Simulation modelling as a tool for knowledge mobilisation in health policy settings: a case study protocol.

BACKGROUND: Evidence-informed decision-making is essential to ensure that health programs and services are effective and offer value for money; however, barriers to the use of evidence persist. Emerging systems science approaches and advances in technology are providing new methods and tools to facilitate evidence-based decision-making. Simulation modelling offers a unique tool for synthesising and leveraging existing evidence, data and expert local knowledge to examine, in a robust, low risk and low cost way, the likely impact of alternative policy and service provision scenarios. This case study will evaluate participatory simulation modelling to inform the prevention and management of gestational diabetes mellitus (GDM). The risks associated with GDM are well recognised; however, debate remains regarding diagnostic thresholds and whether screening and treatment to reduce maternal glucose levels reduce the associated risks. A diagnosis of GDM may provide a leverage point for multidisciplinary lifestyle modification interventions. This research will apply and evaluate a simulation modelling approach to understand the complex interrelation of factors that drive GDM rates, test options for screening and interventions, and optimise the use of evidence to inform policy and program decision-making. METHODS/DESIGN: The study design will use mixed methods to achieve the objectives. Policy, clinical practice and research experts will work collaboratively to develop, test and validate a simulation model of GDM in the Australian Capital Territory (ACT). The model will be applied to support evidence-informed policy dialogues with diverse stakeholders for the management of GDM in the ACT. Qualitative methods will be used to evaluate simulation modelling as an evidence synthesis tool to support evidence-based decision-making. Interviews and analysis of workshop recordings will focus on the participants' engagement in the modelling process; perceived value of the participatory process, perceived commitment, influence and confidence of stakeholders in implementing policy and program decisions identified in the modelling process; and the impact of the process in terms of policy and program change. DISCUSSION: The study will generate empirical evidence on the feasibility and potential value of simulation modelling to support knowledge mobilisation and consensus building in health settings.

Bacillus subtilis vegetative isolate surviving chlorine dioxide exposure: an elusive mechanism of resistance.

AIMS: Oxidizing agents such as chlorine dioxide are widely used microbicides, including for disinfection of medical equipment. We isolated a Bacillus subtilis isolate from a washer-disinfector whose vegetative form demonstrated unique resistance to chlorine dioxide (0·03%) and hydrogen peroxide (7·5%). The aim of this study was to understand the mechanisms of resistance expressed by this isolate. METHODS AND RESULTS: A range of resistance mechanisms were investigated in the B. subtilis isolate and a reference B. subtilis strain (ATCC 6051) to include bacterial cell aggregation, the presence of profuse exopolysaccharide (EPS), and the expression of detoxification enzymes. The basis of resistance of the isolate to high concentrations of oxidizing agents was not linked to the presence of endospores. Although, the presence of EPS, aggregation and expression of detoxification enzymes may play a role in bacterial survival to low concentrations of chlorine dioxide, it is unlikely that the mechanisms helped tested to survive the bactericidal effect of higher oxidizer concentrations. CONCLUSIONS: Overall, the mechanisms conferring resistance to chlorine dioxide and hydrogen peroxide remains elusive. Based on recent advances in the mode of action of oxidizing agents and notably hydrogen peroxide, we postulate that additional efficient intracellular mechanisms may be involved to explain significant resistance to in-use concentrations of commonly used high-level disinfectants. SIGNIFICANCE AND IMPACT OF STUDY: The isolation of a highly resistant vegetative Gram-positive bacterium to a highly reactive oxidizing agent is worrying. Understanding the mechanisms conferring such resistance is essential to effectively control such bacterial isolates. Here, we postulate that there are still mechanisms of bacterial resistance that have not been fully characterized.

Acute neuromuscular respiratory failure: a population-based study of aetiology and outcome in Northern Ireland.

