An observational study protocol to explore loneliness and systemic inflammation in an older adult population with chronic venous leg ulcers.

BACKGROUND: Chronic venous leg ulcers (CVLUs) are the most common type of lower extremity wound. Even when treated with evidenced-based care, 30-50% of CVLUs fail to heal. A specific gap exists about the association between psychosocial stressors, particularly loneliness, and biomarkers of inflammation and immunity. Loneliness is highly prevalent in persons with CVLUs, has damaging effects on health, and contributes to the development of multiple chronic conditions, promotes aberrant inflammation, and diminishes healing. However, the confluence of loneliness, inflammation and the wound healing trajectory has not been elucidated; specifically whether loneliness substantially mediates systemic inflammation and alters healing over time. This study seeks to address whether there is a specific biomarker profile associated with loneliness, CVLUs, and wound healing that is different from non-lonely persons with CVLUs. METHODS: An observational prospective study will identify, characterize and explore associations among psychosocial stressors, symptoms and biomarkers between 2 CVLU groups, with loneliness+ (n = 28) and without loneliness- (n = 28) during 4 weeks of wound treatment, measured at 3 time points. We will examine psychosocial stressors and symptoms using psychometrically-sound measures include PROMIS® and other questionnaires for loneliness, social isolation, depression, anxiety, stigma, sleep, fatigue, pain, quality of life, cognition, and function. Demographics data including health history, sex, age, wound type and size, wound age, and treatment will be recorded from the electronic health record. We will characterize a biomarker panel of inflammatory genes including chemotaxic and growth factors, vascular damage, and immune regulators that express in response to loneliness to loneliness and CVLUs using well-established RNA sequence and PCR methods for whole blood samples. In an exploratory aim we will explore whether age and sex/psychological stressors and symptoms indicate potential moderation/mediation of the effect of loneliness on the biomarker profile over the study period. DISCUSSION: This study will provide insight into the influence of psychosocial stressors, symptoms, and biological mechanisms on wound healing, towards advancing a future healing prediction model and interventions to address these stressors and symptoms experienced by persons with CVLUs.

A Lower Leg Physical Activity Intervention for Individuals With Chronic Venous Leg Ulcers: Randomized Controlled Trial.

BACKGROUND: Individuals with venous leg ulcers (VLUs) suffer disproportionately with multiple chronic conditions, are often physically deconditioned, and demonstrate high levels of physical inactivity. OBJECTIVE: The primary objective of this randomized controlled trial was to establish the feasibility of a mobile health (mHealth) physical activity exercise app for individuals with VLUs to improve lower leg function. METHODS: In a 6-week study, adults with VLUs were recruited from 2 wound centers in South Carolina, United States, and enrolled if they were aged 18 years or older with impaired functional mobility and an ankle-brachial index between 0.8 and 1.3. Participants were randomized 1:1 to receive evidence-based, phased, nonexertive physical conditioning activities for lower leg function (FOOTFIT) or FOOTFIT+ with an added patient-provider communication feature. The mHealth Conditioning Activities for Lower Leg Function app also provided automated educational and motivational messages and user reports. Foot movement on the VLU-affected leg was tracked by a Bluetooth-enabled triaxial accelerometer. The study was guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to assess the feasibility of reach, adherence, acceptability, implementation, and maintenance. RESULTS: A total of 24 patients were recruited, enrolled, and randomized in the study. Most patients reported difficulty following the protocol for exercising and using the accelerometer and mobile phone and did not use the provider contact feature. However, all patients were adherent to the 6-week exercise program more than 85% of the time for duration, whereas 33% (8/24) of patients adhered more than 85% for the frequency of performing the exercises. Across the three exercise levels, adherence did not differ between the two groups. Confidence limits around the difference in proportions ranged from -0.4 to 0.7. Providers in FOOTFIT+ were inconsistent in checking participant progress reports because of lack of time from competing work commitments. The technology became outdated quickly, making maintenance problematic. Participants said they would continue to exercise their foot and legs and liked being able to follow along with the demonstrations of each level of exercise provided through the app. CONCLUSIONS: The findings of this study suggest that despite initial interest in using the app, several components of the program as originally designed had limited acceptability and feasibility. Future refinements should include the use of more modern technology including smaller wearable accelerometers, mobile phones or tablets with larger screens, an app designed with larger graphics, automated reporting for providers, and more engaging user features. TRIAL REGISTRATION: ClinicalTrials.gov NTC02632695; https://clinicaltrials.gov/ct2/show/NCT02632695.

Differential induction of early response genes by adrenomedullin and transforming growth factor-beta1 in human lung cancer cells.

Adrenomedullin (AM) is a hypotensive polypeptide that has been shown to stimulate cyclic AMP and intracellular free Ca2+ agents that are known to induce expression of proto-oncogenes, in various cell types. Transforming growth factor-beta 1 (TGF-beta1) is a multifunctional polypeptide that regulates proliferation, differentiation and cell cycle progression in both normal and malignant epithelial cells. The diverse biological actions of AM and TGF-beta1 may be related to their capacities to initiate different genomic programs in target cells via the induction of expression of multiple genes including early response genes and proto-oncogenes. AM, TGF-beta1 and phorbol-12-myristate-13-acetate (PMA) exert both positive and negative effects on mitogenesis. The effects of AM, TGF-beta1 and PMA were examined in human non-small cell lung cancer (NSCLC) cells. AM caused an increase in its mRNA transcript that peaked by 6 hours and persisted to 24 hours. While expression of TGF-beta1 mRNA was not affected by AM in these cells, the mRNAs for TGF-beta1 and TGF-beta3 decreased by 3 hours. In contrast, TGF-beta1 had no effect on expression of AM mRNA. Interestingly, PMA caused an increase in AM and TGF-beta1 mRNAs in NSCLC cells. While both TGF-beta1 and PMA caused a transient increase in expression of the mRNAs for early response genes including c-fos, c-jun and egr-1 that peaked by 1 hour following treatment, the increase in expression of these mRNAs following treatment with AM peaked only after 3-6 hours. Western blotting analysis showed increases in the levels of c-jun protein following treatment with AM, TGF-beta1 and PMA. The increase in c-jun protein from treatment with AM occurred 10 hours after that from TGF-beta1 and PMA. Activator protein 1 (AP-1) DNA binding activity was also demonstrated to increase following treatment with AM, TGF-beta1 and PMA, with the increase in AP-1 DNA binding activity following AM treatment occurring 10 hours later than that from TGF-beta1 and PMA treatment. These data show that AM can regulate expression of its mRNA transcript in NSCLC cells. Our study suggests that NSCLC cells are important targets of AM and TGF-beta1 and that AM and TGF-beta1 may regulate activities in these malignant lung cells through differential induction of various early response genes.