Cardiomyocyte PANX1 Controls Glycolysis and Neutrophil Recruitment in Hypertrophy.

BACKGROUND: PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. METHOD: We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). RESULTS: PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1MyHC6 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium. CONCLUSIONS: Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.

Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure.

Pannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1 MyHC6 ). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism both in vivo and in vitro . In vitro , treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1 MyHC6 mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1 MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45 + ), particularly neutrophils (CD11b + , Ly6g + ), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.

Important Barriers to COVID-19 Vaccination Among African Americans in Black Belt Region.

BACKGROUND: To identify important barriers to COVID-19 vaccination among African Americans living in the Black Belt region. METHODS: A cross-sectional, web-based questionnaire survey was conducted using best-worst scaling case 1 (the object case). Thirty-two potential barriers to COVID-19 vaccination were identified from the literature and confirmed by an expert. A nested balanced incomplete block design was used to generate 62 sets of 16 choice tasks. Each choice task included six barriers. Participants were asked to choose the most and least important barriers to their COVID-19 vaccination in each choice task of one set. The natural logarithm of the square root of best counts divided by the worst counts of each barrier was calculated to rank the importance of barriers. RESULTS: Responses from a total of 808 participants were included. Among 32 barriers to COVID-19 vaccination, the five most important barriers were "safety concern of COVID-19 vaccines," "rapid mutation of COVID-19," "ingredients of COVID-19 vaccines," "Emergency Use Authorization (Fast-track approval) of COVID-19 vaccines," and "inconsistent information of COVID-19 vaccines." On the other hand, the five least important barriers were "religious reasons," "lack of time to get COVID-19 vaccine," "no support from my family and friends," "political reasons," and "fear of the needle." CONCLUSIONS: Important barriers to the COVID-19 vaccination for African Americans living in the Black Belt region centered around the issues that could be resolved by communication strategies.

Evidence inventory: A patient-centered framework for Centers for Medicare & Medicaid Services to assess the clinical benefit of drugs to inform its maximum fair price negotiation.

The Inflation Reduction Act passed in August 2022 empowers the Centers for Medicare & Medicaid Services (CMS) to negotiate maximum fair prices for certain expensive drugs. In the process of determining maximum fair prices, CMS gathers evidence on the clinical benefits of these drugs as compared with their therapeutic alternative(s) from various sources. As patients are the primary beneficiaries of the treatment, we recommend that CMS should embrace an approach that prioritizes patient experience when evaluating such diverse sources of evidence in the assessment of the clinical benefit. Thus, we propose to draw on several existing frameworks to support the concept of "evidence inventory," a patient-centered approach to systematically evaluate benefits of drugs under consideration. This 4-step process to develop an evidence inventory includes the following: (1) Formulate the research question-in a PICO(T) (P = population, I = Intervention or exposure, C = comparator, O = outcome, and T = time frame) format, (2) Synthesize evidence, (3) Evaluate the evidence-using evidence inventory, and (4) Reevaluate evidence as new information become available. Patients and other relevant stakeholders play a critical role in each of these 4 steps. The proposed evidence inventory holds the potential to provide a structured and transparent patient-centered framework for evaluating the clinical benefits of drugs as compared with their therapeutic alternative(s) informing CMS maximum fair price negotiation.

Using a patient-centered value assessment to optimize fair prices for Inflation Reduction Act's Medicare Drug Price Negotiation Program.

In the United States, various federal agencies, institutions, and foundations, including the Centers for Medicare & Medicaid Services (CMS), have supported the incorporation of patient perspective in health care decision-making. Despite a series of patient-focused listening sessions planned as part of the Inflation Reduction Act's Medicare Drug Price Negotiation Program, the details of these sessions in the guidance developed by CMS remain unclear. CMS has not specified how patients' inputs will be used to determine the maximum fair prices (MFPs) of selected drugs for the first round of the negotiations. In this Viewpoint article, we urge CMS to use patient-centered value assessment methods to optimize MFPs in the Medicare Drug Price Negotiation Program. We focused on a stated preference method, the discrete choice experiment, which has been increasingly used to determine patient preferences and patient's willingness to pay for drugs. We discussed an example using a discrete choice experiment as a patient-centered method to assess the value of Jardiance and optimize its MFP in the negotiation program.

