Preference Testing in Medical Devices: Current Framework and Regulatory Gaps.

Preference testing is a valuable source of information that can be provided by both healthcare professionals (HCPs) and patients (users). It can be used to improve the design and development of medical devices by feeding into device usability and, ultimately, risk management. Furthermore, it can aid with selecting the most appropriate clinical endpoints to be used in the clinical evaluation of a device and increase patient engagement by incorporating patient-relevant outcomes.

Companion Diagnostics: State of the Art and New Regulations.

Companion diagnostics (CDx) hail promise of improving the drug development process and precision medicine. However, there are various challenges involved in the clinical development and regulation of CDx, which are considered high-risk in vitro diagnostic medical devices given the role they play in therapeutic decision-making and the complications they may introduce with respect to their sensitivity and specificity. The European Union (E.

Organ donation in the US and Europe: The supply vs demand imbalance.

Organ donation and transplantation remain the best and most cost-effective clinical solution for end-stage organ failure. Several agencies across the US and Europe provide legislative, regulatory, and humanitarian services to generate smoother applications in all transplantation processes and donor-recipient relationships. US and European statistics present nine types of grafts, with kidneys being the most transplanted organ worldwide.

Impact of Design on Medical Device Safety.

The growing number of emerging medical technologies and sophistication of modern medical devices (MDs) that improve both survival and quality of life indexes are often challenged by alarming cases of vigilance data cover-up and lack of sufficient pre- and post-authorization controls. Combining Quality with Risk Management processes and implementing them as early as possible in the design of MDs has proven to be an effective strategy to minimize residual risk. This article aims to discuss how the design of MDs interacts with their safety profile and how this dipole of intended performance and safety may be supported by Human Factors Engineering (HFE) throughout the Total Product Life-Cycle (TPLC) of an MD in order to capitalize on medical technologies without exposing users and patients to unnecessary risks.

Liver collagen in cirrhosis correlates with portal hypertension and liver dysfunction.

Liver collagen proportionate area (CPA) assessed by computer-assisted digital image analysis has been proposed as an accurate and objective histological variable for subclassifying cirrhosis. The study aimed to examine the relationship between CPA and relevant clinical parameters in cirrhotic patients and to evaluate the sampling variability for CPA. The study included 48 consecutive liver transplantation patients with established cirrhosis.

The effect of ileal interposition surgery on enteroendocrine cell numbers in the UC Davis type 2 diabetes mellitus rat.

Aim: To investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic UC Davis type 2 diabetes mellitus (UCD-T2DM) rat.

Study Design: Two-month old male UCD-T2DM rats underwent either sham (n=5) or IT (n=5) surgery. Intestines were collected 1.

Characterisation of age-dependent beta cell dynamics in the male db/db mice.

Aim: To characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice.

Methods: Blood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology.

Peptidyl arginine deiminase inhibitor effect on hepatic fibrogenesis in a CCl4 pre-clinical model of liver fibrosis.

Unlabelled: Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect fibrogenesis.

Methods: Fibrogenesis was evaluated by quantitative histology and circulating levels of collagen type III in a carbon tetrachloride (CCl4) rat model of liver fibrosis for 6 weeks (n=40+10 untreated controls). The first treatment group (n=20) was treated exclusively with CCl4 for the duration of the study.

Atherofibrosis - a unique and common process of the disease pathogenesis of atherosclerosis and fibrosis - lessons for biomarker development.

The hallmark of a variety of fibrotic diseases such as liver fibrosis, lung fibrosis, skin fibrosis and atherosclerosis is extensive extracellular matrix remodeling (ECMr) of the disease affected tissue. Inflammation often leads to tissue disruption and destruction, upon which locally released battery of proteases such as matrix metalloproteinases and cysteine proteases degrade the surrounding matrix. The degradation products of ECM proteins, the co-called neoepitopes, are released into the systemic circulation.

Circulating citrullinated vimentin fragments reflect disease burden in ankylosing spondylitis and have prognostic capacity for radiographic progression.

Objective: Ankylosing spondylitis (AS) has been considered a seronegative rheumatic disease based on absent or low levels of antibodies against citrullinated proteins. The present study was undertaken to evaluate whether a citrullinated and matrix metalloproteinase-degraded fragment of vimentin (VICM) could be a prognostic biomarker in AS.

