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OBJECTIVE: Greater parity has been associated with cardiovascular disease risk. We sought to find whether the effects on cardiac remodeling and heart failure risk are clear. METHODS: We examined the association of number of live births with echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of nâ¯=â¯12,635 participants in the FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major cardiovascular disease, myocardia infarction and stroke. RESULTS: Among nâ¯=â¯3931 FHS participants (mean age 48 ± 13 years), higher numbers of live births were associated with worse left ventricular fractional shortening (multivariable ß -1.11 (0.31); Pâ¯=â¯0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics, including global circumferential strain and longitudinal and radial dyssynchrony (P < 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥ 5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12; Pâ¯=â¯0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91; Pâ¯=â¯0.02). CONCLUSIONS: Greater numbers of live births are associated with worse cardiac structure and function. There was no association with overall HF, but a higher number of live births was associated with greater risk for incident HFrEF.
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Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Feminino , Gravidez , Adulto , Pessoa de Meia-Idade , Volume Sistólico , Remodelação Ventricular , Nascido Vivo/epidemiologia , Fatores de Risco , Prognóstico , Função Ventricular EsquerdaRESUMO
BACKGROUND: Mechanisms underlying sex differences in heart failure with preserved ejection fraction (HFpEF) are poorly understood. We sought to examine sex differences in measures of arterial stiffness and the association of arterial stiffness measures with left ventricular hemodynamic responses to exercise in men and women. METHODS: We studied 83 men (mean age 62 years) and 107 women (mean age 59 years) with HFpEF who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and arterial stiffness measurement (augmentation pressure [AP], augmentation index [AIx], and aortic pulse pressure [AoPP]). Sex differences were compared using multivariable linear regression. We examined the association of arterial stiffness with abnormal left ventricular diastolic response to exercise, defined as a rise in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO) ≥ 2 mmHg/L/min by using logistic regression models. RESULTS: Women with HFpEF had increased arterial stiffness compared with men. AP was nearly 10 mmHg higher, and AIx was more than 10% higher in women compared with men (P < 0.0001 for both). Arterial stiffness measures were associated with a greater pulmonary capillary wedge pressure response to exercise, particularly among women. A 1-standard deviation higher AP was associated with > 3-fold increased odds of abnormal diastolic exercise response (AP: OR 3.16, 95% CI 1.34-7.42; Pâ¯=â¯0.008 [women] vs OR 2.07, 95% CI 0.95-5.49; Pâ¯=â¯0.15 [men]) with similar findings for AIx and AoPP. CONCLUSIONS: Arterial stiffness measures are significantly higher in women with HFpEF than in men and are associated with abnormally steep increases in pulmonary capillary wedge pressure with exercise, particularly in women. Arterial stiffness may preferentially contribute to abnormal diastolic function during exercise in women with HFpEF compared with men.
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Insuficiência Cardíaca , Rigidez Vascular , Tolerância ao Exercício/fisiologia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pressão Propulsora Pulmonar/fisiologia , Volume Sistólico/fisiologia , Rigidez Vascular/fisiologia , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Arterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise. METHODS AND RESULTS: A total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52-3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption. CONCLUSIONS: Exercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular-vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.
