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1.
J Med Chem ; 64(21): 15949-15972, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34705450

RESUMO

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

2.
ERJ Open Res ; 7(3)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34476247

RESUMO

Improving exercise capacity is a primary objective in COPD. Declines in exercise capacity result in reduced physical activity and health-related quality of life (HRQoL). Self-management interventions can teach patients skills and behaviours to manage their disease. Technology-mediated interventions have the potential to provide easily accessible support for disease self-management. We evaluated the effectiveness of a web-based self-management intervention, focused on physical activity promotion, on exercise capacity in COPD. This 6-month randomised controlled trial (NCT02099799) enrolled 153 persons with COPD at two US sites (VABoston, n=108; VABirmingham, n=45). Participants were allocated (1:1) to the web-based self-management intervention (physical activity promotion through personalised, progressive step-count goals, feedback, online COPD-related education and social support via an online community) or usual care. The primary outcome was exercise capacity (6-min walk distance (6 MWD)). Secondary outcomes included physical activity (daily steps per day), HRQoL (St. George's Respiratory Questionnaire Total Score), dyspnoea, COPD-related knowledge and social support. Change in step-count goals reflected intervention engagement. Participants' mean age was 69 (sd=7), and mean forced expiratory volume in 1 s % predicted was 61% (sd=21%). Change in 6MWD did not differ between groups. Intervention participants improved their mean daily step counts by 1312 more than those in the usual care group (p<0.001). Groups did not differ on other secondary outcomes. VABirmingham participants were significantly more engaged with the intervention, although site did not modify the effect of the intervention on 6MWD or secondary outcomes. The intervention did not improve exercise capacity but improved physical activity at 6 months. Additional intervention modifications are needed to optimise its COPD self-management capabilities.

3.
Front Nutr ; 8: 682137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350205

RESUMO

Across all eating patterns, individuals demonstrate marked differences in treatment response; some individuals gain weight and others lose weight with the same approach. Policy makers and research institutions now call for the development and use of personalized nutrition counseling strategies rather than one-size-fits-all dietary recommendations. However, challenges persist in translating some evidence-based eating patterns into the clinical practice due to the persistent notion that certain dietary approaches-regardless of individuals' preferences and health outcomes-are less healthy than others. For example, low- and very low-carbohydrate ketogenic diets (VLCKDs)-commonly defined as 10-26% and <10% total daily energy from carbohydrate, respectively-are recognized as viable lifestyle change options to support weight loss, glycemic control, and reduced medication use. Yet, critics contend that such eating patterns are less healthy and encourage general avoidance rather than patient-centered use. As with all medical treatments, the potential benefits and risks must be considered in the context of patient-centered, outcome-driven care; this is the cornerstone of evidence-based medicine. Thus, the critical challenge is to identify and safely support patients who may prefer and benefit from dietary carbohydrate restriction. In this Perspective, we propose a pragmatic, 4-stepped, outcome-driven approach to help health professionals use carbohydrate-restricted diets as one potential tool for supporting individual patients' weight loss and metabolic health.

4.
Circulation ; 144(1): 74-84, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34228476

RESUMO

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.

5.
Mol Cancer Ther ; 20(10): 1757-1768, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34330842

RESUMO

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

6.
PLoS One ; 16(5): e0251113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33970945

RESUMO

BACKGROUND: The United States is experiencing a surge in Chlamydia trachomatis (CT) infections representing a critical need to improve sexually transmitted infection (STI) screening and treatment programs. To understand where patients with STIs seek healthcare, we evaluated the relationship between CT infections and the place where individuals report usually receiving healthcare. METHODS: Our study used a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2016. The study population is adult patients, aged 18 to 39 years in whom a urine CT screen was obtained. Logistic regression models were used to determine if location of usual healthcare was predictive of a positive urine CT screen result. Models were adjusted for known confounders including age, gender, race/ethnicity, education, and insurance status. RESULTS: In this nationally representative sample (n = 19,275; weighted n = 85.8 million), 1.9% of individuals had a positive urine CT result. Participants reported usually going to the doctor's office (70.3%), "no place" (24.8%), Emergency Department (ED) (3.3%), or "other" place (1.7%) for healthcare. In adjusted models, the predicted probability of having a positive urine CT result is higher (4.9% vs 3.2%, p = 0.022; OR = 1.58) among those that reported the ED as their usual place for healthcare compared to those that reported going to a doctor's office or clinic. CONCLUSIONS: Individuals having a positive urine CT screen are associated with using the ED as a usual source for healthcare. Understanding this association has the potential to improve STI clinical and policy interventions as the ED may be a critical site in combatting the record high rates of STIs.


