An Exploratory Study Using Electronic Medical Records to Assess the Feasibility of Establishing Cohorts of Patients with Genetic Causes of Parkinson's Disease.

Background: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson's disease (PD).

Objective: To explore the use of the electronic medical records (EMRs) to identify participants with PD.

Methods: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants.

Metadata Framework to Support Deployment of Digital Health Technologies in Clinical Trials in Parkinson's Disease.

Sensor data from digital health technologies (DHTs) used in clinical trials provides a valuable source of information, because of the possibility to combine datasets from different studies, to combine it with other data types, and to reuse it multiple times for various purposes. To date, there exist no standards for capturing or storing DHT biosensor data applicable across modalities and disease areas, and which can also capture the clinical trial and environment-specific aspects, so-called metadata. In this perspectives paper, we propose a metadata framework that divides the DHT metadata into metadata that is independent of the therapeutic area or clinical trial design (concept of interest and context of use), and metadata that is dependent on these factors.

Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth.

Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA.

Design, Setting, And Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019.

Safety and Efficacy of Filgotinib: Up to 4-year Results From an Open-label Extension Study of Phase II Rheumatoid Arthritis Programs.

Objective: The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).

Methods: Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day.

Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science.

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease.

A randomized clinical trial to evaluate the single-dose pharmacokinetics, pharmacodynamics, and safety of sitagliptin in pediatric patients with type 2 diabetes.

Objective: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM).

Study Design: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed.

Role of the Immune Response in Disease Progression and Therapy in Multiple Myeloma.

Multiple myeloma (MM) is a hematologic cancer derived from malignant plasma cells within the bone marrow. Unlike most solid tumors, which originate from epithelial cells, the myeloma tumor is a plasma cell derived from the lymphoid cell lineage originating from a post-germinal B-cell. As such, the MM plasma cell represents an integral component of the immune system in terms of both antibody production and antigen presentation, albeit not efficiently.

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay.

While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15-56 mg/m(2) ), dose-dependent inhibition of c20S and i20S chymotrypsin-like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%].

Disease Severity and Pregnancy Outcomes in Women with Rheumatoid Arthritis: Results from the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project.

Objective: To determine the effect of rheumatoid arthritis (RA) disease severity on pregnancy outcomes in pregnant women with and without autoimmune diseases.

Methods: A prospective cohort study was conducted using the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. Pregnant women with RA enrolled between 2005 and 2013 were selected if they (1) delivered a live-born singleton infant; and (2) completed 3 telephone-based measures of RA disease severity prior to 20 weeks' gestation, including the Health Assessment Questionnaire Disability Index (HAQ-DI), pain score, and patient's global scale.

Discontinuation of tumour necrosis factor inhibitors in patients with rheumatoid arthritis in low-disease activity: persistent benefits. Data from the Corrona registry.

Background: There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit.

Methods: We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications.

Discovery of pyrimidine carboxamides as potent and selective CCK1 receptor agonists.

A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.

Minimally important differences of the gout impact scale in a randomized controlled trial.

Objective: The Gout Impact Scale (GIS) is a gout-specific quality of life instrument that assesses impact of gout during an attack and impact of overall gout. The GIS has five scales and each is scored from 0 to 100 (worse health). Our objective was to assess minimally important differences (MIDs) for the GIS administered in a randomized controlled trial (RCT) assessing rilonacept vs placebo for prevention of gout flares during initiation of allopurinol therapy.

Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events.

Purpose: Bortezomib (Velcade), a dipeptide boronate 20S proteasome inhibitor and an approved treatment option for multiple myeloma, is associated with a treatment-emergent, painful peripheral neuropathy (PN) in more than 30% of patients. Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, currently in clinical investigation in myeloma, is associated with low rates of PN. We sought to determine whether PN represents a target-mediated adverse drug reaction (ADR).

Predictors of doctor-rated and patient-rated gout severity: gout impact scales improve assessment.

Rationale, Aims And Objectives: Our objective was to describe the factors associated with doctor-rated and patient-rated gout severity to explain how doctor assessment involving patient-reported outcomes can improve the clinical management of gout.

