Association of Remote Patient-Reported Outcomes and Step Counts With Hospitalization or Death Among Patients With Advanced Cancer Undergoing Chemotherapy: Secondary Analysis of the PROStep Randomized Trial.

BACKGROUND: Patients with advanced cancer undergoing chemotherapy experience significant symptoms and declines in functional status, which are associated with poor outcomes. Remote monitoring of patient-reported outcomes (PROs; symptoms) and step counts (functional status) may proactively identify patients at risk of hospitalization or death. OBJECTIVE: The aim of this study is to evaluate the association of (1) longitudinal PROs with step counts and (2) PROs and step counts with hospitalization or death. METHODS: The PROStep randomized trial enrolled 108 patients with advanced gastrointestinal or lung cancers undergoing cytotoxic chemotherapy at a large academic cancer center. Patients were randomized to weekly text-based monitoring of 8 PROs plus continuous step count monitoring via Fitbit (Google) versus usual care. This preplanned secondary analysis included 57 of 75 patients randomized to the intervention who had PRO and step count data. We analyzed the associations between PROs and mean daily step counts and the associations of PROs and step counts with the composite outcome of hospitalization or death using bootstrapped generalized linear models to account for longitudinal data. RESULTS: Among 57 patients, the mean age was 57 (SD 10.9) years, 24 (42%) were female, 43 (75%) had advanced gastrointestinal cancer, 14 (25%) had advanced lung cancer, and 25 (44%) were hospitalized or died during follow-up. A 1-point weekly increase (on a 32-point scale) in aggregate PRO score was associated with 247 fewer mean daily steps (95% CI -277 to -213; P<.001). PROs most strongly associated with step count decline were patient-reported activity (daily step change -892), nausea score (-677), and constipation score (524). A 1-point weekly increase in aggregate PRO score was associated with 20% greater odds of hospitalization or death (adjusted odds ratio [aOR] 1.2, 95% CI 1.1-1.4; P=.01). PROs most strongly associated with hospitalization or death were pain (aOR 3.2, 95% CI 1.6-6.5; P<.001), decreased activity (aOR 3.2, 95% CI 1.4-7.1; P=.01), dyspnea (aOR 2.6, 95% CI 1.2-5.5; P=.02), and sadness (aOR 2.1, 95% CI 1.1-4.3; P=.03). A decrease in 1000 steps was associated with 16% greater odds of hospitalization or death (aOR 1.2, 95% CI 1.0-1.3; P=.03). Compared with baseline, mean daily step count decreased 7% (n=274 steps), 9% (n=351 steps), and 16% (n=667 steps) in the 3, 2, and 1 weeks before hospitalization or death, respectively. CONCLUSIONS: In this secondary analysis of a randomized trial among patients with advanced cancer, higher symptom burden and decreased step count were independently associated with and predictably worsened close to hospitalization or death. Future interventions should leverage longitudinal PRO and step count data to target interventions toward patients at risk for poor outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04616768; https://clinicaltrials.gov/study/NCT04616768. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2021-054675.

Clinician Perspectives on Virtual Specialty Palliative Care for Patients With Advanced Illnesses.

Background: Patients with serious illnesses have unmet symptom and psychosocial needs. Specialty palliative care could address many of these needs; however, access varies by geography and health system. Virtual visits and automated referrals could increase access and lead to improved quality of life, health outcomes, and patient-centered care for patients with serious illness. Objectives: We sought to understand referring clinician perspectives on barriers and facilitators to utilizing virtual tools to increase upstream access to palliative care. Design: Participants in this multisite qualitative study included practicing clinicians who commonly place palliative care referrals across multiple specialties, including hematology/oncology, family medicine, cardiology, and geriatrics. All interviews were transcribed and subsequently coded and analyzed by trained research coordinators using Atlas.ti software. Settings/Subjects: This study included 23 clinicians (21 physicians, 2 nonphysicians) across 5 specialties, 4 practice settings, and 7 states in the United States. Results: Respondents felt that community-based specialty palliative services including symptom management, advance care planning, physical therapy, and mental health counseling would benefit their patients. However, they had mixed feelings about automated referrals, with some clinicians feeling hesitant about not being alerted to such referrals. Many respondents were supportive of virtual palliative care, particularly for those who may have difficulty accessing physician offices, but most respondents felt that such care should only be provided after an initial in-person consultation where clinicians can meet face-to-face with patients. Conclusion: Clinicians believe that automated referrals and virtual palliative care could increase access to the benefits of specialty palliative care. However, virtual palliative care models should give attention to iterative communication with primary clinicians and the perceived need for an initial in-person visit.

