Demonstrating the reliability of in vivo metabolomics based chemical grouping: towards best practice.

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography-mass spectrometry (LC-MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.

Corticosteroid Use and Adherence in Patients Treated with Acthar Gel for Advanced Sarcoidosis.

INTRODUCTION: Long-term corticosteroid use in immune-mediated diseases is associated with increased risk of adverse events (AEs) and worsened health-related quality of life (HRQoL). Previous studies report chronic high-dose corticosteroid therapy results in higher rates of healthcare resource use and AE-related medical costs. Recent studies suggest Acthar® Gel (repository corticotropin injection) is an effective steroid-sparing therapy for sarcoidosis. This study compares the corticosteroid-sparing effect between Acthar Gel and comparators and evaluates the impact of Acthar Gel adherence on reduction of corticosteroid burden. METHODS: A retrospective analysis of a large administrative pharmacy and medical claims database (Symphony Health Solutions) was conducted. Patients were included with confirmed ICD-9/10 diagnosis for sarcoidosis in the study period (2014-2020), followed by ≥ 2 Acthar Gel claims or comparators (janus kinase inhibitor (JAKi)/rituximab), ≥ 18 years old, with 12 months coverage pre/post index. Outcomes were compared as change from baseline. Acthar Gel adherence was determined by proportion of days covered in the follow-up period. RESULTS: The Acthar Gel (n = 735) and comparator (n = 626) cohorts were mostly female (68-72%) between 55 and 58 years old. Compared to the comparator cohort at baseline, Acthar Gel patients had greater any corticosteroid use (80% vs. 56%, p < 0.001), extended use (61% vs. 32%, p < 0.001), and mean average daily dose (6.72 vs. 3.03, p < 0.001). After treatment, Acthar Gel patients had greater reduction from baseline in any corticosteroid use (- 9.0% vs. - 3.2%) and extended use (- 10.0% vs. - 3.0%). In the Acthar Gel adherence cohorts, patients with above average adherence had greater reduction in both measures (- 11.2% vs. - 6.1%; - 11.6% vs. - 7.6%, respectively) than patients with below average adherence. Acthar Gel patients had greater reduction of extended use at all dose levels. CONCLUSION: Acthar Gel is associated with reductions in corticosteroid use compared to alternatives. Better adherence is associated with greater reduction in corticosteroid exposure. Key Summary Points.

Patients who use corticosteroids long term for advanced sarcoidosis often suffer from negative health effects. This project aimed to evaluate whether Acthar^® Gel (repository corticotropin injection) use led to reduced corticosteroid use and whether higher adherence to Acthar Gel led to further reduction in corticosteroid use. Pharmacy and medical claims data were used to identify patients who fit certain criteria: the Acthar Gel cohort included patients with sarcoidosis who used Acthar Gel and the comparator cohort included patients with sarcoidosis who used janus kinase (JAK) inhibitors or rituximab. The Acthar Gel cohort was split into high adherence and low adherence. The Acthar Gel cohort was found to have higher corticosteroid use than the comparator group in the baseline period before initiating Acthar Gel or a comparator therapy. After initiating treatment, Acthar Gel patients had a larger reduction in corticosteroid use according to a variety of metrics including number of corticosteroid fills and extended use fills. Furthermore, when comparing those with high Acthar Gel adherence and those with low Acthar Gel adherence, the patients with above average adherence had a larger reduction in the number of corticosteroid fills and extended use fills than patients with below average adherence to Acthar Gel. Patients who use Acthar Gel and more regularly tended to use corticosteroids less, which may allow them to avoid the negative health effects from long-term, high-dosage corticosteroid use. This finding may help providers and health plans evaluate situations in which Acthar Gel treatment may be beneficial to improve patient outcomes.

Prescription opioid utilization patterns, and associated outcomes, among privately insured patients prescribed opioids to manage pain associated with osteoarthritis.

