Nicotine Impairs Smooth Muscle cAMP Signaling and Vascular Reactivity.

OBJECTIVE: This study aimed to determine nicotine's impact on receptor-mediated cyclic adenosine monophosphate (cAMP) synthesis in vascular smooth muscle (VSM). We hypothesize that nicotine impairs ß adrenergic-mediated cAMP signaling in VSM, leading to altered vascular reactivity. METHODS: The effects of nicotine on cAMP signaling and vascular function were systematically tested in aortic VSM cells and acutely isolated aortas from mice expressing the cAMP sensor TEpacVV (Camper), specifically in VSM (e.g., CamperSM). RESULTS: Isoproterenol (ISO)-induced ß-adrenergic production of cAMP in VSM was significantly reduced in cells from second-hand smoke (SHS)-exposed mice and cultured wild-type VSM treated with nicotine. The decrease in cAMP synthesis caused by nicotine was verified in freshly isolated arteries from a mouse that had cAMP sensor expression in VSM (e.g., CamperSM mouse). Functionally, the changes in cAMP signaling in response to nicotine hindered ISO-induced vasodilation, but this was reversed by immediate PDE3 inhibition. CONCLUSIONS: These results imply that nicotine alters VSM ß adrenergic-mediated cAMP signaling and vasodilation, which may contribute to the dysregulation of vascular reactivity and the development of vascular complications for nicotine-containing product users.

Using the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) to study adaptations in lung cancer screening delivery in the Veterans Health Administration: a cohort study.

BACKGROUND: Lung cancer screening is a complex clinical process that includes identification of eligible individuals, shared decision-making, tobacco cessation, and management of screening results. Adaptations to the delivery process for lung cancer screening in situ are understudied and underreported, with the potential loss of important considerations for improved implementation. The Framework for Reporting Adaptations and Modifications-Expanded (FRAME) allows for a systematic enumeration of adaptations to implementation of evidence-based practices. We applied FRAME to study adaptations in lung cancer screening delivery processes implemented by lung cancer screening programs in a Veterans Health Administration (VHA) Enterprise-Wide Initiative. METHODS: We prospectively conducted semi-structured interviews at baseline and 1-year intervals with lung cancer screening program navigators at 10 Veterans Affairs Medical Centers (VAMCs) between 2019 and 2021. Using this data, we developed baseline (1st) process maps for each program. In subsequent years (year 1 and year 2), each program navigator reviewed the process maps. Adaptations in screening processes were identified, documented, and mapped to FRAME categories. RESULTS: We conducted a total of 16 interviews across 10 VHA lung cancer screening programs (n=6 in year 1, n=10 in year 2) to collect adaptations. In year 1 (2020), six programs were operational and eligible. Of these, three reported adaptations to their screening process that were planned or in response to COVID-19. In year 2 (2021), all 10 programs were operational and eligible. Programs reported 14 adaptations in year 2. These adaptations were planned and unplanned and often triggered by increased workload; 57% of year 2 adaptations were related to the identification and eligibility of Veterans and 43% were related to follow-up with Veterans for screening results. Throughout the 2 years, adaptations related to data management and patient tracking occurred in 60% of programs to improve the data collection and tracking of Veterans in the screening process. CONCLUSIONS: Using FRAME, we found that adaptations occurred primarily in the areas of patient identification and communication of results due to increased workload. These findings highlight navigator time and resource considerations for sustainability and scalability of existing and future lung cancer screening programs as well as potential areas for future intervention.

Spatiotemporal Control of Vascular CaV1.2 by α1C S1928 Phosphorylation.

BACKGROUND: L-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia. METHODS: A multiscale approach including patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, calcium imaging' pressure myography, and Laser Speckle imaging was implemented to examine CaV1.2 cooperativity, α1C clustering, myogenic tone, and blood flow in human and mouse arterial myocytes/vessels. RESULTS: CaV1.2 activity and cooperative gating increase in arterial myocytes from patients with type 2 diabetes and type 1 diabetic mice, and in wild-type mouse arterial myocytes after elevating extracellular glucose. These changes were prevented in wild-type cells pre-exposed to a PKA inhibitor or cells from knock-in S1928A but not S1700A mice. In addition, α1C clustering at the surface membrane of wild-type, but not wild-type cells pre-exposed to PKA or P2Y11 inhibitors and S1928A arterial myocytes, was elevated upon hyperglycemia and diabetes. CaV1.2 spatial and gating remodeling correlated with enhanced arterial myocyte Ca2+ influx and contractility and in vivo reduction in arterial diameter and blood flow upon hyperglycemia and diabetes in wild-type but not S1928A cells/mice. CONCLUSIONS: These results suggest that PKA-dependent S1928 phosphorylation promotes the spatial reorganization of vascular α1C into "superclusters" upon hyperglycemia and diabetes. This triggers CaV1.2 activity and cooperativity, directly impacting vascular reactivity. The results may lay the foundation for developing therapeutics to correct CaV1.2 and arterial function during diabetic hyperglycemia.

