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1.
JAMA Cardiol ; 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35442393

RESUMO

Importance: Hypertensive disorders of pregnancy are associated with increased risk of cardiovascular disease, yet few interventions have targeted this population to decrease long-term risk. Objective: To determine whether a digital health intervention improves physical activity in postpartum individuals with hypertensive disorders of pregnancy. Design, Setting, and Participants: This 12-week randomized clinical trial enrolled postpartum individuals who delivered at the University of Pennsylvania and had a hypertensive disorder of pregnancy between October 2019 and June 2020. Analysis was intention to treat. Interventions: All participants received a wearable activity tracker, established a baseline step count, selected a step goal greater than baseline, and were randomly assigned to control or intervention. Participants in the control arm received daily feedback on goal attainment. Participants in the intervention arm were placed on virtual teams and enrolled in a game with points and levels for daily step goal achievement and informed by principles of behavioral economics. Main Outcomes and Measures: The primary outcome was change in mean daily step count from baseline to 12-week follow-up. Secondary outcome was proportion of participant-days that step goal was achieved. Results: A total of 127 participants were randomized (64 in the control group and 63 in the intervention group) and were enrolled a mean of 7.9 weeks post partum. Participants had a mean (SD) age of 32.3 (5.6) years, 70 (55.1%) were Black, and 52 (41.9%) had Medicaid insurance. The mean (SD) baseline step count was similar in the control and intervention arms (6042 [2270] vs 6175 [1920] steps, respectively). After adjustment for baseline steps and calendar month, participants in the intervention arm had a significantly greater increase in mean daily step steps from baseline compared with the control arm (647 steps; 95% CI, 169-1124 steps; P = .009). Compared with the control arm, participants in the intervention arm achieved their steps goals on a greater proportion of participant-days during the intervention period (0.47 vs 0.38; adjusted difference 0.11; 95% CI, 0.04-0.19; P = .003). Conclusions and Relevance: In this study, a digital health intervention using remote monitoring, gamification, and social incentives among postpartum individuals at elevated cardiovascular risk significantly increased physical activity throughout 12 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03311230.

2.
Front Cell Neurosci ; 16: 831061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308116

RESUMO

In order to meet the energetic demands of cell-to-cell signaling, increases in local neuronal signaling are matched by a coordinated increase in local blood flow, termed neurovascular coupling. Multiple different signals from neurons, astrocytes, and pericytes contribute to this control of blood flow. Previously, several groups demonstrated that inhibition/ablation of glutamate transporters attenuates the neurovascular response. However, it was not determined if glutamate transporter activation was sufficient to increase blood flow. Here, we used multiphoton imaging to monitor the diameter of fluorescently labeled cortical arterioles in anesthetized C57/B6J mice. We delivered vehicle, glutamate transporter substrates, or a combination of a glutamate transporter substrate with various pharmacologic agents via a glass micropipette while simultaneously visualizing changes in arteriole diameter. We developed a novel image analysis method to automate the measurement of arteriole diameter in these time-lapse analyses. Using this workflow, we first conducted pilot experiments in which we focally applied L-glutamate, D-aspartate, or L-threo-hydroxyaspartate (L-THA) and measured arteriole responses as proof of concept. We subsequently applied the selective glutamate transport substrate L-THA (applied at concentrations that do not activate glutamate receptors). We found that L-THA evoked a significantly larger dilation than that observed with focal saline application. This response was blocked by co-application of the potent glutamate transport inhibitor, L-(2S,3S)-3-[3-[4-(trifluoromethyl)-benzoylamino]benzyloxy]-aspartate (TFB-TBOA). Conversely, we were unable to demonstrate a reduction of this effect through co-application of a cocktail of glutamate and GABA receptor antagonists. These studies provide the first direct evidence that activation of glutamate transport is sufficient to increase arteriole diameter. We explored potential downstream mechanisms mediating this transporter-mediated dilation by using a Ca2+ chelator or inhibitors of reversed-mode Na+/Ca2+ exchange, nitric oxide synthetase, or cyclo-oxygenase. The estimated effects and confidence intervals suggested some form of inhibition for a number of these inhibitors. Limitations to our study design prevented definitive conclusions with respect to these downstream inhibitors; these limitations are discussed along with possible next steps. Understanding the mechanisms that control blood flow are important because changes in blood flow/energy supply are implicated in several neurodegenerative disorders and are used as a surrogate measure of neuronal activity in widely used techniques such as functional magnetic resonance imaging (fMRI).