Remote Patient-Reported Outcomes and Activity Monitoring to Improve Patient-Clinician Communication Regarding Symptoms and Functional Status: A Randomized Controlled Trial.

PURPOSE: Routine collection of patient-generated health data (PGHD) may promote earlier recognition of symptomatic and functional decline. This trial assessed the impact of an intervention integrating remote PGHD collection with patient nudges on symptom and functional status understanding between patients with advanced cancer and their oncology team. METHODS: This three-arm randomized controlled trial was conducted from November 19, 2020, to December 17, 2021, at a large tertiary oncology practice. We enrolled patients with stage IV GI and lung cancers undergoing chemotherapy. Over 6 months, patients in two intervention arms received PROStep-weekly text message-based symptom surveys and passive activity monitoring using a wearable accelerometer. PGHD were summarized in dashboards given to patients' oncology team before appointments. One intervention arm received an additional text-based active choice prompt to discuss worsening symptoms or functional status with their clinician. Control patients did not receive PROStep. The coprimary outcomes patient perceptions of oncology team symptom and functional understanding at 6 months were measured on a 1-5 Likert scale (5 = high understanding). RESULTS: One hundred eight patients enrolled: 55% male, 81% White, and 77% had GI cancers. Patient-reported clinician understanding did not differ between control and intervention arms for symptoms (4.5 v 4.5; P = .87) or functional status (4.5 v 4.3; P = .31). In the intervention arms, combined patient adherence to weekly symptom reports and daily activity monitoring was 64% and 53%, respectively. Intervention patients in the PROStep versus PROStep + active choice arms reported low burden from wearing the accelerometer (mean burden [standard deviation], 2.7 [1.3] v 2.1 [1.3]; P = .15) and completing surveys (2.1 [1.2] v 1.9 [1.3]; P = .44). CONCLUSION: Patients receiving PROStep reported high understanding of symptoms and functional status from their oncology team, although this did not differ from controls.

Public Views on Medicaid Work Requirements and Mandatory Premiums in Kentucky.

Importance: Federal and state policymakers continue to pursue work requirements and premiums as conditions of Medicaid participation. Opinion polling should distinguish between general policy preferences and specific views on quotas, penalties, and other elements. Objective: To identify views of adults in Kentucky regarding the design of Medicaid work requirements and premiums. Design, Setting, and Participant: A cross-sectional survey was conducted via telephone and the internet from June 27 through July 11, 2019, of 1203 Kentucky residents 9 months before the state intended to implement Medicaid work requirements and mandatory premiums. Statistical analysis was performed from October 2019 to August 2023. Main Outcomes and Measures: Agreement, disagreement, or neutral views on policy components were the main outcomes. Recruitment for the survey used statewide random-digit dialing and an internet panel to recruit residents aged 18 years or older. Findings were weighted to reflect state demographics. Of 39 110 landlines called, 209 reached an eligible person (of whom 150 participated), 8654 were of unknown eligibility, and 30 247 were ineligible. Of 55 305 cell phone lines called, 617 reached an eligible person (of whom 451 participated), 29 951 were of unknown eligibility, and 24 737 were ineligible. Internet recruitment (602 participants) used a panel of adult Kentucky residents maintained by an external data collector. Results: Percentages were weighted to resemble the adult population of Kentucky residents. Of the participants in the study, 52% (95% CI, 48%-55%) were women, 80% (95% CI, 77%-82%) were younger than 65 years, 41% (95% CI, 38%-45%) were enrolled in Medicaid, 36% (95% CI, 32%-39%) were Republican voters, 32% (95% CI, 29%-36%) were Democratic voters, 14% (95% CI, 11%-16%) were members of racial and ethnic minority groups (including but not limited to American Indian or Alaska Native, Asian, Black, Hispanic or Latinx, and Native Hawaiian or Pacific Islander), and 48% (95% CI, 44%-52%) were employed. Most participants supported work requirements generally (69% [95% CI, 66%-72%]) but did not support terminating benefits due to noncompliance (43% [95% CI, 39%-46%]) or requiring quotas of 20 or more hours per week (34% [95% CI, 31%-38%]). Support for monthly premiums (34% [95% CI, 31%-38%]) and exclusion penalties for premium nonpayment (22% [95% CI, 19%-25%]) was limited. Medicaid enrollees were significantly less supportive of these policies than nonenrollees. For instance, regarding work requirements, agreement was lower (64% [95% CI, 59%-69%] vs 72% [95% CI, 68%-77%]) and disagreement higher (26% [95% CI, 21%-31%] vs 20% [95% CI, 16%-24%]) among current Medicaid enrollees compared with nonenrollees (P = .04). Among Medicaid enrollees, some beliefs about work requirements varied significantly by employment status but not by political affiliation. Among nonenrollees, beliefs about work requirements, premiums, and Medicaid varied significantly by political affiliation but not by employment. Conclusions and Relevance: This study suggests that even when public constituencies express general support for Medicaid work requirements or premiums, they may oppose central design features, such as quotas and termination of benefits. Program participants may also hold significantly different beliefs than nonparticipants, which should be understood before policies are changed.

