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In this study, we explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes-associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, YAP, TAZ, and Hippo scaffold, IQGAP1, in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Notably, our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its co-transcriptional activity in both melanoma and breast carcinoma cells. Importantly, our study showcases the potential therapeutic relevance of targeting PANX1, as pharmacological inhibition of PANX1 using selective FDA-approved inhibitors or PANX1 knockdown reduced YAP abundance in melanoma cells. Furthermore, our Clariom ™ S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), β-galactoside binding protein, galectin-3 (LGALS3), that are affected in PANX1-deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment., Competing Interests: Conflict of Interest Statement The authors declare no conflict of interest with this manuscript.

Background and Aims: Medical nutrition therapy is important for diabetes management. This randomized controlled trial investigated the effects of a diabetes-specific formula (DSF) on glycemic control and cardiometabolic risk factors in adults with type 2 diabetes (T2D)., Methods: Participants ( n  = 235) were randomized to either DSF with standard of care (SOC) (DSF group; n  = 117) or SOC only (control group; n  = 118). The DSF group consumed one or two DSF servings daily as meal replacement or partial meal replacement. The assessments were done at baseline, on day 45, and on day 90., Results: There were significant reductions in glycated hemoglobin (-0.44% vs. -0.26%, p =  0.015, at day 45; -0.50% vs. -0.21%, p =  0.002, at day 90) and fasting blood glucose (-0.14 mmol/L vs. +0.32 mmol/L, p =  0.036, at day 90), as well as twofold greater weight loss (-1.30 kg vs. -0.61 kg, p   < 0.001, at day 45; -1.74 kg vs. -0.76 kg, p  < 0.001, at day 90) in the DSF group compared with the control group. The decrease in percent body fat and increase in percent fat-free mass at day 90 in the DSF group were almost twice that of the control group (1.44% vs. 0.79%, p =  0.047). In addition, the percent change in visceral adipose tissue at day 90 in the DSF group was several-fold lower than in the control group (-6.52% vs. -0.95%, p  < 0.001). The DSF group also showed smaller waist and hip circumferences, and lower diastolic blood pressure than the control group (all overall p  ≤ 0.045)., Conclusion: DSF with SOC yielded significantly greater improvements than only SOC in glycemic control, body composition, and cardiometabolic risk factors in adults with T2D., Competing Interests: SLT, GB, BW, and DTTH are employees of Abbott Nutrition. YB was an employee of Cognizant Technology Solutions, a contract research organization that provides statistical services to Abbott Nutrition and has no competing interests. WSSC reports receiving research grants and honoraria for consultancy from Abbott Nutrition and honoraria for consultancy or speaking engagements from Novo Nordisk, Merck, Boehringer Ingelheim, and AstraZeneca. CD reports receiving research grants and honoraria for consultancy and speaking engagements from Abbott. L-LL reports receiving grants and/or honoraria for consultancy or giving lectures from Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Roche, Sanofi, Servier, and Zuellig Pharma. AB reports receiving research grant and honoraria for consultancy and speaking from Abbott, Novartis, and Novo Nordisk, as well as receiving honoraria for consultancy or giving lectures from Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Sanofi, Servier, Bayer, and Zuellig Pharma. The funders were involved in the design of the study; in the collection, analyses, or interpretation of data; and in the writing of the manuscript. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tey, Chee, Deerochanawong, Berde, Lim, Boonyavarakul, Wakefield, Baggs and Huynh.)

BACKGROUND: The availability of Medicare Part D pharmacy coverage may increase veterans' options for obtaining medications outside of the Department of Veterans Affairs (VA) pharmacies. However, availability of Part D coverage raises the potential that veterans may be receiving similar medications from VA and non-VA pharmacies. The VA's personal health record portal, My HealtheVet, allows veterans to self-enter the non-VA medications that they obtained from community-based pharmacies, including those reimbursed by Medicare Part D. The Blue Button medication view feature of My HealtheVet allows veterans to view and download their VA and self-entered non-VA medication history. OBJECTIVE: To examine whether the use by veterans of the Blue Button feature of My HealtheVet was associated with less acquisition of similar medications from VA and community-based pharmacies reimbursed by Medicare Part D. METHODS: This study included a national sample of veterans who were new My HealtheVet users during fiscal year 2013 (October 1, 2012-September 30, 2013) and who used the Blue Button medication view feature of My HealtheVet at least once (users). We compared these veterans with a random sample of veterans who were not registered to use My HealtheVet (nonusers). From these groups, we identified veterans who were enrolled in Part D. We used multiple logistic regression analysis to assess the association of Blue Button medication view use with obtaining medications from the same drug classes (with overlap of 7 or more days) from VA and Part D-reimbursed pharmacies. RESULTS: There were 7,973 My HealtheVet medication view users and 65,985 nonusers. During a 12-month period, medication view users received more 30-day supplies of medications (one 90-day supply equals three 30-day supplies) than nonusers, on average (152.1 vs 71.3, P < 0.001). A larger percentage of users than nonusers obtained medications from VA and Part D-reimbursed pharmacies with overlapping days supply from the same drug classes (30% vs 23%, P < 0.001). However, for veterans who obtained greater numbers of 30-day supplies (82 or more), a significantly smaller percentage of users than nonusers obtained overlapping medications from VA and Part D-reimbursed pharmacies. Moreover, controlling for the total number of 30-day supplies that veterans received, the odds of obtaining medications from VA and Part D-reimbursed pharmacies with days supply that overlapped by at least 7 days for the same drug classes was 18% lower for users than nonusers ( P =0.002). CONCLUSIONS: Veterans who used the Blue Button medication view feature of My HealtheVet obtained a larger number of 30-day supplies of medications from VA pharmacies than nonusers. For veterans who obtained a larger number of 30-day supplies of medications, use of the Blue Button medication view feature of My HealtheVet was associated with less overlap in days supply of medication from the same drug class from VA and Part D-reimbursed pharmacies. DISCLOSURES: This study was funded by the Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service project IIR 14-041-2. The sponsor provided funding but was not involved in the development of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the Health Services Research and Development Service. All authors are employed in some capacity with the Department of Veterans Affairs and have no conflicts of interest to disclose.