3.
J Am Heart Assoc ; 11(2): e020299, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35014861

RESUMO

BACKGROUND Children with single ventricle heart disease have significant morbidity and mortality. The maternal-fetal environment (MFE) may adversely impact outcomes after neonatal cardiac surgery. We hypothesized that impaired MFE would be associated with an increased risk of death after stage 1 Norwood reconstruction. METHODS AND RESULTS We performed a retrospective cohort study of children with hypoplastic left heart syndrome (and anatomic variants) who underwent stage 1 Norwood reconstruction between 2008 and 2018. Impaired MFE was defined as maternal gestational hypertension, preeclampsia, gestational diabetes, and/or smoking during pregnancy. Cox proportional hazards regression models were used to investigate the association between impaired MFE and death while adjusting for confounders. Hospital length of stay was assessed with the competing risk of in-hospital death. In 273 children, the median age at stage 1 Norwood reconstruction was 4 days (interquartile range [IQR], 3-6 days). A total of 72 children (26%) were exposed to an impaired MFE; they had more preterm births (18% versus 7%) and a greater percentage with low birth weights <2.5 kg (18% versus 4%) than those without impaired MFE. Impaired MFE was associated with a higher risk of death (hazard ratio [HR], 6.05; 95% CI, 3.59-10.21; P<0.001) after adjusting for age at surgery, Hispanic ethnicity, genetic syndrome, cardiac diagnosis, surgeon, and birth era. Children with impaired MFE had almost double the risk of prolonged hospital stay (HR, 1.95; 95% CI, 1.41-2.70; P<0.001). CONCLUSIONS Children exposed to an impaired MFE had a higher risk of death following stage 1 Norwood reconstruction. Prenatal exposures are potentially modifiable factors that can be targeted to improve outcomes after pediatric cardiac surgery.


Assuntos
Síndrome do Coração Esquerdo Hipoplásico , Procedimentos de Norwood , Coração Univentricular , Criança , Feminino , Mortalidade Hospitalar , Humanos , Recém-Nascido , Procedimentos de Norwood/efeitos adversos , Gravidez , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
4.
Ann Am Thorac Soc ; 19(4): 562-571, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34499590

RESUMO

Rationale: The effect of insulin resistance on left ventricular function is well documented; however, less is known regarding its effect on the right ventricle (RV). Objectives: To evaluate the association between insulin resistance and RV function by echocardiography in a cohort of adults without baseline cardiovascular disease. Methods: We performed a retrospective cohort study in the MESA (Multi-Ethnic Study of Atherosclerosis). Linear regression was used to examine the association between overall insulin resistance measured by the mean triglyceride (TG) to high-density lipoprotein (HDL) cholesterol ratio (TG:HDL) and change in TG:HDL over time for each participant with echocardiographic RV function. Logistic regression was used to calculate the odds ratios (ORs) of RV systolic and diastolic dysfunction. Results: Among 3,032 participants, higher mean TG:HDL was associated with lower (worse) absolute RV longitudinal strain (ß, -0.38; 95% confidence interval [CI], -0.64 to -0.13; P < 0.01), tricuspid annular plane systolic excursion (ß, -0.05; 95% CI, -0.07 to -0.04; P < 0.001), and higher odds of abnormal RV strain (OR, 1.26; 95% CI, 1.08 to 1.47; P < 0.01) and abnormal tricuspid annular plane systolic excursion (OR, 1.31; 95% CI, 1.14 to 1.51; P < 0.001). TG:HDL was also associated with lower ratio of tricuspid early to late ventricular filling velocities (E/A) (ß, -0.03; 95% CI, -0.04 to -0.01; P < 0.01), higher ratio of early diastolic tricuspid inflow to tricuspid lateral annular velocity (E/e') (ß, 0.15; 95% CI, 0.07 to 0.23; P < 0.001), and higher odds of graded RV diastolic dysfunction (OR, 1.19; 95% CI, 1.03 to 1.39; P < 0.05). These associations remained following multivariable adjustment. Conclusions: Insulin resistance was associated with decreased RV systolic and diastolic function after adjusting for alternative causes of RV dysfunction, suggesting that insulin-resistant individuals are at risk for early RV dysfunction, even in the absence of cardiovascular disease.