Assuntos
Infecções por Chlamydia/epidemiologia , Infecções por Chlamydia/terapia , Chlamydia trachomatis/isolamento & purificação , Doenças Sexualmente Transmissíveis/epidemiologia , Doenças Sexualmente Transmissíveis/terapia , Adolescente , Adulto , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/patologia , Bases de Dados Factuais , Atenção à Saúde/métodos , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Inquéritos Nutricionais/métodos , Prevalência , Estudos Retrospectivos , Doenças Sexualmente Transmissíveis/microbiologia , Doenças Sexualmente Transmissíveis/patologia , Estados Unidos/epidemiologia , Adulto Jovem
7.
Dig Dis Sci ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33939147

RESUMO

BACKGROUND AND AIMS: Lifestyle modification is the main treatment for nonalcoholic fatty liver disease (NAFLD), but remains challenging to implement. The aim of this pilot was to assess the acceptability and feasibility of a mobile-technology based lifestyle program for NAFLD patients. METHODS: We enrolled adult patients with NAFLD in a 6-month mobile-technology based program where participants received a FitBit with weekly tailored step count goals and nutritional assessments. Anthropometrics, hepatic and metabolic parameters, Fibroscan, physical function and activity, and health-related quality of life measures were obtained at enrollment and month 6. Semi-structured exit interviews were conducted to assess patient's experience with the program. RESULTS: 40 (63%) eligible patients were enrolled. Median age was 52.5 with 53% males, 93% whites, 43% with diabetes and median BMI 33.9. On baseline Fibroscan, 59% had F0-2 fibrosis and 70% had moderate-severe steatosis. 33 patients completed the study. Median percentage of days with valid FitBit data collection was 91. 4 patients increased and maintained, 19 maintained, and 8 increased but subsequently returned to baseline weekly step count. 59% of patients reported Fitbit was easy to use and 66% felt step count feedback motivated them to increase their activity. Roughly 50% of patients had reduction in weight, triglycerides and Fibroscan liver stiffness, and 75% had improvement in controlled attenuation parameter and physical function. CONCLUSIONS: A 6-month mobile-technology based pilot lifestyle intervention was feasible and acceptable to NAFLD patients. The program promoted physical activity and was associated with improvement in clinical parameters in some patients.

8.
J Cardiopulm Rehabil Prev ; 41(4): 249-256, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33828045

RESUMO

PURPOSE: The objective of this study was to review randomized controlled trials (RCT), which included a wearable activity tracker in an intervention to promote physical activity among cardiac rehabilitation (CR) participants, and to conduct a meta-analysis for the outcomes of step counts and aerobic capacity (V˙o2max). METHODS: Eight databases were searched for RCTs that included an activity tracker, enrolled adults eligible for CR, and reported outcomes of step count or aerobic capacity. Mean differences were calculated for outcomes in the meta-analyses. RESULTS: Nineteen RCTs with 2429 participants were included in the systematic review and 10 RCTs with 891 participants were included in the meta-analysis. Meta-analysis of three RCTs using a pedometer or accelerometer demonstrated a significant increase in daily step count compared with controls (n = 211, 2587 steps/d [95% CI, 916-5257]; I2 = 74.6% and P = .002). Meta-analysis of three RCTs using a pedometer or accelerometer intervention demonstrated a significant increase in V˙o2max compared with controls (n = 260, 2.6 mL/min/kg [95% CI, 1.6-3.6]; I2 = 0.0% and P < .0001). Meta-analysis of four RCTs using a heart rate monitor demonstrated a significant increase in V˙o2max compared with controls (n = 420, 1.4 mL/min/kg [95% CI, 0.4-2.3]; I2 = 0.0% and P = .006). CONCLUSIONS: Use of activity trackers among CR participants was associated with significant increases in daily step count and aerobic capacity when compared with controls. However, study size was small and variability in intervention supports the need for larger trials to assess use of activity trackers in CR.


Assuntos
Reabilitação Cardíaca , Monitores de Aptidão Física , Adulto , Exercício Físico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
JMIR Res Protoc ; 10(4): e27826, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913819