Behavioural economic interventions to embed palliative care in community oncology (BE-EPIC): study protocol for the BE-EPIC randomised controlled trial.

INTRODUCTION: Palliative care (PC) is a medical specialty focusing on providing relief from the symptoms and stress of serious illnesses such as cancer. Early outpatient specialty PC concurrent with cancer-directed treatment improves quality of life and symptom burden, decreases aggressive end-of-life care and is an evidence-based practice endorsed by national guidelines. However, nearly half of patients with advanced cancer do not receive specialty PC prior to dying. The objective of this study is to test the impact of an oncologist-directed default PC referral orders on rates of PC utilisation and patient quality of life. METHODS AND ANALYSIS: This single-centre two-arm pragmatic randomised trial randomises four clinician-led pods, caring for approximately 250 patients who meet guideline-based criteria for PC referral, in a 1:1 fashion into a control or intervention arm. Intervention oncologists receive a nudge consisting of an electronic health record message indicating a patient has a default pended order for PC. Intervention oncologists are given an opportunity to opt out of referral to PC. Oncologists in pods randomised to the control arm will receive no intervention beyond usual practice. The primary outcome is completed PC visits within 12 weeks. Secondary outcomes are change in quality of life and absolute quality of life scores between the two arms. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at the University of Pennsylvania. Study results will be disseminated in peer-reviewed journals and scientific conferences using methods that describe the results in ways that key stakeholders can best understand and implement. TRIAL REGISTRATION NUMBER: NCT05365997.

Development of Machine Learning Algorithms Incorporating Electronic Health Record Data, Patient-Reported Outcomes, or Both to Predict Mortality for Outpatients With Cancer.

PURPOSE: Machine learning (ML) algorithms that incorporate routinely collected patient-reported outcomes (PROs) alongside electronic health record (EHR) variables may improve prediction of short-term mortality and facilitate earlier supportive and palliative care for patients with cancer. METHODS: We trained and validated two-phase ML algorithms that incorporated standard PRO assessments alongside approximately 200 routinely collected EHR variables, among patients with medical oncology encounters at a tertiary academic oncology and a community oncology practice. RESULTS: Among 12,350 patients, 5,870 (47.5%) completed PRO assessments. Compared with EHR- and PRO-only algorithms, the EHR + PRO model improved predictive performance in both tertiary oncology (EHR + PRO v EHR v PRO: area under the curve [AUC] 0.86 [0.85-0.87] v 0.82 [0.81-0.83] v 0.74 [0.74-0.74]) and community oncology (area under the curve 0.89 [0.88-0.90] v 0.86 [0.85-0.88] v 0.77 [0.76-0.79]) practices. CONCLUSION: Routinely collected PROs contain added prognostic information not captured by an EHR-based ML mortality risk algorithm. Augmenting an EHR-based algorithm with PROs resulted in a more accurate and clinically relevant model, which can facilitate earlier and targeted supportive care for patients with cancer.