Assuntos
Resistência à Insulina , Disfunção Ventricular Direita , Adulto , Ecocardiografia , Humanos , Estudos Retrospectivos , Função Ventricular Direita
5.
Photochem Photobiol ; 98(1): 117-126, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34224156

RESUMO

Treatment de-escalation is sought in the management of precursor lesions of early stage breast cancer, driving the appeal of adjuvant modalities to lumpectomy that reduce toxicity and minimally detract from patient quality of life. We investigate photodynamic therapy (PDT), with the photosensitizing prodrug, 5-aminolevulinic acid (ALA), as adjuvant therapy to complete resection of murine mammary tumor (propagated from TUBO cells). ALA was delivered either systemically (oral, 250 mg kg-1 ) at 5 h before 632 nm illumination or topically (20% solution) to the resection site at 10 min before light delivery to 135 J cm-2 . Treatment with either oral-ALA-PDT (oALA-PDT) or topical-ALA-PDT (tALA-PDT) to the mammary fat pad after TUBO complete resection (CR) produced long-term tumor control with 90-day complete response rates of 21% and 32%, respectively, compared to control rates of 0-5% in mice receiving only CR. Thus, CR/tALA-PDT was equipotent to CR/oALA-PDT despite ~10-fold lower levels of ALA-induced protoporphyrin XI as photosensitizer after topical versus oral-ALA administration. CR/oALA-PDT produced more vascular damage, greater proportion of tissue-resident neutrophils and stronger inflammation when compared to CR/tALA-PDT. Collectively, these data provide rationale for ongoing investigation of ALA-PDT as adjuvant therapy after lumpectomy for increased probability of local control in the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Fotoquimioterapia , Administração Tópica , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Qualidade de Vida
6.
Artigo em Inglês | MEDLINE | ID: mdl-35063614

RESUMO

BACKGROUND: Pericardial fat has been associated with adverse cardiovascular outcomes through adiposity-associated inflammation and insulin resistance, which in turn are linked to cardiac dysfunction. We sought to evaluate the association between pericardial fat volume and cardiac structure and function in adults without baseline cardiovascular disease. METHODS: We analyzed data from the Multi-Ethnic Study of Atherosclerosis. Linear regression was used to examine the association between pericardial fat volume (by cardiac computed tomography during exam 1, 2000-2002) and cardiac function by echocardiography, six-minute walk distance (6MWD), and symptom severity as assessed using the Kansas City Cardiomyopathy Questionnaire-12 (exam 6, 2016-18). RESULTS: Among 3,032 participants, each 1 SD (39.3 cm3) increase in pericardial fat volume was associated with lower (worse) absolute left atrial reservoir strain (ß = -0.98%; 95% CI, -1.29, -0.68; P < .001), right ventricular free wall strain (ß = -0.75%; 95% CI, -1.00, -0.51; P < .001), and right atrial reservoir strain (ß = -0.59%; 95% CI, -1.00, -0.19; P < .01) after adjustment for potential confounders. Greater pericardial fat volume was associated with lower 6MWDs (ß = -5.70 m; 95% CI, -10.34, -1.06; P = .02) but not with Kansas City Cardiomyopathy Questionnaire-12 scores or N-terminal pro b-type natriuretic peptide after multivariable adjustment. CONCLUSIONS: In a population-based cohort of adults, pericardial fat volume was independently associated with subclinical atrial and right ventricular dysfunction and reduced 6MWD. These distinct changes in cardiac structure and function suggest a potential mechanistic role for pericardial fat in early heart failure.

7.
Brain Commun ; 3(4): fcab268, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34934944

RESUMO

Mild traumatic brain injury affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational loading is the most common cause of mild traumatic brain injury and is defined by a rapid rotational acceleration of brain tissue within an intact skull. Injury kinematics-the mechanical descriptors of injury-inducing motion-explain movement of the head, which govern energy transfer, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics-such as angular velocity, angular acceleration, and injury duration-and outcome after mild traumatic brain injury is not completely understood. To address this gap in knowledge, we analysed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mild traumatic brain injury against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea time, extubation time, standing time, and recovery duration. Compared to controls, animals experiencing a mild traumatic brain injury were far more likely to have apnea (P < 0.001), shorter time to extubation (P = 0.023), and longer time from extubation to standing (P = 0.006). Using least absolute shrinkage and selection operator-based regressions, kinematic parameters, including maximum negative angular velocity and time from peak angular velocity to maximum angular deceleration, were selected to explain variation in apnea time, standing time, and recovery duration. Simplified linear models employing the least absolute shrinkage and selection operator-selected variables explained a modest degree of variation in apnea time (adjusted R 2 = 0.18), standing time (adjusted R 2 = 0.19), and recovery duration (adjusted R 2 = 0.27). Neuropathology was correlated with multiple injury kinematics, with maximum angular acceleration exhibiting the strongest correlation (R 2 = 0.66). Together, these data suggest the interplay between multiple injury kinematics, including maximum negative angular velocity (immediately preceding cessation of head motion) and time from peak angular velocity to maximum angular deceleration, best explain acute recovery metrics and neuropathology after mild traumatic brain injury in swine. Future experiments that independently manipulate individual kinematic parameters could be instrumental in developing translational diagnostics for clinical mild traumatic brain injury.