A Preference-Based Value Assessment of the Fear of COVID-19 Contagion.

Purpose: To assess the preference-based value of the fear of COVID-19 contagion. Patients and Methods: We conducted a web-based, cross-sectional discrete choice experiment among 544 US adults. We used a Bayesian efficient design to generate choice sets. Each choice set comprised two hypothetical COVID-19 vaccine options characterized by seven attributes: chance of COVID-19 infection, chance of having severe symptoms from COVID-19 infection, vaccine protection duration, chance of mild to moderate adverse events from vaccination, chance of serious adverse events from vaccination, chance of future exposure to COVID-19 after vaccination, and out-of-pocket cost. We used mixed logit (ML) and latent class (LC) models to analyze data. Furthermore, we calculated the willingness-to-pay for eliminating the chance of future exposure to COVID-19, shedding light on the value attributed to the fear of contagion. Results: The ML model demonstrated all attributes, including the chance of future exposure to COVID-19, were statistically significant. The participants were willing to pay approximately $13,046 to eliminate the chance of future exposure to COVID-19 or their fear of contagion when COVID-19 was still pandemic. The LC model unveiled two participant classes with distinct preference weights for the chance of future exposure to COVID-19 and out-of-pocket cost attributes. Nevertheless, the chance of future exposure to COVID-19 exposure held a significant degree of importance in both classes. Conclusion: The chance of future exposure to COVID-19 exposure or fear of contagion was a significant element in the value assessment of COVID-19 vaccines. Further studies should be conducted to verify the value of fear of contagion and include it in the value assessment of healthcare technologies for infectious diseases.

Measurement and valuation of the attributes of innovation of healthcare technologies: a systematic review.

OBJECTIVE: Innovative technologies (e.g. treatments) play a pivotal role in improving patient's well-being and in consequence population health outcomes. However, there is lack of consensus and comprehensive summary what constitutes innovation. Additionally, valuing them using traditional cost-effectiveness analysis is unlikely to capture the full range of benefits of these innovative technologies. This review aims to understand how innovation attributes were measured and/or valued in healthcare. MATERIALS AND METHODS: We systemically searched four databases, PubMed, Embase, PsycINFO, and Econlit, from inception to April 2021. Studies were included if they measured and/or valued the attributes of innovation for healthcare identified in our previous systematic review. Any other potential recommended methods to measure and/or value the innovation attributes were also extracted. RESULTS: Of 546 articles, a total of 17 articles were finally included in this review. If attributes were measured and traded-off relative to costs, then it was considered as valuation of those attributes. Two specific attributes of innovation, i.e. substantial benefits and convenience and/or adherence were measured using adherence rate and life year or QALY gain. When innovation attribute was non-specific it was described as "overall innovation" and measured using overall innovativeness scale (e.g. point/binary scale). QALY-based cost-effectiveness analysis (CEA) was commonly used to assess and value substantial benefit attribute. Other valuation approaches were (i) rating, (ii) the economic value of life year gain, (iii) multiple criteria decision analysis (MCDA), (iv) incremental net health benefit (INHB), and (v) quality-adjusted cost of care (QACC). ICER threshold adjustment and multiple-criteria decision analysis (MCDA) are two common recommended approaches to capture the innovation comprehensively. We found that MCDA approaches often promoted and discussed but were sub-optimally used to incorporate different value attributes into decision-making. CONCLUSIONS: Existing methods used by payers to measure and value the innovation component of a new product do not reflect the full range of health and cost impacts. They generally do not consider the alternative perspectives of patients, providers, caregivers, and society. Key challenges remain to appropriately measure and value innovation attributes and incorporate them into HTA decision making.