RESUMO

BACKGROUND: Despite current rehabilitation programs, long-term engagement in physical activity remains a significant challenge for patients with chronic obstructive pulmonary disease (COPD) and heart failure (HF). Novel strategies to promote physical activity in these populations are greatly needed. Emerging literature on the benefits of both mind-body interventions and web-based interventions provide the rationale for the development of the Mindful Steps intervention for increasing walking behavior. OBJECTIVE: This study aims to develop a novel multimodal mind-body exercise intervention through adaptation of an existing web-based physical activity intervention and incorporation of mind-body exercise, and to pilot test the delivery of the new intervention, Mindful Steps, in a randomized controlled feasibility trial in older adults with COPD and/or HF. METHODS: In phase 1, guided by a theoretical conceptual model and review of the literature on facilitators and barriers of physical activity in COPD and HF, we convened an expert panel of researchers, mind-body practitioners, and clinicians to inform development of the novel, multimodal intervention. In phase 2, we are conducting a pilot randomized controlled feasibility trial of the Mindful Steps intervention that includes in-person mind-body exercise classes, an educational website, online mind-body videos, and a pedometer with step-count feedback and goals to increase walking behavior in patients with COPD and/or HF. Outcomes include feasibility measures as well as patient-centered measures. RESULTS: The study is currently ongoing. Phase 1 intervention development was completed in March 2019, and phase 2 data collection began in April 2019. CONCLUSIONS: Through the integration of components from a web-based physical activity intervention and mind-body exercise, we created a novel, multimodal program to impact long-term physical activity engagement for individuals with COPD and HF. This developmental work and pilot study will provide valuable information needed to design a future clinical trial assessing efficacy of this multimodal approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT03003780; https://clinicaltrials.gov/ct2/show/NCT03003780. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27826.

10.
Diabetol Metab Syndr ; 13(1): 29, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33691751

RESUMO

INTRODUCTION: Chronic inflammation is associated with the development, progression and long-term complications of type 2 diabetes. Hyperglycemia is associated with chronic low-grade inflammation, and thus has become the focus of many screening and treatment recommendations. We hypothesize that insulin may also be associated with inflammation and may be an additional factor to consider in screening and treatment. METHODS: This study used National Health and Nutrition Examination Survey data from 2005 to 2010 to analyze the association between fasting insulin and C-reactive protein (CRP). A two-part model was used due to the high number of values reported as 0.1 mg/L. Two models were analyzed, both with and without the addition of waist circumference to other covariates in the model. RESULTS: The final sample included 4527 adults with a mean age of 43.31 years. In the first model, higher fasting insulin was associated with increased odds of CRP > 0.1 mg/L (OR = 1.02, p < .001) and with higher CRP (ß = 0.03, p < .001). In the adjusted model, including waist circumference as a covariate, higher fasting insulin was not associated with CRP > 0.1 mg/L (OR = 1.00, p = .307) but the association between higher fasting insulin and higher continuous CRP remained significant (ß = 0.01, p = .012). CONCLUSION: This study found that higher fasting insulin is associated with higher CRP. These results suggest that treatment approaches that simultaneously decrease insulin levels as well as glucose levels may provide additive anti-inflammatory effects, and therefore may improve long-term outcomes for adults with type 2 diabetes.

11.
Telemed J E Health ; 27(11): 1288-1292, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33625893

RESUMO

Objective: To evaluate the cost-effectiveness of a technology-based physical activity (PA) intervention for chronic obstructive pulmonary disease (COPD). Design: A secondary data analysis was performed from a randomized controlled trial in COPD of an activity monitor alone or an activity monitor plus a web-based PA intervention. Models estimated cost per quality-adjusted life year (QALY) and incremental cost-effectiveness ratios (ICERs) compared with usual care. Results: The estimated ICER for both groups was below the willingness-to-pay threshold of $50,000/QALY (activity monitor alone = $10,437/QALY; website plus activity monitor intervention = $13,065/QALY). A probabilistic simulation estimated 76% of the activity monitor-alone group and 78% of the intervention group simulations to be cost-effective. Conclusion(s): Both the activity monitor-alone group and the activity monitor plus website group were cost-effective at the base case by using conventional willingness-to-pay thresholds. Further research would benefit from a more direct estimate of health utilities and downstream health care costs. Clinical Trials.gov NCT01102777.