8.
JAMA Netw Open ; 4(5): e219211, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33944923

RESUMO

Importance: Financial incentives may improve health by rewarding patients for focusing on present actions-such as medication regimen adherence-that provide longer-term health benefits. Objective: To identify barriers to improving statin therapy adherence and control of cholesterol levels with financial incentives and insights for the design of future interventions. Design, Setting, and Participants: This qualitative study involved retrospective interviews with participants in a preplanned secondary analysis of a randomized clinical trial of financial incentives for statin therapy adherence. A total of 636 trial participants from several US insurer or employer populations and an academic health system were rank ordered by change in low-density lipoprotein cholesterol (LDLC) levels. Participants with the most LDLC level improvement (high-improvement group) and those with LDLC levels that did not improve (nonimprovement group) were purposively targeted, stratified across all trial groups, for semistructured telephone interviews that were performed from April 1 to June 30, 2018. Interviews were coded using a team-based, iterative approach. Data were analyzed from July 1, 2018, to October 31, 2020. Main Outcomes and Measures: The primary outcome was mean change in LDLC level from baseline to 12 months; the secondary outcome, statin therapy adherence during the first 6 months. Results: A total of 54 patients were interviewed, divided equally between high-improvement and nonimprovement groups, with a mean (SD) age of 43.5 (10.3) years; 36 (66.7%) were women, 28 (51.9%) had diabetes, and 18 (33.3%) had cardiovascular disease. Compared with the high-improvement group, the nonimprovement group had fewer interviewees with an annual income of greater than $50 000 (11 [40.7%] vs 22 [81.5%]), worse self-reported health (fair to poor, 13 [48.1%] vs 3 [11.1%]), more Black interviewees (16 [59.3%] vs 4 [14.8%]), and lower baseline LDLC levels (>160 mg/dL, 2 [7.4%] vs 25 [92.6%]). Participants in the nonimprovement group had a greater burden of chronic illness (≥2 chronic conditions, 13 [48.1%] vs 6 [22.2%]) and were less frequently employed (full-time, 6 [22.2%] vs 12 [44.4%]). In interviews, the nonimprovement group was less focused on risks of high LDLC levels, described less engagement in LDLC level management, articulated fewer specific nutritional choices for optimizing health, and recounted greater difficulty obtaining healthy food. Participants in both groups had difficulty describing the structure of the financial incentives but did recall features of the electronic pill containers used to track adherence and how those containers affected medication routines. Conclusions and Relevance: Participants in a statin adherence trial whose LDLC levels did not improve found it more difficult to create medication routines and respond to financial incentives in the context of complex living conditions and a high burden of chronic illness. These findings suggest that future studies should be more attentive to socioeconomic circumstances of trial participants. Trial Registration: ClinicalTrials.gov Identifier: NCT01798784.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação , Adulto , Idoso , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Adesão à Medicação/psicologia , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Motivação , Pesquisa Qualitativa
9.
BMC Neurol ; 21(1): 154, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836684

RESUMO

BACKGROUND: The cortical microvascular cerebral blood flow response (CBF) to different changes in head-of-bed (HOB) position has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS) technique. However, the relationship between these relative ΔCBF changes and associated systemic blood pressure changes has not been studied, even though blood pressure is a major driver of cerebral blood flow. METHODS: Transcranial DCS data from four studies measuring bilateral frontal microvascular cerebral blood flow in healthy controls (n = 15), patients with asymptomatic severe internal carotid artery stenosis (ICA, n = 27), and patients with acute ischemic stroke (AIS, n = 72) were aggregated. DCS-measured CBF was measured in response to a short head-of-bed (HOB) position manipulation protocol (supine/elevated/supine, 5 min at each position). In a sub-group (AIS, n = 26; ICA, n = 14; control, n = 15), mean arterial pressure (MAP) was measured dynamically during the protocol. RESULTS: After elevated positioning, DCS CBF returned to baseline supine values in controls (p = 0.890) but not in patients with AIS (9.6% [6.0,13.3], mean 95% CI, p < 0.001) or ICA stenosis (8.6% [3.1,14.0], p = 0.003)). MAP in AIS patients did not return to baseline values (2.6 mmHg [0.5, 4.7], p = 0.018), but in ICA stenosis patients and controls did. Instead ipsilesional but not contralesional CBF was correlated with MAP (AIS 6.0%/mmHg [- 2.4,14.3], p = 0.038; ICA stenosis 11.0%/mmHg [2.4,19.5], p < 0.001). CONCLUSIONS: The observed associations between ipsilateral CBF and MAP suggest that short HOB position changes may elicit deficits in cerebral autoregulation in cerebrovascular disorders. Additional research is required to further characterize this phenomenon.