Characterizing attributes of innovation of technologies for healthcare: a systematic review.

OBJECTIVES: Characterizing and evaluating the holistic value of innovative healthcare technologies (e.g. treatments, services) constitutes a crucial goal to maximize limited resources. However, the characteristics of innovation have not been well identified. This review aims to describe the characteristics of healthcare innovation. METHODS: We performed a comprehensive systematic search using PubMed, Embase, PsycINFO, and Econlit from inception to July 2022. Articles were included if they described innovation or the characteristics of innovation of the technologies in healthcare. Characteristics or definitions of innovation directly or indirectly described as innovation were extracted from the included articles. Two independent reviewers then conceptualized the identified characteristics of innovation to generate innovation attributes in healthcare. RESULTS: In total, 103 articles were included in this review. Eight attributes describing innovation, i.e. novelty, step change, substantial benefits, an improvement over existing technologies, convenience and/or adherence, added value, acceptable cost, and uncounted benefits, were conceptualized. Most of the identified innovation attributes were based on the researchers' perspective. CONCLUSIONS: This study conceptualized innovation attributes in healthcare based on the characteristics of healthcare innovation as defined in the literature. Further research is warranted to obtain a complete understanding of the perspectives of researchers and other stakeholders, including patients, healthcare providers, healthcare payers, and the pharmaceutical industry, on recognizing innovation in healthcare.KEY POINTSThis is the first systematic review to conceptualize attributes of healthcare innovation.We conceptualized eight attributes describing innovation, i.e. novelty, step change, substantial benefits, an improvement over existing technologies, convenience and/or adherence, added value, acceptable cost, and uncounted benefits based on the similar concept.In existing literature, patients' and caregivers' perspectives were less frequently found to describe the innovation attributes.Future research is needed to identify, measure, and value various stakeholders, including patients' and caregivers' perspectives on healthcare innovation.

Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney.

Chronic kidney disease (CKD), characterized by sustained inflammation and progressive fibrosis, is highly prevalent and can eventually progress to end-stage kidney disease. However, current treatments to slow CKD progression are limited. Sphingosine 1-phosphate (S1P), a product of sphingolipid catabolism, is a pleiotropic mediator involved in many cellular functions, and drugs targeting S1P signaling have previously been studied particularly for autoimmune diseases. The primary mechanism of most of these drugs is functional antagonism of S1P receptor-1 (S1P1) expressed on lymphocytes and the resultant immunosuppressive effect. Here, we documented the role of local S1P signaling in perivascular cells in the progression of kidney fibrosis using primary kidney perivascular cells and several conditional mouse models. S1P was predominantly produced by sphingosine kinase 2 in kidney perivascular cells and exported via spinster homolog 2 (Spns2). It bound to S1P1 expressed in perivascular cells to enhance production of proinflammatory cytokines/chemokines upon injury, leading to immune cell infiltration and subsequent fibrosis. A small-molecule Spns2 inhibitor blocked S1P transport, resulting in suppression of inflammatory signaling in human and mouse kidney perivascular cells in vitro and amelioration of kidney fibrosis in mice. Our study provides insight into the regulation of inflammation and fibrosis by S1P and demonstrates the potential of Spns2 inhibition as a treatment for CKD and potentially other inflammatory and fibrotic diseases that avoids the adverse events associated with systemic modulation of S1P receptors.

Patients' Preferences for Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists.

