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1.
Nat Methods ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589837

RESUMO

Current proteomic approaches disassemble and digest nucleosome particles, blurring readouts of the 'histone code'. To preserve nucleosome-level information, we developed Nuc-MS, which displays the landscape of histone variants and their post-translational modifications (PTMs) in a single mass spectrum. Combined with immunoprecipitation, Nuc-MS quantified nucleosome co-occupancy of histone H3.3 with variant H2A.Z (sixfold over bulk) and the co-occurrence of oncogenic H3.3K27M with euchromatic marks (for example, a >15-fold enrichment of dimethylated H3K79me2). Nuc-MS is highly concordant with chromatin immunoprecipitation-sequencing (ChIP-seq) and offers a new readout of nucleosome-level biology.

2.
J Exp Psychol Gen ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475396

RESUMO

Disgust is an adaptation forged under the selective pressure of pathogens. Yet disgust may cause problems in contemporary societies because of its propensity for "false positives" and resistance to corrective information. Here, we investigate whether disgust, as revealed by oculomotor avoidance, might be reduced through the noncognitive process of habituation. In each of three experiments, we repeatedly exposed participants to the same pair of images, one disgusting and one neutral, and recorded gaze. Experiment 1 (N = 104) found no decline in oculomotor avoidance of the disgusting image after 24 prolonged exposures. Experiment 2 (N = 99) replicated this effect and demonstrated its uniqueness to disgust. In Experiment 3 (N = 93), we provided a gaze-contingent reward to ensure perceptual contact with the disgusting image. Participants looked almost exclusively at the disgusting image for 5 min but resumed baseline levels of oculomotor avoidance once the reward ceased. These findings underscore the challenge of reducing disgust. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

3.
Soft Matter ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289747

RESUMO

The bare-nosed wombat (Vombatus ursinus) is a fossorial, herbivorous, Australian marsupial, renowned for its cubic feces. However, the ability of the wombat's soft intestine to sculpt flat faces and sharp corners in feces is poorly understood. In this combined experimental and numerical study, we show one mechanism for the formation of corners in a highly damped environment. Wombat dissections show that cubes are formed within the last 17 percent of the intestine. Using histology and tensile testing, we discover that the cross-section of the intestine exhibits regions with a two-fold increase in thickness and a four-fold increase in stiffness, which we hypothesize facilitates the formation of corners by contractions of the intestine. Using a mathematical model, we simulate a series of azimuthal contractions of a damped elastic ring composed of alternating stiff and soft regions. Increased stiffness ratio and higher Reynolds number yield shapes that are more square. The corners arise from faster contraction in the stiff regions and relatively slower movement in the center of the soft regions. These results may have applications in manufacturing, clinical pathology, and digestive health.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33190872

RESUMO

PURPOSE: To determine the potential impact of referral bias on short- and long-term outcomes following septal myectomy for hypertrophic cardiomyopathy. METHODS: We reviewed 2303 adult patients who underwent transaortic septal myectomy for obstructive hypertrophic cardiomyopathy from January 1993 to April 2016. Patients were divided into 3 groups according to their permanent address: local (state) residents (n = 324), regional (surrounding 5 states) patients (n = 515), and national (outside 5 states) patients (n = 1464). RESULTS: Patient groups were similar for age, sex, preoperative New York Heart Association class, and left ventricular ejection fraction. Local patients had increased prevalence of diabetes mellitus (13%, 11%, 8%; P = .006), coronary artery disease (25%, 21%, 19%; P = .031), severe chronic lung disease (2.3%, 1.9%, 0.4%; P < .001), and atrial fibrillation (24%, 18%, 19%; P = .045) when compared with regional and national patients. Echocardiographic features did not differ between the 3 groups, including prevalence of moderate or greater mitral regurgitation (59%, 61%, 56%; P = .161). Local and regional patients were more likely to undergo concomitant procedures than national patients (P < .001). Mitral valve surgery was performed in 9.6% of the patients, more commonly in local and regional patients (12%, 12%, 8%; P = .018). There were 11 operative deaths (0.5%), and early mortality was similar among the groups. Geographic origin did not impact overall late survival. CONCLUSIONS: Compared with distant referrals, local patients who undergo septal myectomy at our institution have more comorbid conditions, and require more concomitant surgical procedures. Despite these differences, referral patterns did not impact early or late outcomes following transaortic septal myectomy.