Methods: VICM was measured in serum samples from healthy controls (n=35), control patients with rheumatoid arthritis (RA) (n=47), and patients with AS (n=201).

Circulating levels of citrullinated and MMP-degraded vimentin (VICM) in liver fibrosis related pathology.

Aim: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes.

Methods: A monoclonal antibody against the sequence RLRSSVPGV-citrulline (VICM) was developed and evaluated in a carbon tetrachloride (CCl(4)) (n=52 + 28 controls) rat model of liver fibrosis and two clinical cohorts of adult patients with hepatitis C (HCV) (n=92) and non-alcoholic fatty liver disease (NAFLD) (n=62), and compared to healthy controls.

Results: In CCl(4)-treated rats, mean systemic VICM levels increased 31% at week 12 (176 ng/mL, P<0.

Clinical evaluation of a matrix metalloproteinase-12 cleaved fragment of titin as a cardiovascular serological biomarker.

Background: Titin is a muscle-specific protein found in cardiac and skeletal muscles which is responsible for restoring passive tension. Levels and functioning of titin have been shown to be affected by cardiac damage. Due to the inherent difficulty of measuring titin levels in vivo in a clinical setting, we aimed to develop an assay that could reliably measure fragments of degraded titin in serum and potentially be used in the assessment of cardiac muscle damage.

Novel cardiac-specific biomarkers and the cardiovascular continuum.

The concept of the cardiovascular continuum, introduced during the early 1990s, created a holistic view of the chain of events connecting cardiovascular-related risk factors with the progressive development of pathological-related tissue remodelling and ultimately, heart failure and death. Understanding of the tissue-specific changes, and new technologies developed over the last 25-30 years, enabled tissue remodelling events to be monitored in vivo and cardiovascular disease to be diagnosed more reliably than before. The tangible product of this evolution was the introduction of a number of biochemical markers such as troponin I and T, which are now commonly used in clinics to measure myocardial damage.

Enzyme-linked immunosorbent serum assay specific for the 7S domain of Collagen Type IV (P4NP 7S): A marker related to the extracellular matrix remodeling during liver fibrogenesis.

Aim:   The present study describes the ability of a newly developed N-terminal pro-peptides of type IV collagen 7S domain (P4NP 7S) competitive enzyme-linked immunosorbent assay (ELISA) for describing liver fibrosis. The assay applies a monoclonal antibody specific for a PIVNP 7S epitope 100% homologous in the human, rat, and mouse species.

Methods:   Monoclonal antibodies were raised against selected P4NP 7S specific sequences.

MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay.

Background And Aims: During fibrogenesis, in which excessive remodeling of the extracellular matrix occurs, both the quantity of type VI collagen and levels of matrix metalloproteinases, including MMP-2 and MMP-9, increase significantly. Proteolytic degradation of type VI collagen into small fragments, so-called neo-epitopes, may be specific biochemical marker of liver fibrosis. The aim of this study was to develop an ELISA detecting a fragment of type VI collagen generated by MMP-2 and MMP-9, and evaluate this assay in two preclinical models of liver fibrosis.

Circulating CO3-610, a degradation product of collagen III, closely reflects liver collagen and portal pressure in rats with fibrosis.

Background: Hepatic fibrosis is characterized by intense tissue remodeling, mainly driven by matrix metalloproteinases. We previously identified CO3-610, a type III collagen neoepitope generated by matrix metalloproteinase (MMP)-9, and tested its performance as a fibrosis marker in rats with bile-duct ligation. In this study, we assessed whether CO3-610 could be used as a surrogate biomarker of liver fibrosis and portal hypertension in carbon tetrachloride-induced experimental fibrosis.

Immunological detection of the type V collagen propeptide fragment, PVCP-1230, in connective tissue remodeling associated with liver fibrosis.

Aim: Liver fibrosis involves excessive remodeling and deposition of fibrillar extracellular matrix (ECM) components, which leads to malfunction of the organ, causing significant morbidity and mortality. The aim of this study was to assess whether levels of a type V collagen fragment, the propeptide CO5-1230, indicate the amount of collagen deposited during liver fibrosis.