Methods: Patients completed a newly validated gout-specific health-related quality of life instrument, the Gout Impact Scale (GIS) and other questions regarding their gout. Both patients and their doctors gave an overall gout severity assessment.

Gout disease-specific quality of life and the association with gout characteristics.

PURPOSE: Assess the association of gout characteristics with health-related quality of life (HRQoL) using a new gout-specific HRQoL instrument, the Gout Impact Scale (GIS). PATIENTS AND METHODS: Gout patients completed the GIS (five scales [0-100 score each] representing impact of gout overall [three scales] and during an attack [two scales]) and other questions describing recent gout attacks, treatment, gout history, comorbidities, and demographics. Physicians confirmed gout diagnosis, presence of tophi, and most recent serum uric acid (sUA) level.

Patient-derived joint counts are a potential alternative for determining Disease Activity Score.

Objective: To investigate the correlation between the Disease Activity Score using a 28-joint count (DAS28) based on physician-derived joint counts and the DAS28 based on patient-derived joint counts (Pt-DAS28) in rheumatoid arthritis (RA).

Methods: Data from a multicenter, open-label study investigating the immunogenicity of etanercept (ETN) were analyzed. ETN-naive patients with active RA received ETN 50 mg once weekly alone or with methotrexate (MTX).

Immunomodulator therapy: monoclonal antibodies, fusion proteins, cytokines, and immunoglobulins.

The immune system consists of a diverse array of immunocompetent cells and inflammatory mediators that exist in complex networks. These components interact through cascades and feedback circuits, maintaining physiologic inflammation (eg, tissue repair) and immunosurveillance. In various autoimmune and allergic diseases, a foreign antigen or autoantigen might upset this fine balance, leading to dysregulated immunity, persistent inflammation, and ultimately pathologic sequelae.

Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome.

Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits beta5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138+ tumor cells.

Does titration of mitomycin C as an adjunct to trabeculectomy significantly influence the intraocular pressure outcome?

Purpose: To evaluate the benefit of titrating the concentration and exposure time of mitomycin C (MMC) as an adjunct to trabeculectomy.

Methods: This report consists of a retrospective study and a review of the literature. In the study, consecutive glaucoma patients were evaluated who underwent trabeculectomy with adjunctive MMC that was titrated for concentration and exposure time, based on patient's risk factors for surgical failure.

Utilization trends of tumor necrosis factor inhibitors among patients with rheumatoid arthritis in a United States observational cohort study.

Objective: Studies have suggested that early institution of tumor necrosis factor (TNF) inhibitors improves functional status and slows radiographic progression among patients with rheumatoid arthritis (RA). To determine whether these findings have altered practice patterns, we used the Consortium of Rheumatology Researchers of North America (CORRONA) registry to assess the pattern of TNF inhibitor utilization in the US over time.

Methods: Demographics and disease activity data were collected for patients with RA.

Perceptions of disease and health-related quality of life among patients with gout.

Objective: To assess the impact of gout on health-related quality of life (HRQoL) among patients in three large US cities.

Methods: Gout patients completed the Short Form-36 (SF-36) and a series of questions regarding their gout, comorbidities and demographics. Their physicians confirmed the gout diagnosis and evaluated the severity of patient's gout.

A possible pathogenesis for Alzheimer's disease: craniomaxillofacial dysfunction leading to localized cerebrospinal fluid stasis.

In the last two decades, a voluminous amount of research from multiple disciplines has been generated for Alzheimer's disease (AD). Despite the increased knowledge and understanding of AD and the potential therapeutics that are emerging, there is still no clear understanding of the pathogenesis. Without a precise, known mechanism, current potential targets for treatment may fall short of addressing an underlying cause.

Evaluation of an instrument assessing influence of Gout on health-related quality of life.

Objective: To evaluate the reliability and validity of an instrument assessing the influence of gout (acute and chronic) on health-related quality of life (HRQOL).

Methods: Focus groups were used to examine the content of an existing Gout Assessment Questionnaire (GAQ1.0).