Assuntos
Insuficiência Cardíaca , Rigidez Vascular , Adulto , Idoso , Teste de Esforço , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca/diagnóstico , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Metastatic cancer cells invade surrounding tissues by forming dynamic actin-based invadopodia, which degrade the surrounding extracellular matrix and allow cancer cell invasion. Regulatory RNAs, including circular RNA, have been implicated in this process. By microarray, we found that the circular RNA circSKA3 was highly expressed in breast cancer cells and human breast cancer tissues. We further found that the invasive capacity of breast cancer cells was positively correlated with circSKA3 expression, through the formation of invadopodia. Mechanistically, we identified Tks5 and integrin ß1 as circSKA3 binding partners in these tumor-derived invadopodia. Ectopic circSKA3 expression conferred increased tumor invasiveness in vitro and in vivo. We further identified the RNA-protein binding sites between circSKA3, Tks5 and integrin ß1. In tumor formation assays, we found that circSKA3 expression promoted tumor progression and invadopodium formation. Mutation of the circSKA3 binding sites or transfection with blocking oligos abrogated the observed effects. Thus, we provide evidence that the circular RNA circSKA3 promotes tumor progression by complexing with Tks5 and integrin ß1, inducing invadopodium formation.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinogênese/genética , Proteínas de Ciclo Celular/metabolismo , Integrina beta1/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Podossomos/metabolismo , RNA Circular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Sítios de Ligação/genética , Proteínas de Ciclo Celular/genética , Movimento Celular/genética , Progressão da Doença , Feminino , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Proteínas Associadas aos Microtúbulos/genética , Invasividade Neoplásica/genética , Projetos Piloto , Ligação Proteica/genética , RNA Circular/genética , TransfecçãoRESUMO
Upregulation of programmed death ligand 1 (PD-L1) allows cancer cells to evade antitumor immunity. Despite tremendous efforts in developing PD-1/PD-L1 immune checkpoint inhibitors (ICIs), clinical trials using such ICIs have shown inconsistent benefits. Here, we hypothesized that the ICI efficacy would be dictated by the binding strength of the inhibitor to the target proteins. To assess this, hyperbranched, multivalent poly(amidoamine) dendrimers were employed to prepare dendrimer-ICI conjugates (G7-aPD-L1). Binding kinetics measurements using SPR, BLI, and AFM revealed that G7-aPD-L1 exhibits significantly enhanced binding strength to PD-L1 proteins, compared to free aPD-L1. The binding avidity of G7-aPD-L1 was translated into in vitro efficiency and in vivo selectivity, as the conjugates improved the PD-L1 blockade effect and enhanced accumulation in tumor sites. Our results demonstrate that the dendrimer-mediated multivalent interaction substantially increases the binding avidity of the ICIs and thereby improves the antagonist effect, providing a novel platform for cancer immunotherapy.
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Antígeno B7-H1 , Nanopartículas , Anticorpos Monoclonais , Imunoterapia , Receptor de Morte Celular Programada 1RESUMO
Genomics analysis of a historically intriguing and predicted emergent human adenovirus (HAdV) pathogen, which caused pneumonia and death, provides insight into a novel molecular evolution pathway involving "ping-pong" zoonosis and anthroponosis. The genome of this promiscuous pathogen is embedded with evidence of unprecedented multiple, multidirectional, stable, and reciprocal cross-species infections of hosts from three species (human, chimpanzee, and bonobo). This recombinant genome, typed as HAdV-B76, is identical to two recently reported simian AdV (SAdV) genomes isolated from chimpanzees and bonobos. Additionally, the presence of a critical adenoviral replication element found in HAdV genomes, in addition to genes that are highly similar to counterparts in other HAdVs, reinforces its potential as a human pathogen. Reservoirs in nonhuman hosts may explain periods of apparent absence and then reemergence of human adenoviral pathogens, as well as present pathways for the genesis of those thought to be newly emergent. The nature of the HAdV-D76 genome has implications for the use of SAdVs as gene delivery vectors in human gene therapy and vaccines, selected to avoid preexisting and potentially fatal host immune responses to HAdV.IMPORTANCE An emergent adenoviral human pathogen, HAdV-B76, associated with a fatality in 1965, shows a remarkable degree of genome identity with two recently isolated simian adenoviruses that contain cross-species genome recombination events from three hosts: human, chimpanzee, and bonobo. Zoonosis (nonhuman-to-human transmission) and anthroponosis (human to nonhuman transmission) may play significant roles in the emergence of human adenoviral pathogens.
Assuntos
Adenovírus Humanos/genética , Adenovirus dos Símios/genética , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/patogenicidade , Adenovirus dos Símios/patogenicidade , Animais , Biologia Computacional/métodos , DNA Viral/genética , Evolução Molecular , Genoma Viral/genética , Genômica/métodos , Humanos , Pan paniscus/virologia , Pan troglodytes/virologia , Filogenia , Recombinação Genética/genética , ZoonosesRESUMO
Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.
