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BACKGROUND: Many adults aged 60 years or older have functional limitations and require home and community-based services (HCBS) to support their independence and delay the transition to an institutionalized setting. This systematic review provides an evidence map of the existing literature on HCBS identifying evidence gaps for policy and research. METHODS: A comprehensive literature search of multiple databases including Medline, Embase, and Scopus was conducted through December 7, 2023. Interviews with various stakeholders were conducted to solicit additional perspectives. Narrative and thematic synthesis was conducted to evaluate HCBS in terms of populations, interventions, outcomes, person-centeredness, and relevant quality measures. RESULTS: We identified 27 primary studies and 29 quality measures. Populations of HCBS studies can be categorized as those with functional disability, cognitive impairment, high-risk/frail conditions, and disease-specific conditions (Parkinson's disease, Alzheimer's disease, and post-stroke). HCBS interventions targeted optimization of person-centered planning, nonpharmacological approaches for dementia care, physical rehabilitation, self-directed home care, geriatric resources for practical support at home, and interdisciplinary care coordination for high-risk conditions. Person-centered planning and self-direction of HCBS services were not explicitly described in many studies and very few studies focused on addressing health-related social needs, whereas the majority reported primary clinical outcomes. Numerous quality measures exist for HCBS, some of which were validated, addressed multiple person-centered domains, and may apply across various conditions and populations. Key challenges in the literature on HCBS include limited number of randomized trials, inadequate descriptions of interventions to determine person-centeredness, limited information on facilitators and barriers, and limited information on workforce challenges in recruiting, retaining, and training personnel delivering HCBS. DISCUSSION: This evidence map describes the current state of HCBS and identifies evidence gaps for future research and policy decisions.
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This corrects the article DOI: 10.1038/nature22991.
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Osteogenesis imperfecta (OI) is an extracellular matrix disorder characterized by defects in collagen-1 transport or synthesis, resulting in bone abnormalities. Although reduced collagen in OI hearts has been associated with reduced myocardial stiffness and left ventricular remodeling, its impact on cardiomyocyte (CM) function has not been studied. Here, we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI type I. Proteomics and histology confirmed strikingly low expression of collagen 1. Trabecular stretch confirmed low stiffness on the tissue level. However, CMs retained normal viscoelastic properties as revealed by nanoindentation. Interestingly, OI CMs were hypercontractile relative to nonfailing controls after 24 h of culture. In response to 48 h of culture on surfaces with physiological (10 kPa) and pathological (50 kPa) stiffness, OI CMs demonstrated a greater reduction in contractility than nonfailing CMs, suggesting that OI CMs may have an impaired stress response. Levels of detyrosinated α-tubulin, known to be responsive to extracellular stiffness, were reduced in OI CMs. Together these data confirm multiple CM-level adaptations to low stiffness that extend our understanding of OI in the heart and how CMs respond to extracellular stiffness.NEW & NOTEWORTHY In a rare donation of a heart from an individual with osteogenesis imperfecta (OI), we explored cardiomyocyte (CM) adaptations to low stiffness. This represents the first assessment of cardiomyocyte mechanics in OI. The data reveal the hypercontractility of OI CMs with rapid rundown when exposed to acute stiffness challenges, extending our understanding of OI. These data demonstrate that the impact of OI on myocardial mechanics includes cardiomyocyte adaptations beyond known direct effects on the extracellular matrix.
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Osteogênese Imperfeita , Humanos , Adulto , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Miócitos Cardíacos/metabolismo , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , OsteogêneseRESUMO
Background The World Health Organization (WHO) recommends chest radiography to facilitate tuberculosis (TB) screening. However, chest radiograph interpretation expertise remains limited in many regions. Purpose To develop a deep learning system (DLS) to detect active pulmonary TB on chest radiographs and compare its performance to that of radiologists. Materials and Methods A DLS was trained and tested using retrospective chest radiographs (acquired between 1996 and 2020) from 10 countries. To improve generalization, large-scale chest radiograph pretraining, attention pooling, and semisupervised learning ("noisy-student") were incorporated. The DLS was evaluated in a four-country test set (China, India, the United States, and Zambia) and in a mining population in South Africa, with positive TB confirmed with microbiological tests or nucleic acid amplification testing (NAAT). The performance of the DLS was compared with that of 14 radiologists. The authors studied the efficacy of the DLS compared with that of nine radiologists using the Obuchowski-Rockette-Hillis procedure. Given WHO targets of 90% sensitivity and 70% specificity, the operating point of the DLS (0.45) was prespecified to favor sensitivity. Results A total of 165 754 images in 22 284 subjects (mean age, 45 years; 21% female) were used for model development and testing. In the four-country test set (1236 subjects, 17% with active TB), the receiver operating characteristic (ROC) curve of the DLS was higher than those for all nine India-based radiologists, with an area under the ROC curve of 0.89 (95% CI: 0.87, 0.91). Compared with these radiologists, at the prespecified operating point, the DLS sensitivity was higher (88% vs 75%, P < .001) and specificity was noninferior (79% vs 84%, P = .004). Trends were similar within other patient subgroups, in the South Africa data set, and across various TB-specific chest radiograph findings. In simulations, the use of the DLS to identify likely TB-positive chest radiographs for NAAT confirmation reduced the cost by 40%-80% per TB-positive patient detected. Conclusion A deep learning method was found to be noninferior to radiologists for the determination of active tuberculosis on digital chest radiographs. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by van Ginneken in this issue.
