Differential subcellular distribution renders HAI-2 a less effective protease inhibitor than HAI-1 in the control of extracellular matriptase proteolytic activity.

The integral membrane, Kunitz-type serine protease inhibitors HAI-1 and HAI-2, can suppress the proteolytic activity of the type 2 transmembrane serine protease matriptase with high specificity and potency. High levels of extracellular matriptase proteolytic activity have, however, been observed in some neoplastic B-cells with high levels of endogenous HAI-2, indicating that HAI-2 may be an ineffective matriptase inhibitor at the cellular level. The different effectiveness of the HAIs in the control of extracellular matriptase proteolytic activity is examined here. Upon inducing matriptase zymogen activation in the HAI Teton Daudi Burkitt lymphoma cells, which naturally express matriptase with very low levels of HAI-2 and no HAI-1, nascent active matriptase was rapidly inhibited or shed as an enzymatically active enzyme. With increasing HAI-1 expression, cellular matriptase-HAI-1 complex increased, and extracellular active matriptase decreased proportionally. Increasing HAI-2 expression, however, resulted in cellular matriptase-HAI-2 complex levels reaching a plateau, while extracellular active matriptase remained high. In contrast to this differential effect, both HAI-1 and HAI-2, even at very low levels, were shown to promote the expression and cell-surface translocation of endogenous matriptase. The difference in the suppression of extracellular active matriptase by the two closely related serine protease inhibitors could result from the primarily cell surface expression of HAI-1 compared to the mainly intracellular localization of HAI-2. The HAIs, therefore, resemble one another with respect to promoting matriptase expression and surface translocation but differ in their effectiveness in the control of extracellular matriptase enzymatic activity.

Amplification of CCND1 in Urothelial Carcinoma.

OBJECTIVES: Urothelial carcinoma (UC) is the most prevalent form of bladder cancer and a significant cause of mortality in the world each year. As molecular genetic techniques improve, researchers and medical professionals are turning toward finding potential biomarkers to diagnose and characterize UC, guide treatment decisions, and use as therapeutic targets. Located on chromosome 11q13.2, the CCND1 gene encodes Cyclin D1, a CDK-regulating protein that plays a critical role in cell cycle progression. Amplification of CCND1 is seen in about 10% of all bladder cancer patients and has been a target of research due to its potential as a prognostic biomarker and a therapeutic target. However, existing literature on CCND1 amplification and Cyclin D1 expression report conflicting information about their clinical significance and association with disease staging, pointing to the need for more research to determine mechanistic pathways. Additionally, while there are currently no approved therapies or drugs that directly target CCND1 or Cyclin D1 in UC, several clinical trials with drugs targeting CDK4/CDK6 in the Cyclin D1 pathway are already underway. This paper aims to provide an update on the amplification of CCND1 in urothelial carcinoma, including an overview of recent research on elucidated pathways, clinical significance, relevant therapies under development, and directions for future research.

The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease.

Positron emission tomography (PET) ligands play an important role in the development of therapeutics by serving as target engagement or pharmacodynamic biomarkers. Here, we describe the discovery and translation of the PET tracer [11C]MK-6884 from rhesus monkeys to patients with Alzheimer's disease (AD). [3H]MK-6884/[11C]MK-6884 binds with high binding affinity and good selectivity to an allosteric site on M4 muscarinic cholinergic receptors (M4Rs) in vitro and shows a regional distribution in the brain consistent with M4R localization in vivo. The tracer demonstrates target engagement of positive allosteric modulators of the M4R (M4 PAMs) through competitive binding interactions. [11C]MK-6884 binding is enhanced in vitro by the orthosteric M4R agonist carbachol and indirectly in vivo by the acetylcholinesterase inhibitor donepezil in rhesus monkeys and healthy volunteers, consistent with its pharmacology as a highly cooperative M4 PAM. PET imaging of [11C]MK-6884 in patients with AD identified substantial regional differences quantified as nondisplaceable binding potential (BPND) of [11C]MK-6884. These results suggest that [11C]MK-6884 is a useful target engagement biomarker for M4 PAMs but may also act as a sensitive probe of neuropathological changes in the brains of patients with AD.

Survey of Current Institutional Practices in the Use of High-Flow Nasal Cannula for Pediatric Patients.