Assuntos
Ciclina A/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fatores de Transcrição Forkhead/metabolismo , RNA não Traduzido/metabolismo , Animais , Sítios de Ligação , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Ciclina A/genética , Ciclina E/genética , Quinase 2 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Citoplasma/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Humanos , Camundongos , Células NIH 3T3 , Conformação de Ácido Nucleico , Especificidade de Órgãos , Ligação Proteica , RNA não Traduzido/química , RNA não Traduzido/genética , Transdução de SinaisAssuntos
Teste de Esforço/normas , Insuficiência Cardíaca/diagnóstico , Hemodinâmica/fisiologia , Fenótipo , Pressão Propulsora Pulmonar/fisiologia , Volume Sistólico/fisiologia , Adulto , Idoso , Estudos de Coortes , Teste de Esforço/métodos , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, in which dangerous situations can lead to unpleasant outcomes in unpredictable ways. In the current experiments, we varied the timing of aversive events after predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of cornu ammonis 1 cells during aversive negative prediction errors prevented this enhancement of fear without affecting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial-reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning.
Assuntos
Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Reforço Psicológico , Animais , Humanos , Masculino , Optogenética , Ratos , Ratos Long-EvansRESUMO
Gait coordination is generated by neuronal inter-connections between central pattern generators in the spinal cord governed by cortical areas. Malfunction of central vestibular processing areas generates vestibular symptoms in the absence of an identifiable peripheral vestibular system lesion. Walking in the dark enforces a coordinated afference primarily from the vestibular and somatosensory systems. We hypothesized that patients with aberrant central vestibular processing would demonstrate unique gait characteristics, and have impaired gait coordination compared with those patients with abnormal peripheral vestibular function and healthy controls. One-hundred and eighteen subjects were recruited. Peripheral vestibular function was determined based on laboratory and clinical examinations. Patients with abnormal central vestibular processing had normal peripheral vestibular function. Subjects were instructed to walk at a comfortable pace during three visual conditions; eyes open, eyes open and closed intermittently, and eyes closed. Both patient groups showed a similar spatiotemporal gait pattern, significantly different from the pattern of the healthy controls. However, only the central vestibular patient group had an abnormal coordination of gait as measured by the phase coordination index (PCI). There were no significant interactions between the groups and walking conditions. Peripheral vestibular deficits impair gait though our data suggest that it is the central processing of such peripheral vestibular information that has a greater influence. This impairment may be related to a neural un-coupling between the brain and central pattern generator of the spinal cord based on the abnormal PCI, which seems to be a good indicator of the integrity of this linkage.
Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Doenças Vestibulares/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos , Criança , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/complicações , Doenças Vestibulares/complicações , Velocidade de Caminhada/fisiologia , Adulto JovemRESUMO
BACKGROUND: African American adults achieve smaller amounts of weight loss than their white counterparts when exposed to the same intervention and are more likely to regain weight during long-term follow-up. OBJECTIVE: To identify perceived motivators, barriers, and facilitators to weight loss and behavior change among African American adults. METHODS: Two focus groups were conducted between April and May 2015 at an urban community health center in Baltimore City, Maryland. A total of 13 participants took part in the discussions. Eligible participants were obese (BMI 30+) African American adults aged 21-70 who had at least one obesity-related comorbidity. Discussion questions were designed to identify the personal, social, and environmental factors that influence weight loss and behavior change among urban minority populations. RESULTS: Statements were first classified as a motivator, barrier, or facilitator, then divided further as a personal, social, or environmental factor influencing weight loss and behavior change. Among the findings, several novel motivators (reducing or eliminating medication, improving physical intimacy) and barriers (personal transportation, lack of access to scales) emerged that were not previously characterized in the existing literature. CONCLUSIONS: This study was intended to provide preliminary evidence that may be used to guide the development of innovative and culturally relevant weight-loss interventions in the future. Results are applicable to similar urban minority populations.