5.
Environ Int ; 146: 106196, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33160161

RESUMO

BACKGROUND: Liquefied petroleum gas (LPG) stoves have been promoted in low- and middle-income countries (LMICs) as a clean energy alternative to biomass burning cookstoves. OBJECTIVE: We sought to characterize kitchen area concentrations and personal exposures to nitrogen dioxide (NO2) within a randomized controlled trial in the Peruvian Andes. The intervention included the provision of an LPG stove and continuous fuel distribution with behavioral messaging to maximize compliance. METHODS: We measured 48-hour kitchen area NO2 concentrations at high temporal resolution in homes of 50 intervention participants and 50 control participants longitudinally within a biomass-to-LPG intervention trial. We also collected 48-hour mean personal exposures to NO2 among a subsample of 16 intervention and 9 control participants. We monitored LPG and biomass stove use continuously throughout the trial. RESULTS: In 367 post-intervention 24-hour kitchen area samples of 96 participants' homes, geometric mean (GM) highest hourly NO2 concentration was 138 ppb (geometric standard deviation [GSD] 2.1) in the LPG intervention group and 450 ppb (GSD 3.1) in the biomass control group. Post-intervention 24-hour mean NO2 concentrations were a GM of 43 ppb (GSD 1.7) in the intervention group and 77 ppb (GSD 2.0) in the control group. Kitchen area NO2 concentrations exceeded the WHO indoor hourly guideline an average of 1.3 h per day among LPG intervention participants. GM 48-hour personal exposure to NO2 was 5 ppb (GSD 2.4) among 35 48-hour samples of 16 participants in the intervention group and 16 ppb (GSD 2.3) among 21 samples of 9 participants in the control group. DISCUSSION: In a biomass-to-LPG intervention trial in Peru, kitchen area NO2 concentrations were substantially lower within the LPG intervention group compared to the biomass-using control group. However, within the LPG intervention group, 69% of 24-hour kitchen area samples exceeded WHO indoor annual guidelines and 47% of samples exceeded WHO indoor hourly guidelines. Forty-eight-hour NO2 personal exposure was below WHO indoor annual guidelines for most participants in the LPG intervention group, and we did not measure personal exposure at high temporal resolution to assess exposure to cooking-related indoor concentration peaks. Further research is warranted to understand the potential health risks of LPG-related NO2 emissions and inform current campaigns which promote LPG as a clean-cooking option.

6.
Liver Transpl ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33217178

RESUMO

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective intervention for portal hypertensive complications, but its effect on renal function is not well-characterized. Here, we describe renal function and characteristics associated with renal dysfunction at 30-days post-TIPS. METHODS: Adults with cirrhosis who underwent TIPS at nine hospitals in the US 2010-2015 were included. We defined "post-TIPS renal dysfunction" as a change in estimated glomerular filtration rate (ΔeGFR) ≤ -15ml/min/1.73m2 and eGFR ≤ 60ml/min/1.73m2 , or new renal replacement therapy (RRT) at day 30. We identified the characteristics associated with post-TIPS renal dysfunction by logistic regression and evaluated survival using adjusted competing risk regressions. RESULTS: Of 673 patients: median age 57 years, 38% female, 26% had diabetes, median MELDNa 17. Thirty days post-TIPS, 66 (10%) had renal dysfunction, of which 23 (35%) required new RRT. Patients with post-TIPS renal dysfunction, compared to those with stable renal function, were more likely to have NAFLD (33% versus 17%, p = 0.01) and comorbid diabetes (42% versus 24%, p < 0.01). Multivariate logistic regressions showed NAFLD (OR 2.04, 95%CI 1.00 to 4.17, p = 0.05), serum sodium (OR 1.06 per mEq/L, 95%CI 1.01 to 1.12, p = 0.03), and diabetes (OR 2.04, 95%CI 1.16 to 3.61, p = 0.01) were associated with post-TIPS renal dysfunction. Competing risk regressions showed those with post-TIPS renal dysfunction were at higher sub-hazard of death (sHR 1.74, 95%CI 1.18 to 2.56, p = 0.01). CONCLUSIONS: In this large multi-center cohort, we found NAFLD, diabetes, and baseline serum sodium associated with post-TIPS renal dysfunction. This study suggests that patients with NAFLD and diabetes undergoing TIPS evaluation may require additional attention to cardiac and renal comorbidities prior to proceeding with the procedure.

