Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed.

Reporting and analysis of sex in vascular surgery research.

OBJECTIVE: To examine sex in human vascular surgery research by quantifying the inclusion and analysis of sex-based data in high-impact vascular surgery journals. METHODS: A bibliographic review of original articles published in the European Journal of Vascular and Endovascular Surgery, Journal of Vascular Surgery, JVS: Venous and Lymphatic Disorders, Journal of Endovascular Therapy, and Annals of Vascular Surgery from January 1, 2018, to December 31, 2020, and from January 1, 2023, to December 31, 2023, was conducted. Abstracted data included sex-based data analysis, inclusion of sex as a variable in multivariable analysis, inclusion of sex as an independent variable, and a discussion of sex-based results. RESULTS: Of the 3762 articles that included human, animal, or cell subjects, 249 (6.6%) did not state sex. Of those 249 articles, 183 included human subjects, 55 included animal subjects, and 11 used cell lines as the subjects. These were removed from analysis as well as the remaining 68 articles with animal subjects. In addition, 23 researched a sex-specific pathology and were removed from analysis. Of the remaining 3422 articles included in our study, 42.3% analyzed sex, 46.9% included sex in multivariable analysis, 4.8% included sex as an independent variable, and 26.6% included a discussion of sex. There were no significant differences in all four sex variables between 2018, 2019, and 2020. Between 2018-2020 and 2023, there were significant increases in all four sex variables. Multicenter studies had significantly higher rates of independent analysis of sex over single-center studies (7.4% vs 3.3%, P < .001). There was no significant difference in independent analysis of sex between U.S.-based and non-U.S.-based studies. Only 191 articles (5.6%) had 90% or greater matching of men and women in their study. CONCLUSIONS: Equitable inclusion and analysis of sex is rare in vascular surgery research. Less than 5% of articles included an independent analysis of data by sex, and few studies included males and females equally. Clinical research is the basis for evidence-based medicine; therefore, it is important to strive for equitable inclusion, analysis, and reporting of data to foster generalizability of clinical research to men and women.

Dietary omega-3 fatty acids modulate the production of platelet-derived microvesicles in an in vivo inflammatory arthritis model.

PURPOSE: The aim of this study was to investigate the effects of different ω-3 polyunsaturated fatty acid (PUFA) enriched diets, including a novel renewable plant source of ω-3 fatty acids (Buglossoides arvensis), on the development and progression of rheumatoid arthritis (RA). METHODS: RA was induced in mice consuming experimental diets using the K/BxN model. The experimental diets consisted of either a western control diet (control), diets containing B. arvensis oil or fish oil. The effects of the diets on platelets, platelet microvesicles (PMVs), and inflammatory markers such as clinical index, ankle thickness and cytokine/chemokine release were measured. RESULTS: While ω-3 PUFA-enriched diets did not prevent the development of arthritis in the K/BxN model, a significant decrease in ankle swelling was observed compared to the control group. Platelets isolated from mice consuming either low content of B. arvensis oil or fish oil diets exhibited significantly decreased PMVs production compared to mice consuming the control diet. CONCLUSION: Our study provides insight into the contribution of ω-3 PUFA supplementation in modulating the pro-inflammatory phenotype of platelets in RA pathology. Furthermore, our study suggests that low concentrations of dietary B. arvensis oil may have similar anti-inflammatory potential seen with dietary fish oil supplementation.

Paradoxical Changes: EMMPRIN Tissue and Plasma Levels in Marfan Syndrome-Related Thoracic Aortic Aneurysms.

Background: Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. Methods: Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. Results: EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. Conclusions: In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.

Locomotor activity as an effective measure of the severity of inflammatory arthritis in a mouse model.

OBJECTIVE: Mouse models are valuable in preclinical studies of inflammatory arthritis. However, current methods for measuring disease severity or responses to treatment are not optimal. In this study a smart cage system using multiple sensors to measure locomotor activity was evaluated in the K/BxN serum transfer model of inflammatory arthritis. METHODS: Arthritis was induced in C57BL/6 mice with injections of K/BxN serum. Clinical index and ankle thickness were measured for 14 days. Locomotor activity was measured in smart cages for 23 h periods on Days 0, 7, and 13. The same measurements were taken in mice consuming diets supplemented or not with fish oil to evaluate a preventative treatment. RESULTS: Initiation, peak and resolution phases of disease could be measured with the smart cages. Locomotor activity including speed, travel distance, number of active movements and rear movements were all significantly lower on Days 7-8 of illness (peak) compared to Days 0 and 13-14 (resolution) (one-way repeated measures analyses, p<0.05). The clinical index and ankle thickness measurements did not capture differences between dietary groups. Significantly increased activity was measured in most of the locomotor parameters in the fish oil group compared to the control mice at both Days 8 and 14 (2-way repeated measures ANOVA, p<0.05). CONCLUSION: The measurement of locomotor activity provided a more detailed evaluation of the impact of inflammatory arthritis on animal well-being and mobility than that provided by measuring clinical index and ankle thickness, and could be a valuable tool in preclinical studies of inflammatory arthritis.