Using the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) to study lung cancer screening adaptations in the Veterans Health Administration.

Background: Lung cancer screening includes identification of eligible individuals, shared decision-making inclusive of tobacco cessation, and management of screening results. Adaptations to the implemented processes for lung cancer screening in situ are understudied and underreported, with potential loss of important considerations for improved implementation. The Framework for Reporting Adaptations and Modifications-Expanded (FRAME) allows for systematic enumeration of adaptations to implementations of evidence-based practices. We used FRAME to study adaptations in lung cancer screening processes that were implemented as part of a Veterans Health Administration (VHA) Enterprise-Wide Initiative. Methods: We conducted semi-structured interviews at baseline and 1-year intervals with lung cancer screening program navigators at 10 Veterans Affairs Medical Centers (VAMC) between 2019-2021. Using this data, we developed baseline (1st) process maps for each program. In subsequent years (year 1 and year 2), each program navigator reviewed the process maps. Adaptations in screening processes were identified, recorded and mapped to FRAME categories. Results: A total of 14 program navigators across 10 VHA lung cancer screening programs participated in 20 interviews. In year 1 (2019-2020), seven programs were operational and of these, three reported adaptations to their screening process that were either planned and in response to COVID-19. In year 2 (2020-2021), all 10 programs were operational. Programs reported 14 adaptations in year 2. These adaptations were both planned and unplanned and often triggered by increased workload; 57% of year 2 adaptations were related to identification and eligibility of Veterans and 43% were related to follow-up with Veterans for screening results. Throughout the 2 years, adaptations related to data management and patient tracking occurred in 6 of 10 programs to improve the data collection and tracking of Veterans in the screening process. Conclusions: Using FRAME, we found that adaptations occurred throughout the lung cancer screening process but primarily in the areas of patient identification and communication of results. These findings highlight considerations for lung cancer screening implementation and potential areas for future intervention.

Secondhand Smoke Exposure Impairs Ion Channel Function and Contractility of Mesenteric Arteries.

Cigarette smoke, including secondhand smoke (SHS), has significant detrimental vascular effects, but its effects on myogenic tone of small resistance arteries and the underlying mechanisms are understudied. Although it is apparent that SHS contributes to endothelial dysfunction, much less is known about how this toxicant alters arterial myocyte contraction, leading to alterations in myogenic tone. The study's goal is to determine the effects of SHS on mesenteric arterial myocyte contractility and excitability. C57BL/6J male mice were randomly assigned to either filtered air (FA) or SHS (6 h/d, 5 d/wk) exposed groups for a 4, 8, or 12-weeks period. Third and fourth-order mesenteric arteries and arterial myocytes were acutely isolated and evaluated with pressure myography and patch clamp electrophysiology, respectively. Myogenic tone was found to be elevated in mesenteric arteries from mice exposed to SHS for 12 wk but not for 4 or 8 wk. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 wk of SHS exposure. Moreover, 12 wk SHS exposed arterial myocytes have reduced total potassium channel current density, which correlates with a depolarized membrane potential (Vm). These results suggest that SHS exposure induces alterations in key ionic conductances that modulate arterial myocyte contractility and myogenic tone. Thus, chronic exposure to an environmentally relevant concentration of SHS impairs mesenteric arterial myocyte electrophysiology and myogenic tone, which may contribute to increased blood pressure and risks of developing vascular complications due to passive exposure to cigarette smoke.

Moving electronic medical records upstream: incorporating social determinants of health.

BACKGROUND: Knowledge of the biological pathways and mechanisms connecting social factors with health has increased exponentially over the past 25 years, yet in most clinical settings, screening and intervention around social determinants of health are not part of standard clinical care. Electronic medical records provide new opportunities for assessing and managing social needs in clinical settings, particularly those serving vulnerable populations. PURPOSE: To illustrate the feasibility of capturing information and promoting interventions related to social determinants of health in electronic medical records. METHODS: Three case studies were examined in which electronic medical records have been used to collect data and address social determinants of health in clinical settings. RESULTS: From these case studies, we identified multiple functions that electronic medical records can perform to facilitate the integration of social determinants of health into clinical systems, including screening, triaging, referring, tracking, and data sharing. CONCLUSIONS: If barriers related to incentives, training, and privacy can be overcome, electronic medical record systems can improve the integration of social determinants of health into healthcare delivery systems. More evidence is needed to evaluate the impact of such integration on health care outcomes before widespread adoption can be recommended.