OBJECTIVE: To describe utilization patterns, negative clinical outcomes and economic burden of patients diagnosed with osteoarthritis (OA) of the hip and/or knee who received a prescription for tramadol or non-tramadol opioids vs. non-opioid drugs. METHODS: Optum Healthcare Solutions, Inc. commercial claims data were used (1/2012--3/2017). Adults with ≥2 diagnoses of OA of the hip and/or knee, and ≥30 days supply of pain medications were identified during the three-year period from the date of first prescription (index date) after the first OA diagnosis. Drug utilization statistics in the follow-up period were summarized by initial treatment (i.e. tramadol, non-tramadol opioids, non-opioid drugs). Opioid initiators were matched to those initiated on non-opioid treatments using a propensity score model accounting for baseline characteristics. Matched pairs analysis compared outcomes for these cohorts. RESULTS: Of 62,715 total patients, 15,270 (24.3%) initiated treatment with opioids, including 3,513 (5.6%) on tramadol and 11,757 (18.7%) on non-tramadol opioids. Opioid initiators had more comorbidities, higher baseline healthcare costs, and were more likely to have OA of the hip. Among non-opioid initiators, 27.5% switched to tramadol and 63% switched to non-tramadol opioids. Among tramadol initiators, 71% switched to non-tramadol opioids. Patients initiated on opioids had 20.4% (p < .01) higher all-cause healthcare costs and higher percentages experiencing multiple negative clinical outcomes (all p < .01) compared to matched controls. CONCLUSIONS: Most patients with OA of the hip and/or knee either initiate on or switch to opioids for long-term management of OA-related pain despite known risks. This highlights the need for new treatments that delay or prevent use of opioids.

The mismatch of narratives and local ecologies in the everyday governance of water access and mosquito control in an urbanizing community.

Mosquito-borne disease presents a significant threat to urban populations, but risk can be uneven across a city due to underlying environmental patterns. Urban residents rely on social and economic processes to control the environment and mediate disease risk, a phenomenon known as everyday governance. We studied how households employed everyday governance of urban infrastructure relevant to mosquito-borne disease in Bengaluru, India to examine if and how inequalities in everyday governance manifest in differences in mosquito control. We found that governance mechanisms differed for water access and mosquitoes. Economic and social capital served different roles for each, influenced by global narratives of water and vector control.

Risk Factors Associated with Falls and Fractures Following Prescription of Opioids Among Privately Insured Patients with Osteoarthritis.

Background: While prior research has shown that patients with osteoarthritis (OA) who are prescribed opioids have higher rates of falls and fractures following drug initiation, there is a limited body of work establishing a comprehensive model of factors that influence the risk of falls or fractures among these patients. Objective: Opioids are associated with negative clinical outcomes, including increased risk of falls and fractures. This study assessed the frequency, treatment characteristics, and risk factors associated with falls or fractures among patients with OA taking opioids. Methods: Optum Healthcare Solutions, Inc data (January 2012-March 2017) were used to identify patients over 18 with at least 2 diagnoses of hip and/or knee OA, and at least 90 days' supply of opioids. Patients with cancer were excluded. Falls or fractures outcomes were assessed in the 36-month follow-up period after the date of the first opioid prescription after first OA diagnosis. Demographic, treatment, and clinical characteristics associated with falls or fractures were assessed using logistic regression. Results: Of 16 663 patients meeting inclusion criteria, 3886 (23%) had at least 1 fall or fracture during follow-up. Of these 3886 patients, 1349 (35%) had at least 1 fall with an average of 3 fall claims, and 3299 (85%) patients had at least 1 fracture with an average of 8 claims during follow-up. Spine (15.8%) and hip (12.5%) fractures were most common. Median time to fall or fracture was 18.6 and 13.9 months, respectively. Significant (P<.05) risk factors associated with at least 1 fall or fracture during the follow-up period included alcohol use (odds ratio [OR], 3.41), history of falling (OR, 2.19), non-tramadol opioid use (OR, 1.31), age (OR, 1.03), benzodiazepine use (OR, 1.21), and at least 1 osteoporosis diagnosis (OR, 2.06). Discussion: This study is among only a few that clearly identifies the substantial impact and frequency of falls and fractures associated with prescribing non-tramadol opioids to patients with OA. Findings suggest that fall or fracture risks need to be considered when managing OA pain with opioids. Conclusion: Falls and fractures impose a major clinical burden on patients prescribed opioids for OA-related pain management. Falls or fracture risks should be an important consideration in the ongoing treatment of patients with OA.

