiple linear regressions assessed the associations between FoMO and psychological and sociocultural factors. RESULTS: Both regressions were statistically significant. First, FoMO was positively associated with social media addiction, depression, and Machiavellianism. Second, FoMO was positively associated with familial honor and negatively associated with familial interconnectedness and ethnic social relations. CONCLUSIONS: Associations between FoMO and psychological factors are consistent with past literature, yet they highlight the need for prospective studies to assess temporality. The fact that FoMO was related uniquely to familistic attitudes suggests the importance of family in FoMO perceptions and the need to assess these associations in a more nuanced manner. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

20.
Semin Cancer Biol ; 81: 145-159, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33276091

RESUMO

Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.


Assuntos
Neoplasias , Poliploidia , Núcleo Celular , Cromatina/genética , Genoma , Humanos , Neoplasias/genética , Neoplasias/terapia
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