16.
JMIR Diabetes ; 6(1): e21400, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33427667

RESUMO

BACKGROUND: High levels of psychosocial distress are correlated with worse glycemic control as measured by glycosylated hemoglobin levels (HbA1c). Some interventions specifically targeting diabetes distress have been shown to lead to lower HbA1c values, but the underlying mechanisms mediating this improvement are unknown. In addition, while type 2 diabetes mellitus (T2D) disproportionately affects low-income racial and ethnic minority populations, it is unclear whether interventions targeting distress are differentially effective depending on participants' baseline characteristics. OBJECTIVE: Our objective was to evaluate the mediators and moderators that would inform interventions for improvements in both glycemic control and diabetes distress. METHODS: Our target population included 290 Veterans Affairs patients with T2D enrolled in a comparative effectiveness trial of peer support alone versus technology-enhanced peer support with primary and secondary outcomes including HbA1c and diabetes distress at 6 months. Participants in both arms had significant improvements in both HbA1c and diabetes distress at 6 months, so the arms were pooled for all analyses. Goal setting, perceived competence, intrinsic motivation, and decisional conflict were evaluated as possible mediators of improvements in both diabetes distress and HbA1c. Baseline patient characteristics evaluated as potential moderators included age, race, highest level of education attained, employment status, income, health literacy, duration of diabetes, insulin use, baseline HbA1c, diabetes-specific social support, and depression. RESULTS: Among the primarily African American male veterans with T2D, the median age was 63 (SD 10.2) years with a baseline mean HbA1c of 9.1% (SD 1.7%). Improvements in diabetes distress were correlated with improvements in HbA1c in both bivariate and multivariable models adjusted for age, race, health literacy, duration of diabetes, and baseline HbA1c. Improved goal setting and perceived competence were found to mediate both the improvements in diabetes distress and in HbA1c, together accounting for 20% of the effect of diabetes distress on change in HbA1c. Race and insulin use were found to be significant moderators of improvements in diabetes distress and improved HbA1c. CONCLUSIONS: Prior studies have demonstrated that some but not all interventions that improve diabetes distress can lead to improved glycemic control. This study found that both improved goal setting and perceived competence over the course of the peer support intervention mediated both improved diabetes distress and improved HbA1c. This suggests that future interventions targeting diabetes distress should also incorporate elements to increase goal setting and perceived competence. The intervention effect of improvements in diabetes distress on glycemic control in peer support may be more pronounced among White and insulin-dependent veterans. Additional research is needed to understand how to better target diabetes distress and glycemic control in other vulnerable populations.

18.
Public Health Nutr ; 24(3): 549-560, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32993845

RESUMO

OBJECTIVE: To develop and implement a community-tailored, food agency-based cooking programme at a community health centre (CHC) and evaluate the effect of the intervention on cooking confidence and food waste. DESIGN: This study used an exploratory, sequential mixed methods design. Focus groups (n 38) were conducted to inform the development of a cooking intervention, then six cooking classes (n 45) were planned and piloted in the health centre's teaching kitchen. Changes in cooking confidence and related outcomes were assessed using pre- and post-class surveys. Follow-up interviews (n 12) were conducted 2-4 months post-intervention to assess satisfaction and short-term outcomes. SETTING: A CHC in Detroit, MI. PARTICIPANTS: Spanish- and English-speaking adults aged ≥18 years recruited at the CHC. RESULTS: In the formative focus groups, patients identified multiple barriers to cooking healthy meals, including trade-offs between quality, cost and convenience of food, chronic disease management and lack of time and interest. Each cooking class introduced a variety of cooking techniques and food preservation strategies. Participants demonstrated increased confidence in cooking (P 0·004), experimenting with new ingredients (P 0·006) and knowing how to make use of food before it goes bad (P 0·017). In post-class interviews, participants reported that they valued the social interaction and participatory format and that they had used the recipes and cooking techniques at home. CONCLUSIONS: A community-tailored, hands-on cooking class was an effective way to engage patients at a CHC and resulted in increased cooking confidence.


Assuntos
Culinária/métodos , Adulto , Idoso , Centros Comunitários de Saúde , Feminino , Educação em Saúde , Humanos , Masculino , Refeições , Pessoa de Meia-Idade , Eliminação de Resíduos
20.
Pulm Circ ; 10(4): 2045894020974926, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343883

RESUMO

Exercise rehabilitation is underutilized in patients with pulmonary arterial hypertension despite improving exercise capacity and quality of life. We sought to understand the association between (1) patient characteristics and (2) patient-perceived barriers and referral to exercise rehabilitation. We performed a cross-sectional survey of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension attending an International PAH meeting. Predictors of referral considered included gender, body mass index, subjective socioeconomic status, insurance type, age, and World Health Organization functional class and perceived barriers assessed using the Cardiac Rehabilitation Barriers Scale. Among 65 participants, those in the lowest subjective socioeconomic status tertile had reduced odds of referral compared to the highest tertile participants (odds ratio 0.22, 95% confidence interval: 0.05-0.98, p = 0.047). Several patient-perceived barriers were associated with reduced odds of referral. For every 1-unit increase in a reported barrier on a five-point Likert scale, odds of referral were reduced by 85% for my doctor did not feel it was necessary; 85% for prefer to take care of my health alone, not in a group; 78% many people with heart and lung problems don't go, and they are fine; and 78% for I didn't know about exercise therapy. The lack of perceived need subscale and overall barriers score were associated with a 92% and 77% reduced odds of referral, respectively. These data suggest the need to explore interventions to promote referral among low socioeconomic status patients and address perceived need for the therapy.

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