Drug utilization, clinical and economic outcomes of patients with osteoarthritis of the hip and/or knee treated with long-term use of traditional NSAIDs, topical NSAIDs, and COX-2 inhibitors.

OBJECTIVES: To describe and compare baseline characteristics, healthcare and drug utilization, and negative clinical outcomes of commercially-insured patients diagnosed with OA of the hip and/or knee who initiated treatment on traditional oral NSAIDs (tNSAIDs), topical NSAIDs, or cyclooxygenase-2 inhibitors (COX-2s). METHODS: A commercial claims database (1/2012-3/2017) was used to identify patients ≥18 years old, with ≥2 diagnoses of hip and/or knee OA, and ≥90 days supply of NSAIDs. Patients were assigned to cohorts based on the type of NSAID initially prescribed and observed in the 6 months before (baseline) and 36 months after (follow-up) the date of their first NSAID prescription after the first OA diagnosis. Analyses estimated baseline demographic and clinical characteristics and follow-up period drug utilization. Logistic regressions assessed the risk of gastrointestinal (GI) and acute renal failure (ARF) events. RESULTS: tNSAIDs were the most frequently prescribed treatment. During the follow-up period, less than 15% of patients prescribed tNSAIDs switched to either COX-2s or topical NSAIDs and 37% of patients prescribed a COX-2 and 56% of patients prescribed a topical NSAID switched to tNSAIDs. GI and ARF events during the follow-up period ranged from 7.3-8.1% and 8.0-11.0%, respectively, across cohorts. The tNSAIDs and COX-2s cohorts had increased risk of both types of events relative to patients prescribed topical NSAIDs, controlling for other characteristics. CONCLUSIONS: Analyses characterize the long-term real-world utilization of NSAIDs and associated outcomes for patients with OA of the hip and/or knee. Study results highlight the likelihood of switching and the risk of negative clinical outcomes associated with long-term use.

Clinical and economic burden of prescribing tramadol and other opioids for patients with osteoarthritis in a commercially insured population in the United States.

ABSTRACT: In 2019, the American College of Rheumatology conditionally recommended tramadol and conditionally recommended against nontramadol opioids for patients with hip and knee osteoarthritis. Although tramadol is known to be less prone to opioid use disorders, little is known about the differing magnitude of negative clinical outcomes, health care resource utilization, and costs of tramadol relative to nontramadol opioids. Administrative claims records for commercially insured patients with osteoarthritis who were prescribed opioids were used to compare clinical and cost outcomes during a 3-year follow-up period by conducting a pre-post analysis and a matched case-cohort analysis. Data for 14,491 patients were analyzed: 4048 (28%) were initiated on tramadol, and 10,443 (72%) were initiated on nontramadol opioids. After matching, 4048 patients per cohort were analyzed. In each empirical analysis, tramadol patients did develop opioid use disorders; however, opioid use disorder rates were 3.5-fold higher in the nontramadol cohort (1.2% vs 4.2%). In addition, rates of other opioid-related clinical outcomes (falls, fractures, nausea, fatigue, and constipation) were also directionally lower among the tramadol cohort, although quantitatively similar (<5% difference) to the nontramadol cohort. Finally, in both analyses, the nontramadol cohort incurred higher levels of inpatient and emergency department visits and all-cause costs during the 3-year follow-up period. However, tramadol patients incur a higher incremental change (+$24,013) in costs relative to their pretreatment baseline compared with nontramadol (+$18,191). These real-world findings demonstrated lower risks with tramadol relative to other opioids, albeit risks and increased health care costs were present with tramadol, highlighting the need for further strategies to improve outcomes.

Establishment and maintenance of DNA methylation in nematode feeding sites.