Background: Medication nonadherence is a public health issue that contributes to poor health outcomes and health-care costs. Factors influencing long-term medication adherence are known; however, little is known about short-course medication adherence., Objective: This study examined patient perspectives on adherence and factors that influence adherence to short-course pharmacotherapy in diarrhea-predominant irritable bowel syndrome., Method: Twenty-seven participants were interviewed to identify their perceptions of barriers and facilitators to thrice-daily, 14-day rifaximin., Results: Participants were primarily female (89%), aged 18 to 65 years. Sixty-eight percent of interviewees were identified as "low-adherers," meaning the percentage of days with correct daily dosing of rifaximin was <80%. The final coding framework identified social/economic-related (family support and medication expense), system-related (relationship with provider and medication knowledge), condition-related (symptom severity), therapy-related (inconvenient dosing), and patient-related (forgetfulness and busyness of daily life) factors that influenced adherence., Conclusion: The resulting patient perspectives highlight a diverse set of factors that influence short-course adherence and the need for tailored interventions that address these various factors resulting in enhanced patient outcomes., Competing Interests: Declaration of Conflicting Interests: The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Background: Delivery of comprehensive care for persons with human immunodeficiency virus (HIV) infection in rural and low prevalence settings presents many challenges. We developed and evaluated a telehealth collaborative care (TCC) program for persons with HIV in a rural area., Objective: To determine the feasibility of TCC, and identify factors influencing implementation in rural settings., Design: Mixed methods evaluation of a quality improvement program with pre-measures and post-measures., Patients: Veterans with HIV infection in Iowa and Illinois., Intervention: TCC integrated HIV specialty care delivered by clinical video telehealth, with primary care delivered by generalist providers, in seven Community Based Outpatient Clinics (CBOCs) serving rural areas. Principles guiding TCC design were: 1) clear delineation of specialty and primary care clinic roles in co-managed care; 2) creation of processes to improve care coordination between specialty and primary care teams; and 3) use of a patient registry for population management across sites., Measures: Veterans Affairs (VA) healthcare system performance measures for care for HIV infection and common comorbidities, patient travel time to obtain care, and patient satisfaction. Qualitative evaluation involved semi-structured telephone interviews with patients., Key Results: Thirty of 32 eligible patients chose TCC over traveling to the HIV clinic for all care. Among 24 patients in TCC during the June 2011-May 2012 evaluation period, median age was 54 (range, 40-79), most (96 %) were men, and median CD4 count was 707 cells/cm(3) (range, 233-1307). VA performance measures were met for > 90 % of TCC patients. Median yearly travel time decreased from 320 min per patient prior to TCC to 170 min during TCC (p < 0.001). Interview themes included: 1) overcoming privacy concerns during care in local primary care clinics; 2) tradeoffs between access, continuity, and care coordination; and 3) the role of specialist involvement in collaborative care., Discussion: Telehealth Collaborative Care is a feasible approach to providing accessible and comprehensive care for persons with HIV in rural settings.

Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors.

Background: Many healthcare organizations have embraced eHealth technologies in their efforts to promote patient-centered care, increase access to services, and improve outcomes., Objective: Using the Department of Veterans Affairs (VA) as a case study, this paper presents two specific eHealth technologies, the Care Coordination Home Telehealth (CCHT) Program and the My HealtheVet (MHV) personal health record (PHR) portal with integrated secure messaging, and articulates a vision of how they might be implemented as part of a patient-centric healthcare model and used in a complementary manner to enhance access to care and to support patient-centered care., Methods: Based on our experience and ongoing work with both programs, we offer a series of recommendations for pursuing and ultimately achieving this vision., Conclusion: VA's CCHT and MHV programs are examples of an expanding repertoire of eHealth applications available to patients and healthcare teams. VA's new patient-centric healthcare model represents a significant shift in the way that services are delivered and a profound opportunity to incorporate eHealth technologies like the CCHT and MHV programs into clinical practice to increase access to care, and to ensure the responsiveness of such technologies to the preferences and circumstances of patients.