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Negro ou Afro-Americano/psicologia , Comportamentos Relacionados com a Saúde/etnologia , Motivação , Determinantes Sociais da Saúde/etnologia , Redução de Peso/etnologia , Adulto , Idoso , Baltimore , Feminino , Grupos Focais , Disparidades nos Níveis de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Apoio Social , Saúde da População Urbana/etnologiaRESUMO
CD40 is an important stimulator of autophagy and autophagic killing of Toxoplasma gondii in host cells. In contrast to autophagy induced by nutrient deprivation or pattern recognition receptors, less is known about the effects of cell-mediated immunity on Beclin 1 and ULK1, key regulators of autophagy. Here we studied the molecular mechanisms by which CD40 stimulates autophagy in macrophages. CD40 ligation caused biphasic Jun N-terminal protein kinase (JNK) phosphorylation. The second phase of JNK phosphorylation was dependent on autocrine production of tumor necrosis factor alpha (TNF-α). TNF-α and JNK signaling were required for the CD40-induced increase in autophagy. JNK signaling downstream of CD40 caused Ser-87 phosphorylation of Bcl-2 and dissociation between Bcl-2 and Beclin 1, an event known to stimulate the autophagic function of Beclin 1. However, TNF-α alone was unable to stimulate autophagy. CD40 also stimulated autophagy via a pathway that included calcium/calmodulin-dependent kinase kinase ß (CaMKKß), AMP-activated protein kinase (AMPK), and ULK1. CD40 caused AMPK phosphorylation at its activating site, Thr-172. This effect was mediated by CaMKKß and was not impaired by neutralization of TNF-α. CD40 triggered AMPK-dependent Ser-555 phosphorylation of ULK1. CaMKKß, AMPK, and ULK1 were required for CD40-induced increase in autophagy. CD40-mediated autophagic killing of Toxoplasma gondii is known to require TNF-α. Knockdown of JNK, CaMKKß, AMPK, or ULK1 prevented T. gondii killing in CD40-activated macrophages. The second phase of JNK phosphorylation-Bcl-2 phosphorylation-Bcl-2-Beclin 1 dissociation and AMPK phosphorylation-ULK1 phosphorylation occurred simultaneously at â¼4 h post-CD40 stimulation. Thus, CaMKKß and TNF-α are upstream molecules by which CD40 acts on ULK1 and Beclin 1 to stimulate autophagy and killing of T. gondii.
Assuntos
Anti-Infecciosos/farmacologia , Autofagia/imunologia , Antígenos CD40/imunologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Toxoplasma/imunologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1/metabolismo , Humanos , Imunidade Celular/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Many previous studies have suggested that the number of lymph nodes retrieved should serve as a benchmark for assessing the adequacy of the resection. The aim was to retrospectively observe the impact of nodal retrieval after educating the pathologist. METHODS: Patients undergoing a pancreaticoduodenectomy (PD) between September 2005 and March 2009 were included in the study. The PDs performed between September 2005 and March 2008 were designated as Group A. The pathologists were educated regarding the importance of nodal counts in PD by the surgeon on the 1st April 2008. PDs performed between April 2008 and March 2009 were designated as Group B. RESULTS: Ninety-eight PDs performed by a single surgeon (D.R.J.) for peri-ampullary malignancy were evaluated. The median number of lymph nodes retrieved in Group A was 11(3-32) nodes. The median number of lymph nodes retrieved in Group B was 22 (10-29) nodes (P < 0.001).The lymph node ratio (positive/total nodes), median number of positive nodes retrieved, and the node positivity (node positive compared to node negative) rate did not change. DISCUSSION: A single intervention with the pathologists did impact the number of lymph nodes retrieved from PD specimens. However, the lymph node ratio and lymph node positivity rate remained unchanged. The pathologist is critical to nodal retrieval in PD, but the use of this lymph node number for benchmark of surgical adequacy may be simplistic.
