Obtaining Patient Priorities in a Multiple Sclerosis Comprehensive Care Center: Beyond Patient-Reported Outcomes.

BACKGROUND: In order to provide patient center care, our multiple sclerosis (MS) clinic assesses patient concerns before clinical encounters, first by asking the optional qualitative question "What is the most important thing you what your health-care provider to know today" (most important concern of the patient [MIPC]) and then completing quantitative patient-reported outcome measures (PROMs) including Quality of Life in Neurological Disorders (Neuro-QoL). Both sets of questions are designed to facilitate encounters that address patients' values and preferences. OBJECTIVE: Determine whether the qualitative MIPC responses provided unique information not included in PROMs or clinical assessments. METHODS: We randomly selected 400 first-time MIPC responders and 400 first-time MIPC nonresponders from 2788 participants in our database. We categorized MIPC responses by content and number of unique concerns and appended them to the Neuro-QoL framework. Nonresponders were compared to those who provided 1 and 2 or more responses. RESULTS: Several MIPCs MS symptoms categories were added to the Neuro-QoL Physical domain. Most important concern of the patients work and cost-of-care categories were added to the Social Domain. Domains regarding treatment satisfaction and disease management were added. Two hundred thirty (58%) MIPC respondents reported 1 concern, 140 (35%) expressed 2 to 6 concerns, and 30 (7%) reported MS-unrelated concerns and not analyzed. Physical symptoms were the most common MIPC (69.9%). Respondents with more concerns were more likely African American, lacked private insurance, and worse disability. CONCLUSIONS: Importantly, MIPC responders described idiosyncratic symptoms, disease management, and social concerns not included in the PROMS, suggesting the MIPC question offered patients a unique opportunity to share specific concerns with their providers.

Multiple sclerosis management during the COVID-19 pandemic.

BACKGROUND: People with multiple sclerosis (MS) may be at higher risk for complications from the 2019 coronavirus (COVID-19) pandemic due to use of immunomodulatory disease modifying therapies (DMTs) and greater need for medical services. OBJECTIVES: To evaluate risk factors for COVID-19 susceptibility and describe the pandemic's impact on healthcare delivery. METHODS: Surveys sent to MS patients at Cleveland Clinic, Johns Hopkins, and Vall d'Hebron-Centre d'Esclerosi Múltiple de Catalunya in April and May 2020 collected information about comorbidities, DMTs, exposures, COVID-19 testing/outcomes, health behaviors, and disruptions to MS care. RESULTS: There were 3028/10,816 responders. Suspected or confirmed COVID-19 cases were more likely to have a known COVID-19 contact (odds ratio (OR): 4.38; 95% confidence interval (CI): 1.04, 18.54). In multivariable-adjusted models, people who were younger, had to work on site, had a lower education level, and resided in socioeconomically disadvantaged areas were less likely to follow social distancing guidelines. 4.4% reported changes to therapy plans, primarily delays in infusions, and 15.5% a disruption to rehabilitative services. CONCLUSION: Younger people with lower socioeconomic status required to work on site may be at higher exposure risk and are potential targets for educational intervention and work restrictions to limit exposure. Providers should be mindful of potential infusion delays and MS care disruption.

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

BACKGROUND: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice. METHOD: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments. RESULTS: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates. CONCLUSIONS: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.

Teleneurology as a Solution for Outpatient Care During the COVID-19 Pandemic.

Background: The coronavirus disease of 2019 (COVID-19) pandemic and the need for social distancing have dramatically changed health care delivery. There is an urgent need to continue to deliver outpatient care for chronic neurological disease and teleneurology has the potential to fulfill this gap. Introduction: This study reports the implementation and utilization of teleneurology across all neurological subspecilities during the COVID-19 pandemic. Materials and Methods: This is a retrospective observational study that identified all in-person and teleneurology outpatient nonprocedural visits from January 5 to April 4, 2020, across neurological specialties at a single academic center. Visit volumes were assessed weekly and practice patterns were compared before and after March 15, 2020, as this was the date of a major statewide stay-at-home order in Ohio. Results: Before March 15 the mean in-person visit per week was 5129.4 and decreased to 866.7 after that date. The mean teleneurology visits per week increased from 209.1 to 2619.3 for the same time period. The overall teleneurology visit volume in the 3 weeks after March 15 increased by 533%. Discussion: In a relatively short time frame of 3 weeks, a single academic center was able to dramatically increase teleneurology visits to provide outpatient neurological care. Conclusions: This study demonostrates that teleneruology can be a solution for outpatient neurological care in the context of COVID-19. The increased utilization of teleneurology during this crisis has the potential to expand teleneurology and improve access to neurological care in the future outside the pandemic setting.