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Aprendizado Profundo , Tuberculose Pulmonar , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Radiografia Torácica/métodos , Estudos Retrospectivos , Radiografia , Tuberculose Pulmonar/diagnóstico por imagem , Radiologistas , Sensibilidade e EspecificidadeRESUMO
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
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Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Medicina de Precisão/métodos , Sequência de Aminoácidos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Neoplasias/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/química , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Aprendizado de Máquina , Melanoma/genética , Mutação , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Segurança do Paciente , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
BACKGROUND: Individuals with schizophrenia spectrum disorders have a chronic disease process that is difficult to manage. Medication nonadherence increases the risk for relapse and subsequent rehospitalization. Long-acting injectable (LAI) antipsychotics have greater effectiveness in promoting medication adherence. AIMS: To determine whether text message reminders for LAI antipsychotic administration improve medication adherence. METHODS: The setting is a community mental health clinic in the west Texas region. Reminders deliver upon scheduling the appointment 3 weeks, 3 days, and 3 hr before the medication is due. This project aimed to determine the effectiveness of text reminders for LAI compliance in patients with schizophrenia spectrum disorders. Primary outcome measures include compliance percentage and target day variability. After exclusion criteria, there was a sample size of 49 patients. RESULTS: This pre- and post-intervention study utilized descriptive statistics and nonparametric analysis. Pre-intervention metrics outline 84.39% compliance with 3.55 target day variability. Post-intervention data resulted in a significant increase in compliance percentage to 91.24% (p = .014) and a decrease in target day variability to 1.33 days (p < .05). CONCLUSION: Text message reminders may be an effective intervention in increasing LAI compliance for individuals with schizophrenia spectrum disorders.
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Background Developing deep learning models for radiology requires large data sets and substantial computational resources. Data set size limitations can be further exacerbated by distribution shifts, such as rapid changes in patient populations and standard of care during the COVID-19 pandemic. A common partial mitigation is transfer learning by pretraining a "generic network" on a large nonmedical data set and then fine-tuning on a task-specific radiology data set. Purpose To reduce data set size requirements for chest radiography deep learning models by using an advanced machine learning approach (supervised contrastive [SupCon] learning) to generate chest radiography networks. Materials and Methods SupCon helped generate chest radiography networks from 821 544 chest radiographs from India and the United States. The chest radiography networks were used as a starting point for further machine learning model development for 10 prediction tasks (eg, airspace opacity, fracture, tuberculosis, and COVID-19 outcomes) by using five data sets comprising 684 955 chest radiographs from India, the United States, and China. Three model development setups were tested (linear classifier, nonlinear classifier, and fine-tuning the full network) with different data set sizes from eight to 85. Results Across a majority of tasks, compared with transfer learning from a nonmedical data set, SupCon reduced label requirements up to 688-fold and improved the area under the receiver operating characteristic curve (AUC) at matching data set sizes. At the extreme low-data regimen, training small nonlinear models by using only 45 chest radiographs yielded an AUC of 0.95 (noninferior to radiologist performance) in classifying microbiology-confirmed tuberculosis in external validation. At a more moderate data regimen, training small nonlinear models by using only 528 chest radiographs yielded an AUC of 0.75 in predicting severe COVID-19 outcomes. Conclusion Supervised contrastive learning enabled performance comparable to state-of-the-art deep learning models in multiple clinical tasks by using as few as 45 images and is a promising method for predictive modeling with use of small data sets and for predicting outcomes in shifting patient populations. © RSNA, 2022 Online supplemental material is available for this article.
