Objective
Diet‐induced obesity (DIO) causes several pathophysiological changes in adipose tissue. Increased inflammation reduces white adipose tissue (WAT) insulin sensitivity and contributes to the ...development of diabetes. However, little is known about how DIO alters the function of brown adipose tissue (BAT), an organ that consumes calories by β3‐adrenergic receptor (AR)‐mediated thermogenesis and helps regulate energy balance.
Methods
To test the effects of DIO on BAT, we fed 6‐week‐old C57BL/6 mice either a normal chow diet (NCD) or a high‐fat diet (HFD). After 16 additional weeks, we measured body fat, WAT, and BAT mRNA expression, glucose tolerance, and rates of glucose uptake in response to insulin and the β3‐AR agonist mirabegron.
Results
Compared with NCD, HFD increased body fat and impaired glucose tolerance. Both WAT and BAT had higher mRNA levels of markers of inflammation, including TNFα and F4/80. Insulin signaling in BAT and WAT was reduced, with decreased Akt phosphorylation. Diet‐normalized BAT glucose uptake rates were lower in response to mirabegron.
Conclusions
These results support a model in which DIO leads to BAT inflammation and insulin resistance, leading to a broader impairment of BAT function.
Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of β3-adrenergic receptor (AR) agonists ...stimulates rodent BAT, but this activity has never been demonstrated in humans. Here we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a β3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via 18F-fluorodeoxyglucose (18F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 ± 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a β3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease.
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•The β3-AR agonist mirabegron acutely activates human BAT glucose uptake•The β3-AR agonist mirabegron acutely activates human WAT lipolysis•Mirabegron stimulates brown/beige fat in multiple depots.•Mirabegron-induced BAT activity is a predictor of whole-body thermogenesis
Preclinical models indicate that activation of brown adipose tissue (BAT) can improve obesity and diabetes. Cypess et al. show that the β3-adrenergic receptor agonist mirabegron, currently approved for overactive bladder, stimulates human BAT thermogenesis and energy expenditure, suggesting that this pharmacological approach may be a promising treatment for metabolic disease.
The imbalance between energy intake and expenditure is the underlying cause of the current obesity and diabetes pandemics. Central to these pathologies is the fat depot: white adipose tissue (WAT) ...stores excess calories, and brown adipose tissue (BAT) consumes fuel for thermogenesis using tissue-specific uncoupling protein 1 (UCP1). BAT was once thought to have a functional role in rodents and human infants only, but it has been recently shown that in response to mild cold exposure, adult human BAT consumes more glucose per gram than any other tissue. In addition to this nonshivering thermogenesis, human BAT may also combat weight gain by becoming more active in the setting of increased whole-body energy intake. This phenomenon of BAT-mediated diet-induced thermogenesis has been observed in rodents and suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic dysregulation. In this study, we isolated anatomically defined neck fat from adult human volunteers and compared its gene expression, differentiation capacity and basal oxygen consumption to different mouse adipose depots. Although the properties of human neck fat vary substantially between individuals, some human samples share many similarities with classical, also called constitutive, rodent BAT.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction
This real-world, cross-sectional study compared sociodemographic, clinical and treatment characteristics, and patient-reported outcomes (PROs) among racial/ethnic groups in patients with ...atopic dermatitis (AD) who are candidates for systemic therapy.
Methods
This study included adults with dermatologist- or dermatology practitioner-diagnosed AD enrolled in the CorEvitas AD Registry (July 2020–July 2021). All patients initiated systemic therapy within 12 months prior to or at enrollment or had moderate-to-severe AD (vIGA-AD
®
≥ 3 and Eczema Area and Severity Index EASI ≥ 12) at enrollment. Patients were categorized into five mutually exclusive racial/ethnic groups: non-Hispanic White, Black, Asian, Other/Multiracial, and Hispanic (any race). Patient, clinical, and treatment characteristics were captured at enrollment. Differences in means or proportions of characteristics among racial/ethnic groups were descriptively summarized using effect sizes. Adjusted prevalence ratios and mean differences were estimated (White race/ethnicity group as the reference category) with 95% confidence intervals (CI).
Results
Among 1288 patients, 64% (
n
= 822) were White, 13% (
n
= 167) Black, 10% (
n
= 129) Asian, 8% (
n
= 97) Hispanic, and 6% (
n
= 73) Other/Multiracial. In adjusted analyses, statistically more severe EASI lichenification was noted among Black compared with White patients at the head and neck (mean difference, 0.21, 95% CI 0.06, 0.36;
p
= 0.01), trunk (0.32, 0.17, 0.47;
p
< 0.001), upper extremities (0.27, 0.09, 0.44;
p
= 0.008), and lower extremities (0.39, 0.21, 0.57;
p
< 0.001). Statistically more severe EASI lichenification was observed among Asian vs White patients in certain areas (mean difference, head and neck, 0.22 0.04, 0.39,
p
= 0.01; trunk, 0.25 0.07, 0.43,
p
< 0.001; lower extremities, 0.22 0.01, 0.43,
p
< 0.001) and SCORing for AD lichenification (mean difference: 0.34 0.15, 0.52;
p
< 0.001). Significantly higher mean pruritus over the past 7 days for Black (mean difference: 0.63 0.01, 1.26 and Hispanic patients (0.60 0.11, 1.09;
p
= 0.03) vs White patients was observed. Among AD clinical features, the prevalence of facial erythema was significantly lower among Black compared with White patients (prevalence ratio = 0.38, 0.22, 0.67;
p
= 0.007).