BACKGROUND: Acute neuromuscular respiratory failure (NMRF) is a life-threatening feature of a variety of neurological conditions that can present in extremis prior to the establishment of a definitive diagnosis, so early clinical decision making is difficult. Population-based data on the frequency, outcome and aetiological spectrum are lacking. OBJECTIVE: To establish accurate epidemiological descriptive statistics in this patient group. METHODS: The regional Intensive Care National Audit and Research Centre (ICNARC) database was searched for patients admitted with acute NMRF from 1/1/2000 to 31/12/2010. Demographics, diagnosis, length of intensive care unit (ICU) stay, follow-up and outcome (modified Rankin score (mRS)) were recorded. A comparison dataset of all non-NMRF neurology patients admitted to ICU was obtained. RESULTS: 55 patients were identified; age 17-88 (median 66 years), M:F ratio 1:1.5, incidence rate (IR) 2.81 (2.12 to 3.66) cases per million person-years and mortality rate (MR) 0.26 (0.08 to 0.60) deaths per million person-years. Causes included inflammatory neuropathy (65%), myasthenia gravis (18%), rhabdomyolysis (2%) and amyotrophic lateral sclerosis (9%), and 5% were undiagnosed. Follow-up ranged from 0 to 7 years (median 500.5 days); long-term mRS 1 (range 0-6). NMRF patients were older (p<0.0001), had longer ICU stay (p<0.0001), but significantly better outcome (p<0.0001) than 93 non-NMRF neurology patients requiring ICU admission. CONCLUSION: Inflammatory and degenerative neuromuscular conditions can present in acute NMRF. Long-term outcome is good and MR is low, and significantly better than in other neurology patients requiring ICU admission despite longer ICU stay.

A new quantitative method for determining patient risk for reusable medical device categorization based on using and interpreting Kremer's cleaning classification system.

The cleaning of reusable medical devices involves inherent challenges that can impact on the effectiveness of the cleaning process; consequently, the subsequent safety of patients. Fluid dynamics play a critical role in determining the flow and distribution of cleaning agents where the design of the device can either facilitate or hinder this important process. Complex geometries, narrow channels, or irregular surfaces can impede effective flushing of contaminants leading to incomplete cleaning that creates a greater likelihood for patient contamination risks. Device features (n =23) were exposed to the most challenging cleaning conditions to find the point of failure in both fluid dynamics and soil retention. Experimental results obtained from the aforementioned along with associated compound risks were used to assign a risk value. Using the "hardest to clean" device feature approach as the base risk value, the total quantitative risk score was calculated for different reusable medical devices from numerical values obtained from addressing 14 questions focusing on variability in geometry, material use, types of cleaning, and intended patient use. Patient risk values for devices with different features were calculated from using Kremer's cleaning categories based on position within value ranges. Occurrences less than 18 correspond to minimal risk devices while a total risk score between the values of 18-39 are moderate and equal to or above 40 scores corresponds to the maximal category. Application of this quantitative assessment approach will facilitate appropriate mitigation of risk for cleaning reusable medical devices by informing use of targeted effective interventions. Future use of this Kremer cleaning classification will complement and augment disinfection and sterilization modalities.

A proposed cleaning classification system for reusable medical devices to complement the Spaulding classification.

A central tenet in infection prevention is application of the Spaulding classification system for the safe use of medical devices. Initially defined in the 1950s, this system defines devices and surfaces as being critical, semi-critical or non-critical depending on how they will be used on a patient. Different levels of antimicrobial treatment, defined as various levels of disinfection or sterilization, are deemed appropriate to reduce patient risk of infection. However, a focus on microbial inactivation is insufficient to address this concern, which has been particularly highlighted in routine healthcare facility practices, emphasizing the underappreciated importance of cleaning and achieving acceptable levels of cleanliness. A deeper understanding of microbiology has evolved since the 1950s, which has led to re-evaluation of the Spaulding classification along with a commensurate emphasis on achieving appropriate cleaning. Albeit underappreciated, cleaning has always been important as the presence of residual materials on surfaces can interfere with the efficacy of the antimicrobial process to inactivate micro-organisms, as well as other risks to patients including device damage, malfunction and biocompatibility concerns. Unfortunately, this continues to be relevant, as attested by reports in the literature on the occurrence of device-related infections and outbreaks due to failures in processing expectations. This reflects, in part, increasing sophistication in device features and reuse, along with commensurate manufacturer's instructions for use. Consequently, this constitutes the first description and recommendation of a new cleaning classification system to complement use of the traditional Spaulding definitions to help address these modern-day technical and patient risk challenges. This quantitative risk-based classification system highlights the challenge of efficient cleaning based on the complexity of device features present, as an isolated variable impacting cleaning. This cleaning classification can be used in combination with the Spaulding classification to improve communication of cleaning risk of a reusable medical device between manufacturers and healthcare facilities, and improve established cleaning practices. This new cleaning classification system will also inform future creation, design thinking and commensurate innovations for the sustainable safe reuse of important medical devices.

A review of Spaulding's classification system for effective cleaning, disinfection and sterilization of reusable medical devices: Viewed through a modern-day lens that will inform and enable future sustainability.