Discordance of patient-reported outcome measures with objectively assessed walking decline in peripheral artery disease.

OBJECTIVE: Among people with peripheral artery disease (PAD), perceived change in walking difficulty over time, compared with people without PAD, is unclear. Among people reporting no change in walking difficulty over time, differences in objectively measured change in walking performance between people with and without PAD are unknown. METHODS: A total of 1289 participants were included. Eight hundred seventy-four participants with PAD (aged 71.1 ± 9.1 years) were identified from noninvasive vascular laboratories and 415 without PAD (aged 69.9 ± 7.6 years) were identified from people with normal vascular laboratory testing or general medical practices in Chicago. The Walking Impairment Questionnaire and 6-minute walk were completed at baseline and 1-year follow-up. The Walking Impairment Questionnaire assessed perceived difficulty walking due to symptoms in the calves or buttocks on a Likert scale (range, 0-4). Symptom change was determined by comparing difficulty reported at 1-year follow-up to difficulty reported at baseline. RESULTS: At 1-year follow-up, 31.9% of participants with and 20.6% of participants without PAD reported walking difficulty that was improved (P < .01), whereas 41.2% vs 55%, respectively, reported walking difficulty that was unchanged (P < .01). Among all reporting no change in walking difficulty, participants with PAD declined in 6-minute walk, whereas participants without PAD improved (-10 vs +15 meters; mean difference, -25; 95% confidence interval, -38 to -13; P < .01). CONCLUSIONS: Most people with PAD reported improvement or no change in walking difficulty from calf or buttock symptoms at one-year follow-up. Among all participants who perceived stable walking ability, those with PAD had significant greater declines in objectively measured walking performance, compared with people without PAD.

Systemic peptide amphiphile nanofiber delivery following subcutaneous injection.

Peptide amphiphile (PA) nanofibers have been shown to target and deliver drugs when administered via an intravenous (IV) injection. Subcutaneous administration can broaden the applicability of PA nanofibers in the medical field. The ability of PA nanofibers to be absorbed into systemic circulation after subcutaneous administration was investigated. Four PA molecules with different amino acid sequences were designed to understand the effect of nanofiber cohesion and charge on uptake. Solution small-angle X-ray scattering confirmed nanostructure morphology and provided characteristic lengths for co-assemblies. Circular dichroism and solution wide-angle X-ray scattering confirmed PA secondary structure and molecular order. PAs were co-assembled in a 95 %:5 % molar ratio of unlabeled PA to fluorescently labeled PA. Male and female Sprague Dawley rats were injected in the nape of the neck with PA co-assemblies. In vivo normalized abdominal fluorescence was measured 1-72 h after injection. PA nanofibers with a negative charge and low internal order showed the highest amount of systemic absorption at 1, 6, and 24 h. At 24 h after injection, white blood cell count decreased and glucose was elevated. Glucose began to decrease at 48 h. These data indicate that PA nanofibers can be absorbed into the systemic circulation after subcutaneous injection.

Home-Based Walking Exercise and Supervised Treadmill Exercise in Patients With Peripheral Artery Disease: An Individual Participant Data Meta-Analysis.

Importance: Few people with lower extremity peripheral artery disease (PAD) participate in supervised treadmill exercise covered by the Center for Medicare and Medicaid Services. In people with PAD, the benefits of home-based walking exercise, relative to supervised exercise, remain unclear. Objective: To study whether home-based walking exercise improves 6-minute walk (6MW) more than supervised treadmill exercise in people with PAD (defined as Ankle Brachial Index ≤0.90). Data Sources: Data were combined from 5 randomized clinical trials of exercise therapy for PAD using individual participant data meta-analyses, published from 2009 to 2022. Study Selection: Of the 5 clinical trials, 3 clinical trials compared supervised treadmill exercise to nonexercise control (N = 370) and 2 clinical trials compared an effective home-based walking exercise intervention to nonexercise control (N = 349). Data Extraction and Synthesis: Individual participant-level data from 5 randomized clinical trials led by 1 investigative team were combined. The 5 randomized clinical trials included 3 clinical trials of supervised treadmill exercise and 2 effective home-based walking exercise interventions. Main Outcomes and Measures: Change in 6MW distance, maximum treadmill walking distance, and Walking Impairment Questionnaire at 6-month follow-up. The supervised treadmill exercise intervention consisted of treadmill exercise in the presence of an exercise physiologist, conducted 3 days weekly for up to 50 minutes per session. Home-based walking exercise consisted of a behavioral intervention in which a coach helped participants walk for exercise in or around home for up to 5 days per week for 50 minutes per session. Results: A total of 719 participants with PAD (mean [SD] age, 68.8 [9.5] years; 46.5% female) were included (349 in a home-based exercise clinical trial and 370 in a supervised exercise trial). Compared with nonexercise control, supervised treadmill exercise was associated with significantly improved 6MW by 32.9 m (95% CI, 20.6-45.6; P < .001) and home-based walking exercise was associated with significantly improved 6MW by 50.7 m (95% CI, 34.8-66.7; P < .001). Compared with supervised treadmill exercise, home-based walking exercise was associated with significantly greater improvement in 6MW distance (between-group difference: 23.8 m [95% CI, 3.6, 44.0; P = .02]) but significantly less improvement in maximum treadmill walking distance (between-group difference:-132.5 m [95% CI, -192.9 to -72.1; P < .001]). Conclusions and Relevance: In this individual participant data meta-analyses, compared with supervised exercise, home-based walking exercise was associated with greater improvement in 6MW in people with PAD. These findings support home-based walking exercise as a first-line therapy for walking limitations in PAD.

