Compliance with Good Manufacturing Practice in the Assessment of Immunomodulation Potential of Clinical Grade Multipotent Mesenchymal Stromal Cells Derived from Wharton's Jelly.

BACKGROUND: The selection of assays suitable for testing the potency of clinical grade multipotent mesenchymal stromal cell (MSC)-based products and its interpretation is a challenge for both developers and regulators. Here, we present a bioprocess design for the production of Wharton's jelly (WJ)-derived MSCs and a validated immunopotency assay approved by the competent regulatory authority for batch release together with the study of failure modes in the bioprocess with potential impact on critical quality attributes (CQA) of the final product. Methods: The lymphocyte proliferation assay was used for determining the immunopotency of WJ-MSCs and validated under good manufacturing practices (GMP). Moreover, failure mode effects analysis (FMEA) was used to identify and quantify the potential impact of different unexpected situations on the CQA. Results: A production process based on a two-tiered cell banking strategy resulted in batches with sufficient numbers of cells for clinical use in compliance with approved specifications including MSC identity (expressing CD73, CD90, CD105, but not CD31, CD45, or HLA-DR). Remarkably, all batches showed high capacity to inhibit the proliferation of activated lymphocytes. Moreover, implementation of risk management tools led to an in-depth understanding of the manufacturing process as well as the identification of weak points to be reinforced. Conclusions: The bioprocess design showed here together with detailed risk management and the use of a robust method for immunomodulation potency testing allowed for the robust production of clinical-grade WJ-MSCs under pharmaceutical standards.

Prognostic factors for long-term work disability due to musculoskeletal disorders.

The objective of this study is to identify risk factors for permanent work disability (PWD) related to musculoskeletal disorders (MSDs). This is a secondary data analysis of a randomized controlled intervention study in Temporary Work Disability (TWD) due to MSDs. The association of PWD (claim submission and status recognition) with baseline clinical, sociodemographic, work-related administrative and occupational factors was analyzed by Cox proportional hazards models. Of 3,311 patients with TWD, 47 submitted a PWD claim, of whom 32 achieved PWD status. The main alleged causes of the PWD were back pain, sciatica, and inflammatory diseases. The following factors were independently associated with an increased probability of PWD claim submission: age (odds ratio (OR) 5.1), being woman (OR 2.1), self-employment (OR 3.4), unemployment (OR 13.8), previous musculoskeletal surgery (OR 16), repeated TWD (OR 3.4), sitting (OR 2.8), and raising arms frequently (OR 3.1). Patients with inflammatory disease were more likely to file PWD claims (OR 10.4) while tendonitis was associated with lower probability (OR 0.3). The sociodemographic factors that better predicted PWD status recognition were age (OR 5.7), low educational level (OR 4.2), previous musculoskeletal surgery (OR 14.9), unemployment (OR 17.6), sitting (OR 2.6), and raising arms frequently (OR 2.7). Inflammatory diseases were the diagnoses associated with a higher rate of PWD status recognition (OR 6.1). Inflammatory diseases have a high chronic disability potential in active workers. Sociodemographic, work-related, occupational factors, and other clinical factors, some of which are modifiable, may explain the development of long-term work disability related to MSDs.

Effectiveness of an early cognitive-behavioral treatment in patients with work disability due to musculoskeletal disorders.

OBJECTIVE: To evaluate whether an early cognitive-behavioral treatment complementary to a rheumatologic care program, for patients with recent-onset temporary work disability caused by musculoskeletal disorders (MSDs) is effective. METHODS: Patients with an MSD-related temporary work disability episode from 3-8 weeks' duration who were in a rheumatologic care program were randomized into a control group (rheumatologic care program) or an intervention group (rheumatologic care program plus cognitive-behavioral treatment). Enrollment lasted 24 months and followup lasted 6-24 months. Efficacy variables included duration of temporary work disability episodes, total number of work days saved, relative efficacy, and relative rate to return to work. An economic evaluation was also performed. RESULTS: One hundred eighty-one patients were included (66 control and 115 intervention patients), generating 222 episodes of MSD-related temporary work disability. Episodes tended to be shorter in the intervention group than in the control group (mean 98 versus 127 days; P = 0.053), with a relative efficacy of 22.9%. There were no differences in duration of the first episode between groups (mean 105 versus 110 days; P = 0.79), but relapse episodes were significantly shorter in the intervention group (mean 63 days versus 197 days; P = 0.0002). Costs were also lower in the intervention group. To save 1 day of temporary work disability, $13.50 had to be invested in the program. Each dollar invested generated a benefit of $4.08. The program had a net benefit of $172,607. CONCLUSION: Early cognitive-behavioral treatment complementary to a rheumatologic care program is cost-effective, adds >20% efficacy to the rheumatologic care program, and reduces the duration of relapses.

A health system program to reduce work disability related to musculoskeletal disorders.

BACKGROUND: Musculoskeletal disorders (MSDs) are a frequent cause of work disability, accounting for productivity losses in industrialized societies equivalent to 1.3% of the U.S. gross national product. OBJECTIVE: To evaluate whether a population-based clinical program offered to patients with recent-onset work disability caused by MSDs is cost-effective. DESIGN: Randomized, controlled intervention study. The inclusion and follow-up periods each lasted 12 months. SETTING: Three health districts in Madrid, Spain. PATIENTS: All patients with MSD-related temporary work disability in 1998 and 1999. INTERVENTION: The control group received standard primary care management, with referral to specialized care if needed. The intervention group received a specific program, administered by rheumatologists, in which care was delivered during regular visits and included 3 main elements: education, protocol-based clinical management, and administrative duties. MEASUREMENTS: Efficacy variables were 1) days of temporary work disability and 2) number of patients with permanent work disability. All analyses were done on an intention-to-treat basis. RESULTS: 1,077 patients were included in the study, 7805 in the control group and 5272 in the intervention group, generating 16,297 episodes of MSD-related temporary work disability. These episodes were shorter in the intervention group than in the control group (mean, 26 days compared with 41 days; P < 0.001), and the groups had similar numbers of episodes per patient. Fewer patients received long-term disability compensation in the intervention group (n = 38 [0.7%]) than in the control group (n = 99 [1.3%]) (P < 0.005). Direct and indirect costs were lower in the intervention group than in the control group. To save 1 day of temporary work disability, 6.00 dollars had to be invested in the program. Each dollar invested generated a benefit of 11.00 dollars. The program's net benefit was in excess of 5 million dollars. LIMITATIONS: The study was unblinded. CONCLUSIONS: Implementation of the program, offered to the general population, improves short- and long-term work disability outcomes and is cost-effective.

Valoración de la función ventricular por cateterismo, ecocardiografía y medicina nuclear

Se estudiaron 66 pacientes del servicio de Cardiología del Hospital Militar Central, con diferentes tipos de patologías cardíacas, que tuvieran dos de los siguientes estudios: cateterismo cardíaco, ecocardiografía y cardioangiografía de equilibrio con Tc 99m. Se determinó la fracción de eyección de cada paciente por dos de los métodos mencionados, observandose las siguientes correlaciones: 1. Fracción de eyección por cateterismo y medicina nuclear, r=0,91. 2. Fracción de eyección por cateterismo y ecocardiograma, r=0,81. 3. Fracción de eyección por ecocardiograma y medicine nuclear, r=0,8