7.
Neurobiol Aging ; 96: 205-222, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33038808

RESUMO

We used graph theoretical measures to investigate the hypothesis that structural brain connectivity constrains the influence of functional connectivity on the relation between age and fluid cognition. Across 143 healthy, community-dwelling adults 19-79 years of age, we estimated structural network properties from diffusion-weighted imaging and functional network properties from resting-state functional magnetic resonance imaging. We confirmed previous reports of age-related decline in the strength and efficiency of structural networks, as well as in the connectivity strength within and between structural network modules. Functional networks, in contrast, exhibited age-related decline only in system segregation, a measure of the distinctiveness among network modules. Aging was associated with decline in a composite measure of fluid cognition, particularly tests of executive function. Functional system segregation was a significant mediator of age-related decline in executive function. Structural network properties did not directly influence the age-related decline in functional system segregation. The raw correlational data underlying the graph theoretical measures indicated that structural connectivity exerts a limited constraint on age-related decline in functional connectivity.

8.
Liver Transpl ; 26(11): 1492-1503, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33047893

RESUMO

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65 years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3 years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P < 0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1 year and 82.4% at 3 years compared with 88.9% at 1 year and 80.4% at 3 years for non-NASH patients (log-rank P = 0.58 and P = 0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

9.
JAMA Intern Med ; 180(9): 1215-1224, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32897386

RESUMO

Importance: Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear. Objective: To assess the extent to which the use of an SDM tool affects the quality of SDM and anticoagulant treatment decisions in at-risk patients with AF. Design, Setting, and Participants: This encounter-randomized trial recruited patients with nonvalvular AF who were considering starting or reviewing anticoagulant treatment and their clinicians at academic, community, and safety-net medical centers between January 30, 2017 and June 27, 2019. Encounters were randomized to either the standard care arm or care that included the use of an SDM tool (intervention arm). Data were analyzed from August 1 to November 30, 2019. Interventions: Standard care or care using the Anticoagulation Choice Shared Decision Making tool (which presents individualized risk estimates and compares anticoagulant treatment options across issues of importance to patients) during the clinical encounter. Main Outcomes and Measures: Quality of SDM (which included quality of communication, patient knowledge about AF and anticoagulant treatment, accuracy of patient estimates of their own stroke risk [within 30% of their estimate], decisional conflict, and satisfaction), decisions made during the encounter, duration of the encounter, and clinician involvement of patients in the SDM process. Results: The clinical trial enrolled 922 patients (559 men [60.6%]; mean [SD] age, 71 [11] years) and 244 clinicians. A total of 463 patients were randomized to the intervention arm and 459 patients to the standard care arm. Participants in both arms reported high communication quality, high knowledge, and low decisional conflict, demonstrated low accuracy in their risk perception, and would similarly recommend the approach used in their encounter. Clinicians were significantly more satisfied after intervention encounters (400 of 453 encounters [88.3%] vs 277 of 448 encounters [61.8%]; adjusted relative risk, 1.49; 95% CI, 1.42-1.53). A total of 747 of 873 patients (85.6%) chose to start or continue receiving an anticoagulant medication. Patient involvement in decision-making (as assessed through video recordings of the encounters using the Observing Patient Involvement in Decision Making 12-item scale) scores were significantly higher in the intervention arm (mean [SD] score, 33.0 [10.8] points vs 29.1 [13.1] points, respectively; adjusted mean difference, 4.2 points; 95% CI, 2.8-5.6 points). No significant between-arm difference was found in encounter duration (mean [SD] duration, 32 [16] minutes in the intervention arm vs 31 [17] minutes in the standard care arm; adjusted mean between-arm difference, 1.1; 95% CI, -0.3 to 2.5 minutes). Conclusion and Relevance: The use of an SDM encounter tool improved several measures of SDM quality and clinician satisfaction, with no significant effect on treatment decisions or encounter duration. These results help to calibrate expectations about the value of implementing SDM tools in the care of patients with AF. Trial Registration: ClinicalTrials.gov Identifier: NCT02905032.