A growing body of evidence indicates that epigenetic mechanisms, particularly DNA methylation, play key regulatory roles in plant-nematode interactions. Nevertheless, the transcriptional activity of key genes mediating DNA methylation and active demethylation in the nematode feeding sites remains largely unknown. Here, we profiled the promoter activity of 12 genes involved in maintenance and de novo establishment of DNA methylation and active demethylation in the syncytia and galls induced respectively by the cyst nematode Heterodera schachtii and the root-knot nematode Meloidogyne incognita in Arabidopsis roots. The promoter activity assays revealed that expression of the CG-context methyltransferases is restricted to feeding site formation and development stages. Chromomethylase1 (CMT1), CMT2, and CMT3 and Domains Rearranged Methyltransferase2 (DRM2) and DRM3, which mediate non-CG methylation, showed similar and distinct expression patterns in the syncytia and galls at various time points. Notably, the promoters of various DNA demethylases were more active in galls as compared with the syncytia, particularly during the early stage of infection. Mutants impaired in CG or CHH methylation similarly enhanced plant susceptibility to H. schachtii and M. incognita, whereas mutants impaired in CHG methylation reduced plant susceptibility only to M. incognita. Interestingly, hypermethylated mutants defective in active DNA demethylation exhibited contrasting responses to infection by H. schachtii and M. incognita, a finding most likely associated with differential regulation of defense-related genes in these mutants upon nematode infection. Our results point to methylation-dependent mechanisms regulating plant responses to infection by cyst and root-knot nematodes.

Generalized Electrical Substitution Methods and Detectors for Absolute Optical Power Measurements.

We have developed generalized methods for electrical substitution optical measurements, as well as cryogenic detectors which can be used to implement them. The new methods detailed here enable measurement of arbitrary periodic waveforms by an electrical substitution radiometer (ESR), which means that spectral and dynamic optical power can be absolutely calibrated directly by a primary standard detector. Cryogenic ESRs are not often used directly by researchers for optical calibrations due to their slow response times and cumbersome operation. We describe two types of ESRs with fast response times, including newly developed cryogenic bolometers with carbon nanotube absorbers, which are manufacturable by standard microfabrication techniques. These detectors have response times near 10 ms, spectral coverage from the ultraviolet to far-infrared, and are ideal for use with generalized electrical substitution. In our first tests of the generalized electrical substitution method with FTS, we have achieved uncertainty in detector response of 0.13 % (k=1) and total measurement uncertainty of 1.1 % (k=1) in the mid-infrared for spectral detector responsivity calibrations. The generalized method and fast detectors greatly expand the range of optical power calibrations which can be made using a wideband primary standard detector, which can shorten calibration chains and improve uncertainties.

Development of electrical substitution Fourier transform spectrometry for absolute optical power measurements.

We have demonstrated the first continuous-scan electrical substitution Fourier transform spectrometer (ES-FTS), which serves initially as an apparatus for absolute spectral responsivity calibrations of detectors over the wavelength range from 1.5 µm to 11 µm. We present data on the realization of a spectral detector-comparator system with high accuracy, high dynamic range, high spectral resolution and fast measurement in the infrared region, which is tied directly to an absolute power scale through electrical substitution. The ES-FTS apparatus employs a commercial Fourier transform spectrometer and a custom electrical substitution bolometer detector to enable spectrally-resolved absolute optical power measurements. A generalization of electrical substitution techniques enables determination of the voltage waveform that must be applied to the bolometer's electrical heater to cancel the optical signal from a Michelson interferometer in order to quantify the time-dependent optical power incident on the bolometer. The noise floor of the electrical substitution bolometer is on the order of 10 pW/Hz½ and its response is expected to be linear from the noise floor to 1 mW. A direct comparison between a pyroelectric standard detector and the ES-FTS has been performed, and experimental results reported here show great potential for this technique.

A harm reduction model to assess the impact of new treatments for pain over standard of care among patients with osteoarthritis.