OBJECTIVES: High-flow nasal cannula (HFNC) is an oxygen delivery device that provides heated humidified air with higher flow rates. The purpose of this survey is to look at institutional practice patterns of HFNC initiation, weaning, and disposition for pediatric patients across the United States. METHODS: Survey was sent via electronic listservs to pediatric physicians in emergency medicine, hospital medicine, critical care, and urgent care. The questionnaire was divided into demographics and HFNC practices (initiation, management, and weaning). One response per institution was included in the analysis. RESULTS: Two hundred twenty-four responses were included in the analysis, composed of 40% pediatric emergency medicine physicians, 46% pediatric hospitalists, 13% pediatric intensive care unit (PICU) physicians, and 1% pediatric urgent care physicians. Ninety-eight percent of the participants have HFNC at their institution. Thirty-seven percent of the respondents had a formal guideline for HFNC initiation. Nearly all guideline and nonguideline institutions report HFNC use in bronchiolitis. Guideline cohort is more likely to have exclusion criteria for HFNC (42% in the guideline cohort vs 17% in the nonguideline cohort; P < 0.001) and less frequently mandates PICU admissions once on HFNC (11% in the guideline cohort vs 56% in the nonguideline cohort; P < 0.001). Forty-six percent of guideline cohort had an objective scoring system to help determine the need for HFNC, and 73% had a weaning guideline. CONCLUSIONS: Although there is general agreement to use HFNC in bronchiolitis, great practice variation remains in the initiation, management, and weaning of HFNC across the United States. There is also a discordance on PICU use when a patient is using HFNC.

c-MYC Amplification in AML.

OBJECTIVES: Acute myeloid leukemia (AML) is a clonal disorder of myeloid lineage precursors. Identification of cytogenetic aberrations is essential for classification and risk stratification of AML, with many demonstrating unique associations with various clinicopathologic features. One such abnormality is MYC amplification, a rare occurrence identified in less than 1% of AML patients. MYC is most commonly amplified in the form of double minutes, but may also occur via ring and marker chromosomes or homogeneously staining regions. Amplification of MYC often involves various chromosomal aberrations, including trisomies 4 and 6 and aneusomy of the sex chromosomes. In many cases, the presence of MYC amplicons is also associated with other negative prognostic factors, including complex karyotype and advanced age. Although MYC has been extensively investigated as a therapeutic target in various cancers, there are few studies examining the clinical significance of MYC amplification in AML. In this review, we explore recurrent cytogenetic abnormalities and demographic characteristics associated with amplification of MYC in patients with AML and discuss their diagnostic and therapeutic implications.

Fostering diversity work as a process of lifelong learning: A partnership case study with an immigrant services organisation.

Diversity work is an area of growing interest for organisations in both the private and public sectors. In a nutshell, the term refers to the work conducted within an organisation that promotes inclusive and equitable engagement with people and communities across social differences such as gender, race, ethnicity, sexuality and religion. Related research has generated relatively more knowledge about the challenges and problems of diversity initiatives than about effective practices that genuinely foster social equity and inclusion. This article contributes to the latter with a partnership case study involving the United Chinese Community Enrichment Services Society (S.U.C.C.E.S.S.), a large non-profit immigrant services organisation headquartered in Vancouver, Canada. Specifically, the study presented here focuses on the organisational practices that are constitutive of frontline workers' engagement with diversity work and learning. It shows that (1) building a diverse and inclusive organisation, (2) supporting continuous learning opportunities at work, and (3) providing diversity training, both directive and generative, form the organisation's diversity "curriculum". This study also demonstrates that the strength of this workplace curriculum is that it has the potential to challenge the boundary between instrumentalism (harnessing diversity work to business success) and equity activism (prioritising diversity work in its own right), and that it creates space for collective reflection in the presence of others. Conceptually drawing on the practice turn in social sciences, particularly Steven Billet and Jennifer Newton's learning practice, and what David Boud terms "the reflective turn", this article positions diversity work as a reflective and iterative process of lifelong learning for both organisations and individual workers.