Conclusion
Racial/ethnic differences exist in sociodemographic, clinical and treatment characteristics, disease severity, and PROs among real-world AD patients who are candidates for systemic therapy. Recognizing these variations may be of critical importance for dermatologists for the design and delivery of targeted/personalized medicine approaches.
Introduction
This observational study evaluated response in patients with rheumatoid arthritis (RA) who switched from an interleukin-6 receptor inhibitor (IL-6Ri) to a Janus kinase inhibitor (JAKi) ...and vice versa.
Methods
Adult patients with RA, who initiated IL-6Ri or JAKi (following discontinuation of JAKi or IL-6Ri, respectively) during/after December 2012 and had a 6-month follow-up visit were enrolled. Clinical outcomes were evaluated at baseline and the follow-up visit. Continuous outcomes included Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire (HAQ), pain, fatigue, tender joint count, swollen joint count, Physician Global Assessment (MDGA), Patient Global Assessment (PtGA), and morning stiffness duration. Categorical outcomes included the proportion of patients achieving CDAI low disease activity (LDA), remission, and minimal clinically important differences (MCIDs) for HAQ, pain, fatigue, MDGA, and PtGA. Continuous outcomes were summarized as mean changes from baseline, and categorical outcomes as response rates. Differences in the outcome measures between groups were evaluated using linear and logistic regression models.
Results
Between IL-6Ri (
n
= 100) and JAKi initiators (
n
= 129), no significant differences were noted for continuous outcomes. Within both groups, a significant proportion of patients achieved LDA, remission, and MCIDs for other measures, although the odds of achieving LDA were higher among IL-6Ri (vs. JAKi) initiators with moderate-to-severe disease (adjusted odds ratio: 3.30 1.01, 10.78).
Conclusions
Patients with RA can achieve improvement in response when switching between IL-6Ri and JAKi. Although both therapies affect the IL-6 pathway, there are distinct mechanisms of action, which likely contribute to their clinical improvement, when reciprocally switched as follow-on treatments.
Longitudinal follow-up of older persons living with HIV is essential for the ascertainment of aging-related clinical and behavioral outcomes, and self-administered questionnaires are necessary for ...collecting behavioral information in research involving persons living with HIV. Web-based self-reported data collection results in higher data quality than paper-and-pencil questionnaires in a wide range of populations. The option of remote web-based surveys may also increase retention in long-term research studies. However, the acceptability and feasibility of web-based data collection in clinical research involving older persons living with HIV have never been studied.
This study aims to assess the acceptability and feasibility of a web-based survey to collect information on sexual, substance use, and physical activity behaviors; compare the data quality of the web-based survey with that of a paper-and-pencil questionnaire; and summarize web-based survey metrics.
This pilot study took place within the AIDS Clinical Trials Group A5322 study, a longitudinal cohort of men and women living with HIV (aged ≥40 years), followed at 32 clinical sites in the United States and Puerto Rico. A total of 4 sites participated in this study. A web-based survey was created using self-administered questionnaires typically completed in A5322 via paper and pencil. Pilot study participants completed these questionnaires via web-based survey at one research visit in lieu of paper-and-pencil administration. Two questions were added to assess feasibility, defined as participants' perception of the ease of web-based survey completion (very hard, hard, easy, very easy), and their preferred format (computer or tablet, paper and pencil, no preference) for completing the questions in the future (acceptability). Feasibility and acceptability were summarized overall and by demographic and clinical characteristics; the proportion of evaluable data by web-based survey versus previously administered paper-and-pencil questionnaires (data quality) was compared for each question.
Acceptability and feasibility were high overall: 50.0% (79/158) preferred computer or tablet, 38.0% (60/158) reported no preference, and 12.0% (19/158) preferred paper and pencil; 93.0% (147/158) reported survey completion easy or very easy. Older age was associated with lower odds of preferring computer or tablet to paper and pencil (odds ratio per 1-year increase in age: 0.91, 95% CI 0.85-0.98). Individuals who found the survey hard or very hard had a lower median neurocognitive test score than those who found it easy or very easy. Data quality with web-based survey administration was similar to or higher than that with paper-and-pencil administration for most questions.