Despite advances in medicine and innovations in many underpinning fields including disease prevention and control, the Spaulding classification system, originally proposed in 1957, remains widely used for defining the disinfection and sterilization of contaminated re-usable medical devices and surgical instruments. Screening PubMed and Scopus databases using a PRISMA guiding framework generated 272 relevant publications that were used in this review. Findings revealed that there is a need to evolve how medical devices are designed, and processed by cleaning, disinfection (and/or sterilization) to mitigate patient risks, including acquiring an infection. This Spaulding Classification remains in use as it is logical, easily applied and understood by users (microbiologists, epidemiologists, manufacturers, industry) and by regulators. However, substantial changes have occurred over the past 65 years that challenge interpretation and application of this system that includes inter alia emergence of new pathogens (viruses, mycobacteria, protozoa, fungi), a greater understanding of innate and adaptive microbial tolerance to disinfection, toxicity risks, increased number of vulnerable patients and associated patient procedures, and greater complexity in design and use of medical devices. Common cited examples include endoscopes that enable non- or minimal invasive procedures but are highly sophisticated with various types of materials (polymers, electronic components etc), long narrow channels, right angle and heat-sensitive components and various accessories (e.g., values) that can be contaminated with high levels of microbial bioburden and patient tissues after use. Contaminated flexible duodenoscopes have been a source of several significant infection outbreaks, where at least 9 reported cases were caused by multidrug resistant organisms [MDROs] with no obvious breach in processing detected. Despite this, there is evidence of the lack of attention to cleaning and maintenance of these devices and associated equipment. Over the last few decades there is increasing genomic evidence of innate and adaptive resistance to chemical disinfectant methods along with adaptive tolerance to environmental stresses. To reduce these risks, it has been proposed to elevate classification of higher-risk flexible endoscopes (such as duodenoscopes) from semi-critical [contact with mucous membrane and intact skin] to critical use [contact with sterile tissue and blood] that entails a transition to using low-temperature sterilization modalities instead of routinely using high-level disinfection; thus, increasing the margin of safety for endoscope processing. This timely review addresses important issues surrounding use of the Spaulding classification system to meet modern-day needs. It specifically addresses the need for automated, robust cleaning and drying methods combined with using real-time monitoring of device processing. There is a need to understand entire end-to-end processing of devices instead of adopting silo approaches that in the future will be informed by artificial intelligence and deep-learning/machine learning. For example, combinational solutions that address the formation of complex biofilms that harbour pathogenic and opportunistic microorganisms on the surfaces of processed devices. Emerging trends are addressed including future sustainability for the medical devices sector that can be enabled via a new Quintuple Helix Hub approach that combines academia, industry, healthcare, regulators, and society to unlock real world solutions.

Bacterial spore structures and their protective role in biocide resistance.

The structure and chemical composition of bacterial spores differ considerably from those of vegetative cells. These differences largely account for the unique resistance properties of the spore to environmental stresses, including disinfectants and sterilants, resulting in the emergence of spore-forming bacteria such as Clostridium difficile as major hospital pathogens. Although there has been considerable work investigating the mechanisms of action of many sporicidal biocides against Bacillus subtilis spores, there is far less information available for other species and particularly for various Clostridia. This paucity of information represents a major gap in our knowledge given the importance of Clostridia as human pathogens. This review considers the main spore structures, highlighting their relevance to spore resistance properties and detailing their chemical composition, with a particular emphasis on the differences between various spore formers. Such information will be vital for the rational design and development of novel sporicidal chemistries with enhanced activity in the future.

A standardized method for evaluating test soils used to demonstrate cleaning efficacy.

BACKGROUND: Cleaning and associated validation requirements are essential for the safe use of reusable devices. In the past, test methods and associated endpoints for cleaning validations have varied worldwide. Recent international standards have updated the requirements to include cleaning endpoints and requirements for the use of test soils for demonstrating cleaning efficacy of washer-disinfectors. METHODS: A quantitative comparison of test soils used in cleaning efficacy studies was conducted using a new standardized test method as published in Annexe B ISO 15883-5:2021. Test soils included Artificial Test Soil (ATS 2015), Blood Test Soil (BTS), Coagulated Blood, Defibrinated Blood Soil (DBLSO), Modified Coagulated Blood Soil, Two Component Blood Test Soil and the UK Test Soil (Edinburgh Soil). CONCLUSION: All the test soils demonstrated acceptable performance in accordance with the standard.

Decontamination efficacy against Mycoplasma.