Encourager le travail de diversité en tant que processus d'apprentissage tout au long de la vie : étude de cas en partenariat avec une organisation de services aux immigrants ­ Le travail de diversité (diversity work en anglais) est un domaine qui suscite un intérêt croissant tant dans le secteur privé que dans le secteur public. Pour faire court, cette expression renvoie au travail mené au sein d'une organisation qui promeut un engagement inclusif et équitable auprès de personnes et de communautés en dépassant les différences sociales comme le genre, la race, l'ethnicité, la sexualité et la religion. Les recherches liées à cela ont produit relativement plus de connaissances concernant les défis et problèmes des projets sur la diversité que sur les pratiques efficaces qui favorisent réellement l'équité sociale et l'inclusion. Cet article contribue à ces dernières en présentant une étude de cas en partenariat avec la United Chinese Community Enrichment Services Society (S.U.C.C.E.S.S.), grande organisation à but non lucratif de services aux immigrants, dont le siège se situe au Canada, à Vancouver. L'étude présentée ici est axée en particulier sur les pratiques organisationnelles constitutives de l'engagement des travailleurs sur le terrain en matière du travail de diversité et d'apprentissage. Elle montre que (1) créer une organisation diverse et inclusive, (2) soutenir des possibilités d'apprentissage continu au travail et (3) proposer une formation à la diversité, tant directive que générative, façonne le « curriculum ¼ de l'organisation en matière de diversité. Cette étude démontre également que la puissance de ce curriculum sur le lieu de travail réside dans ses possibilités de repousser les limites entre l'instrumentalisme (qui exploite le travail de diversité pour la réussite de l'entreprise) et l'activisme en matière d'équité (qui priorise le travail de diversité à part entière). S'appuyant sur le plan conceptuel sur le tournant pratique dans les sciences sociales (practice turn en anglais), notamment sur la pratique de l'apprentissage de Steven Billet et Jennifer Newton, et sur ce que David Boud appelle « le tournant réflexif ¼ (the reflexive turn), cet article positionne le travail de diversité en tant que processus réflexif et itératif d'apprentissage tout au long de la vie, tant pour les organisations que pour les travailleurs individuels.

Cellphone enabled point-of-care assessment of breast tumor cytology and molecular HER2 expression from fine-needle aspirates.

Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we have developed a multimodal cellphone-based platform-the EpiView-D4-that can evaluate both cellular morphology and molecular expression of clinically relevant biomarkers directly from fine-needle aspiration (FNA) of breast tissue specimens within 1 h. The EpiView-D4 is comprised of two components: (1) an immunodiagnostic chip built upon a "non-fouling" polymer brush-coating (the "D4") which quantifies expression of protein biomarkers directly from crude cell lysates, and (2) a custom cellphone-based optical microscope ("EpiView") designed for imaging cytology preparations and D4 assay readout. As a proof-of-concept, we used the EpiView-D4 for assessment of human epidermal growth factor receptor-2 (HER2) expression and validated the performance using cancer cell lines, animal models, and human tissue specimens. We found that FNA cytology specimens (prepared in less than 5 min with rapid staining kits) imaged by the EpiView-D4 were adequate for assessment of lesional cellularity and tumor content. We also found our device could reliably distinguish between HER2 expression levels across multiple different cell lines and animal xenografts. In a pilot study with human tissue (n = 19), we were able to accurately categorize HER2-negative and HER2-positve tumors from FNA specimens. Taken together, the EpiView-D4 offers a promising alternative to invasive-and often unavailable-pathology services and may enable the democratization of effective breast cancer management in limited-resource settings.

Experimental Medicine Study to Measure Immune Checkpoint Receptors PD-1 and GITR Turnover Rates In Vivo in Humans.

Development of monoclonal antibodies (mAbs) targeting immune-checkpoint receptors (IMRs) for the treatment of cancer is one of the most active areas of investment in the biopharmaceutical industry. A key decision in the clinical development of anti-IMR mAbs is dose selection. Dose selection can be challenging because the traditional oncology paradigm of administering the maximum tolerated dose is not applicable to anti-IMR mAbs. Instead, dose selection should be informed by the pharmacology of immune signaling. Engaging an IMR is a key initial step to triggering pharmacologic effects, and turnover (i.e., the rate of protein synthesis) of the IMR is a key property to determining the dose level needed to engage the IMR. Here, we applied the stable isotope labeling mass spectrometry technique using 13 C6 -leucine to measure the in vivo turnover rates of IMRs in humans. The 13 C6 -leucine was administered to 10 study participants over 15 hours to measure 13 C6 -leucine enrichment kinetics in 2 IMR targets that have been clinically pursued in oncology: GITR and PD-1. We report the first measurements of GITR and PD-1 median half-lives associated with turnover to be 55.6 and ≥ 49.5 hours, respectively. The approach outlined here can be applied to other IMRs and, more generally, to protein targets.

Consensus survey on pre-procedural safety practices in radiological examinations: a multicenter study in seven Asian regions.

