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1.
J Huntingtons Dis ; 10(1): 165-173, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33579859

RESUMO

The use of genome wide association studies (GWAS) in Huntington's disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

3.
Aust J Gen Pract ; 49(9): 568-573, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32864671

RESUMO

BACKGROUND: Mucosal diseases of the oral cavity are relatively common, and patients often seek initial assessment from their general practitioner. OBJECTIVE: The aim of this article is to provide an overview of common oral mucosal diseases to help with formulating a differential diagnosis and stratifying the urgency of referral. DISCUSSION: Pathological mucosal conditions of the oral cavity and jaws commonly present as a mucosal ulcer or a white, red or pigmented lesion. In this review, the authors outline the most common conditions organised according to their clinical presentation and describe their typical appearance and management.

4.
Aust J Gen Pract ; 49(9): 575-580, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32864672

RESUMO

BACKGROUND: Conditions that present as a 'swelling' in the oral cavity are relatively common, and patients may seek initial assessment from their general practitioners. OBJECTIVE: The aim of this article is to provide an overview of common causes of a 'swelling' in the oral cavity to help with formulating a differential diagnosis and stratifying the urgency of referral. DISCUSSION: Pathological conditions in the oral cavity (excluding mucosal presentations) may present as a swelling in the submucosa or jaws, symptoms related to teeth and/or gums or an incidental finding on imaging. In this review, the authors outline the most common submucosal or jaw swellings, organised according to their clinical presentations, and describe their typical appearance and management.

5.
J Cardiovasc Magn Reson ; 22(1): 61, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32878639

RESUMO

The aim of this document is to provide specific recommendations on the use of cardiovascular magnetic resonance (CMR) protocols in the era of the COVID-19 pandemic. In patients without COVID-19, standard CMR protocols should be used based on clinical indication as usual. Protocols used in patients who have known / suspected active COVID-19 or post COVID-19 should be performed based on the specific clinical question with an emphasis on cardiac function and myocardial tissue characterization. Short and dedicated protocols are recommended.


Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Infecções por Coronavirus/prevenção & controle , Controle de Infecções/organização & administração , Imagem Cinética por Ressonância Magnética/normas , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Guias de Prática Clínica como Assunto , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pandemias/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Índice de Gravidade de Doença , Sociedades Médicas , Estados Unidos
6.
J Cardiovasc Magn Reson ; 22(1): 58, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32772930

RESUMO

During the peak phase of the COVID-19 pandemic, alterations of standard operating procedures were necessary for health systems to protect patients and healthcare workers and ensure access to vital hospital resources. As the peak phase passes, re-activation plans are required to safely manage increasing clinical volumes. In the context of cardiovascular magnetic resonance (CMR), re-activation objectives include continued performance of urgent CMR studies and resumption of CMR in patients with semi-urgent and elective indications in an environment that is safe for both patients and health care workers.


Assuntos
Betacoronavirus , Doenças Cardiovasculares/diagnóstico por imagem , Infecções por Coronavirus/prevenção & controle , Imagem por Ressonância Magnética/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Guias de Prática Clínica como Assunto , Sistema Cardiovascular/diagnóstico por imagem , Humanos , Valor Preditivo dos Testes , Sociedades Médicas
7.
JACC Cardiovasc Imaging ; 13(11): 2343-2354, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32563637

RESUMO

OBJECTIVES: This study examined how extracellular volume (ECV) and global longitudinal strain (GLS) relate to each other and to outcomes. BACKGROUND: Among myriad changes occurring in diseased myocardium, left ventricular imaging metrics of either the interstitium (e.g., ECV) or contractile function (e.g., GLS) may consistently associate with adverse outcomes yet correlate minimally with each other. This scenario suggests that ECV and GLS potentially represent distinct domains of cardiac vulnerability. METHODS: The study included 1,578 patients referred for cardiovascular magnetic resonance (CMR) without amyloidosis, and it quantified how ECV associated with GLS in linear regression models. ECV and GLS were then compared in their associations with incident outcomes (death and hospitalization for heart failure). RESULTS: ECV and GLS correlated minimally (R2 = 0.04). Over a median follow-up of 5.6 years, 339 patients experienced adverse events (149 hospitalizations for heart failure, 253 deaths, and 63 with both). GLS (univariable hazard ratio: 2.07 per 5% increment; 95% CI: 1.86 to 2.29) and ECV (univariable hazard ratio: 1.66 per 4% increment; 95% CI: 1.51 to 1.82) were principal variables associating with outcomes in univariable and multivariable Cox regression models. Similar results were observed in several clinically important subgroups. In the whole cohort, ECV added prognostic value beyond GLS in univariable and multivariable Cox regression models. CONCLUSIONS: GLS and ECV may represent principal but distinct domains of cardiac vulnerability, perhaps reflecting their distinct cellular origins. Whether combining ECV and GLS may advance pathophysiological understanding for a given patient, optimize risk stratification, and foster personalized medicine by targeted therapeutics requires further investigation.