AIMS: Mycoplasma is minute bacteria that can be found ubiquitously in the environment and also in human, animal and plant tissues. In addition to their public health importance as aetiological agents of infections and possible association with certain cancers, mycoplasma is a major contamination concern in biotechnology. These bacterial cells are very small, can form biofilms and survive for extended periods of time when dried onto surfaces. Despite these concerns, there is little information concerning their resistance to currently used disinfection methods. The objective of this study was to evaluate commonly used biocidal treatments against three representative mycoplasma species. METHODS AND RESULTS: Mycoplasma was dried onto stainless steel coupons and exposed to decontamination products. All strains survived drying and any significant viability loss because of the test method (including neutralization), as demonstrated by a ≤0·5 log(10) for each tested species. The quaternary ammonium compound (QAC) tested presented poor efficacy, whereas 70% ethanol was fully efficient with complete inactivation after 5-min exposure. Alkaline cleaner formulations presented increasing efficacy when tested at 0·2, 0·4 and 0·8% concentrations, with complete kill observed at 0·8% of two products tested. Decontamination with vaporized (gaseous) hydrogen peroxide (VHP) was very efficient at concentrations used for room and small enclosures decontamination (180-1200 ppm with various time exposures), as well as for device sterilization applications. CONCLUSIONS: Ethanol and alkaline detergent formulations were particularly efficient against mycoplasma, but a QAC formulation was not. VHP in room disinfection and device sterilization applications was effective against all mycoplasma species tested. SIGNIFICANCE AND IMPACT OF THE STUDY: Mycoplasma can provide resistance to environmental factors (such as drying) and disinfectants. Further studies are required to confirm the effectiveness of other disinfectants and the mechanisms of mycoplasma resistance.

COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register.

BACKGROUND: In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS). OBJECTIVES: Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19. METHODS: Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second 'waves' of the pandemic. RESULTS: Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave. CONCLUSIONS: Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.

Transient cardiomyopathy as the presenting feature of acute disseminated encephalomyelitis.

Brainstem lesions are rarely associated with neurogenic pulmonary oedema (NPO) in multiple sclerosis and other disorders. The exact mechanism for this is unknown. We describe a case of a 15-year-old boy who presented with transient cardiomyopathy and severe acute pulmonary oedema. Several days after his initial presentation he developed an ataxic syndrome with limb, truncal and gait ataxia and nystagmus on primary gaze. Investigations confirmed acute disseminated encephalomyelitis (ADEM). For the first time, we describe a case of transient cardiomyopathy and NPO as the initial manifestation of ADEM.

Resistance and cross-resistance to oxidising agents of bacterial isolates from endoscope washer disinfectors.

Bacteria isolated from washer disinfectors using chlorine dioxide as a high-level disinfectant were exposed to peracetic acid, chlorine dioxide and hydrogen peroxide to investigate their susceptibility and possible bacterial cross-resistance to these highly reactive oxidising biocides. A standard suspension test was used to establish a rate of kill of these biocides against two stable isolates (Bacillus subtilis and Micrococcus luteus). Suspension tests demonstrated that 'in use' concentrations were not always effective to provide the required disinfection efficacy within recommended exposure times and in some instances a 60min exposure was necessary to achieve a reduction in number by a factor of 10(5). It appears that vegetative Gram-positive isolates can become resistant to oxidising agents in vitro, and that cross-resistance to related compounds can occur. Since these bacteria are deemed to be susceptible to highly reactive biocides, there should be further study of the resistance mechanisms in these isolates to explain their survival.

Validating the portal population of the United Kingdom Multiple Sclerosis Register.

The UK Multiple Sclerosis Register (UKMSR) is a large cohort study designed to capture 'real world' information about living with multiple sclerosis (MS) in the UK from diverse sources. The primary source of data is directly from people with Multiple Sclerosis (pwMS) captured by longitudinal questionnaires via an internet portal. This population's diagnosis of MS is self-reported and therefore unverified. The second data source is clinical data which is captured from MS Specialist Treatment centres across the UK. This includes a clinically confirmed diagnosis of MS (by Macdonald criteria) for consented patients. A proportion of the internet population have also been consented at their hospital making comparisons possible. This dataset is called the 'linked dataset'. The purpose of this paper is to examine the characteristics of the three datasets: the self-reported portal data, clinical data and linked data, in order to assess the validity of the self-reported portal data. The internet (n = 11,021) and clinical (n = 3,003) populations were studied for key shared characteristics. We found them to be closely matched for mean age at diagnosis (clinical = 37.39, portal = 39.28) and gender ratio (female %, portal = 73.1, clinical = 75.2). The Two Sample Kolmogorov-Smirnov test was for the continuous variables to examine is they were drawn from the same distribution. The null hypothesis was rejected only for age at diagnosis (D = 0.078, p < 0.01). The populations therefore, were drawn from different distributions, as there are more patients with relapsing disease in the clinical cohort. In all other analyses performed, the populations were shown to be drawn from the same distribution. Our analysis has shown that the UKMSR portal population is highly analogous to the entirely clinical (validated) population. This supports the validity of the self-reported diagnosis and therefore that the portal population can be utilised as a viable and valid cohort of people with Multiple Sclerosis for study.