Purpose: To determine patients' preferences for sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs). Patients and Methods: A cross-sectional, web-based discrete choice experiment was conducted among US adults with type 2 diabetes mellitus (T2DM) in May 2021. Six attributes-the route and frequency of administration, the chance of reaching target HbA1c in six months, the percentage reduction in the risk of major adverse cardiovascular events (MACE), the chance of gastrointestinal side effects, the chance of genital infection, and out-of-pocket cost per month-were identified from literature review and consultation with patients and clinicians. A Bayesian efficient design was used to generate choice sets. Each choice set contained two hypothetical SGLT-2i and GLP-1 RA alternatives described by the attributes and an opt-out alternative. A total of 176 patients were asked to select the most preferred option from each choice set. Mixed logit (ML) and latent class (LC) models were developed. The conditional relative importance of each attribute was determined. Results: The ML model showed the out-of-pocket cost had the highest conditional relative importance, followed by the chance of reaching the target HbA1c. The best LC model revealed two patient classes. All attributes were significantly important to the patients in both classes, except the chance of genital infection in class 2. Compared to the patients in class 2, the patients in class 1 were older (approximately 65 vs 56 years) and had a higher number of comorbidities (approximately three vs two). Conclusion: T2DM patients placed different preference weights or importance across SGLT-2i and GLP-1 RA attributes. Preference heterogeneity was found among patients with different ages and numbers of comorbidities.

Development of a photoacoustic microscopy technique to assess peritubular capillary function and oxygen metabolism in the mouse kidney.

Microcirculatory changes and oxidative stress have long been associated with acute kidney injury. Despite substantial progress made by two-photon microscopy of microvascular responses to acute kidney injury in rodent models, little is known about the underlying changes in blood oxygen delivery and tissue oxygen metabolism. To fill this gap, we developed a label-free kidney imaging technique based on photoacoustic microscopy, which enables simultaneous quantification of hemoglobin concentration, oxygen saturation of hemoglobin, and blood flow in peritubular capillaries in vivo. Based on these microvascular parameters, microregional oxygen metabolism was quantified. We demonstrated the utility of this technique by studying kidney hemodynamic and oxygen-metabolic responses to acute kidney injury in mice subject to lipopolysaccharide-induced sepsis. Dynamic photoacoustic microscopy of the peritubular capillary function and tissue oxygen metabolism revealed that sepsis induced an acute and significant reduction in peritubular capillary oxygen saturation of hemoglobin, concomitant with a marked reduction in kidney ATP levels and contrasted with nominal changes in peritubular capillary flow and plasma creatinine. Thus, our technique opens new opportunities to study microvascular and metabolic dysfunction in acute and chronic kidney diseases.

Using Electronic Medical Records and Health Claim Data to Develop a Patient Engagement Score for Patients With Multiple Chronic Conditions: An Exploratory Study.

The study objective was to (1) develop a statistical model that creates a novel patient engagement score (PES) from electronic medical records (EMR) and health claim data, and (2) validate this developed score using health-related outcomes and charges of patients with multiple chronic conditions (MCCs). This study used 2014-16 EMR and health claim data of patients with MCCs from Sanford Health. Patient engagement score was created based on selected patients' engagement behaviors using Gaussian finite mixture model. The PES was validated using multiple logistic and linear regression analyses to examine the associations between the PES and health-related outcomes, and hospital charges, respectively. Patient engagement score was generated from 5095 patient records and included low, medium, and high levels of patient engagement. The PES was a significant predictor for low-density lipoprotein, emergency department visit, hemoglobin A1c, estimated glomerular filtration rate, hospitalization, and hospital charge. The PES derived from patient behaviors recorded in EMR and health claim data can potentially serve as a patient engagement measure. Further study is needed to refine and validate the newly developed score.

Incorporating patients' preferences in the value assessment of disease-modifying therapies for multiple sclerosis: a narrative review.

Introduction: Despite the increasing role of patients in the US healthcare system, patients have yet been engaged in the value assessment of their treatments, including disease-modifying therapies (DMTs) for multiple sclerosis (MS). The objectives of this review were therefore to summarize existing studies on cost-effectiveness analysis (CEA) with quality-adjusted life years (QALYs) and patients' preferences of DMTs for MS, and to discuss how to incorporate patients' preferences into the value assessment of DMTs.Area covered: We reviewed previous systematic reviews and conducted further search until November 2020 for studies on CEA with QALYs and patients' preferences of DMTs for MS. We identified the outcomes that were assessed or valued in the CEA studies and the DMT attributes that were important to patients with MS.Expert opinion: Our literature review showed that the studies using CEA with QALYs failed to capture some important DMT attributes, e.g., route and frequency of administration, identified in the studies on the patients' preferences. Various approaches were available for incorporating the patients' preferences in the value assessment of DMTs for MS. We supported this incorporation, which subsequently would increase patient access to preferred DMTs.