8.
J Am Coll Cardiol ; 75(21): 2649-2660, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32466879

RESUMO

BACKGROUND: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

9.
Cancer Metastasis Rev ; 39(2): 455-469, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32440845

RESUMO

Caveolin-1 (CAV1) has long been implicated in cancer progression, and while widely accepted as an oncogenic protein, CAV1 also has tumor suppressor activity. CAV1 was first identified in an early study as the primary substrate of Src kinase, a potent oncoprotein, where its phosphorylation correlated with cellular transformation. Indeed, CAV1 phosphorylation on tyrosine-14 (Y14; pCAV1) has been associated with several cancer-associated processes such as focal adhesion dynamics, tumor cell migration and invasion, growth suppression, cancer cell metabolism, and mechanical and oxidative stress. Despite this, a clear understanding of the role of Y14-phosphorylated pCAV1 in cancer progression has not been thoroughly established. Here, we provide an overview of the role of Src-dependent phosphorylation of tumor cell CAV1 in cancer progression, focusing on pCAV1 in tumor cell migration, focal adhesion signaling and metabolism, and in the cancer cell response to stress pathways characteristic of the tumor microenvironment. We also discuss a model for Y14 phosphorylation regulation of CAV1 effector protein interactions via the caveolin scaffolding domain.

10.
Sensors (Basel) ; 20(10)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429533

RESUMO

Volatile organic compounds (VOCs) are prevalent in daily life, from the lab environment to industrial applications, providing tremendous functionality but also posing significant health risk. Moreover, individual VOCs have individual risks associated with them, making classification and sensing of a broad range of VOCs important. This work details the application of electrochemically dealloyed nanoporous gold (NPG) as a VOC sensor through measurements of the complex electrical frequency response of NPG. By leveraging the effects of adsorption and capillary condensation on the electrical properties of NPG itself, classification and regression is possible. Due to the complex nonlinearities, classification and regression are done through the use of a convolutional neural network. This work also establishes key strategies for improving the performance of NPG, both in sensitivity and selectivity. This is achieved by tuning the electrochemical dealloying process through manipulations of the starting alloy and through functionalization with 1-dodecanethiol.

14.
J Clin Med Res ; 12(1): 18-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32010418

RESUMO

Background: Over the past several decades, diabetes mellitus has contributed to a significant disease burden in the general population. Evidence suggests that patients with a coexisting diabetes diagnosis consume more hospital resources, and have higher readmission rates compared to those who do not. Against the backdrop of bundled-payment programs, healthcare systems cannot underestimate the importance of monitoring patient health information at the population level. Methods: Using the data from the Centers for Medicare and Medicaid Services (CMS) administrative claims database, we created a dashboard prototype to enable hospitals to examine the impact of diabetes on their all-cause readmission rates and financial implications if diabetes was present at the index hospitalization. The technical design involved loading the relevant 10th revision of International Classification of Diseases (ICD-10) codes provided by the medical team and flagging diabetes patients at the claim. These patients were then tagged for readmissions within the same database. The odds ratios were determined based on data from two groups: those with diabetes at index hospitalization which include type 1 only, type 2 only, and type 1 and type 2 diabetes, plus those without diabetes at index hospitalization. Results: The dashboard presents summary data of diabetes readmissions quality metrics at a national level. Users can visualize summary data of each state and compare odds ratios for readmissions as well as raw hospitalization data at their facility. Dashboard users can also view data classified by a diagnosis-related group (DRG) system. In addition to a "national" data view, for users who inquire about data specific to demographic regions, the DRG view can be further stratified at the state level or county level. At the DRG level, users can view data about the cost per readmissions for all index hospitalization with and without diabetes. Conclusions: The dashboard prototype offers users a virtual interface which displays visual data for quick interpretation, monitors changes at a population level, and enables administrators to benchmark facility data against local and national trends. This is an important step in using data analytics to drive population level decision making to ultimately improve medical systems.