BACKGROUND: Osteoarthritis (OA) affects millions of adults in the United States and can result in substantial pain, functional impairment, and significant clinical and economic burden. To manage chronic pain associated with OA, treatment guidelines recommend a variety of pharmacologic treatments, including traditional oral nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors (COX-2s), and opioids. While these drug treatments can be effective at pain management, they are also associated with significant clinical and economic burden. New treatments for chronic pain among patients with OA of the hip and/or knee have the potential to reduce the occurrence of such negative clinical outcomes, including cardiovascular events, renal events, and opioid use disorder (OUD), thereby reducing health care resource use (HRU) and medical costs. OBJECTIVE: To develop a harm reduction model (HRM) to assess potential reductions of negative clinical outcomes, HRU, and medical costs associated with the use of new treatments in place of oral NSAIDs, tramadol, and non-tramadol opioids among patients with OA of the hip and/or knee in the United States. METHODS: The HRM model integrated findings from the literature and inputs from a variety of sources, along with assumptions regarding potential ability of new treatments to replace existing treatments and market penetration into a unified framework to estimate outcomes and costs. The model outputs included estimated per-patient and population-level reductions in negative clinical outcomes associated with prescribing new treatments in place of oral NSAIDs or opioids along with number needed to treat (NNT) associated with new treatments. The model assumed that new treatments will primarily be used in place of non-tramadol opioids, but more modest adoption in place of oral NSAIDs and tramadol. RESULTS: Among patients with OA of the hip and/or knee who were prescribed oral NSAIDs, tramadol, or non-tramadol opioids for chronic use (≥ 90 days), the HRM estimated total cost savings of $3.8 billion, $5.1 billion, and $29.9 billion, respectively, from prescribing new treatments for OA pain over a 36-month period. The reduced economic burden was driven by significant reductions in the incidence of negative clinical outcomes. Estimates of the NNT to avoid a negative clinical event related to NSAID and opioid treatment initiation were low for most outcomes. Estimates of NNT associated with NSAID use ranged from 4 to 17 patients, depending on outcome, and estimates of NNT associated with opioid use was 35 non-tramadol and 134 tramadol patients for OUD and ranged from 6 to 21 patients for the other clinical outcomes, depending on treatment and outcome. CONCLUSIONS: Results from the HRM suggest that prescribing new treatments in place of oral NSAIDs and/or opioids for OA pain results in a potentially substantial reduction in patients experiencing negative clinical outcomes and reductions in all-cause HRU and costs. DISCLOSURES: This study was sponsored by Pfizer and Eli Lilly and Company. Silverman was a paid consultant to Pfizer and Eli Lilly and Company in connection with this study. Beck and Schepman are employees of Pfizer with stock and/or stock options. Robinson is an employee and minor stockholder of Eli Lilly and Company. Rice, White, and Fernan are employees of the Analysis Group, who were paid consultants to Pfizer and Eli Lilly and Company for this study and development of the manuscript.

Perseverance rover reveals an ancient delta-lake system and flood deposits at Jezero crater, Mars.

Observations from orbital spacecraft have shown that Jezero crater on Mars contains a prominent fan-shaped body of sedimentary rock deposited at its western margin. The Perseverance rover landed in Jezero crater in February 2021. We analyze images taken by the rover in the 3 months after landing. The fan has outcrop faces, which were invisible from orbit, that record the hydrological evolution of Jezero crater. We interpret the presence of inclined strata in these outcrops as evidence of deltas that advanced into a lake. In contrast, the uppermost fan strata are composed of boulder conglomerates, which imply deposition by episodic high-energy floods. This sedimentary succession indicates a transition from sustained hydrologic activity in a persistent lake environment to highly energetic short-duration fluvial flows.

Particle transport constraints via Bayesian spectral fitting of multiple atomic lines.