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COVID-19 , Aprendizado Profundo , Humanos , Radiografia Torácica/métodos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Pandemias , COVID-19/diagnóstico por imagem , Estudos Retrospectivos , Radiografia , Aprendizado de MáquinaRESUMO
RATIONALE: Impaired myocardial relaxation is an intractable feature of several heart failure (HF) causes. In human HF, detyrosinated microtubules stiffen cardiomyocytes and impair relaxation. Yet the identity of detyrosinating enzymes have remained ambiguous, hindering mechanistic study and therapeutic development. OBJECTIVE: We aimed to determine if the recently identified complex of VASH1/2 (vasohibin 1/2) and SVBP (small vasohibin binding protein) is an active detyrosinase in cardiomyocytes and if genetic inhibition of VASH-SVBP is sufficient to lower stiffness and improve contractility in HF. METHODS AND RESULTS: Transcriptional profiling revealed that VASH1 transcript is >10-fold more abundant than VASH2 in human hearts. Using short hairpin RNAs (shRNAs) against VASH1, VASH2, and SVBP, we showed that both VASH1- and VASH2-SVBP complexes function as tubulin carboxypeptidases in cardiomyocytes, with a predominant role for VASH1. We also generated a catalytically dead version of the tyrosinating enzyme TTL (TTL-E331Q) to separate the microtubule depolymerizing effects of TTL from its enzymatic activity. Assays of microtubule stability revealed that both TTL and TTL-E331Q depolymerize microtubules, while VASH1 and SVBP depletion reduce detyrosination independent of depolymerization. We next probed effects on human cardiomyocyte contractility. Contractile kinetics were slowed in HF, with dramatically slowed relaxation in cardiomyocytes from patients with HF with preserved ejection fraction. Knockdown of VASH1 conferred subtle kinetic improvements in nonfailing cardiomyocytes, while markedly improving kinetics in failing cardiomyocytes. Further, TTL, but not TTL-E331Q, robustly sped relaxation. Simultaneous measurements of calcium transients and contractility demonstrated that VASH1 depletion speeds kinetics independent from alterations to calcium cycling. Finally, atomic force microscopy confirmed that VASH1 depletion reduces the stiffness of failing human cardiomyocytes. CONCLUSIONS: VASH-SVBP complexes are active tubulin carboxypeptidases in cardiomyocytes. Inhibition of VASH1 or activation of TTL is sufficient to lower stiffness and speed relaxation in cardiomyocytes from patients with HF, supporting further pursuit of detyrosination as a therapeutic target for diastolic dysfunction.
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Proteínas de Ciclo Celular/metabolismo , Insuficiência Cardíaca/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Células Cultivadas , Células HEK293 , Insuficiência Cardíaca/fisiopatologia , Humanos , Mutação , Miócitos Cardíacos/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Diastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified posttranslationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium. METHODS: Experiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from nonfailing and HF hearts and viscoelasticity was characterized after interventions targeting microtubules. Next, intact left ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and posttreatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains. RESULTS: Viscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared with nonfailing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a 2-fold reduction in energy dissipation upon microtubule depolymerization. Post hoc subgroup analysis revealed that myocardium from patients with HF with reduced ejection fraction were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction, which were relatively more viscous. Colchicine reduced viscoelasticity in both HF with preserved ejection fraction and HF with reduced ejection fraction myocardium. CONCLUSIONS: Failing cardiomyocytes exhibit elevated viscosity and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.
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Insuficiência Cardíaca/patologia , Microtúbulos/fisiologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/ultraestrutura , Adulto , Idoso , Colchicina/farmacologia , Diástole , Elasticidade , Feminino , Humanos , Masculino , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Pessoa de Meia-Idade , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Sesquiterpenos/farmacologia , Estresse Mecânico , Volume Sistólico , Tirosina/metabolismo , Disfunção Ventricular Esquerda/patologia , ViscosidadeRESUMO
Recent studies have highlighted the promise of targeting tumor neoantigens to generate potent antitumor immune responses and provide strong motivation for improving our understanding of antigen-T-cell receptor (TCR) interactions. Advances in single-cell sequencing technologies have opened the door for detailed investigation of the TCR repertoire, providing paired information from TCRα and TCRß, which together determine specificity. However, a need remains for efficient methods to assess the specificity of discovered TCRs. We developed a streamlined approach for matching TCR sequences with cognate antigen through on-demand cloning and expression of TCRs and screening against candidate antigens. Here, we first demonstrate the system's capacity to identify viral-antigen-specific TCRs and compare the functional avidity of TCRs specific for a given antigen target. We then apply this system to identify neoantigen-specific TCR sequences from patients with melanoma treated with personalized neoantigen vaccines and characterize functional avidity of neoantigen-specific TCRs. Furthermore, we use a neoantigen-prediction pipeline to show that an insertion-deletion mutation in a putative chronic lymphocytic leukemia (CLL) driver gives rise to an immunogenic neoantigen mut-MGA, and use this approach to identify the mut-MGA-specific TCR sequence. This approach provides a means to identify and express TCRs, and then rapidly assess antigen specificity and functional avidity of a reconstructed TCR, which can be applied for monitoring antigen-specific T-cell responses, and potentially for guiding the design of effective T-cell-based immunotherapies.