Assuntos
Pressão Arterial , Estenose das Carótidas/fisiopatologia , Circulação Cerebrovascular , AVC Isquêmico/fisiopatologia , Decúbito Dorsal/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo/fisiologia , Pressão Sanguínea , Isquemia Encefálica/fisiopatologia , Estudos de Casos e Controles , Feminino , Decúbito Inclinado com Rebaixamento da Cabeça/fisiologia , Hemodinâmica , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/fisiopatologia
11.
Med Decis Making ; 41(1): 9-20, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33218296

RESUMO

Behavioral interventions involving electronic devices, financial incentives, gamification, and specially trained staff to encourage healthy behaviors are becoming increasingly prevalent and important in health innovation and improvement efforts. Although considerations of cost are key to their wider adoption, cost information is lacking because the resources required cannot be costed using standard administrative billing data. Pragmatic clinical trials that test behavioral interventions are potentially the best and often only source of cost information but rarely incorporate costing studies. This article provides a guide for researchers to help them collect and analyze, during the trial and with little additional effort, the information needed to inform potential adopters of the costs of adopting a behavioral intervention. A key challenge in using trial data is the separation of implementation costs, the costs an adopter would incur, from research costs. Based on experience with 3 randomized clinical trials of behavioral interventions, this article explains how to frame the costing problem, including how to think about costs associated with the control group, and describes methods for collecting data on individual costs: specifications for costing a technology platform that supports the specialized functions required, how to set up a time log to collect data on the time staff spend on implementation, and issues in getting data on device, overhead, and financial incentive costs.


Assuntos
Terapia Comportamental/economia , Comportamentos Relacionados com a Saúde , Terapia Comportamental/estatística & dados numéricos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise Custo-Benefício/métodos , Humanos
12.
JAMA Netw Open ; 3(10): e2019429, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33034639

RESUMO

Importance: Financial incentives can improve medication adherence and cardiovascular disease risk, but the optimal design to promote sustained adherence after incentives are discontinued is unknown. Objective: To determine whether 6-month interventions involving different financial incentives to encourage statin adherence reduce low-density lipoprotein cholesterol (LDL-C) levels from baseline to 12 months. Design, Setting, and Participants: This 4-group, randomized clinical trial was conducted from August 2013 to July 2018 among several large US insurer or employer populations and the University of Pennsylvania Health System. The study population included adults with elevated risk of cardiovascular disease, suboptimal LDL-C control, and evidence of imperfect adherence to statin medication. Data analysis was performed from July 2017 to June 2019. Interventions: The interventions lasted 6 months during which all participants received daily medication reminders and an electronic pill bottle. Statin adherence was measured by opening the bottle. For participants randomized to the 3 intervention groups, adherence was rewarded with financial incentives. The sweepstakes group involved incentives for daily adherence. In the deadline sweepstakes group, incentives were reduced if participants were adherent only after a reminder. The sweepstakes plus deposit contract group split incentives between daily adherence and a monthly deposit reduced for each day of nonadherence. Main Outcomes and Measures: The primary outcome was change in LDL-C level from baseline to 12 months. Results: Among 805 participants randomized (199 in the simple daily sweepstakes group, 204 in the deadline sweepstakes group, 201 in the sweepstakes plus deposit contract group, and 201 in the control group), the mean (SD) age was 58.5 (10.3) years; 519 participants (64.5%) were women, 514 (63.9%) had diabetes, and 273 (33.9%) had cardiovascular disease. The mean (SD) baseline LDL-C level was 143.2 (42.5) mg/dL. Measured adherence at 6 months (defined as the proportion of 180 days with electronic pill bottle opening) in the control group (0.69; 95% CI, 0.66-0.72) was lower than that in the simple sweepstakes group (0.84; 95% CI, 0.81-0.87), the deadline sweepstakes group (0.86; 95% CI, 0.83-0.89), and the sweepstakes plus deposit contract group (0.87; 95% CI, 0.84-0.90) (P < .001 for each incentive group vs control). LDL-C levels were measured for 636 participants at 12 months. Mean LDL-C level reductions from baseline to 12 months were 33.6 mg/dL (95% CI, 28.4-38.8 mg/dL) in the control group, 32.4 mg/dL (95% CI, 27.3-37.6 mg/dL) in the sweepstakes group, 33.2 mg/dL (95% CI, 28.1-38.3 mg/dL) in the deadline sweepstakes group, and 36.5 mg/dL (95% CI, 31.3-41.7 mg/dL) in the sweepstakes plus deposit contract group (adjusted P > .99 for each incentive group vs control). Conclusions and Relevance: Compared with the control group, different financial incentives improved measured statin adherence but not LDL-C levels. This result points to the importance of directly measuring health outcomes, rather than simply adherence, in trials aimed at improving health behaviors. Trial Registration: ClinicalTrials.gov Identifier: NCT01798784.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Participação do Paciente/economia , Reembolso de Incentivo/estatística & dados numéricos , Recompensa , Adulto , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Adesão à Medicação/psicologia , Pessoa de Meia-Idade , Motivação , Participação do Paciente/psicologia , Fatores de Tempo
13.
Cancers (Basel) ; 12(6)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32549354

RESUMO

Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.