12.
Nat Commun ; 11(1): 3343, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620905

RESUMO

The expanded polyglutamine (polyQ) tract form of ataxin-1 drives disease progression in spinocerebellar ataxia type 1 (SCA1). Although known to form distinctive intranuclear bodies, the cellular pathways and processes that polyQ-ataxin-1 influences remain poorly understood. Here we identify the direct and proximal partners constituting the interactome of ataxin-1[85Q] in Neuro-2a cells, pathways analyses indicating a significant enrichment of essential nuclear transporters, pointing to disruptions in nuclear transport processes in the presence of elevated levels of ataxin-1. Our direct assessments of nuclear transporters and their cargoes confirm these observations, revealing disrupted trafficking often with relocalisation of transporters and/or cargoes to ataxin-1[85Q] nuclear bodies. Analogous changes in importin-ß1, nucleoporin 98 and nucleoporin 62 nuclear rim staining are observed in Purkinje cells of ATXN1[82Q] mice. The results highlight a disruption of multiple essential nuclear protein trafficking pathways by polyQ-ataxin-1, a key contribution to furthering understanding of pathogenic mechanisms initiated by polyQ tract proteins.


Assuntos
Ataxina-1/metabolismo , Núcleo Celular/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Células de Purkinje/metabolismo , Transporte Ativo do Núcleo Celular/genética , Animais , Ataxina-1/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HeLa , Humanos , Camundongos , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Peptídeos/genética , Ligação Proteica , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
13.
JAMA Intern Med ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32702079

RESUMO

Importance: Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear. Objective: To assess the extent to which the use of an SDM tool affects the quality of SDM and anticoagulant treatment decisions in at-risk patients with AF. Design, Setting, and Participants: This encounter-randomized trial recruited patients with nonvalvular AF who were considering starting or reviewing anticoagulant treatment and their clinicians at academic, community, and safety-net medical centers between January 30, 2017 and June 27, 2019. Encounters were randomized to either the standard care arm or care that included the use of an SDM tool (intervention arm). Data were analyzed from August 1 to November 30, 2019. Interventions: Standard care or care using the Anticoagulation Choice Shared Decision Making tool (which presents individualized risk estimates and compares anticoagulant treatment options across issues of importance to patients) during the clinical encounter. Main Outcomes and Measures: Quality of SDM (which included quality of communication, patient knowledge about AF and anticoagulant treatment, accuracy of patient estimates of their own stroke risk [within 30% of their estimate], decisional conflict, and satisfaction), decisions made during the encounter, duration of the encounter, and clinician involvement of patients in the SDM process. Results: The clinical trial enrolled 922 patients (559 men [60.6%]; mean [SD] age, 71 [11] years) and 244 clinicians. A total of 463 patients were randomized to the intervention arm and 459 patients to the standard care arm. Participants in both arms reported high communication quality, high knowledge, and low decisional conflict, demonstrated low accuracy in their risk perception, and would similarly recommend the approach used in their encounter. Clinicians were significantly more satisfied after intervention encounters (400 of 453 encounters [88.3%] vs 277 of 448 encounters [61.8%]; adjusted relative risk, 1.49; 95% CI, 1.42-1.53). A total of 747 of 873 patients (85.6%) chose to start or continue receiving an anticoagulant medication. Patient involvement in decision-making (as assessed through video recordings of the encounters using the Observing Patient Involvement in Decision Making 12-item scale) scores were significantly higher in the intervention arm (mean [SD] score, 33.0 [10.8] points vs 29.1 [13.1] points, respectively; adjusted mean difference, 4.2 points; 95% CI, 2.8-5.6 points). No significant between-arm difference was found in encounter duration (mean [SD] duration, 32 [16] minutes in the intervention arm vs 31 [17] minutes in the standard care arm; adjusted mean between-arm difference, 1.1; 95% CI, -0.3 to 2.5 minutes). Conclusion and Relevance: The use of an SDM encounter tool improved several measures of SDM quality and clinician satisfaction, with no significant effect on treatment decisions or encounter duration. These results help to calibrate expectations about the value of implementing SDM tools in the care of patients with AF. Trial Registration: ClinicalTrials.gov Identifier: NCT02905032.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32415916