Patient and caregiver opinions about an FDA-developed generic drug educational handout: A pilot cross-sectional survey.

OBJECTIVE: To examine patient and caregiver opinions and "receptivity" regarding generic drug educational material in terms of content, format and design, delivery channel, and level of satisfaction. METHODS: Interviewer-administered surveys were conducted with patients and caregivers who were clients of a regional medication management program or pharmacy services clinic to gather perceptions about generic drugs and input on a generic drug educational handout developed by the U.S. Food and Drug Administration (FDA). Survey questions were developed by the investigators and pretested before use. Data were analyzed using descriptive statistics, and responses to open-ended questions were assessed using qualitative content analysis. Survey psychometrics were examined using exploratory factor analysis (EFA). RESULTS: Of the 100 survey participants, most (93%) had positive perceptions about generic drug safety and effectiveness after reading the handout. Most participants were satisfied or very satisfied with the handout's content (87%) as well as format and design (92%). However, more than 20% of participants were still unsure about the benefits and risks of generic drugs compared with those of brand drugs, and more than 15% were still unsure about which benefits and risks mattered most to them. The participants' preferred source for the handout was a pharmacy (49%) or doctor's office (27%). In an EFA of the survey instrument, 2 factors emerged related to the educational handout's content: (1) generic drug information, a 7-item factor (Cronbach alpha = 0.882); and (2) personal relevance, a 3-item factor (Cronbach alpha = 0.692). CONCLUSION: The findings indicate an overall positive "receptiveness" toward generic drug informational materials from patients and caregivers, which highlights the feasibility and importance of educational outreach programs about generic drugs targeted toward this population. Future studies may focus on more diverse populations and tailor materials to the needs of specific patient and caregiver subgroups and health literacy levels.

Peritubular Capillary Oxygen Consumption in Sepsis-Induced AKI: Multi-Parametric Photoacoustic Microscopy.

Understanding and measuring parameters responsible for the pathogenesis of sepsis-induced AKI (SI-AKI) is critical in developing therapies. Blood flow to the kidney is heterogeneous, partly due to the existence of dynamic networks of capillaries in various regions, responding differentially to oxygen demand in cortex versus medulla. High energy demand regions, especially the outer medulla, are susceptible to hypoxia and subject to damage during SI-AKI. Proximal tubule epithelial cells in the cortex and the outer medulla can also undergo metabolic reprogramming during SI-AKI to maintain basal physiological status and to avoid potential damage. Current data on the assessment of renal hemodynamics and oxygen metabolism during sepsis is limited. Preclinical and clinical studies show changes in renal hemodynamics associated with SI-AKI, and in clinical settings, interventions to manage renal hemodynamics seem to help improve disease outcomes in some cases. Lack of proper tools to assess temporospatial changes in peritubular blood flow and tissue oxygen metabolism is a barrier to our ability to understand microcirculatory dynamics and oxygen consumption and their role in the pathogenesis of SI-AKI. Current tools to assess renal oxygenation are limited in their usability as these cannot perform continuous simultaneous measurement of renal hemodynamics and oxygen metabolism. Multi-parametric photo-acoustic microscopy (PAM) is a new tool that can measure real-time changes in microhemodynamics and oxygen metabolism. Use of multi-parametric PAM in combination with advanced intravital imaging techniques has the potential to understand the contribution of microhemodynamic and tissue oxygenation alterations to SI-AKI.

Xylosyltransferase 2 deficiency and organ homeostasis.