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Antígenos de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Vacinas Anticâncer/uso terapêutico , Células Cultivadas , Clonagem Molecular/métodos , Células HEK293 , Humanos , Células Jurkat , Leucemia Linfocítica Crônica de Células B/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.
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Complemento C1r/genética , Complemento C1s/genética , Síndrome de Ehlers-Danlos/genética , Deleção de Genes , Mutação de Sentido Incorreto , Periodontite/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Síndrome de Ehlers-Danlos/diagnóstico , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Exoma , Feminino , Loci Gênicos , Humanos , Masculino , Linhagem , Periodontite/diagnóstico , Conformação Proteica , Adulto JovemRESUMO
BACKGROUND: Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS: In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS: After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS: In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).
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Doenças da Medula Óssea/tratamento farmacológico , Danazol/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Telômero/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Idoso , Feminino , Cor de Cabelo/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Telomerase/genética , Telomerase/metabolismo , Telômero/ultraestrutura , Regulação para Cima , Adulto JovemRESUMO
In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, ß-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts-consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats.
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Frequência Cardíaca , Coração/embriologia , Animais , Embrião de Galinha , Junções Comunicantes/fisiologia , Modelos Biológicos , Contração Miocárdica , Miócitos Cardíacos/fisiologiaRESUMO
Right ventricular dysfunction (RVD) is associated with end-organ dysfunction and mortality, but has been an overlooked condition in the ICU. We hypothesized that analysis of the arterial waveform in the presence of ventricular extrasystoles could differentiate patients with RVD from patients with a normally functioning right ventricle, because the 2nd and 3rd post-ectopic beat could reflect right ventricular state (pulmonary transit time) during the preceding ectopy. We retrospectively identified patients with echocardiographic evidence of moderate-to-severe RVD and patients with a normal functioning right ventricle (control) from the MIMIC database. We identified waveform records where ECG and arterial pressure were available in combination, simultaneously with echocardiographic evaluation. Ventricular extrasystoles were visually confirmed and the median systolic blood pressure (SBP) of the 2nd and 3rd post-ectopic beats compared with the median SBP of the ten sinus beats preceding the extrasystole. We identified 34 patients in the control group and 24 patients in the RVD group with ventricular extrasystoles. The mean SBP reduction at the 2nd and 3rd beat was lower in the RVD group compared with the control group [- 1.7 (SD: 1.9) % vs. - 3.6 (SD: 1.9) %, p < 0.001], and this characteristic differentiated RVD subjects from control subjects with an AUC of 0.76 (CI [0.64; 0.89]), with a specificity of 91% and sensitivity of 50%. In this proof-of-concept study, we found that post-extrasystolic ABP characteristics were associated with RVD.