Optimized operation of fusion devices demands detailed understanding of plasma transport, a problem that must be addressed with advances in both measurement and data analysis techniques. In this work, we adopt Bayesian inference methods to determine experimental particle transport, leveraging opportunities from high-resolution He-like ion spectra in a tokamak plasma. The Bayesian spectral fitting code is used to analyze resonance (w), forbidden (z), intercombination (x, y), and satellite (k, j) lines of He-like Ca following laser blow-off injections on Alcator C-Mod. This offers powerful transport constraints since these lines depend differently on electron temperature and density, but also differ in their relation to Li-like, He-like, and H-like ion densities, often the dominant Ca charge states over most of the C-Mod plasma radius. Using synthetic diagnostics based on the AURORA package, we demonstrate improved effectiveness of impurity transport inferences when spectroscopic data from a progressively larger number of lines are included.

Electrochemical Detection of Serum Antibodies Against Mycobacterium avium Subspecies paratuberculosis.

Mycobacterium avium subsp. paratuberculosis (MAP) causes a chronic inflammatory intestinal disease, called Johne's disease (JD) in many ruminants. In the dairy industry, JD is responsible for significant economic losses due to decreased milk production and premature culling of infected animals. Test-and-cull strategy in conjunction with risk management is currently recommended for JD control in dairy herds. However, current diagnostic tests are labor-intensive, time-consuming, and/or too difficult to operate on site. In this study, we developed a new method for the detection of anti-M. paratuberculosis antibodies from sera of M. paratuberculosis-infected animals. M. paratuberculosis antigen-coated magnetic beads were sequentially reacted with bovine serum followed by a horseradish peroxidase (HRP)-labeled secondary antibody. The reaction of HRP with its substrate was then quantitatively measured electrochemically using a redox-active probe, ferrocyanide. After optimization of electrochemical conditions and concentration of the redox-active probe, we showed that the new electrochemical detection method could distinguish samples of M. paratuberculosis-infected cattle from those of uninfected cattle with greater separation between the two groups of samples when compared with a conventional colorimetric testing method. Since electrochemical detection can be conducted with an inexpensive, battery-operated portable device, this new method may form a basis for the development of an on-site diagnostic system for JD.

Consequences of insurance denials among U.S. patients prescribed repository corticotropin injection (Acthar Gel) for nephrotic syndrome.

INTRODUCTION: Repository corticotropin injection (RCI; Acthar Gel) is indicated to induce a diuresis or a remission of proteinuria in nephrotic syndrome (NS) without uremia of the idiopathic type or that due to lupus erythematosus. This study compares patient characteristics and measurable healthcare resource utilization (HCRU) between NS patients who received a prescription for RCI and then were either approved or denied treatment by their insurers. METHODS: A retrospective analysis of adults with NS from January 2015 to December 2018 was conducted using a de-identified open-source claims database. Patients were included in the study if they had ≥1diagnosis associated with NS, were age 18+, and had medical claims activity at some point in the year preceding ("baseline") and year following ("follow up") their first approved or denied RCI prescription. Baseline characteristics were reported with p-values indicating the significance of characteristics between cohorts. To assess outcomes, approved and denied patients were matched (1:1) using propensity-matching to account for underlying differences. RESULTS: Overall, 1,232 patients met inclusion criteria for the study. At baseline, approved patients were older than denied patients (mean age 53.9 vs. 48.4) and had higher rates of comorbidities. A greater proportion of approved patients required inpatient admissions (34.1 vs. 28.0%) and "high" doses of corticosteroids (CS) (26.2 vs. 20.7%) at baseline. Matched outcomes showed directionally more denied patients with inpatient admissions compared to approved (64 vs. 52) and a greater utilization of deep vein thrombosis ultrasound (12.2 vs. 6.6%) and dialysis (10.5 vs. 6.1%). Matched, denied patients had directionally greater CS use during follow-up both in the number of patients receiving CS (104 vs. 95) and the average annualized daily dose (4.1 vs. 3.4 mg). CONCLUSION: Patients denied access to RCI treatment had directionally higher HCRU compared to matched, approved counterparts. Thus, the results of this study may aid providers and payers in evaluating scenarios where RCI may be beneficial and improve quality of care for NS patients.

Consequences of Insurance Denials Among U.S. Patients Prescribed Repository Corticotropin Injection for Acute Exacerbations of Multiple Sclerosis.