15.
Local Reg Anesth ; 13: 1-9, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021414

RESUMO

Non-operating room anesthesia (NORA) represents a growing field of medicine with an increasing trend in the number of cases performed over the previous decade. As a result, anesthesia providers will need to enhance their familiarity with the resources, personnel, and environment outside of the operating room. Anesthesia delivery in NORA settings should be held with the same high-quality standards as that within the operating room. This review looks at special considerations in patient selection and the preoperative, intraoperative, and postoperative periods. In addition, there is a discussion on the unique aspects of specific NORA areas and the considerations that come with them.

16.
Circ Cardiovasc Imaging ; 13(2): e010249, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32063053

RESUMO

BACKGROUND: Technetium-99 m pyrophosphate protocols for transthyretin cardiac amyloidosis diagnosis have variably used 1- and 3-hour imaging time points. We investigated whether imaging at 1 hour with superior efficiency had comparable diagnostic accuracy as 3-hour imaging. METHODS: This is a registry analysis of patients with suspected transthyretin cardiac amyloidosis referred for technetium-99 m pyrophosphate at a single tertiary center from June 2015 through January 2019. Patients underwent planar and single-photon emission computed tomography (SPECT) imaging at 1 and 3 hours. A positive Tc-99m pyrophosphate study was defined by the presence of diffuse myocardial tracer uptake on SPECT. For planar imaging, visual semiquantitative (grades 0-3, ≥2 considered positive) and quantitative heart to contralateral ratios (≥1.5 considered positive) were used. RESULTS: Two hundred thirty-three patients (69% men; median age, 77 [69-83] years) underwent the study protocol. There were 60 (25.8%) patients with diffuse myocardial uptake, 1 (0.4%) with regional uptake, and 172 (73.8%) with no myocardial uptake. Results of SPECT were identical at 1 and 3 hours. Planar imaging at 1 hour had 98% sensitivity and 96% specificity. Planar grade 0 uptake or heart to contralateral ratio ≤1.2 and planar grade 3 uptake or heart to contralateral ratio ≥2.0 were always associated with negative and positive SPECT, respectively. For planar grades 1 and 2 uptake and heart to contralateral ratio 1.3 to 1.9, SPECT was needed to make a diagnosis. No patient with light-chain cardiac amyloidosis had positive SPECT. CONCLUSIONS: An efficient 1-hour technetium-99 m pyrophosphate protocol had comparable diagnostic performance to a 3-hour protocol.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Pirofosfato de Tecnécio Tc 99m/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Masculino , Compostos Radiofarmacêuticos/farmacologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo
18.
J Electrocardiol ; 58: 80-86, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31785580

RESUMO

INTRODUCTION: Left ventricular hypertrophy (LVH), defined as an increased left ventricular mass (LVM), can manifest as increased wall thickness, ventricular dilatation, or both. Existing LVH criteria from the electrocardiogram (ECG) have poor sensitivity. However, it is unknown whether changes in wall thickness and mass, respectively, can be separately detected by the ECG. METHODS: Patients undergoing cardiovascular magnetic resonance and resting 12-lead ECG were included. Exclusion criteria were clinical confounders that might influence the ECG, including myocardial scar. Advanced ECG (A-ECG) analysis included conventional ECG measures and amplitudes, derived vectorcardiographic and polarcardiographic measures, and singular value decomposition of waveform complexity. A-ECG scores for 1) increased LVM index (LVMI), and 2) increased global wall thickness index (GTI) beyond the upper limit of normal in healthy volunteers, respectively, were derived using multivariable logistic regression. The area under the curve (AUC) and its bootstrapped confidence interval (CI) for each score were compared to those of conventional ECG-LVH criteria including Cornell voltage, Cornell product, and Sokolow-Lyon voltage criteria. RESULTS: Out of 485 patients (median [interquartile range] age 51 [38-61] years, 54% female), 51 (11%) had increased LVMI and 65 (13%) had increased GTI. The A-ECG scores for increased LVMI (AUC [95% CI] 0.84 [0.78-0.90]), and increased GTI (0.80 [0.74-0.85]) differed, and had a higher AUC than the conventional ECG-LVH criteria (p < 0.001 for all). CONCLUSIONS: Increased LVMI differed from increased GTI in its electrocardiographic manifestation by A-ECG. New A-ECG scores outperform conventional ECG criteria for LVH in determining increased LVMI and GTI, respectively.