Better together: novel methods for measuring and modeling development of executive function diversity while accounting for unity.

Introduction: Executive functions (EFs) are linked to positive outcomes across the lifespan. Yet, methodological challenges have prevented precise understanding of the developmental trajectory of their organization. Methods: We introduce novel methods to address challenges for both measuring and modeling EFs using an accelerated longitudinal design with a large, diverse sample of students in middle childhood (N = 1,286; ages 8 to 14). We used eight adaptive assessments hypothesized to measure three EFs, working memory, context monitoring, and interference resolution. We deployed adaptive assessments to equate EF challenge across ages and a data-driven, network analytic approach to reveal the evolving diversity of EFs while simultaneously accounting for their unity. Results and discussion: Using this methodological paradigm shift brought new precision and clarity to the development of these EFs, showing these eight tasks are organized into three stable components by age 10, but refinement of composition of these components continues through at least age 14.

Testing the whole number interference hypothesis: Contributions of inhibitory control and whole number knowledge to fraction understanding.

The present study tests two predictions stemming from the hypothesis that a source of difficulty with rational numbers is interference from whole number magnitude knowledge. First, inhibitory control should be an independent predictor of fraction understanding, even after controlling for working memory. Second, if the source of interference is whole number knowledge, then it should hinder fraction understanding. These predictions were tested in a racially and socioeconomically diverse sample of U.S. children (N = 765; 337 female) in Grades 3 (ages 8-9), 5 (ages 10-11), and 7 (ages 12-13) who completed a battery of computerized tests. The fraction comparison task included problems with both shared components (e.g., 3/5 > 2/5) and distinct components (e.g., 2/3 > 5/9), and problems that were congruent (e.g., 5/6 > 3/4) and incongruent (e.g., 3/4 > 5/7) with whole number knowledge. Inhibitory control predicted fraction comparison performance over and above working memory across component and congruency types. Whole number knowledge did not hinder performance and instead positively predicted performance for fractions with shared components. These results highlight a role for inhibitory control in rational number understanding and suggest that its contribution may be distinct from inhibiting whole number magnitude knowledge. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Gender Bias in Clinical Trial Enrollment: Female Authorship Matters.

BACKGROUND: Despite initiatives to promote equal enrollment of human subjects in clinical trials, females continue to be underrepresented. The goal of this work is to determine if female enrollment in human clinical trials published in 3 high-impact journals from 2015 to 2019 is correlated with gender of first and/or senior authors. METHODS: Clinical trials published in the Journal of the American Medical Association (JAMA), The Lancet, and the New England Journal of Medicine (NEJM) from January 1, 2015, to December 31, 2019, were reviewed. Trials were excluded for ongoing enrollment, sex-specific disease research, or author name without gender assignment. One-sample χ2 pairwise comparisons and two-tailed proportion tests on the proportion of females between gender author pairings were done overall and for each subset analysis. RESULTS: In total, 1,427 articles enrolled a total of 2,104,509 females and 2,616,981 males (44.6% vs. 55.4%, P ≤ 0.0001) in clinical trials. Overall, more females were enrolled if both first and senior authors were female (51.7% vs. 48.3%, P ≤ 0.0001). Proportion of females enrolled decreased with the following first and senior author pairings: female-male (48.9%), male-female (48.6%), and male-male (40.5%, P ≤ 0.0001 compared to female-female authorship). Greater female enrollment in clinical trials with female-female compared to male-male authorship persisted in subset analyses by funding source, phase, randomization for study participants, drug and/or device trial, and geographic location. Female enrollment was higher in 3 surgical specialties: neurosurgery (all authors: 52%, P ≤ 0.01), ophthalmology (all authors: 53.6%, P ≤ 0.0001), and surgery (all authors: 54.4%, P ≤ 0.0001). The majority of surgical specialties did not publish trials with female-female authorship but when stratifying by author gender pairing, surgical oncology had the highest female enrollment with female-female authorship (98.4%, P ≤ 0.0001). CONCLUSIONS: Female authorship of clinical trial publications, specifically having both first and senior authors as female, was correlated with higher female enrollment in clinical trials when compared to male authorship and endured with multiple subset analyses.