A smartphone sensor-based digital outcome assessment of multiple sclerosis.

BACKGROUND: Sensor-based monitoring tools fill a critical gap in multiple sclerosis (MS) research and clinical care. OBJECTIVE: The aim of this study is to assess performance characteristics of the Floodlight Proof-of-Concept (PoC) app. METHODS: In a 24-week study (clinicaltrials.gov: NCT02952911), smartphone-based active tests and passive monitoring assessed cognition (electronic Symbol Digit Modalities Test), upper extremity function (Pinching Test, Draw a Shape Test), and gait and balance (Static Balance Test, U-Turn Test, Walk Test, Passive Monitoring). Intraclass correlation coefficients (ICCs) and age- or sex-adjusted Spearman's rank correlation determined test-retest reliability and correlations with clinical and magnetic resonance imaging (MRI) outcome measures, respectively. RESULTS: Seventy-six people with MS (PwMS) and 25 healthy controls were enrolled. In PwMS, ICCs were moderate-to-good (ICC(2,1) = 0.61-0.85) across tests. Correlations with domain-specific standard clinical disability measures were significant for all tests in the cognitive (r = 0.82, p < 0.001), upper extremity function (|r|= 0.40-0.64, all p < 0.001), and gait and balance domains (r = -0.25 to -0.52, all p < 0.05; except for Static Balance Test: r = -0.20, p > 0.05). Most tests also correlated with Expanded Disability Status Scale, 29-item Multiple Sclerosis Impact Scale items or subscales, and/or normalized brain volume. CONCLUSION: The Floodlight PoC app captures reliable and clinically relevant measures of functional impairment in MS, supporting its potential use in clinical research and practice.

Correction: Adherence and Satisfaction of Smartphone- and Smartwatch-Based Remote Active Testing and Passive Monitoring in People With Multiple Sclerosis: Nonrandomized Interventional Feasibility Study.

[This corrects the article DOI: 10.2196/14863.].

Adherence and Satisfaction of Smartphone- and Smartwatch-Based Remote Active Testing and Passive Monitoring in People With Multiple Sclerosis: Nonrandomized Interventional Feasibility Study.

BACKGROUND: Current clinical assessments of people with multiple sclerosis are episodic and may miss critical features of functional fluctuations between visits. OBJECTIVE: The goal of the research was to assess the feasibility of remote active testing and passive monitoring using smartphones and smartwatch technology in people with multiple sclerosis with respect to adherence and satisfaction with the FLOODLIGHT test battery. METHODS: People with multiple sclerosis (aged 20 to 57 years; Expanded Disability Status Scale 0-5.5; n=76) and healthy controls (n=25) performed the FLOODLIGHT test battery, comprising active tests (daily, weekly, every two weeks, or on demand) and passive monitoring (sensor-based gait and mobility) for 24 weeks using a smartphone and smartwatch. The primary analysis assessed adherence (proportion of weeks with at least 3 days of completed testing and 4 hours per day passive monitoring) and questionnaire-based satisfaction. In-clinic assessments (clinical and magnetic resonance imaging) were performed. RESULTS: People with multiple sclerosis showed 70% (16.68/24 weeks) adherence to active tests and 79% (18.89/24 weeks) to passive monitoring; satisfaction score was on average 73.7 out of 100. Neither adherence nor satisfaction was associated with specific population characteristics. Test-battery assessments had an at least acceptable impact on daily activities in over 80% (61/72) of people with multiple sclerosis. CONCLUSIONS: People with multiple sclerosis were engaged and satisfied with the FLOODLIGHT test battery. FLOODLIGHT sensor-based measures may enable continuous assessment of multiple sclerosis disease in clinical trials and real-world settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02952911; https://clinicaltrials.gov/ct2/show/NCT02952911.

Effects of Kelatorphan and morphine before and after noxious stimulation on immediate-early gene expression in rat spinal cord neurons.