14.
Resuscitation ; 152: 28-35, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376347

RESUMO

AIM OF THE STUDY: Since over 80% of sudden cardiac arrests occur in the home, cardiopulmonary resuscitation (CPR) training for family members of high-risk cardiac patients represents a promising intervention. The use of mobile application-based (mApp) CPR training may facilitate this approach, but evidence regarding its efficacy is lacking. METHODS: We conducted a multicenter, pragmatic, cluster-randomized trial assessing CPR training for family members of cardiac patients. The interventions were mApp (video, no manikin) and VSI (video + manikin). CPR skills were evaluated 6-months post-training. We hypothesized that chest compression (CC) rate from training with an mApp would be no worse than 5 compressions per minute (CPM) lower compared to VSI. RESULTS: From 01/2016 to 01/2018, we enrolled 1325 eligible participants (mean age 51.6 years, 68.2% female and 59.4% white). CPR skills were evaluated 6-months post-training in 541 participants (275 VSI, 266 mApp). Mean rate was 84.6 CPM (95% CI: 80.4, 88.6) in VSI, compared to 82.7 CPM (95% CI: 76.2, 89.1) in the mApp, and mean depth was 42.1 mm (95% CI: 40.3, 43.8) in VSI, compared to 38.9 mm (95% CI: 36.2, 41.6) in the mApp. After adjustment, the mean difference in CC rate was -2.3 CPM (95% CI -9.4, 4.8, p = 0.25, non-inferiority) and CC depth was -3.2 mm (95% CI -5.9, 0.1, p = 0.056). CONCLUSION: In this large prospective trial of CPR skill retention for family members of cardiac patients, mApp training was associated with lower CC quality. Future work is required to understand additional approaches to improve CPR skill retention. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov, Identifier: NCT02548793.


Assuntos
Reanimação Cardiopulmonar , Aplicativos Móveis , Feminino , Hospitais , Humanos , Masculino , Manequins , Pessoa de Meia-Idade , Alta do Paciente , Estudos Prospectivos
15.
Development ; 147(11)2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471820

RESUMO

Although widely used, assisted reproductive technologies (ARTs) are associated with adverse perinatal outcomes. To elucidate their underlying causes, we have conducted a longitudinal analysis of placental development and fetal growth using a mouse model to investigate the effects of individual ART procedures: hormone stimulation, in vitro fertilization (IVF), embryo culture and embryo transfer. We demonstrate that transfer of blastocysts naturally conceived without hormone stimulation and developed in vivo prior to transfer can impair early placentation and fetal growth, but this effect normalizes by term. In contrast, embryos cultured in vitro before transfer do not exhibit this compensation but rather display placental overgrowth, reduced fetal weight, reduced placental DNA methylation and increased levels of sFLT1, an anti-angiogenic protein implicated in causing the maternal symptoms of preeclampsia in humans. Increases in sFLT1 observed in this study suggest that IVF procedures could increase the risk for preeclampsia. Moreover, our results indicate that embryo culture is the major factor contributing to most placental abnormalities and should therefore be targeted for optimization.


Assuntos
Placenta/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Metilação de DNA , Transferência Embrionária , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário , Feminino , Fertilização In Vitro , Masculino , Camundongos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/veterinária , Gravidez , Risco , Simportadores/genética , Simportadores/metabolismo , Trofoblastos/citologia , Trofoblastos/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
16.
Ann Thorac Surg ; 110(1): 241-250, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31634442