COVID-19 contact tracing app reviews reveal concerns and motivations around adoption.

BACKGROUND: Google and Apple's Exposure Notifications System (ENS) was developed early in the COVID-19 pandemic to complement existing contact tracing efforts while protecting user privacy. An analysis by the Associated Press released in December 2020 estimated approximately 1 in 14 people had downloaded apps in states one was available. In this study, we assessed the motivation and experience of individuals who downloaded ENS apps from the Google Play and Apple App Stores. METHODS: We collected review text, star rating, and date of rating for all the reviews on ENS apps in the Google Play and Apple App stores. We extracted the relative frequency of single words and phrases from reviews and created an open vocabulary language, with themes categorized by the research team, to study the salient themes around reviews with high (3-5 stars), neutral (3 stars), and negative (1-2 stars) ratings using logistic regression. RESULTS: Of 7622 reviews obtained from 26 states between 04/07/2020 to 03/31/2021, 6364 were from Google Play Store, and 1258 were from Apple App Store. We obtained reviews for a total of 38 apps, with 25 apps from the Google Play Store and 13 apps from the Apple Play Store. 78% of the reviews are either 1 star or 5 stars. Positive reviews were driven by ease of use, support for the state government in creating the app, and encouragement for others to download, as well as engage in other COVID-19 precautions. Negative and neutral reviews focused on issues with app functionality (i.e., installation and tracking errors). CONCLUSIONS: Uptake was the largest barrier to success for ENS apps, but states can use insight from app store reviews to better position themselves if they choose to develop further public health apps.

Oncologist Perceptions of Algorithm-Based Nudges to Prompt Early Serious Illness Communication: A Qualitative Study.

Background: Early serious illness conversations (SICs) about goals of care and prognosis improve mood, quality of life, and end-of-life care quality. Algorithm-based behavioral nudges to oncologists increase the frequency and timeliness of such conversations. However, clinicians' perspectives on such nudges are unknown. Design: Qualitative study consisting of semistructured interviews among medical oncology clinicians who participated in a stepped-wedge cluster randomized trial of Conversation Connect, an algorithm-based intervention consisting of behavioral nudges to promote early SICs in the outpatient oncology setting. Results: Of 79 eligible oncology clinicians, 56 (71%) were approached to participate in interviews and 25 (45%) accepted. Key facilitators to algorithm-based nudges included prompting documentation of conversations, peer comparisons, performance reports, and validating norms around early conversations. Barriers included cancer-specific heterogeneity in algorithm performance and the frequency and tone of text messages. Areas of improvement included utilizing different information channels, identifying patients earlier in the disease trajectory, and incorporating patient-targeted messaging that emphasizes the value of early conversations. Conclusions: Oncology clinicians identified key facilitators and barriers to Conversation Connect. These insights inform future algorithm-based supportive care interventions in oncology. Controlled trial (NCT03984773).

Patient and clinician nudges to improve symptom management in advanced cancer using patient-generated health data: study protocol for the PROStep randomised controlled trial.

INTRODUCTION: Patients with advanced cancers often face significant symptoms from their cancer and adverse effects from cancer-associated therapy. Patient-generated health data (PGHD) are routinely collected information about symptoms and activity levels that patients either directly report or passively record using devices such as wearable accelerometers. The objective of this study was to test the impact of an intervention integrating remote collection of PGHD with clinician and patient nudges to inform communication between patients with advanced cancer and their oncology team regarding symptom burden and functional status. METHODS AND ANALYSIS: This single-centre prospective randomised controlled trial randomises patients with metastatic gastrointestinal or lung cancers into one of three arms: (A) usual care, (B) an intervention that integrates PGHD (including weekly text-based symptom surveys and passively recorded step counts) into a dashboard delivered to oncology clinicians at each visit and (C) the same intervention as arm B but with an additional text-based active choice intervention to patients to encourage discussing their symptoms with their oncology team. The study will enrol approximately 125 participants. The coprimary outcomes are patient perceptions of their oncology team's understanding of their symptoms and their functional status. Secondary outcomes are intervention utility and adherence. ETHICS AND DISSEMINATION: This study has been approved by the institutional review board at the University of Pennsylvania. Study results will be disseminated using methods that describe the results in ways that key stakeholders can best understand and implement. TRIAL REGISTRATION NUMBERS: NCT04616768 and 843 616.