Expression of the immediate-early genes (IEG) c-FOS, NGF1-A and c-JUN was induced by noxious thermal stimulation in neurons of the rat spinal cord dorsal horn. Intravenous injection of Kelatorphan (5, 10 and 20 mg/kg), an inhibitor of multiple enkephalin-degrading enzymes, 20 min before noxious stimulation reduced the overall number of dorsal horn neurons expressing c-FOS and NGF1-A by up to 20-30%. While c-FOS expression was suppressed in superficial and deep laminae of the spinal cord, NGF1-A and c-JUN was only suppressed in superficial laminae. Morphine (5, 7.5 and 10 mg/kg) produced a dose-dependent reduction of c-FOS expression by up to 70% only when injected before noxious stimulation. Morphine injected 10 min after the noxious treatment was virtually ineffective. The depressant effect of Kelatorphan and morphine could be prevented by prior application of the opioid antagonist naloxone. Naloxone itself slightly increased the overall number of c-FOS-positive neurons in all laminae of the spinal cord. The present data support the existence of a tonic release of endogenous opioid peptides at the spinal level and show that inhibition of their peptidase-induced degradation modulates IEG expression in dorsal horn neurons of the rat. The finding that opioid agonists were ineffective when applied after stimulation underline the necessity of pre-emptive analgesia to prevent long-term activity-dependent changes in spinal cord neurons.

Effects of morphine withdrawal on micro-opioid receptor-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate autoradiography in rat brain.

Abstinence from chronic morphine results in characteristic withdrawal symptoms in humans and experimental animals. Despite a large number of studies, the cellular mechanisms underlying opiate withdrawal symptoms are not clearly understood, in particular, the regulation of micro-opioid receptor function during this process. The present study investigated the micro-opioid receptor-stimulated G-protein activity using guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]-GTPgammaS) autoradiography. [35S]-GTPgammaS binding was performed using coronal rat brain sections (20 microm) in the presence or absence of the micro-opioid selective agonist [D-Ala(2),N-MePhe(4)Gly(5)-ol] enkephalin (DAMGO). In experiment 1, rats (male, Sprague-Dawley) were injected every 12 h with increasing doses of morphine (5-100 mg/kg, s.c.) for 12 days; a separate group of rats which received saline injections served as control. Opiate withdrawal was induced by abstinence from morphine. Thirty-six hours after the last morphine injection, spontaneous withdrawal symptoms were assessed. Rats were then decapitated and brains rapidly removed. In experiment 2, withdrawal symptoms were precipitated with the opioid receptor antagonist naloxone (1 mg/kg). Brains were taken at 5, 10, 20 and 60 min after naloxone injection. In experiment 3, morphine dependence was induced by implantation of three morphine pellets (75 mg per pellet). After 7 days, withdrawal symptoms were precipitated by naloxone (1 mg/kg) and brains were removed 30 min after naloxone injection. [35S]-GTPgammaS binding was measured in the locus coeruleus, nucleus parabrachialis, nucleus accumbens and central nucleus of amygdala. Although clear withdrawal symptoms were observed in all morphine-withdrawn rats, no significant changes in [35S]-GTPgammaS binding were detected in animals undergoing withdrawal. The present lack of differences between morphine-withdrawn and control rats indicates that micro-opioid receptor-stimulated G-protein activity is not modulated by chronic morphine administration and is not involved in the expression of opiate withdrawal.

The burden of chronic low back pain with and without a neuropathic component: a healthcare resource use and cost analysis.

