Improving Diverse and Equitable Involvement of Patients and Caregivers in Research in CKD: Report of a Better Evidence and Translation - Chronic Kidney Disease (BEAT-CKD) Workshop.

Patient and caregiver involvement can enhance the uptake and impact of research, however, the involvement of patients and caregivers who are underserved and marginalized is often limited. A better understanding of how to make involvement in research more broadly accessible, supportive, and inclusive for patients with CKD and caregivers is needed. We conducted a national workshop involving patients, caregivers, clinicians and researchers across Australia to identify strategies to increase the diversity of patients and caregivers involved in CKD research. Six themes were identified. Building trust and a sense of safety was considered pivotal to establishing meaningful relationships to support knowledge exchange. Establishing community and connectedness was expected to generate a sense of belonging to motivate involvement. Balancing stakeholder goals, expectations and responsibilities involved demonstrating commitment and transparency by researchers. Providing adequate resources andsupport included strategies to minimize the burden of involvement for patients and caregivers. Making research accessible and relatable was about nurturing patient and caregiver interest by appealing to intrinsic motivators. Adapting to patient and caregiver needs and preferences required tailoring the approach for individuals and the target community. Strategies and actions to support these themes may support more diverse and equitable involvement of patients and caregivers in research in CKD.

Partnering with patients and caregivers to enrich research and care in kidney disease: values and strategies.

Patient and caregiver involvement broadens the scope of new knowledge generated from research and can enhance the relevance, quality and impact of research on clinical practice and health outcomes. Incorporating the perspectives of people with lived experience of chronic kidney disease (CKD) affords new insights into the design of interventions, study methodology, data analysis and implementation and has value for patients, healthcare professionals and researchers alike. However, patient involvement in CKD research has been limited and data on which to inform best practice is scarce. A number of frameworks have been developed for involving patients and caregivers in research in CKD and in health research more broadly. These frameworks provide an overall conceptual structure to guide the planning and implementation of research partnerships and describe values that are essential and strategies considered best practice when working with diverse stakeholder groups. This article aims to provide a summary of the strategies most widely used to support multistakeholder partnerships, the different ways patients and caregivers can be involved in research and the methods used to amalgamate diverse and at times conflicting points of view.

The Impact of the COVID-19 Pandemic on Patients With CKD: Systematic Review of Qualitative Studies.

RATIONALE & OBJECTIVE: COVID-19 disproportionately affects people with comorbidities, including chronic kidney disease (CKD). We describe the impact of COVID-19 on people with CKD and their caregivers. STUDY DESIGN: A systematic review of qualitative studies. SETTING & STUDY POPULATIONS: Primary studies that reported the experiences and perspectives of adults with CKD and/or caregivers were eligible. SEARCH STRATEGY & SOURCES: MEDLINE, Embase, PsycINFO, CINAHL searched from database inception to October 2022. DATA EXTRACTION: Two authors independently screened the search results. Full texts of potentially relevant studies were assessed for eligibility. Any discrepancies were resolved by discussion with another author. ANALYTICAL APPROACH: A thematic synthesis was used to analyze the data. RESULTS: Thirty-four studies involving 1,962 participants were included. Four themes were identified: exacerbating vulnerability and distress (looming threat of COVID-19 infection, intensifying isolation, aggravating pressure on families); uncertainty in accessing health care (overwhelmed by disruption of care, confused by lack of reliable information, challenged by adapting to telehealth, skeptical about vaccine efficacy and safety); coping with self-management (waning fitness due to decreasing physical activity, diminishing ability to manage diet, difficulty managing fluid restrictions, minimized burden with telehealth, motivating confidence and autonomy); and strengthening sense of safety and support (protection from lockdown restrictions, increasing trust in care, strengthened family connection). LIMITATIONS: Non-English studies were excluded, and inability to delineate themes based on stage of kidney and treatment modality. CONCLUSIONS: Uncertainty in accessing health care during the COVID-19 pandemic exacerbated vulnerability, emotional distress, and burden, and led to reduced capacity to self-manage among patients with CKD and their caregivers. Optimizing telehealth and access to educational and psychosocial support may improve self-management and the quality and effectiveness of care during a pandemic, mitigating potentially catastrophic consequences for people with CKD. PLAIN-LANGUAGE SUMMARY: During the COVID-19 pandemic, patients with chronic kidney disease (CKD) faced barriers and challenges to accessing care and were at an increased risk of worsened health outcomes. To understand the perspectives about the impact of COVID-19 among patients with CKD and their caregivers, we conducted a systematic review of 34 studies involving 1,962 participants. Our findings demonstrated that uncertainty in accessing care during the COVID-19 pandemic exacerbated the vulnerability, distress, and burden of patients and impaired their abilities for self-management. Optimizing the use of telehealth and providing education and psychosocial services may mitigate the potential consequences for people with CKD during a pandemic.