Prion inactivation using a new gaseous hydrogen peroxide sterilisation process.

Prions pose a challenge to decontamination, particularly before the re-use of surgical instruments. They have relatively high resistance to standard decontamination methods and require extreme chemical and/or heat-based treatments for devices used in known or suspected cases of disease. This study investigated the effectiveness of a new gaseous hydrogen peroxide sterilisation process for prions as an alternative low-temperature method. Gaseous peroxide, in addition to known antimicrobial efficacy, was shown to inactivate prions both in in-vitro and in-vivo assays. In contrast to the gas form, liquid peroxide was not effective. The mechanism of action of gaseous peroxide suggested protein unfolding, some protein fragmentation and higher sensitivity to proteolytic digestion. Hydrogen peroxide liquid showed a degree of protein clumping and full resistance to protease degradation. The use of gaseous peroxide in a standard low-temperature sterilisation process may present a useful method for prion inactivation.

Quantitative bone histology in the hypercalcemia of malignant disease.

Quantitative bone histology was studied in 23 patients with malignant hypercalcemia (MH) due to carcinoma (16) or immunoproliferative disease (7). Plasma calcium was 3.37 +/- 0.47 (mean +/- SD) mmol/liter. Bone resorbing surface (RS) was measured using a sensitive histochemical stain to identify osteoclasts. In the MH patients with carcinoma, the RS was 3.1 +/- 2.6% compared to 1.0 +/- 0.3% in controls (P less than 0.02). In the myeloma patients it was 2.3 +/- 1.7%, and in normocalcemic patients with malignant disease 0.8 +/- 1.1%. RS did not correlate with serum PTH, and several high RS values were associated with undetectable PTH. RS correlated with forming surface (FS) in MH patients (r = 0.44, P less than 0.05) and controls (r = 0.68, P less than 0.005), but there was a greater RS relative to FS in MH patients than in controls (P less than 0.005). "Excess" RS in the MH patients was calculated by subtracting the RS accounted for by the measured FS, using the relationship defined by the controls. Bone loss, as reflected in urinary calcium excretion, correlated weakly with excess RS (r = 0.44, P less than 0.05) but was high even when excess RS was zero. Thus, the histological findings do not account for the bone loss, and additional resorption around bone metastases is likely; the results of this study are consistent with a humoral substance produced by the malignant tissue causing generalized bone resorption in addition to bone dissolution around metastases.

An epidemiologic study of multiple sclerosis in Northern Ireland.

We wanted to establish the point prevalence of MS in Northern Ireland. Northern Ireland has been a known high-risk area for MS since the original work of Allison and Millar in 1951. Studies demonstrated a rising prevalence in 1951 of 41 (95% CI, 37 to 44), in 1961 of 57 (95% CI, 53 to 61), and in 1986 of 104 (95% CI, 85 to 128)/10(5) population for probable/early probable and latent disease. We surveyed four districts (area 2,030 km2, population 151,000). Case sources included Regional Neurology Service records, postal survey of general medical practitioners, hospital databases, MS charities, and MS respite facilities. We used the Poser and Allison and Millar criteria in diagnosis. From a provisional list of 402 patients, 254 (177 female, 77 male, ratio 2.3:1) were identified with definite or probable disease by the Poser criteria, prevalence 168.2/10(5) (95% CI, 147.5 to 188.9/10(5)) with 34 suspected patients and an overall prevalence 190.7/10(5) (95% CI, 168.7 to 212.7/10(5)). We interviewed and examined over 87% of these 288 patients. There were 246 patients classified as probable/early probable and latent by Allison and Millar, prevalence 162.9/10(5) (95% CI, 142.6 to 183.3/10(5)). Seventy-six probable or definite patients had onset between 1985 and 1992 (estimated incidence, 6.5/10(5)/yr). Age range of prevalent patients was 18 to 79 years (mean +/- SD, 49.2 +/- 13.3 years). Mean age at onset was 31.6 +/- 10.1 years. Overall, 12.5% had primary progressive disease and 20% had benign MS. Northern Ireland has an extremely high and rising MS prevalence. This may reflect a true increase in disease incidence or may be explained by increasing survival, improved case ascertainment, increased disease awareness, or improved laboratory and radiologic diagnosis.