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Pressão Arterial , Complexos Cardíacos Prematuros , Ventrículos do Coração , Monitorização Fisiológica/métodos , Sístole , Disfunção Ventricular Direita/diagnóstico , Área Sob a Curva , Pressão Sanguínea , Cuidados Críticos , Ecocardiografia , Hemodinâmica , Humanos , Unidades de Terapia Intensiva , Estudos Retrospectivos , Sensibilidade e Especificidade , Processamento de Sinais Assistido por ComputadorRESUMO
BACKGROUND: Microtubules (MTs) buckle and bear load during myocyte contraction, a behavior enhanced by post-translational detyrosination. This buckling suggests a spring-like resistance against myocyte shortening, which could store energy and aid myocyte relaxation. Despite this visual suggestion of elastic behavior, the precise mechanical contribution of the cardiac MT network remains to be defined. METHODS: Here we experimentally and computationally probe the mechanical contribution of stable MTs and their influence on myocyte function. We use multiple approaches to interrogate viscoelasticity and cell shortening in primary murine myocytes in which either MTs are depolymerized or detyrosination is suppressed and use the results to inform a mathematical model of myocyte viscoelasticity. RESULTS: MT ablation by colchicine concurrently enhances both the degree of shortening and speed of relaxation, a finding inconsistent with simple spring-like MT behavior and suggestive of a viscoelastic mechanism. Axial stretch and transverse indentation confirm that MTs increase myocyte viscoelasticity. Specifically, increasing the rate of strain amplifies the MT contribution to myocyte stiffness. Suppressing MT detyrosination with parthenolide or via overexpression of tubulin tyrosine ligase has mechanical consequences that closely resemble colchicine, suggesting that the mechanical impact of MTs relies on a detyrosination-dependent linkage with the myocyte cytoskeleton. Mathematical modeling affirms that alterations in cell shortening conferred by either MT destabilization or tyrosination can be attributed to internal changes in myocyte viscoelasticity. CONCLUSIONS: The results suggest that the cardiac MT network regulates contractile amplitudes and kinetics by acting as a cytoskeletal shock-absorber, whereby MTs provide breakable cross-links between the sarcomeric and nonsarcomeric cytoskeleton that resist rapid length changes during both shortening and stretch.
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Movimento Celular , Elasticidade , Microtúbulos/metabolismo , Células Musculares/citologia , Animais , Fenômenos Biomecânicos , Modelos Biológicos , Ratos , ViscosidadeRESUMO
OBJECTIVE: The purpose of this project was to achieve sustained improvement in mammographic breast positioning in our department. MATERIALS AND METHODS: Between June 2013 and December 2016, we conducted a team-based performance improvement initiative with the goal of improving mammographic positioning. The team of technologists and radiologists established quantitative measures of positioning performance based on American College of Radiology (ACR) criteria, audited at least 35 mammograms per week for positioning quality, displayed performance in dashboards, provided technologists with positioning training, developed a supportive environment fostering technologist and radiologist communication surrounding mammographic positioning, and employed a mammography positioning coach to develop, improve, and maintain technologist positioning performance. Statistical significance in changes in the percentage of mammograms passing the ACR criteria were evaluated using a two-proportion z test. RESULTS: A baseline mammogram audit performed in June 2013 showed that 67% (82/122) met ACR passing criteria for positioning. Performance improved to 80% (588/739; p < 0.01) after positioning training and technologist and radiologist agreement on positioning criteria. With individual technologist feedback, positioning further improved, with 91% of mammograms passing ACR criteria (p < 0.01). Seven months later, performance temporarily decreased to 80% but improved to 89% with implementation of a positioning coach. The overall mean performance of 91% has been sustained for 23 months. The program cost approximately $30,000 to develop, $42,000 to launch, and $25,000 per year to maintain. Almost all costs were related to personnel time. CONCLUSION: Dedicated performance improvement methods may achieve significant and sustained improvement in mammographic breast positioning, which may better enable facilities to pass the recently instated Enhancing Quality Using the Inspection Program portion of a practice's annual Mammography Quality Standards Act inspections.
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Neoplasias da Mama/diagnóstico por imagem , Mamografia/normas , Programas de Rastreamento/normas , Posicionamento do Paciente , Melhoria de Qualidade , Radiologia/educação , Centros Médicos Acadêmicos , Feminino , Humanos , Capacitação em ServiçoRESUMO
BACKGROUND: Monitoring of glycemic control with hemoglobin A1c (A1c) in hemodialysis patients may be compromised by anemia and erythropoietin therapy. Glycated albumin (GA) is an alternative measure of glycemic control but is not commonly used because of insufficient evidence of association to clinical outcomes. We tested whether GA measurements were associated with mortality in hemodialysis patients with diabetes mellitus. METHODS: The German Diabetes and Dialysis Study (4D) investigated effects of atorvastatin on survival in 1255 patients with diabetes mellitus receiving hemodialysis. We measured GA during months 0, 6, and 12. Cox proportional hazards analysis was used to measure associations between GA and A1c and all-cause mortality. RESULTS: Patients with high baseline GA (fourth quartile) had a 42% higher 4-year mortality compared to those in the first quartile (HR 1.42; 95% CI, 1.09-1.85, P = 0.009). Repeated measurements of GA during year one also demonstrated that individuals in the top quartile for GA (analyzed as a time-varying covariate) had a 39% higher 4-year mortality (HR 1.39; 95% CI, 1.05-1.85, P = 0.022). The associations between high A1c and mortality using similar analyses were less consistent; mortality in individuals with baseline A1c values in the 3rd quartile was increased compared to 1st quartile (HR 1.36; 95% CI, 1.04-1.77, P = 0.023), but risk was not significantly increased in the 2nd or 4th quartiles, and there was a less consistent association between time-varying A1c values and mortality. CONCLUSIONS: High GA measurements are consistently associated with increased mortality in patients with diabetes mellitus on hemodialysis.