OBJECTIVE: To understand the status of pre-procedural safety practices in radiological examinations at radiology residency training institutions in various Asian regions. METHODS: A questionnaire based on the Joint Commission International Accreditation Standards was electronically sent to 3 institutions each in 10 geographical regions across 9 Asian countries. Questions addressing 45 practices were divided into 3 categories. A five-tier scale with numerical scores was used to evaluate safety practices in each institution. Responses obtained from three institutions in the United States were used to validate the execution rate of each surveyed safety practice. RESULTS: The institutional response rate was 70.0% (7 Asian regions, 21 institutions). 44 practices (all those surveyed except for the application of wrist tags for identifying patients with fall risks) were validated using the US participants. Overall, the Asian participants reached a consensus on 89% of the safety practices. Comparatively, most Asian participants did not routinely perform three pre-procedural practices in the examination appropriateness topic. CONCLUSION: Based on the responses from 21 participating Asian institutions, most routinely perform standard practices during radiological examinations except when it comes to examination appropriateness. This study can provide direction for safety policymakers scrutinizing and improving regional standards of care. ADVANCES IN KNOWLEDGE: This is the first multicenter survey study to elucidate pre-procedural safety practices in radiological examinations in seven Asian regions.

Choosing Wisely Canada's emergency medicine recommendations: Time for a revision.

Choosing Wisely Canada (CWC) is a national initiative designed to encourage patient-clinician discussions about the appropriate, evidence-based use of medical tests, procedures and treatments. The Canadian Association of Emergency Physicians' (CAEP) Choosing Wisely Canada (CWC) working group developed and released ten recommendations relevant to Emergency Medicine in June 2015 (items 1-5) and October 2016 (items 6-10). In November 2016, the CAEP CWC working group developed a process for updating the recommendations. This process involves: 1) Using GRADE to evaluate the quality of evidence, 2) reviewing relevant recommendations on an ad hoc basis as new evidence emerges, and 3) reviewing all recommendations every five years. While the full review of the CWC recommendations will be performed in 2020, a number of high-impact studies were published after our initial launch that prompted an ad hoc review of the relevant three of our ten recommendations prior to the full review in 2020. This paper describes the results of the CAEP CWC working group's ad hoc review of three of our ten recommendations in light of recent publications.

L'initiative nationale Choisir avec soin a été conçue pour favoriser les discussions entre patients et cliniciens sur l'utilisation appropriée et fondée sur des données probantes des examens médicaux, des interventions et des traitements. Le groupe de travail sur l'initiative, de l'Association canadienne des médecins d'urgence, a élaboré et diffusé dix recommandations relatives à la pratique de la médecine d'urgence, d'abord en juin 2015 (points 1-5), puis en octobre 2016 (points 6-10). En novembre 2016, le groupe de travail sur l'initiative s'est penché sur un processus de mise à jour des recommandations. Ce dernier comprend trois éléments : 1) l'application de l'instrument GRADE pour évaluer la qualité des données probantes; 2) une révision ponctuelle des recommandations pertinentes suivant la diffusion de nouvelles données; 3) un réexamen quinquennal de toutes les recommandations. La révision complète des recommandations présentées dans l'initiative est prévue en 2020; toutefois, un certain nombre d'études ayant une incidence importante ont déjà été publiées après le premier lancement des recommandations, ce qui a incité le groupe de travail à procéder à une révision ponctuelle de trois recommandations pertinentes sur les dix existantes, avant l'examen complet prévu en 2020. Il sera donc question, dans l'article, des résultats de la révision ponctuelle de ces trois recommandations, réalisée à la lumière des récentes publications, par le groupe de travail sur l'initiative.

Quality improvement primer part 3: Evaluating and sustaining a quality improvement project in the emergency department.

Quality improvement (QI) and patient safety are two areas that have grown into important operational and academic fields in recent years in health care, including in emergency medicine (EM). This is the third and final article in a series designed as a QI primer for EM clinicians. In the first two articles we used a fictional case study of a team trying to decrease the time to antibiotic therapy for patients with sepsis who were admitted through their emergency department. We introduced concepts of strategic planning, including stakeholder engagement and root cause analysis tools, and presented the Model for Improvement and Plan-Do-Study-Act (PDSA) cycles as the backbone of the execution of a QI project. This article will focus on the measurement and evaluation of QI projects, including run charts, as well as methods that can be used to ensure the sustainability of change management projects.

Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis.

AIMS: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. METHODS: This was an open-label, fixed-sequence, two-period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7-day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), were assessed. RESULTS: Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL-6 or hs-CRP. Treatment with tildrakizumab was generally well tolerated. CONCLUSION: In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug-drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti-inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

Quality improvement primer part 2: executing a quality improvement project in the emergency department.