RESUMO

BACKGROUND: Posterior intercostal lymph nodes, previously undescribed for cancer staging, are part of the lymphatic drainage of the pleural space. This study assessed the impact of posterior intercostal lymph nodes on survival in patients undergoing extended pleurectomy/decortication for malignant pleural mesothelioma. METHODS: As part of the thoracic lymphadenectomy, posterior intercostal lymph nodes were accessed by incising the endothoracic fascia at the level of the rib heads. These nodes were systematically harvested in 56 consecutive patients undergoing extended pleurectomy decortication in a clinical trial. The impact of these nodes on progression-free (PFS) and overall survival (OS) was analyzed by multiple statistical methods. RESULTS: Median PFS and OS were 11.6 and 25.5 months, respectively. In 6 of 56 patients (11%), posterior intercostal lymph nodes were the only positive nodes, and overall, 48.2% had posterior intercostal lymph node metastases. Patients with N2 disease had significantly poorer prognosis if the posterior intercostal lymph nodes were involved: PFS (7.3 vs 14.9 months, P = .002) and OS (14.4 vs 26.1 months, P = .028). In the multivariable models, after adjustment for nodal stage and other prognostic factors, intercostal nodes remained associated with a 2.5-fold elevated risk of progression (P < .001) and a 2.3-fold elevated risk of death (P < .001). CONCLUSIONS: Metastases to posterior intercostal lymph nodes independently more than doubled the risk of progression and death and were the only site of nodal metastases in 11% of patients. These nodes warrant further investigation, including nonoperative techniques to identify and factor them into treatment decision making.


Assuntos
Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Mesotelioma/mortalidade , Mesotelioma/patologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Idoso , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Linfonodos/cirurgia , Masculino , Mediastino , Mesotelioma/cirurgia , Mesotelioma Maligno , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Pleurais/cirurgia , Taxa de Sobrevida
17.
Open Heart ; 6(1): e001025, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297226

RESUMO

Objective: We sought to determine how sex and dexrazoxane therapy influence cardiac remodelling in children with sarcoma receiving high-dose doxorubicin. Methods: In a retrospective cohort of 85 children with sarcoma receiving high-dose doxorubicin, echocardiography measures prior to, early after (within 6 months of doxorubicin completion) and 1 - 2 years after doxorubicin completion were quantified. At each follow-up visit, multivariable, propensity-adjusted linear regression models evaluated dexrazoxane's effects on changes in left ventricular (LV) shortening fraction (SF), structure, strain and wall stress for subgroups divided by sex. Likelihood ratio tests assessed the interaction between sex and dexrazoxane in determining these changes. Results: Early after doxorubicin completion, males not treated with dexrazoxane (n = 15) developed increased cavity size and diminished circumferential strain; females (n = 8) developed diminished SF and strain indices, and increased cavity size and wall stress. With dexrazoxane, males (n = 33) demonstrated less deterioration in circumferential strain by 3.4% (95% CI 0.01 to 6.8), and females (n = 29) demonstrated less reduction in SF by 5.7% (95% CI 2.1 to 9.3), and had mitigation of increases in cavity size and wall stress. In interaction analyses, females had greater protection with dexrazoxane with regard to SF (p = 0.019) and cavity size in diastole (p = 0.002) and systole (p ≤ 0.001). These findings largely persisted 1 - 2 years after doxorubicin therapy. Conclusions: Early, sustained alterations in LV structure and function occur in children with sarcoma after high-dose doxorubicin, with adverse changes and protective effects of dexrazoxane more pronounced in females as compared with males. Dexrazoxane may have sex-specific cardioprotective effects.

18.
Clin Trials ; 16(4): 399-409, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31148473

RESUMO

BACKGROUND: Low adherence to statin (HMG-CoA reductase inhibitors) medication is common. Here, we report on the design and implementation of the Habit Formation trial. This clinical trial assessed whether the interventions, based on principles from behavioral economics, might improve statin adherence and lipid control in at-risk populations. We describe the rationale and methods for the trial, recruitment, conduct and follow-up. We also report on several barriers we encountered with recruitment and conduct of the trial, solutions we devised and efforts we will make to assess their impact on our study. METHODS: Habit Formation is a four-arm randomized controlled trial. Recruitment of 805 participants at elevated risk of atherosclerotic cardiovascular disease with evidence of sub-optimal statin adherence and low-density lipoprotein (LDL) control is complete. Initially, we recruited from large employers (Employers) and a national health insurance company (Insurers) using mailed letters; individuals with a statin Medication Possession Ratio less than 80% were invited to participate. Respondents were enrolled if a laboratory measurement of low-density lipoprotein was >130 mg/dL. Subsequently, we recruited participants from the Penn Medicine Health System; individuals with usual-care low-density lipoprotein of >100 mg/dL in the electronic medical record were recruited using phone, text, email, and regular mail. Eligible participants self-reported incomplete medication adherence. During a 6-month intervention period, all participants received a wireless-enabled pill bottle for their statins and daily reminder messages to take their medication. Principles of behavioral economics were used to design three financial incentives, specifically a Simple Daily Sweepstakes rewarding daily medication adherence, a Deadline Sweepstakes where participants received either a full or reduced incentive depending on whether they took their medication before or after a daily reminder or Sweepstakes Plus Deposit Contract with incentives divided between daily sweepstakes and a monthly deposit. Six months post-incentives, we compared the primary outcome, mean change from baseline low-density lipoprotein, across arms. RESULTS AND LESSONS LEARNED: Health system recruitment yielded substantially better enrollment and was cost-efficient. Despite unexpected systematic failure and/or poor availability of two wireless pill bottles, we achieved enrollment targets and implemented the interventions. For new trials, we will routinely monitor device function and have contingency plans in the event of systemic failure. CONCLUSION: Interventions used in the Habit Formation trial could be translated into clinical practice. Within a large health system, successful recruitment depended on identification of eligible individuals through their electronic medical record, along with flexible ways of contacting these individuals. Challenges with device failure were manageable. The study will add to our understanding of optimally structuring and implementing incentives to motivate durable behavior change.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação , Motivação , Adulto , Idoso , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/epidemiologia , Economia Comportamental , Humanos , Lipoproteínas LDL/sangue , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistemas de Alerta , Projetos de Pesquisa , Telecomunicações , Envio de Mensagens de Texto , Resultado do Tratamento
19.
Stat Methods Med Res ; 28(3): 801-821, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29179645