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Educação Médica Continuada , Excisão de Linfonodo , Linfonodos/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Patologia/educação , Benchmarking , Humanos , Excisão de Linfonodo/normas , Linfonodos/patologia , Metástase Linfática , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/normas , Patologia/normas , Valor Preditivo dos Testes , Indicadores de Qualidade em Assistência à Saúde , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community. METHODS: Research volunteers with dyspnea and obesity underwent resting echocardiography; participants with possible pulmonary hypertension qualified for invasive cardiopulmonary exercise testing. HFpEF was defined using rest or exercise pulmonary capillary wedge pressure criteria (≥15 mmâ Hg or Δpulmonary capillary wedge pressure/Δcardiac output slope, >2.0 mmâ Hg·L-1·min-1). RESULTS: Among n=78 participants (age, 53±13 years; 65% women; body mass index, 37.3±6.8 kg/m2), 40 (51%) met echocardiographic criteria to undergo invasive cardiopulmonary exercise testing. In total, 24 participants (60% among the cardiopulmonary exercise testing group, 31% among the total sample) were diagnosed with HFpEF by rest or exercise pulmonary capillary wedge pressure (n=12) or exercise criteria (n=12). There were no differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide; 79 [62-104] versus 73 [57-121] pg/mL) or resting echocardiography (mitral E/e' ratio, 9.1±3.1 versus 8.0±2.7) among those with versus without HFpEF (P>0.05 for all). Distributions of HFpEF diagnostic scores were similar, with the majority classified as intermediate risk (100% versus 93.75% [H2FPEF] and 87.5% versus 68.75% [HFA-PEFF (Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing, and final etiology)] in those with versus without HFpEF). CONCLUSIONS: Among adults with obesity and dyspnea without known cardiovascular disease, at least a third had clinically unrecognized HFpEF uncovered on invasive cardiopulmonary exercise testing. Clinical, biomarker, resting echocardiography, and diagnostic scores were similar among those with and without HFpEF. These results suggest clinical underdiagnosis of HFpEF among individuals with obesity and dyspnea and highlight limitations of noninvasive testing in the identification of HFpEF.
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Dispneia , Teste de Esforço , Insuficiência Cardíaca , Obesidade , Volume Sistólico , Humanos , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Dispneia/fisiopatologia , Obesidade/fisiopatologia , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/diagnóstico , Idoso , Ecocardiografia , Adulto , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Pressão Propulsora Pulmonar/fisiologia , Função Ventricular Esquerda/fisiologia , Biomarcadores/sangue , PrevalênciaRESUMO
Five genomes of human subspecies B1 adenoviruses isolated from cases of acute respiratory disease have been sequenced and archived for reference. These include representatives of two prevalent genomic variants of HAdV-7, i.e., HAdV-7h and HAdV-7d2. The other three are HAdV-3/16, HAdV-16 strain E26, and HAdV-3+7 strain Takeuchi. All are recombinant genomes. Genomics and bioinformatics provide detailed views into the genetic makeup of these pathogens and insight into their molecular evolution. Retrospective characterization of particularly problematic older pathogens such as HAdV-7h (1987) and intriguing isolates such as HAdV-3+7 strain Takeuchi (1958) may provide clues to their phenotypes and serology and may suggest protocols for prevention and treatment.