Impact of Behavioral Nudges on the Quality of Serious Illness Conversations Among Patients With Cancer: Secondary Analysis of a Randomized Controlled Trial.

PURPOSE: Serious Illness Conversations (SICs) are structured conversations between clinicians and patients about prognosis, treatment goals, and end-of-life preferences. Although behavioral interventions may prompt earlier or more frequent SICs, their impact on the quality of SICs is unclear. METHODS: This was a secondary analysis of a randomized clinical trial (NCT03984773) among 78 clinicians and 14,607 patients with cancer testing the impact of an automated mortality prediction with behavioral nudges to clinicians to prompt more SICs. We analyzed 318 randomly selected SICs matched 1:1 by clinicians (159 control and 159 intervention) to compare the quality of intervention vs. control conversations using a validated codebook. Comprehensiveness of SIC documentation was used as a measure of quality, with higher integer numbers of documented conversation domains corresponding to higher quality conversations. A conversation was classified as high-quality if its score was ≥ 8 of a maximum of 10. Using a noninferiority design, mixed effects regression models with clinician-level random effects were used to assess SIC quality in intervention vs. control groups, concluding noninferiority if the adjusted odds ratio (aOR) was not significantly < 0.9. RESULTS: Baseline characteristics of the control and intervention groups were similar. Intervention SICs were noninferior to control conversations (aOR 0.99; 95% CI, 0.91 to 1.09). The intervention increased the likelihood of addressing patient-clinician relationship (aOR = 1.99; 95% CI, 1.23 to 3.27; P < .01) and decreased the likelihood of addressing family involvement (aOR = 0.56; 95% CI, 0.34 to 0.90; P < .05). CONCLUSION: A behavioral intervention that increased SIC frequency did not decrease their quality. Behavioral prompts may increase SIC frequency without sacrificing quality.

Oral health and oral health care use among able-bodied adults enrolled in Medicaid in Kentucky after Medicaid expansion: A mixed methods study.

BACKGROUND: Oral health care use remains low among adult Medicaid recipients, despite the Patient Protection and Affordable Care Act's expansion increasing access to care in many states. It remains unclear the extent to which low use reflects either low demand for care or barriers to accessing care. The authors aimed to examine factors associated with low oral health care use among adults enrolled in Medicaid. METHODS: The authors conducted a survey from May through September 2018 among able-bodied (n = 9,363) Medicaid recipients who were aged 19 through 65 years and nondisabled childless adults in Kentucky. The survey included questions on perceived oral health care use. Semistructured interviews were also conducted from May through November 2018 among a subset of participants (n = 127). RESULTS: More than one-third (37.8%) of respondents reported fair or poor oral health, compared with 26.2% who reported fair or poor physical health. Although 47.6% of respondents indicated needing oral health care in the past 6 months, only one-half of this group reported receiving all of the care they needed. Self-reported barriers included lack of coverage for needed services and lack of access to care (for example, low provider availability and transportation difficulties). CONCLUSIONS: Low rates of oral health care use can be attributed to a subset of the study population having low demand and another subset facing barriers to accessing care. Although Medicaid-covered services might be adequate for beneficiaries with good oral health, those with advanced dental diseases and a history of irregular care might benefit from coverage for more extensive restorative services. PRACTICAL IMPLICATIONS: These results can inform dentists and policy makers about how to design effective interventions and policies to improve oral health care use and oral health outcomes.

Losartan protects endothelium-dependent relaxation in vivo in a murine model of rheumatoid arthritis.

Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis.

Protease activated receptor 2 and matriptase expression in the joints of cats with and without osteoarthritis.