Web-based survey administration was acceptable and feasible in this cohort of older adults living with HIV, and data quality was high. Web-based surveys can be a useful tool for valid data collection and can potentially improve retention in long-term follow-up studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Despite low plasma human immunodeficiency virus (HIV) RNA, HIV controllers have evidence of viral replication and elevated inflammation. We assessed the effect of antiretroviral ...therapy (ART) on HIV suppression, immune activation, and quality of life (QoL).
Methods
A5308 was a prospective, open-label study of rilpivirine/emtricitabine/tenofovir disoproxil fumarate in ART-naive HIV controllers (N = 35), defined as having HIV RNA <500 copies/mL for ≥12 months. The primary outcome measured change in %CD38+HLA-DR+ CD8+ T cells. Residual plasma viremia was measured using the integrase single-copy assay. QoL was measured using the EQ-5D questionnaire. Outcomes were evaluated using repeated measures general estimating equations models.
Results
Before ART, HIV controllers with undetectable residual viremia <0.6 HIV-1 RNA copies/mL had higher CD4+ counts and lower levels of T-cell activation than those with detectable residual viremia. ART use was effective in further increasing the proportion of individuals with undetectable residual viremia (pre-ART vs after 24–48 weeks of ART: 19% vs 94%, P < .001). Significant declines were observed in the %CD38+HLA-DR+CD8+ T cells at 24–48 (−4.0%, P = .001) and 72–96 (−7.2%, P < .001) weeks after ART initiation. ART use resulted in decreases of several cellular markers of immune exhaustion and in a modest but significant improvement in self-reported QoL. There were no significant changes in CD4+ counts or HIV DNA.
Conclusions
ART in HIV controllers reduces T-cell activation and improves markers of immune exhaustion. These results support the possible clinical benefits of ART in this population.
A5308 was a prospective, open-label study of rilpivirine/emtricitabine/tenofovir disoproxil fumarate in antiretroviral therapy (ART)-naive human immunodeficiency virus (HIV) controllers. ART further suppressed low-level viremia with reductions in T-cell activation and markers of immune exhaustion, suggesting possible clinical benefits for HIV controllers.
Psoriasis patients with poor therapeutic response to multiple biologic agents are not well-characterized.
To describe the characteristics associated with development of multiple biologic failure ...(MBF) versus good clinical response (GR) to the first biologic.
This prospective cohort analysis evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for ≥24 months. Multivariable logistic regression identified sociodemographic, clinical, and patient-reported outcomes that differed between MBF (discontinued ≥2 biologics of different classes, each used for ≥90 days, due to inadequate efficacy) and GR (continued use of first biologic for ≥2 years) patients.
One thousand thirty-nine patients were analyzed (490 GR 47.2%, 65 MBF 6.3%). Female sex, shorter psoriasis duration, earlier year of biologic initiation, prior nonbiologic systemic therapy use, history of hyperlipidemia, and Medicaid insurance were significantly associated with MBF, though the latter 2 variables exhibited wider confidence intervals, indicating a lower level of support. The first-to-second biologic sequence most observed with MBF was Tumor necrosis factor-α inhibitor to IL-17 inhibitor use.
Biologic adherence between visits was not evaluated.
Approximately 6% of psoriasis patients met MBF criteria. The results identify characteristics associated with MBF that may distinguish patients warranting more frequent follow-up.
BACKGROUND:Mental health conditions are common among persons with HIV (PWH). An understanding of factors associated with prescription medication use for these conditions and clinical impact of the ...prescription medications may improve care of mental health disorders in PWH.
METHODS:Psychotropic medication use was examined among PWH within the AIDS Clinical Trials Group A5322 (HAILO) study. Multivariable logistic models and Cox regression models estimated the association between psychotropic medications (any/none) with baseline and incident slow gait (>1 s/m) and neurocognitive impairment (NCI) for more than 4 years.
RESULTS:Of 1035 participants, the median age was 51 years.81% were men, 30% black, non-Hispanic, and 20% Hispanic. Psychotropic medication use was similar between men (34%) and women (38%; P = 0.19). PWH using psychotropic medications had greater odds of baseline slow gait {odds ratio 1.61, 95% confidence interval (CI)1.23 to 2.10; P < 0.001}. Men but not women using psychotropic medications had an increased risk of developing slow gait hazard ratio 1.85; (1.29 to 2.65) vs 0.77; (CI0.35 to 1.68), P interaction = 0.045. The sex-specific odds ratios for medication use and NCI were qualitatively but not statistically different men1.79; (1.14–2.80); women1.27; (0.56–2.90); P interaction = 0.47. Psychotropic medication use was associated with an increased risk of incident NCI hazard ratio 2.18; (95% CI1.23 to 3.84), P = 0.007 in both men and women.
CONCLUSIONS:Psychotropic medications are associated with impairment in functional outcomes of aging, with a greater risk of baseline NCI and incident slow gait among men. Further investigation is needed to optimize outcomes in PWH and prescription of psychotropic medications among both men and women.
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