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.

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.

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.