RESUMO

BACKGROUND: The healthcare burden posed by the coronavirus disease 2019 (COVID-19) pandemic in the New York Metropolitan area has necessitated the postponement of elective procedures resulting in a marked reduction in cardiac catheterization laboratory (CCL) volumes with a potential to impact interventional cardiology (IC) fellowship training. METHODS: We conducted a web-based survey sent electronically to 21 Accreditation Council for Graduate Medical Education accredited IC fellowship program directors (PDs) and their respective fellows. RESULTS: Fourteen programs (67%) responded to the survey and all acknowledged a significant decrease in CCL procedural volumes. More than half of the PDs reported part of their CCL being converted to inpatient units and IC fellows being redeployed to COVID-19 related duties. More than two-thirds of PDs believed that the COVID-19 pandemic would have a moderate (57%) or severe (14%) adverse impact on IC fellowship training, and 21% of the PDs expected their current fellows' average percutaneous coronary intervention (PCI) volume to be below 250. Of 25 IC fellow respondents, 95% expressed concern that the pandemic would have a moderate (72%) or severe (24%) adverse impact on their fellowship training, and nearly one-fourth of fellows reported performing fewer than 250 PCIs as of March 1st. Finally, roughly one-third of PDs and IC fellows felt that there should be consideration of an extension of fellowship training or a period of early career mentorship after fellowship. CONCLUSIONS: The COVID-19 pandemic has caused a significant reduction in CCL procedural volumes that is impacting IC fellowship training in the NY metropolitan area. These results should inform professional societies and accreditation bodies to offer tailored opportunities for remediation of affected trainees.

19.
Antiviral Res ; 177: 104760, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135219

RESUMO

Infection by RNA viruses such as human immunodeficiency virus (HIV)-1, influenza, and dengue virus (DENV) represent a major burden for human health worldwide. Although RNA viruses replicate in the infected host cell cytoplasm, the nucleus is central to key stages of the infectious cycle of HIV-1 and influenza, and an important target of DENV nonstructural protein 5 (NS5) in limiting the host antiviral response. We previously identified the small molecule ivermectin as an inhibitor of HIV-1 integrase nuclear entry, subsequently showing ivermectin could inhibit DENV NS5 nuclear import, as well as limit infection by viruses such as HIV-1 and DENV. We show here that ivermectin's broad spectrum antiviral activity relates to its ability to target the host importin (IMP) α/ß1 nuclear transport proteins responsible for nuclear entry of cargoes such as integrase and NS5. We establish for the first time that ivermectin can dissociate the preformed IMPα/ß1 heterodimer, as well as prevent its formation, through binding to the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity. We show that ivermectin inhibits NS5-IMPα interaction in a cell context using quantitative bimolecular fluorescence complementation. Finally, we show for the first time that ivermectin can limit infection by the DENV-related West Nile virus at low (µM) concentrations. Since it is FDA approved for parasitic indications, ivermectin merits closer consideration as a broad spectrum antiviral of interest.

20.
J Dent Educ ; 84(5): 534-542, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32064617

RESUMO

Operationalizing faculty contributions in ways that align with organizational mission can be difficult, particularly when monetizing effort. Conventional compensation methods may result in faculty effort going undefined, resulting in more subjectivity in recognition and compensation. Inequities lead to faculty marginalization, fragmentation, decreased motivation, and attrition. Dental faculty retirements are expected to increase, as 81% of men and 19% of women faculty aged 60 years and older in 2015-2016. We present opposing perspectives on the use of educational value units (EVUs) in academic dentistry. The first viewpoint articulates that such models improve recruitment and retention by objectifying (a) faculty performance measurement, (b) academic productivity improvements, and (c) compensation determination. The counterpoint suggests EVUs are deterrents to faculty retention due to challenges with objectively quantifying performance measures, a potential inherent bias linked to gender, and the undervaluing of teaching quality or collaborative practices.


Assuntos
Docentes de Odontologia , Faculdades de Odontologia , Idoso , Eficiência , Docentes de Medicina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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