OBJECTIVES: The aim of this study was to determine the presence of protease-activated receptor 2 (PAR2) and matriptase proteins and quantify PAR2 and matriptase mRNA expression in the articular cartilage and synovial membrane of cats with and without osteoarthritis (OA). METHODS: A total of 28 articular cartilage samples from adult cats (14 OA and 14 normal), 10 synovial membranes from adult cats (five OA and five normal) and three cartilage samples from 9-week-old fetal cats were used. The presence of PAR2 and matriptase in the cartilage and synovial membrane of the adult samples was detected by immunohistochemical (IHC) staining, while real-time PCR was used for mRNA expression analyses in all samples. RESULTS: PAR2 was detected in all OA and normal articular cartilage and synovial membrane samples but confined to only a few superficial chondrocytes in the normal samples. Matriptase was only detected in OA articular cartilage and synovial membrane samples. PAR2 and matriptase mRNA expression were, however, detected in all cartilage and synovial membrane samples. PAR2 and matriptase mRNA expression levels in OA articular cartilage were five (P <0.001) and 3.3 (P <0.001) times higher than that of the healthy group, respectively. There was no significant difference (P = 0.05) in the OA synovial membrane PAR2 and matriptase mRNA expression compared with the normal samples. CONCLUSIONS AND RELEVANCE: Detection of PAR2 and matriptase proteins and gene expression in feline articular tissues is a novel and important finding, and supports the hypothesis that serine proteases are involved in the pathogenesis of feline OA. The consistent presence of PAR2 and matriptase protein in the cytoplasm of OA chondrocytes suggests a possible involvement of proteases in cartilage degradation. Further investigations into the PAR2 and matriptase pathobiology could enhance our understanding of the proteolytic cascades in feline OA, which might lead to the development of novel therapeutic strategies.

The design of a randomized controlled trial to evaluate multi-dimensional effects of a section 1115 Medicaid demonstration waiver with community engagement requirements.

Section 1115 demonstration waivers provide a mechanism for states to implement changes to their Medicaid programs. While such waivers are mandated to include evaluations of their impact, randomization - the gold standard for assessing causality - has not typically been a consideration. In a critical departure, the Commonwealth of Kentucky opted to pursue a two-arm randomized controlled trial (RCT) for their controversial 2018 Medicaid Demonstration waiver, which included work requirements as a condition for the subset of beneficiaries deemed able-bodied to maintain eligibility for benefits. Beneficiaries were randomized 9:1 to the new waiver program or a control group who would retain their current benefits as part of the existing Medicaid expansion program. To address potential bias from differential attrition from the Medicaid program that would accrue from solely analyzing administrative data, our team designed a rich, prospective, longitudinal survey to collect primary and secondary outcomes from six categories of interest to policymakers: insurance coverage, health care utilization and quality, health behaviors, socioeconomic measures, personal finances, and health outcomes. At baseline, a subset of survey participants was invited to participate in the collection of biometric samples via in-person follow-up visits, and a cross-section were also invited to participate in qualitative interviews. While the demonstration waiver was terminated before the program began, our study design illustrates that it is possible for other researchers and state agencies seeking to evaluate Medicaid demonstration waivers and other demonstration policies to work together to implement high quality randomized trials - even for controversial policies.

Rheumatic Disease: Protease-Activated Receptor-2 in Synovial Joint Pathobiology.

Protease-activated receptor-2 (PAR2) is one member of a small family of transmembrane, G-protein-coupled receptors. These receptors are activated via cleavage of their N terminus by serine proteases (e.g., tryptase), unveiling an N terminus tethered ligand which binds to the second extracellular loop of the receptor. Increasing evidence has emerged identifying key pathophysiological roles for PAR2 in both rheumatoid arthritis (RA) and osteoarthritis (OA). Importantly, this includes both pro-inflammatory and destructive roles. For example, in murine models of RA, the associated synovitis, cartilage degradation, and subsequent bone erosion are all significantly reduced in the absence of PAR2. Similarly, in experimental models of OA, PAR2 disruption confers protection against cartilage degradation, subchondral bone osteosclerosis, and osteophyte formation. This review focuses on the role of PAR2 in rheumatic disease and its potential as an important therapeutic target for treating pain and joint degradation.

Endothelium-derived contraction in a model of rheumatoid arthritis is mediated via angiotensin II type 1 receptors.