BACKGROUND: This research addresses the need for population-based studies on the burden of chronic low back pain (CLBP) by examining healthcare service use and costs for patients with and without neuropathic components in the US population. METHODS: Data were analyzed from PharMetrics IMS LifeLink™ US Claims Database (2006-2008). Patients (≥18 years) with 36 months continuous enrollment, ICD-9 code for low back pain, and claims in 3 out of 4 consecutive months in the 12-month prospective period were included and classified with CLBP. Patients were further classified with a neuropathic component (wNP) and without a neuropathic component (woNP) based on ICD-9 codes. Healthcare resources, physical therapy, prescription medication use, and associated costs were assessed for the period January 1-December 31, 2008. RESULTS: A number of patients (39,425) were identified with CLBP (90.4% wNP). Patients wNP included more women, were older and more likely to have clinically diagnosed depression, and made significantly greater use of any prescription medication at index event, opioids (particularly schedule II), and healthcare resources. Total direct costs of CLBP-related resource use were ∼US$96 million over a 12-month follow-up. CLBP wNP accounted for 96% of total costs and mean annual cost of care/patient was ∼160% higher than CLBP patients woNP (US$ 2577 vs US$ 1007, p < 0.0001). LIMITATIONS: This study was descriptive and was not designed to demonstrate causality between diagnosis, treatment, and outcomes. Resource use and costs for reasons other than LBP were not included. Patients with neuropathic pain are more likely to seek treatment; therefore CLBP patients with a non-neuropathic component may be under-represented. CONCLUSIONS: The disproportionately high share of interventional resource use in CLBP wNP suggests greater need for new treatment options that more comprehensively manage the range of pain symptoms and signaling mechanisms involved, to help improve patient outcomes and reduce the burden on healthcare systems.

Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective.

BACKGROUND: Inpatient care to manage relapse of patients with schizophrenia contributes greatly to the overall financial burden of treatment. The present study explores to what extent this is influenced by duration of illness. METHODS: Medical and pharmaceutical claims data for patients diagnosed with schizophrenia (ICD-9 295.xx) were obtained from the PharMetrics Integrated Database, a large, regionally representative US insurance claims database, for the period 1998-2007. Recently diagnosed (n = 970) and chronic patients (n = 2996) were distinguished based on ICD-9 295.xx classification, age and claims history relative to the first year (recently diagnosed) and the third year onwards (chronic) after the first index schizophrenia event. RESULTS: The medical resource use and costs during the year following the index schizophrenia event differed significantly between cohorts. A higher proportion of recently diagnosed patients were hospitalised compared with chronic patients (22.3% vs 12.4%; p < 0.0001), spending a greater mean number of days in hospital (5.1 days vs 3.0 days; p = 0.0065) as well as making more frequent use of emergency room (ER) resources during this time. The mean annual healthcare costs of recently diagnosed patients were also greater ($20,654 vs $15,489; p < 0.0001) with inpatient costs making up a higher proportion of total costs (62.9%) compared with chronic patients (38.5%). CONCLUSIONS: There is a considerably higher overall economic burden in the year following their first schizophrenia event in the treatment of recently diagnosed schizophrenia patients compared with chronic patients. Since hospitalisations and ER visits are the most significant components contributing to this finding, efforts that focus on measures to reduce the risk of relapse, particularly amongst recently diagnosed patients, such as improved adherence programs, may lead to better clinical and economic outcomes in the management of schizophrenia. LIMITATIONS: Only commercially insured patients and direct medical costs were included, therefore, results may underestimate the economic burden of schizophrenia.

Effect of the catechol-O-methyltransferase inhibitor entacapone on the steady-state pharmacokinetics and pharmacodynamics of warfarin.

AIMS: To investigate the influence of a multiple-dose regimen with the catechol-O-methyltransferase inhibitor entacapone on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a randomized, double-blind, two-way cross-over study, 12 healthy subjects (gender ratio 1 : 1) received treatment for 1 week with either entacapone 200 mg four times daily or placebo during individually optimized treatment with warfarin (INR 1.4-1.8). The effect of entacapone on the steady-state pharmacokinetics of both R- and S-warfarin was determined and, in addition, INR values were measured. The key pharmacokinetic variables were AUCss, Cmax and tmax. RESULTS: Entacapone increased the exposure to R-warfarin by 18% (90% CI: 111, 126%), and caused a 13% (6, 19%) increase in INR values. No effect was seen on the pharmacokinetics of the pharmacologically more potent S-enantiomer. Safety and tolerability variables did not show any difference between the treatment phases. CONCLUSIONS: In healthy subjects, entacapone displays a slight pharmacokinetic interaction with R-warfarin but, based on the lack of a clinically relevant pharmacodynamic interaction, it appears that it can also be used safely in Parkinson's disease patients who are receiving warfarin.