19.
JACC Cardiovasc Imaging ; 13(1 Pt 1): 44-54, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31103587

RESUMO

OBJECTIVES: Because risk stratification data represents a key domain of biomarker validation, we compared associations between outcomes and various cardiovascular magnetic resonance (CMR) metrics quantifying myocardial fibrosis (MF) in noninfarcted myocardium: extracellular volume fraction (ECV), native T1, post-contrast T1, and partition coefficient. BACKGROUND: MF associates with vulnerability to adverse events (e.g., mortality and hospitalization for heart failure [HHF]), but investigators still debate its optimal measurement; most histological validation data show strongest ECV correlations with MF. METHODS: We enrolled 1,714 consecutive patients without amyloidosis or hypertrophic cardiomyopathy from a single CMR referral center serving an integrated healthcare network. We measured T1 (MOdified Look-Locker Inversion recovery [MOLLI]) in nonenhanced myocardium, averaged from 2 short-axis slices (basal and mid) before and 15 to 20 min after a gadolinium contrast bolus. We compared chi-square test values from CMR MF measures in univariable and multivariable Cox regression models. We assessed "dose-response" relationships in Kaplan-Meier curves using log-rank statistics for quartile strata. We also computed net reclassification improvement (NRI) and integrated discrimination improvement (IDI for Cox models with ECV vs. native T1). RESULTS: Over a median of 5.6 years, 374 events occurred after CMR (162 HHF events and 279 deaths, 67 with both). ECV yielded the best separation of Kaplan-Meier curves and the highest log-rank statistics. In univariable and multivariable models, ECV associated most strongly with outcomes, demonstrating the highest chi-square test values. Native T1 or post-contrast T1 did not associate with outcomes in the multivariable model. ECV provided added prognostic value to models with native T1, for example, in multivariable models IDI = 0.0037 (95% confidence interval [CI]: 0.0009 to 0.0071), p = 0.02; NRI = 0.151 (95% CI: 0.022 to 0.292), p = 0.04. CONCLUSIONS: Analogous to histological previously published validation data, ECV myocardial fibrosis measures exhibited more robust associations with outcomes than other surrogate CMR MF measures. Superior risk stratification by ECV supports claims that ECV optimally measures MF in noninfarcted myocardium.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Volume Sistólico , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Amiloidose/mortalidade , Amiloidose/patologia , Amiloidose/fisiopatologia , Cardiomiopatia Hipertrófica/mortalidade , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Meios de Contraste/administração & dosagem , Progressão da Doença , Feminino , Fibrose , Gadolínio/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco
20.
Clin Neurol Neurosurg ; 185: 105463, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442742

RESUMO

OBJECTIVES: Over the last two decades, various studies have evaluated the impact of weekend admission to the hospital on inpatient mortality. Our study sought to identify whether or not the "weekend effect" was true for patients with Intracranial Hemorrhage (ICH) admitted to United States hospitals and whether or not the introduction of comprehensive stroke centers (CSCs) made an impact on the "weekend effect" for ICH. PATIENTS AND METHODS: Searched the Nationwide Inpatient Sample for the ICH discharges between 2006 and 2014. Multivariate regression analysis was performed to evaluate the factors that impacted in-hospital mortality. Additional subgroup analysis was performed based on two time periods, before CSCs (2006-2009) and afterward (2010-2014). RESULTS: 146,587 discharges with ICH were reported by the NIS with 37,471 (25.6%) weekend admissions. The weekday admission cohort was 50.6% male with a mean age of 67.1 years. There was a total of 35,362 deaths among ICH admissions. The in-hospital mortality rate was significantly higher for weekend admissions compared to that of weekday admissions (25.2% vs. 23.8%, p < 0.001). Multivariate analysis of mortality for the 2006-2009 subgroup demonstrated a statistically significant higher odds of death with weekend admission (OR = 1.15, 95% CI [1.10, 1.20], p = 0) but not for the 2010-2014 subgroup (OR = 1.03, 95% CI [0.99, 1.07], p = 0.09). CONCLUSION: Our study showed that in-hospital mortality was found to be increased for patients with ICH admitted on a weekend; however, this association was lost after the initiation of CSCs. Further prospective studies are warranted to gain a better understanding regarding this association.


Assuntos
Mortalidade Hospitalar/tendências , Hemorragias Intracranianas/mortalidade , Acidente Vascular Cerebral/mortalidade , Plantão Médico , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitais Rurais , Hospitais de Ensino , Hospitais Urbanos , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
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