A role for endothelium-derived constricting factors (EDCF), and the angiotensin II type 1 receptor (AT1R) pathway, in the vascular impairment found in the rat Freund's complete adjuvant (FCA)-model of rheumatoid arthritis (RA) was examined. FCA arthritis was induced in rats±losartan. Vehicle-treated rats served as controls. Knee-joint swelling and red blood cell (RBC) aggregation were measured as indicators of inflammation and endothelium reactivity assessed by response to acetylcholine (ACh) on aortic rings. Results show that knee-joint swelling and RBC aggregation were elevated in the FCA+vehicle group and restored to control levels in the FCA+losartan-treated animals. ACh-induced relaxation of aortic rings taken from FCA+vehicle animals was significantly impaired compared to vehicle-controls and this vasoreactivity was restored to control levels in the FCA+losartan-treated group. Further examination of aorta from the FCA+vehicle animals revealed an EDCF that was reliant on cyclooxygenase-2 (but not cyclooxygenase-1), generation of superoxide anion generation (but not hydrogen peroxide) and activation of thromboxane-prostanoid receptor. Losartan administration in vivo or ex vivo (to aortic rings) prevented the generation of the EDCF. In summary, this is the first evidence of an EDCF in a model of RA and identifies this mechanism as potentially significant in the cardiovascular disorder associated with the disease.

The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover.

Increasing evidence implicates serine proteinases in the proteolytic cascades leading to the pathological destruction of extracellular matrices such as cartilage in osteoarthritis (OA). We have previously demonstrated that the type II transmembrane serine proteinase (TTSP) matriptase acts as a novel initiator of cartilage destruction via the induction and activation of matrix metalloproteinases (MMPs). Hepsin is another TTSP expressed in OA cartilage such that we hypothesized this proteinase may also contribute to matrix turnover. Herein, we demonstrate that addition of hepsin to OA cartilage in explant culture induced significant collagen and aggrecan release and activated proMMP-1 and proMMP-3. Furthermore, hepsin directly cleaved the aggrecan core protein at a novel cleavage site within the interglobular domain. Hepsin expression correlated with synovitis as well as tumour necrosis factor α expression, and was induced in cartilage by a pro-inflammatory stimulus. However, a major difference compared to matriptase was that hepsin demonstrated markedly reduced capacity to activate proteinase-activated receptor-2. Overall, our data suggest that hepsin, like matriptase, induces potent destruction of the extracellular matrix whilst displaying distinct efficiencies for the cleavage of specific substrates.

Retinal Remodeling and Metabolic Alterations in Human AMD.

Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression. The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this article is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina. Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease.

Effects of a beverage rich in (poly)phenols on established and novel risk markers for vascular disease in medically uncomplicated overweight or obese subjects: A four week randomized placebo-controlled trial.

OBJECTIVE: To determine if (poly)phenols alter cardiovascular risk factors, we assessed the potential of a high (poly)phenol beverage drink, rich in hydroxycinnamates and flavonoids, to modify vascular function in middle aged, overweight or obese subjects without medical co-morbidity in a randomized placebo controlled pilot study. METHODS: Randomly assigned active 250 ml beverages containing 361 mg of (poly)phenols and 120 mg of vitamin C or placebo (no polyphenol/vitamin C) were taken twice daily for 4 weeks. Both beverages contained 40 kcals/250 ml. The primary end-points were pulse wave velocity (PWV) and cutaneous microvascular responses to sodium nitroprusside (SNP) and acetyl choline (ACh) laser doppler iontophoresis. A range of established and novel plasma markers were also measured. RESULTS: Twenty subjects received active beverage and 19 placebo; all completed the study. There was no difference in cutaneous vascular response to either SNP or ACh with mean group differences (logΔ area under perfusion curve) of 0.30 (-0.65, 1.26) and 0.35 (-0.11, 0.81) respectively. Nor was there evidence of a change in log PWV with a mean group difference of 0.029 m/s (-0.042, 0.10). No significant differences were seen in plasma leptin, apolipoproteins, cystatin C, insulin, adiponectin, CRP, ICAM-1, E-Selectin or t-PA, but IL-6 increased in active versus placebo recipients (0.32 vs - 0.18 pg/ml; p=0.010). CONCLUSION: There was no evidence for a short-term beneficial effect of (poly)phenol intervention on microcutaneous vascular response or pulse wave velocity, and no evidence for a benefit on established or novel risk factors in overweight or obese subjects. Our results do not support a short-term benefit of (poly)phenol supplementation on cardiometabolic risk. REGISTRATION: Clinical Trials.gov (NCT00795834).