INTRODUCTION: Repository corticotropin injection (RCI; Acthar® Gel) is indicated for the treatment of acute exacerbations of multiple sclerosis (MS) in adults. Despite the well-documented clinical and economic benefits of RCI, many patients are denied use of the therapy by third-party payers. This study aims to understand the demographic and clinical characteristics of MS relapse patients who received a prescription for RCI from their physicians and then were either approved or denied treatment by their insurers. The study compares measurable clinical outcomes and healthcare resource utilization (HCRU) between approved and denied cohorts. METHODS: A retrospective analysis of adults experiencing MS relapse from January 2015 to December 2018 was conducted using a de-identified open-source claims database [Symphony Health Integrated Dataverse® (IDV)]. Patients were identified using ICD codes for MS and considered to have relapsing/remitting type according to established claims-based methodology. Clinical characteristics and HCRU were analyzed during the year preceding ("baseline") and the year following ("follow-up") each patient's index date, defined as the date of a patient's first approved RCI claim (for patients with ≥ 1 approved claim) or first denied RCI claim (for patients with only denied claims). Baseline characteristics were reported with unadjusted differences and p values indicating the significance of characteristics between the two cohorts. For outcomes, match-adjusted results were reported using propensity matching to account for underlying differences between cohorts. RESULTS: The study sample included 1902 MS relapse patients with at least one claim for RCI. At baseline, approved patients were slightly older compared to denied patients (mean age 48.0 vs. 47.2), had higher rates of hemiplegia/paraplegia (6.7% vs. 3.3%), greater mobility impairment (17% vs. 11.5%), more exacerbation episodes (66.2% vs. 59.9%), and a higher number of physical therapy/rehab claims (23.5 vs. 14.0), respectively. Outcomes among the matched sample show an increased use of corticosteroids for patients denied access to RCI compared to approved patients (51.1% vs. 42.4%), more exacerbation episodes (36.6% vs. 28.2%), and an increased number of physical therapy/rehab claims (11.5% vs. 9.9%), respectively. CONCLUSION: The results of this study may aid providers and payers in evaluating scenarios where RCI may be beneficial and improve quality of care for patients experiencing MS relapse.

Involving research participants in a pan-European research initiative: the EPAD participant panel experience.

BACKGROUND: Including participants in patient and public involvement activities is increasingly acknowledged as a key pillar of successful research activity. Such activities can influence recruitment and retention, as well as researcher experience and contribute to decision making in research studies. However, there are few established methodologies of how to set up and manage participant involvement activities. Further, there is little discussion of how to do so when dealing with collaborative projects that run across countries and operate in multiple linguistic and regulatory contexts. METHODS: In this paper we describe the set-up, running and experiences of the EPAD participant panel. The EPAD study was a pan-European cohort study with the aim to understand risks for developing Alzheimer's disease and build a readiness cohort for Phase 2 clinical trials. Due to the longitudinal nature of this study, combined with the enrolment of healthy volunteers and those with mild cognitive impairments, the EPAD team highlighted participant involvement as crucial to the success of this project. The EPAD project employed a nested model, with local panels meeting in England, France, Scotland, Spain and The Netherlands, and feeding into a central study panel. The local panels were governed by terms of reference which were adaptable to local needs. RESULTS: The impact of the panels has been widespread, and varies from feedback on documentation, to supporting with design of media materials and representation of the project at national and international meetings. CONCLUSIONS: The EPAD panels have contributed to the success of the project and the model established is easily transferable to other disease areas investigating healthy or at-risk populations.

Recovery from Mosaic Caused by Sorghum Mosaic Virus in Sugarcane and Impact on Yield.