The topics of quality improvement (QI) and patient safety have become important themes in health care in recent years, particularly in the emergency department setting, which is a frequent point of contact with the health care system for patients. In the first of three articles in this series meant as a QI primer for emergency medicine clinicians, we introduced the strategic planning required to develop an effective QI project using a fictional case study as an example. In this second article we continue with our example of improving time to antibiotics for patients with sepsis, and introduce the Model for Improvement. We will review what makes a good aim statement, the various categories of measures that can be tracked during a QI project, and the relative merits and challenges of potential change concepts and ideas. We will also present the Model for Improvement's rapid-cycle change methodology, the Plan-Do-Study-Act (PDSA) cycle. The final article in this series will focus on the evaluation and sustainability of QI projects.

Quality improvement primer part 1: Preparing for a quality improvement project in the emergency department.

Emergency medicine (EM) providers work in a fast-paced and often hectic environment that has a high risk for patient safety incidents and gaps in the quality of care. These challenges have resulted in opportunities for frontline EM providers to play a role in quality improvement (QI) projects. QI has developed into a mature field with methodologies that can dramatically improve the odds of having a successful project with a sustainable impact. However, this expertise is not yet commonly taught during professional training. In this first of three articles meant as a QI primer for EM clinicians, we will introduce QI methodology and strategic planning using a fictional case study as an example. We will review how to identify a QI problem, define components of an effective problem statement, and identify stakeholders and core change team members. We will also describe three techniques used to perform root cause analyses-Ishikawa diagrams, Pareto charts and process mapping-and how they relate to preparing for a QI project. The next two papers in this series will focus on the execution of the QI project itself using rapid-cycle testing and on the evaluation and sustainability of QI projects.

Magnetic resonance imaging of the hand and wrist in a randomized, double-blind, multicenter, placebo-controlled trial of infliximab for rheumatoid arthritis: Comparison of dynamic contrast enhanced assessments with semi-quantitative scoring.

The objective of this study was to compare the scope and the discriminative power of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) to those of semi-quantitative MRI scoring for evaluating treatments for rheumatoid arthritis (RA) in multicenter randomized clinical trials (RCTs). Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. The most symptomatic wrist and metacarpophalangeal joints (MCPs) were imaged using MRI. In addition to clinical assessments with DAS28(CRP), the severity of inflammation was measured as synovial leak of gadolinium based contrast agent (GBCA) using DCE-MRI (Ktrans, primary endpoint) at weeks 0, 2, 4, and 14. Two radiologists independently scored synovitis, osteitis and erosion using RA MRI Score (RAMRIS) and cartilage loss using a 9-point MRI scale (CARLOS). Infliximab showed greater decrease from baseline in DAS28(CRP), DCE-MRI Ktrans of wrist and MCP synovium, and RAMRIS synovitis and osteitis at all visits compared with placebo (p<0.001). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08; 90% CI (0.63-1.53)) and MRI inflammation endpoints: wrist Ktrans (1.00 (0.55-1.45)), RAMRIS synovitis (0.85 (0.38-1.28)) and RAMRIS osteitis (0.99 (0.52-1.43)). Damage measures of bone erosion (RAMRIS) and cartilage loss (CARLOS) were reduced with infliximab compared to with placebo at 14 weeks (p≤0.025). DCE-MRI and RAMRIS were equally sensitive and responsive to the anti-inflammatory effects of infliximab. RAMRIS and CARLOS showed suppression of erosion and cartilage loss, respectively, at 14 weeks. (ClinicalTrials.gov registration: NCT01313520).

Patients' Perspectives on Outcomes of Care After Discharge From the Emergency Department: A Qualitative Study.

STUDY OBJECTIVE: Much effort has been expended to understand what care experiences patients value in the emergency department (ED), yet little is known about which outcomes patients value after ED care. Our goal is to define outcomes of ED care that are valued by patients discharged from the ED, with the goal of informing the development of a patient-reported outcome measure for ED care. METHODS: We conducted qualitative semistructured interviews with patients recruited during their care at 1 of 2 EDs and interviewed in either English or French 1 to 9 days after their visit. Patients who were hospitalized were excluded. Interviews focused on perceived outcomes of care since the ED visit and expectations of care before the ED visit. We identified themes with standard descriptive content analysis techniques and a modified version of the constant comparative method, drawing on grounded theory methods. RESULTS: We interviewed 46 patients in English (n=38) or French (n=8). Participants with diverse reasons for seeking care appeared to value common outcomes from ED care that centered around 4 themes: understanding the cause and expected trajectory of their symptoms; reassurance; symptom relief; and having a plan to manage their symptoms, resolve their issue, or pursue further medical care. These themes were also reflected in the expectations participants recalled having when they decided to seek care in the ED. CONCLUSION: The 4 outcomes defined constitute areas for improvement and will inform the development of an ED patient-reported outcome questionnaire. Consideration should be given to measuring patient-reported outcomes separately from patient experience.