In this paper we characterize the function of Xylosyltransferase 2 (XylT2) in different tissues to investigate the role XylT2 has in the proteoglycan (PG) biochemistry of multiple organs. The results show that in all organs examined there is a widespread and significant decrease in total XylT activity in Xylt2 knock out mice (Xylt2-/-). This decrease results in increased organ weight differences in lung, heart, and spleen. These findings, in addition to our previous findings of increased liver and kidney weight with loss of serum XylT activity, suggest systemic changes in organ function due to loss of XylT2 activity. The Xylt2-/- mice have splenomegaly due to enlargement of the red pulp area and enhanced pulmonary response to bacterial liposaccharide. Tissue glycosaminoglycan composition changes are also found. These results demonstrate a role of XylT2 activity in multiple organs and their PG content. Because the residual XylT activity in the Xylt2-/- is due to xylosyltransferase 1 (XylT1), these studies indicate that both XylT1 and XylT2 have important roles in PG biosynthesis and organ homeostasis.

Motivational Interviewing as a Strategy to Impact Outcomes in Heart Failure Patients: A Systematic Review.

BACKGROUND: Heart failure (HF) hospitalization is an expensive healthcare utilization event. Motivational interviewing (MI) has been studied for effects on HF self-management behaviors. OBJECTIVE: The objective of this systematic review was to conduct an exploration and report of evidence and gaps in the literature regarding the impact of MI on HF outcomes. DATA SOURCES: A modified Cochrane systematic review was conducted via a literature search in the MEDLINE, CINAHL, Cochrane Collaborative Systematic Reviews, PsycINFO, Health Source: Nursing/Academic Edition, and Google Scholar databases. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Randomized controlled trials (RCTs) or controlled experimental studies published in English from January 1990 to February 2019 that included adults (18 years and older) diagnosed with HF New York Heart Association (NYHA) class I, II, II, or IV were eligible for inclusion. Interventions evaluated were an MI-based face-to-face communication or telephone-based conversation provided by any healthcare provider type. STUDY APPRAISAL AND SYNTHESIS METHODS: The Cochrane method for assessing risk of bias was used to analyze the methodological quality of retained studies. RESULTS: Of 167 initial articles, nine were retained, describing eight unique studies (758 total patients, range 30-241; age range 58-79 years; attrition range 13-36%). The impact of MI was examined for general self-care behaviors (SCBs) (physical activity specifically), quality of life (QoL), and/or hospital readmission prevention. Eight of nine articles reported a positive impact of MI over advice-giving, seven being statistically significant. MI interventions used an initial face-to-face encounter with three to five follow-up telephone encounters. LIMITATIONS: This systematic review had the following limitations: most retained studies included intervention activities conducted in hospital/clinic settings, which limits generalizability of the intervention in other care settings; intervention fidelity, blinding, selection, interventionist training, and random assignment were not clear in all studies; retained studies did not include potential covariates such as health literacy, patient age, and perception of disease/health risks; and some retained studies relied on patient self-report of outcomes, which may introduce recall or social desirability bias. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: MI demonstrated a positive effect on the SCB hospital readmission prevention factor and on QoL. MI delivered with greater frequency and over a longer duration may improve the immediate risk of hospital readmission as well as long-term outcomes through better medication adherence and SCBs. However, heterogeneity in the methods, design, intervention type, and structure challenged comparisons across studies and further research is warranted.

Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment.

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5'-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-ß immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73-/- kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.

Pannexins in Acute Kidney Injury.

Acute kidney injury (AKI) is highly prevalent among hospitalized patients and is associated with serious consequences with limited pharmacological treatment options. Pannexin 1 (Panx1) channel is a ubiquitously expressed nonselective membrane transport channel that efficiently effluxes ATP and plays a central role in the progression of inflammatory diseases. Animal models that target Panx1 through pharmacological inhibition or genetic deficiency have better outcomes in minimizing inflammation and associated pathology. Given the involvement of Panx1 at multiple steps of -inflammatory pathology, Panx1 could be a potential therapeutic target in the treatment of AKI. Further research is needed in elaborating the mechanisms and identifying Panx1-specific inhibitor molecules to better understand the role of Panx1 in AKI pathology arising due to diverse insults.