Methods: A specific competitive enzyme-linked immunosorbent assay (ELISA) was developed to measure CO5-1230 levels.

Development and validation of an enzyme-linked immunosorbent assay for the quantification of a specific MMP-9 mediated degradation fragment of type III collagen--A novel biomarker of atherosclerotic plaque remodeling.

Objective: Degradation of collagen in the arterial wall by matrix metalloproteinases is the hallmark of atherosclerosis. We have developed an ELISA for the quantification of type III collagen degradation mediated by MMP-9 in urine.

Design And Methods: A monoclonal antibody targeting a specific MMP-9 generated fragment of collagen III was used in a competitive ELISA.

Measurement of CO3-610, a potential liver biomarker derived from matrix metalloproteinase-9 degradation of collagen type iii, in a rat model of reversible carbon-tetrachloride-induced fibrosis.

Background And Aim: The current study utilized a carbon tetrachloride (CCl(4))-induced liver fibrosis model to measure levels of the MMP9-mediated collagen type III degradation fragment CO3-610 (site of cleavage: KNGETGPQGP), during disease progression and regression, and to investigate a potential prognostic role of the biomarker.

Materials And Methods: 72 female Sprague-Dawley rats aged 6 months old were injected with CCl(4) twice a week over different periods of time to induce varying degrees of liver fibrosis. After 4, 6 and 8 weeks of treatment, administration of CCl(4) was stopped.

Measurement of matrix metalloproteinase 9-mediated collagen type III degradation fragment as a marker of skin fibrosis.

Background: The current study utilized a Bleomycin-induced model of skin fibrosis to investigate the neo-epitope CO3-610 (KNGETGPQGP), a fragment of collagen III released during matrix metalloproteinase-9 (MMP9) degradation of the protein, we have previously described as a novel biomarker for liver fibrosis. The aim was to investigate CO3-610 levels in another well characterised model of fibrosis, to better describe the biomarker in relation to additional fibrotic pathologies.

Methods: Skin fibrosis was induced by daily injections of Bleomycin to a total of 52 female C3 H mice, while control mice (n = 28) were treated with phosphate buffered saline (PBS), for 2, 4, 6 or 8 weeks.

Matrix metalloproteinase-9-mediated type III collagen degradation as a novel serological biochemical marker for liver fibrogenesis.

Background: During fibrogenesis in the liver, in which excessive remodelling of the extracellular matrix (ECM) occurs, both the quantity of type III collagen (CO3) and levels of matrix metalloproteinases (MMPs), including MMP-9, increase significantly. MMPs play major roles in ECM remodelling, via their activity in the proteolytic degradation of extracellular macromolecules such as collagens, resulting in the generation of specific cleavage fragments. These neo-epitopes may be used as markers of fibrosis.

Novel combinations of Post-Translational Modification (PTM) neo-epitopes provide tissue-specific biochemical markers--are they the cause or the consequence of the disease?

The aim of this review is to discuss the potential usefulness of novel advances in the class of biochemical markers, neo-epitopes. Neo-epitopes are post-translational modifications (PTMs) of proteins formed by processes such as protease cleavage, citrullination, nitrosylation, glycosylation and isomerization. Each modification results from a specific local physiological or pathobiologial process.

Procollagen type I N-terminal propeptide (PINP) is a marker for fibrogenesis in bile duct ligation-induced fibrosis in rats.

Background: Fibrosis can be described as the excess deposition of extracellular matrix (ECM) components, such as collagens and proteoglycans. Fibrosis of the liver, which eventually leads to cirrhosis, is a major global health problem. Being able to measure fibrosis progression may enable timely preventative intervention.

Passive stiffness of myocardium from congenital heart disease and implications for diastole.

Background: In ventricular dilatation or hypertrophy, an elevated end-diastolic pressure is often assumed to be secondary to increased myocardial stiffness, but stiffness is rarely measured in vivo because of difficulty. We measured in vitro passive stiffness of volume- or pressure-overloaded myocardium mainly from congenital heart disease.

Methods And Results: Endocardial ventricular biopsies were obtained at open heart surgery (n=61; pressure overload, 36; volume-overload, 19; dilated cardiomyopathy, 4; normal donors, 2).