Mosaic is a historically important viral disease of sugarcane in Louisiana caused by Sugarcane mosaic virus and, currently, by Sorghum mosaic virus (SrMV). Sugarcane clones can have variable responses to mosaic for different traits, including susceptibility to infection and yield loss. Disease incidence and rate of increase within a multiple-year crop cycle is affected by susceptibility and other epidemiological factors, possibly including recovery from symptom expression and virus infection. Recovery (defined as the emergence of asymptomatic plants from buds on planted symptomatic stalks) and the impact of mosaic on yield components were evaluated in two sugarcane cultivars, HoCP 09-804 and L 10-147. Recovery varied between the two cultivars. Across two experiments, L 10-147 had a higher frequency of recovery (range 9.4 to 19.8%) than HoCP 09-804 (range 0.9 to 2.3%). A reverse-transcription PCR assay did not detect SrMV in 96.5% of 143 L 10-147 leaf samples and 83.3% of 6 HoCP 09-804 leaf samples collected from recovered plants. When comparing symptomatic and asymptomatic plantings, mosaic reduced cane and sucrose yield in HoCP 09-804 but not L 10-147, suggesting a possible association between recovery and tolerance to virus infection.

Identification of Differentially Methylated miRNA Genes During Compatible and Incompatible Interactions Between Soybean and Soybean Cyst Nematode.

DNA methylation is a widespread epigenetic mark that affects gene expression and transposon mobility during plant development and stress responses. However, the role of DNA methylation in regulating the expression of microRNA (miRNA) genes remains largely unexplored. Here, we analyzed DNA methylation changes of miRNA genes using a pair of soybean (Glycine max) near-isogenic lines (NILs) differing in their response to soybean cyst nematode (SCN; Heterodera glycines). Differences in global DNA methylation levels over miRNA genes in response to SCN infection were observed between the isogenic lines. miRNA genes with significant changes in DNA methylation levels in the promoter and primary transcript-coding regions were detected in both lines. In the susceptible isogenic line (NIL-S), 82 differentially methylated miRNAs were identified in response to SCN infection whereas, in the resistant isogenic line (NIL-R), only 16 differentially methylated miRNAs were identified. Interestingly, gma-miR5032, gma-miR5043, gma-miR1520b, and gma-2107-ch16 showed opposite methylation patterns in the isogenic lines. In addition, the miRNA paralogs gma-miR5770a and gma-miR5770b showed hypermethylation and hypomethylation in NIL-S and NIL-R, respectively. Gene expression quantification of gma-miR5032, gma-miR5043, gma-miR1520b, and gma-miR5770a/b and their confirmed targets indicated a role of DNA methylation in regulating miRNA expression and, thus, their targets upon SCN infection. Furthermore, overexpression of these four miRNAs in NIL-S using transgenic hairy root system enhanced plant resistance to SCN to various degrees with a key role observed for miR5032. Together, our results provide new insights into the role of epigenetic mechanisms in controlling miRNA regulatory function during SCN-soybean interactions.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Speech-based characterization of dopamine replacement therapy in people with Parkinson's disease.

People with Parkinson's (PWP) disease are under constant tension with respect to their dopamine replacement therapy (DRT) regimen. Waiting too long between doses results in more prominent symptoms, loss of motor function, and greater risk of falling per step. Shortened pill cycles can lead to accelerated habituation and faster development of disabling dyskinesias. The Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is the gold standard for monitoring Parkinson's disease progression but requires a neurologist to administer and therefore is not an ideal instrument to continuously evaluate short-term disease fluctuations. We investigated the feasibility of using speech to detect changes in medication states, based on expectations of subtle changes in voice and content related to dopaminergic levels. We calculated acoustic and prosodic features for three speech tasks (picture description, reverse counting, and diadochokinetic rate) for 25 PWP, each evaluated "ON" and "OFF" DRT. Additionally, we generated semantic features for the picture description task. Classification of ON/OFF medication states using features generated from picture description, reverse counting and diadochokinetic rate tasks resulted in cross-validated accuracy rates of 0.89, 0.84, and 0.60, respectively. The most discriminating task was picture description which provided evidence that participants are more likely to use action words in ON than in OFF state. We also found that speech tempo was modified by DRT. Our results suggest that automatic speech assessment can capture changes associated with the DRT cycle. Given the ease of acquiring speech data, this method shows promise to remotely monitor DRT effects.