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Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/genética , Genoma Viral , Infecções Respiratórias/virologia , Doença Aguda , Adenovírus Humanos/classificação , Adenovírus Humanos/isolamento & purificação , Sequência de Bases , Humanos , Dados de Sequência MolecularRESUMO
INTRODUCTION: The classification and management of pulmonary hypertension (PH) is challenging due to clinical heterogeneity of patients. We sought to identify distinct multimorbid phenogroups of patients with PH that are at particularly high-risk for adverse events. METHODS: A hospital-based cohort of patients referred for right heart catheterization between 2005-2016 with PH were included. Key exclusion criteria were shock, cardiac arrest, cardiac transplant, or valvular surgery. K-prototypes was used to cluster patients into phenogroups based on 12 clinical covariates. RESULTS: Among 5208 patients with mean age 64±12 years, 39% women, we identified 5 distinct multimorbid PH phenogroups with similar hemodynamic measures yet differing clinical outcomes: (1) "young men with obesity", (2) "women with hypertension", (3) "men with overweight", (4) "men with cardiometabolic and cardiovascular disease", and (5) "men with structural heart disease and atrial fibrillation." Over a median follow-up of 6.3 years, we observed 2182 deaths and 2002 major cardiovascular events (MACE). In age- and sex-adjusted analyses, phenogroups 4 and 5 had higher risk of MACE (HR 1.68, 95% CI 1.41-2.00 and HR 1.52, 95% CI 1.24-1.87, respectively, compared to the lowest risk phenogroup 1). Phenogroup 4 had the highest risk of mortality (HR 1.26, 95% CI 1.04-1.52, relative to phenogroup 1). CONCLUSIONS: Cluster-based analyses identify patients with PH and specific comorbid cardiometabolic and cardiovascular disease burden that are at highest risk for adverse clinical outcomes. Interestingly, cardiopulmonary hemodynamics were similar across phenogroups, highlighting the importance of multimorbidity on clinical trajectory. Further studies are needed to better understand comorbid heterogeneity among patients with PH.
Assuntos
Fibrilação Atrial , Cardiopatias , Hipertensão Pulmonar , Hipertensão , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Hipertensão Pulmonar/genética , Análise por ConglomeradosRESUMO
Poor access to diagnostic testing in resource limited settings restricts surveillance for emerging infections, such as dengue virus (DENV), to clinician suspicion, based on history and exam observations alone. We investigated the ability of machine learning to detect DENV based solely on data available at the clinic visit. We extracted symptom and physical exam data from 6,208 pediatric febrile illness visits to Kenyan public health clinics from 2014-2019 and created a dataset with 113 clinical features. Malaria testing was available at the clinic site. DENV testing was performed afterwards. We randomly sampled 70% of the dataset to develop DENV and malaria prediction models using boosted logistic regression, decision trees and random forests, support vector machines, naïve Bayes, and neural networks with 10-fold cross validation, tuned to maximize accuracy. 30% of the dataset was reserved to validate the models. 485 subjects (7.8%) had DENV, and 3,145 subjects (50.7%) had malaria. 220 (3.5%) subjects had co-infection with both DENV and malaria. In the validation dataset, clinician accuracy for diagnosis of malaria was high (82% accuracy, 85% sensitivity, 80% specificity). Accuracy of the models for predicting malaria diagnosis ranged from 53-69% (35-94% sensitivity, 11-80% specificity). In contrast, clinicians detected only 21 of 145 cases of DENV (80% accuracy, 14% sensitivity, 85% specificity). Of the six models, only logistic regression identified any DENV case (8 cases, 91% accuracy, 5.5% sensitivity, 98% specificity). Without diagnostic testing, interpretation of clinical findings by humans or machines cannot detect DENV at 8% prevalence. Access to point-of-care diagnostic tests must be prioritized to address global inequities in emerging infections surveillance.
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Glutathione (GSH) is an abundant metabolite within eukaryotic cells that can act as a signal, a nutrient source, or serve in a redox capacity for intracellular bacterial pathogens. For Francisella, GSH is thought to be a critical in vivo source of cysteine; however, the cellular pathways permitting GSH utilization by Francisella differ between strains and have remained poorly understood. Using genetic screening, we discovered a unique pathway for GSH utilization in Francisella. Whereas prior work suggested GSH catabolism initiates in the periplasm, the pathway we define consists of a major facilitator superfamily (MFS) member that transports intact GSH and a previously unrecognized bacterial cytoplasmic enzyme that catalyzes the first step of GSH degradation. Interestingly, we find that the transporter gene for this pathway is pseudogenized in pathogenic Francisella, explaining phenotypic discrepancies in GSH utilization among Francisella spp. and revealing a critical role for GSH in the environmental niche of these bacteria.