RESUMO

Incomplete block crossover trials with period-specific baseline and post-baseline (outcome) measures for each subject are often used in clinical drug development; without loss of generality, we focus on the three-treatment two-period ( 3×2 ) crossover. Data from such trials are commonly analyzed using a mixed effects model with indicator terms for treatment and period, and an unstructured covariance matrix for the vector of intra-subject measurements. It is well-known that treatment effect estimates from this analysis are complex functions of both within-subject and between-subject treatment contrasts. We caution that the associated type I error rate and power for hypothesis testing can be non-trivially influenced by how the baselines are utilized. Specifically, the mixed effects analysis which uses change from baseline as the dependent variable is shown to consistently underperform corresponding analyses in which the outcome is the dependent variable and linear combinations of the baselines are used as period-specific and/or period-invariant covariates. A simpler fixed effects analysis of covariance involving only within-subject contrasts is also described for small sample situations in which the mixed effects analyses can suffer from increased type I error rates. Theoretical insights, simulation results and an illustrative example with real data are used to develop the main points.


Assuntos
Estudos Cross-Over , Análise de Dados , Projetos de Pesquisa , Algoritmos , Análise de Variância , Pesquisa Biomédica , Interpretação Estatística de Dados , Modelos Estatísticos
20.
Sci Rep ; 8(1): 14654, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279592

RESUMO

Lonidamine (LND), a metabolic modulator, sensitizes DB-1 human melanoma to doxorubicin (DOX) chemotherapy by acidifying and de-energizing the tumor. This report compares the effects of LND on two human melanoma lines, DB-1 and WM983B, which exhibit different metabolic properties. Using liquid chromatography mass spectrometry and Seahorse analysis, we show that DB-1 was more glycolytic than WM983B in vitro. 31P magnetic resonance spectroscopy (MRS) indicates that LND (100 mg/kg, i.p.) induces similar selective acidification and de-energization of WM983B xenografts in immunosuppressed mice. Over three hours, intracellular pH (pHi) of WM983B decreased from 6.91 ± 0.03 to 6.59 ± 0.10 (p = 0.03), whereas extracellular pH (pHe) of this tumor changed from 7.03 ± 0.05 to 6.89 ± 0.06 (p = 0.19). A decline in bioenergetics (ß-NTP/Pi) of 55 ± 5.0% (p = 0.03) accompanied the decline in pHi of WM983B. Using 1H MRS with a selective multiquantum pulse sequence and Hadamard localization, we show that LND induced a significant increase in tumor lactate levels (p < 0.01). LND pre-treatment followed by DOX (10 mg/kg, i.v.) produced a growth delay of 13.7 days in WM983B (p < 0.01 versus control), a growth delay significantly smaller than the 25.4 days that occurred with DB-1 (p = 0.03 versus WM983B). Differences in relative levels of glycolysis may produce differential therapeutic responses of DB-1 and WM983B melanomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Doxorrubicina/farmacologia , Metabolismo Energético/efeitos dos fármacos , Indazóis/farmacologia , Melanoma/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Doxorrubicina/uso terapêutico , Sinergismo Farmacológico , Glucose/análise , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Indazóis/uso terapêutico , Ácido Láctico/análise , Ácido Láctico/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Melanoma/patologia , Camundongos , Camundongos Nus , Oxigênio/análise , Oxigênio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
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