Novel Endpoints in Solid Organ Transplantation: Targeting Patient-reported Outcome Measures.

Although solid organ transplantation improves survival and quality of life in many patients with organ failure, treatment complications and side effects can have debilitating consequences for patients. Patient-reported outcome measures (PROMs) capture how patients feel and function, including quality of life, symptoms, and side effects that are assessed directly by patients. Yet, they remain infrequently reported in trials in solid organ transplantation. Barriers to implementing PROMs in trials include uncertainty in selecting appropriate PROMs, concerns about resources limitations, patient burden, and limited evidence to support the psychometric robustness of measures for use in transplant recipients. In recent years, there have been increasing efforts to include patient-reported outcomes that are important to patients in trials to ensure that trials provide patient-centered information for decision-making. This article will provide an overview of PROMs, discuss PROs that are important to solid organ transplant recipients and those that are used in trials in solid organ transplantation, and outline approaches for selecting PROMs for clinical trials.

The Role and Regulation of Thromboxane A2 Signaling in Cancer-Trojan Horses and Misdirection.

Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.

The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis.

Thromboxane A(2) (TXA(2)) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A(2) synthase (TXA(2)S), on prostaglandin endoperoxide (PGH(2)). TXA(2) is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. Thromboxane A(2) synthase and TP are the two necessary components for the functioning of this potent bioactive lipid. Thromboxane A(2) is widely implicated in a range of cardiovascular diseases, owing to its acute and chronic effects in promoting platelet aggregation, vasoconstriction, and proliferation. In recent years, additional functional roles for both TXA(2)S and TP in cancer progression have been indicated. Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA(2) as a downstream metabolite of the COX-2-derived PGH(2). Several studies suggest potential involvement of TXA(2)S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis. There have been several recent reviews of TXA(2)S and TP but thus far none have discussed its role in cancer progression and metastasis in depth. This review will focus on some of the more recent findings and advances with a significant emphasis on understanding the functional role of TXA(2)S and TP in cancer progression and metastasis.

Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes.

Phospholipase D (PLD) is an enzyme producing phosphatidic acid and choline through hydrolysis of phosphatidylcholine. The enzyme has been identified as a member of a variety of signal transduction cascades and as a key regulator of numerous intracellular vesicle trafficking processes. A role for PLD in regulating glucose homeostasis is emerging as the enzyme has recently been identified in events regulating exocytosis of insulin from pancreatic beta-cells and also in insulin-stimulated glucose uptake through controlling GLUT4 vesicle exocytosis in muscle and adipose tissue. We present methodologies for assessing cellular PLD activity in secretagogue-stimulated insulin-secreting pancreatic beta-cells and also insulin-stimulated adipocyte and muscle cells, two of the principal insulin-responsive cell types controlling blood glucose levels.

The role of phosphoinositide 3-kinase C2alpha in insulin signaling.

The members of the class II phosphoinositide 3-kinase (PI3K) family can be activated by several stimuli, indicating that these enzymes can regulate many intracellular processes. Nevertheless, to date, there has been no definitive identification of their in vivo product, their mechanism(s) of activation, or their precise intracellular roles. By metabolic labeling, we here identify phosphatidylinositol 3-phosphate as the sole in vivo product of the insulin-dependent activation of PI3K-C2alpha, confirming the emerging role of such a phosphoinositide in signaling. We demonstrate that activation of PI3K-C2alpha involves its recruitment to the plasma membrane and that activation is mediated by the GTPase TC10. This is the first report showing a membrane targeting-mediated mechanism of activation for PI3K-C2alpha and that a small GTP-binding protein can activate a class II PI3K isoform. We also demonstrate that PI3K-C2alpha contributes to maximal insulin-induced translocation of the glucose transporter GLUT4 to the plasma membrane and subsequent glucose uptake, definitely assessing the role of this enzyme in insulin signaling.

Phospholipid signalling through phospholipase D and phosphatidic acid.

Phospholipase D (PLD) hydrolyzes the phosphodiester bond of the predominant membrane phospholipid, phosphatidylcholine producing phosphatidic acid and free choline. This activity can participate in signal transduction pathways and impact on vesicle trafficking for secretion and endocytosis, as well as receptor signalling. Phospholipids can regulate PLD activity directly, through specific intermolecular interactions, or indirectly, through their effect on the localization or activity of PLD's protein effectors. This short review highlights these various phospholipid inputs into the regulation of PLD activity and also reviews potential roles for PLD-generated phosphatidic acid, particularly a mechanism by which the phospholipid may participate in the process of vesicular trafficking.