Elevated serum and CSF levels of soluble CD30 during clinical remission in multiple sclerosis.

OBJECTIVE: To ascertain the presence of the Th2 response in MS patients by evaluating the level of soluble (s) CD30 across the clinical spectrum of MS and during relapse and remission. BACKGROUND: MS is considered a T-cell-mediated disorder with the immune attack dominated by a Thl cytokine response. Elevated levels of sCD30 have been associated with CD4+ cells that secrete Th2-type cytokines. METHODS: Levels of sCD30 were determined in the serum and CSF of patients with primary progressive MS, secondary progressive MS, relapsing-remitting MS (RRMS), both in relapse and remission, and in patients with other inflammatory neurologic disease (IND) and noninflammatory neurologic disease (NIND). None of the patients were on immunomodulatory treatment. RESULTS: Higher serum levels of sCD30 were detected in all MS subgroups and IND patients compared with NIND patients. RRMS patients in remission had significantly higher levels than those in relapse (median, 45.7 U/mL versus 18.3 U/mL; p = 0.04). Significantly higher CSF levels were also found in all groups, except those with RRMS in relapse compared with NIND patients. Again, RRMS patients in remission had higher CSF sCD30 levels compared with those in relapse (median, 4.0 U/mL versus 3.0 U/mL; p = 0.08). CONCLUSIONS: Serum and CSF levels of sCD30 are increased in MS, particularly during remission. The results provide additional evidence for the presence of a Th2 response and indicate that sCD30 may be of value as a marker of lesion resolution.

Raised CSF levels of soluble adhesion molecules across the clinical spectrum of multiple sclerosis.

Endothelial activation is considered an important step in multiple sclerosis (MS) lesion formation, elevated cerebrospinal fluid (CSF) and serum levels of certain adhesion molecules being associated with varying stages of disease activity and clinical course. CSF and serum sVCAM-1, sICAM-1, sE-selectin and sL-selectin were measured by ELISA in 16 primary progressive (PPMS), 16 secondary progressive (SPMS) and 43 relapsing-remitting MS patients (RRMS) and compared with 20 inflammatory (IND) and 46 non-inflammatory neurological disease (NIND) controls. CSF sVCAM-1 and sICAM-1 were increased in all MS groups vs. NIND with no significant differences between the MS groups. CSF sE-selectin (p = 0.007) and the sE-selectin index (p = 0.01) were elevated in PPMS vs. RRMS in relapse, whilst serum sE-selectin was significantly raised in PPMS compared to RRMS in remission (p = 0.005), RRMS in relapse (p = 0.004), NIND (p = 0.03) and IND (p = 0.05). Adhesion molecule levels in both progressive MS groups were similar. These results provide evidence for a distinct inflammatory component in PPMS and for immunological heterogeneity between the clinical subgroups of MS.

Serum and cerebrospinal fluid soluble Fas levels in clinical subgroups of multiple sclerosis.

Elevated sFas levels have been described in multiple sclerosis (MS) patients with active disease. The aim of this study was to assess the diagnostic potential of serum and cerebrospinal fluid (CSF) sFas measurements in differentiating clinically defined MS patient subgroups. Levels of sFas and sFas indices were determined in patients with stable relapsing-remitting MS (RRMS), active RRMS, primary progressive MS (PPMS), secondary progressive MS (SPMS) and patients with inflammatory (IND) and noninflammatory neurological diseases (NIND). Serum sFas modulation over 32 weeks IFN-beta1a therapy was also investigated. Serum and CSF sFas levels and sFas indices were elevated in MS compared to NIND and IND patients. Within the MS group, serum and CSF sFas levels were highest in PPMS, with active RRMS patients demonstrating the highest sFas indices. This may reflect an ongoing disease process which is occurring acutely (active disease) or incessantly (progressive disease). IFN-beta1a induced a transient increase in circulating sFas following initiation of therapy. Whilst evidence was provided for variable sFas expression in clinical subgroups of MS, there was insufficient definition between the respective groups to advocate sFas measurements as a diagnostic marker of clinical subgroups of MS.