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Diabetes Mellitus/sangue , Diabetes Mellitus/terapia , Diálise Renal , Albumina Sérica/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus/mortalidade , Feminino , Produtos Finais de Glicação Avançada , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem , Albumina Sérica GlicadaRESUMO
OBJECTIVES: To determine US societal burden of illness, including direct and indirect costs and annual bleed rate (ABR), for persons with hemophilia B (HB), a rare and debilitating genetic disorder, and to examine associations of hemophilia severity and treatment regimens with costs and ABR. METHODS: From 2009 to 2014, the Hemophilia Utilization Group Studies Part Vb collected prospective data from 10 US hemophilia treatment centers. Participants with HB completed initial surveys on sociodemographic characteristics, clinical characteristics, and treatment patterns. During the 2-year follow-up, participants reported bleeding episodes, work absenteeism, and caregiver time quarterly. These data were used to calculate ABR and indirect costs. Direct costs were calculated using 1-year clinical chart records and 2-year dispensing records. RESULTS: Of the 148 participants, 112 with complete medical records and one or more follow-up survey were included. Total mean annual per-person costs were $85,852 (median $20,160) for mild/moderate HB, $198,733 (median $147,891) for severe HB, and $140,240 (median $63,617) for all participants without inhibitors (P < 0.0001). Mean ABR for participants with severe HB on prophylaxis (5.5 ± 7.9 bleeds/y) was almost half that of those treated episodically. Clotting factor and indirect costs accounted for 85% and 9% of total costs, respectively. Compared with episodic treatment, prophylaxis use was associated with 2.5-fold higher clotting factor costs (P < 0.01), low but significantly more missed parental workdays (P < 0.0001) and clinician (P < 0.001) or nursing visits (P < 0.0001), less part-time employment and unemployment, and lower hospitalizations costs (P = 0.17) and ABR (P < 0.0001). CONCLUSIONS: HB is associated with high economic burden, primarily because of clotting factor costs. Nevertheless, prophylaxis treatment leads to clinical benefits and may reduce other nonfactor costs.
Assuntos
Fatores de Coagulação Sanguínea/administração & dosagem , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde/estatística & dados numéricos , Hemofilia B/terapia , Hemorragia/terapia , Absenteísmo , Adolescente , Adulto , Fatores de Coagulação Sanguínea/economia , Cuidadores/estatística & dados numéricos , Criança , Pré-Escolar , Emprego/estatística & dados numéricos , Feminino , Seguimentos , Hemofilia B/economia , Hemofilia B/fisiopatologia , Hemorragia/economia , Hemorragia/etiologia , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Estados Unidos , Adulto JovemAssuntos
COVID-19 , Adaptação Psicológica , Idoso , Ansiedade , Humanos , Solidão , Saúde Mental , Pandemias , SARS-CoV-2RESUMO
Intimate partner violence (IPV) is a major health concern in the United States (ACOG 2013). The World Health Organization (WHO) describes IPV as any physical, sexual, psychological harm by a current or former intimate partner (WHO 2016). Due to the psychosocial depth and nature of discussions within genetic counseling sessions, patients may disclose and/or discuss IPV as it relates to sexual well-being, reproductive and overall health. This study aims to assess the role for IPV screening, counseling and intervention in genetic counseling practice by investigating the incidence, experiences and attitudes about IPV among genetic counseling patients. Patients receiving genetic counseling at an urban metropolitan hospital were anonymously surveyed about experiences and perspectives on IPV as a topic of discussion during genetic counseling sessions. Among 60 eligible patients, 50 completed the survey (49 females, 1 male, of which, 5 identified as LGBT) ages 20 to 66. The incidence of IPV in this group was 16.0 % (n = 8). Majority of participants had never been asked about IPV by a healthcare provider (n = 32; 64.0%), would have felt comfortable answering questions about IPV by their healthcare provider (n = 34; 68.0%), and would have felt comfortable answering questions about IPV by their genetic counselor (n = 39; 78.0%). Perspectives from all participants, notably those with IPV history, provided insights to the role of genetic counselors in areas for IPV screening and counseling training.