Technology-enabled comprehensive characterization of multiple sclerosis in clinical practice.

BACKGROUND: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets. OBJECTIVES: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort. METHODS: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result. RESULTS: 997 unique patients (age 47.7 ±â€¯11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R2=0.46). For CST, significant variables included age and NQ-LE (adjusted R2 = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R2=0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R2=0.39). CONCLUSIONS: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.

Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways.

Cardiotonic steroids (CTS) are Na⁺/K⁺-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/-). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/- mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

Paraoxonase 2 prevents the development of heart failure.

BACKGROUND: Mitochondrial oxidation is a major source of reactive oxygen species (ROS) and mitochondrial dysfunction plays a central role in development of heart failure (HF). Paraoxonase 2 deficient (PON2-def) mitochondria are impaired in function. In this study, we tested whether PON2-def aggravates HF progression. METHODS AND RESULTS: Using qPCR, immunoblotting and lactonase activity assay, we demonstrate that PON2 activity was significantly decreased in failing hearts despite increased PON2 expression. To determine the cardiac-specific function of PON2, we performed heart transplantations in which PON2-def and wild type (WT) donor hearts were implanted into WT recipient mice. Beating scores of the donor hearts, assessed at 4 weeks post-transplantation, were significantly decreased in PON2-def hearts when compared to WT donor hearts. By using a transverse aortic constriction (TAC) model, we found PON2 deficiency significantly exacerbated left ventricular remodeling and cardiac fibrosis post-TAC. We further demonstrated PON2 deficiency significantly enhanced ROS generation in heart tissues post-TAC. ROS generation was measured through dihydroethidium (DHE) using high-pressure liquid chromatography (HPLC) with a fluorescent detector. By using neonatal cardiomyocytes treated with CoCl2 to mimic hypoxia, we found PON2 deficiency dramatically increased ROS generation in the cardiomyocytes upon CoCl2 treatment. In response to a short CoCl2 exposure, cell viability and succinate dehydrogenase (SDH) activity assessed by MTT assay were significantly diminished in PON2-def cardiomyocytes compared to those in WT cardiomyocytes. PON2-def cardiomyocytes also had lower baseline SDH activity. By using adult mouse cardiomyocytes and mitochondrial ToxGlo assay, we found impaired cellular ATP generation in PON2-def cells compared to that in WT cells, suggesting that PON2 is necessary for proper mitochondrial function. CONCLUSION: Our study suggests a cardioprotective role for PON2 in both experimental and human heart failure, which may be associated with the ability of PON2 to improve mitochondrial function and diminish ROS generation.

High-density lipoprotein-associated paraoxonase-1 activity for prediction of adverse outcomes in outpatients with chronic heart failure.

AIMS: Decreased arylesterase (ArylE) activity of paraoxonase-1, a HDL-associated protein with anti-inflammatory and antioxidant properties, has been associated with increased risk of cardiac events in patients with ischaemic heart failure (HF). We aim to investigate the prognostic significance of changes in serum ArylE activity over time. METHODS AND RESULTS: We examined the association between baseline and follow-up serum ArylE activity and HF outcomes (death, cardiac transplantation, or ventricular assist device implantation) in 299 patients with HF enrolled in a prospective cohort study from January 2008 to July 2009, with 145 patients having available follow-up levels at 1 year. A significant drop in ArylE activity on follow-up was defined as a drop of ≥25% vs. baseline levels. Mean baseline and follow-up ArylE activity levels were 110.6 ± 29.9 µmol/min/mL and 106.2 ± 29.9 µmol/min/mL, respectively. After a mean follow-up of 2.8 ± 1.1 years, low baseline ArylE activity was associated with increased risk of adverse HF events [hazard ratio (HR; lowest vs highest tertile) 2.6, 95% confidence interval (CI) 1.3-5.5, P = 0.01] and HF-related hospitalization [incidence rate ratio (lowest vs. highest tertile) 2.1, 95% CI 1.2-4.1, P = 0.016], which remained significant after adjustment for age, male gender, systolic blood pressure, diabetes, creatinine clearance, CAD, and HDL-cholesterol levels. Patients who had a significant drop in ArylE activity on follow-up (n = 18) had a significantly increased risk of HF events (HR 4.9, 95% CI 1.6-14.6, P = 0.005), even after adjustment for baseline levels of ArylE activity. CONCLUSIONS: Reduced baseline ArylE activity and decreased levels on follow-up are associated with adverse outcomes in stable outpatients with HF.

Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure.

BACKGROUND: Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. METHODS AND RESULTS: We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥ 280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (≥ 25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. CONCLUSIONS: Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.

Interference with akt signaling protects against myocardial infarction and death by limiting the consequences of oxidative stress.

The intricacy of multiple feedback loops in the pathways downstream of Akt allows this kinase to control multiple cellular processes in the cardiovascular system and precludes inferring consequences of its activation in specific pathological conditions. Akt1, the major Akt isoform in the heart and vasculature, has a protective role in the endothelium during atherosclerosis. However, Akt1 activation may also have detrimental consequences in the cardiovascular system. Mice lacking both the high-density lipoprotein receptor SR-BI (scavenger receptor class B type I) and ApoE (apolipoprotein E), which promotes clearance of remnant lipoproteins, are a model of severe dyslipidemia and spontaneous myocardial infarction. We found that Akt1 was activated in these mice, and this activation correlated with cardiac dysfunction, hypertrophy, and fibrosis; increased infarct area; cholesterol accumulation in macrophages and atherosclerosis; and reduced life span. Akt1 activation was associated with inflammation, oxidative stress, accumulation of oxidized lipids, and increased abundance of CD36, a major sensor of oxidative stress, and these events created a positive feedback loop that exacerbated the consequences of oxidative stress. Genetic deletion of Akt1 in this mouse model resulted in decreased mortality, alleviation of multiple complications of heart disease, and reduced occurrence of spontaneous myocardial infarction. Thus, interference with Akt1 signaling in vivo could be protective and improve survival under dyslipidemic conditions by reducing oxidative stress and responses to oxidized lipids.

Integrin ß3 crosstalk with VEGFR accommodating tyrosine phosphorylation as a regulatory switch.

Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between ß(3) integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of ß(3) and VEGFR2. Specifically, the membrane-proximal motif around (801)YLSI in VEGFR2 mediates its binding to non-phosphorylated ß(3)CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y(747) phosphorylation of ß(3) enhances the above interaction. To demonstrate the importance of ß(3) phosphorylation in endothelial cell functions, we synthesized ß(3)CT-mimicking Y(747) phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y(747) but not F(747) significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y(747) peptide exhibits inhibitory effect only in WT but not in ß(3) integrin knock-out or ß(3) integrin knock-in cells expressing ß(3) with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2.

A novel transcriptional mechanism of cell type-specific regulation of vascular gene expression by glucose.

OBJECTIVE: Vascular diabetic complications are associated with abnormal extracellular matrix and dysfunction of vascular cells, which later result in aberrant angiogenesis and development of atherosclerotic lesions. The tissue and cell specificity of the effects of high glucose are well recognized, but the underlying cell type-specific molecular mechanisms controlled by glucose are still unclear. We sought to identify cell type-specific mechanisms by which high glucose regulates transcription of genes in vascular cells. METHODS AND RESULTS: Thrombospondin-1 is a potent antiangiogenic protein associated with development of several diabetic complications and regulated by high glucose in multiple cell types. We report that distinct cell type-specific mechanisms regulate thrombospondin-1 gene (THBS1) transcription in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in response to high glucose: although a proximal fragment of 280 nucleotides is sufficient to drive transcription in ECs, THBS1 was regulated cooperatively by interaction between proximal (-272 to -275) and distal (-1016 to -1019) promoter elements in VSMCs. Transcription factors activated by high glucose in VSMCs were cell type-specific. The formation of a single complex interacting with both distal and proximal glucose-responsive elements of THBS1 promoter in VSMCs was confirmed using gel-shift assays, binding sequence decoy oligomers, and specific mutant promoter fragments. CONCLUSIONS: Transcriptional response of vascular cells to high glucose is cell type-specific and involves activation of distinct transcription factors, providing a basis for tissue-specific changes of vasculature in diabetics.