Family members play an important role in the physical and mental recovery of soldiers returning from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Posttraumatic stress disorder (PTSD) has been associated with strained marital and family relations and parenting difficulties, and many veterans with PTSD experience difficulty finding and maintaining employment. Family members who assist with the veteran's recovery also experience significant strain and may have to leave employment to care for the veteran. Our objective was to identify appropriate assessment measures for examining the well-being of spouses assisting with veterans' recovery and to identify opportunities for supporting veterans' spouses. We used a combination of expert panel input and qualitative methods (focus group interviews) to develop a battery of instruments for use in future research with OIF/OEF family members to examine well-being. Research is needed to elucidate and refine the special needs and issues surrounding PTSD in current and future OIF/OEF veterans and their families. This study provides a first step toward understanding appropriate measures. Expert panel methods and focus group interviews yielded valuable input on the domains and measures that should be included in the assessment battery as well as opportunities for assisting spouses.

Objective: A limitation of studies comparing outcomes of Veterans Affairs (VA) and private sector hospitals is uncertainty about the methods of accounting for risk factors in VA populations. This study estimates whether use of VA services is a marker for increased risk by comparing outcomes of VA users and other patients undergoing coronary revascularization in private sector hospitals., Data Sources: Males 67 years and older undergoing coronary artery bypass graft (CABG; n=687,936) surgery or percutaneous coronary intervention (PCI; n=664,124) during 1996-2002 were identified from Medicare administrative data. Patients using VA services during the 2 years preceding the Medicare admission were identified using VA administrative files., Study Design: Thirty-, 90-, and 365-day mortality were compared in patients who did and did not use VA services, adjusting for demographic and clinical risk factors using generalized estimating equations and propensity score analysis., Results: Adjusted mortality after CABG was higher (p<.001) in VA users compared with nonusers at 30, 90, and 365 days: odds ratio (OR)=1.07 (95 percent confidence interval [CI], 1.03-1.11), 1.07 (95 percent CI, 1.04-1.10), and 1.09 (95 percent CI, 1.06-1.12), respectively. For PCI, mortality at 30 and 90 days was similar (p>.05) for VA users and nonusers, but was higher at 365 days (OR=1.09; 95 percent CI, 1.06-1.12). The increased risk of death in VA users was limited to patients with service-connected disabilities or low incomes. Odds of death for VA users were slightly lower using samples matched by propensity scores., Conclusions: A small difference in risk-adjusted outcomes for VA users and nonusers undergoing revascularization in private sector hospitals was found. This difference reflects unmeasured severity in VA users undergoing revascularization in private sector hospitals.

Background: We have reported that digitalis-like substances (cardiotonic steroids), including marinobufagenin (MBG), induce endocytosis of the plasmalemmal Na/K-ATPase in LLC-PK1 cells. The current report addresses the potential relevance of plasmalemmal Na/K-ATPase redistribution to in vivo salt handling., Methods: Male Sprague-Dawley rats were given 1 week of a high salt (4.0% NaCl) or normal salt (0.4% NaCl) diet. Urinary sodium excretion, as well as MBG excretion, was monitored, and proximal tubules were isolated using a Percoll gradient method. Tubular (86)Rb uptake, Na/K-ATPase enzymatic activity, and Na/K-ATPase alpha1 subunit density were determined., Results: The high salt diet increased urinary sodium (17.8 +/- 1.8 vs. 2.5 +/- 0.3 mEq/day, P < 0.01) and MBG excretion (104 +/- 12 vs. 26 +/- 4 pmol/day), and decreased proximal tubular (86)Rb uptake (0.44 +/- 0.07 vs. 1.00 +/- 0.10, P < 0.01) and Na/K-ATPase enzymatic activity (5.1 +/- 1.1 vs. 9.9 +/- 1.6 micromol/mg pr/hr, P < 0.01) relative to the normal diet. Proximal tubular Na/K-ATPase alpha1 protein density was decreased in the plasmalemma fraction but increased in both early and late endosomes following the high salt diet. In rats fed a high salt diet, anti-MBG antibody caused a 60% reduction in urinary sodium excretion, substantial increases in proximal tubule (86)Rb uptake, and Na/K-ATPase enzymatic activity, as well as significant decreases in the early and late endosomal Na/K-ATPase alpha1 protein content., Conclusion: These data suggest that redistribution of the proximal tubule Na/K-ATPase in response to endogenous cardiotonic steroids plays an important role in renal adaptation to salt loading.