Cystic Fibrosis screen positive, inconclusive diagnosis (CFSPID) to Cystic Fibrosis: Detecting disease with serial assessments.

We present the case of a child given a CFSPID designation in early life who was later reclassified as having CF based on a combination of recurrent respiratory symptoms and CFTR functional testing, despite normal sweat chloride levels. Here we demonstrate the importance of monitoring these children, each time reviewing the diagnosis based on updated understanding of individual CFTR mutation phenotypes or clinical findings inconsistent with the designation. This case identifies situations in which the CFSPID designation should be challenged, and gives an approach for this when CF is suspected.

PrEP Use, Sexual Behaviour, and PrEP Adherence Among Men who have Sex with Men Living in Wales Prior to and During the COVID-19 Pandemic.

We examined PrEP use, condomless anal sex (CAS), and PrEP adherence among men who have sex with men (MSM) attending sexual health clinics in Wales, UK. In addition, we explored the association between the introduction of measures to control transmission of SARS-CoV-2 on these outcomes. We conducted an ecological momentary assessment study of individuals in receipt of PrEP in Wales. Participants used an electronic medication cap to record PrEP use and completed weekly sexual behaviour surveys. We defined adherence to daily PrEP as the percentage of CAS episodes covered by daily PrEP (preceded by ≥ 3 days of PrEP and followed by ≥ 2 days). Sixty participants were recruited between September 2019 and January 2020. PrEP use data prior to the introduction of control measures were available over 5785 person-days (88%) and following their introduction 7537 person-days (80%). Data on CAS episodes were available for 5559 (85%) and 7354 (78%) person-days prior to and following control measures respectively. Prior to the introduction of control measures, PrEP was taken on 3791/5785 (66%) days, there were CAS episodes on 506/5559 (9%) days, and 207/406 (51%) of CAS episodes were covered by an adequate amount of daily PrEP. The introduction of pandemic-related control measures was associated with a reduction in PrEP use (OR 0.44, 95%CI 0.20-0.95), CAS (OR 0.35, 95%CI 0.17-0.69), and PrEP adherence (RR = 0.55, 95%CI 0.34-0.89) and this may have implications for the health and wellbeing of PrEP users and, in addition to disruption across sexual health services, may contribute to wider threats across the HIV prevention cascade.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Fludrocortisone-a treatment for tubulopathy post-paediatric renal transplantation: A national paediatric nephrology unit experience.

Calcineurin inhibitors post-renal transplantation are recognized to cause tubulopathies in the form of hyponatremia, hyperkalemia, and acidosis. Sodium supplementation may be required, increasing medication burden and potentially resulting in poor compliance. Fludrocortisone has been beneficial in addressing tubulopathies in adult studies, with limited paediatric data available. A retrospective review of data from an electronic renal database from December 2014 to January 2016 was carried out. Forty-seven post-transplant patients were reviewed with 23 (49%) patients on sodium chloride or bicarbonate. Nine patients, aged 8.3 years (range 4.9-16.4), commenced fludrocortisone 22 months (range 1-80) after transplant and were followed up for 9 months (range 2-20). All patients stopped sodium bicarbonate; all had a reduction or no increase in total daily doses of sodium chloride. Potassium levels were significantly lower on fludrocortisone, 5.2 vs 4.5 mmol/L, P = .04. No difference was noted in renal function (eGFR 77.8 vs 81.7 mL/min/1.73 m2 , P = .45) and no significant increase in systolic blood pressure (z-scores 0.99 vs 0.85, P = .92). No side effects secondary to treatment with fludrocortisone were reported. A significant proportion of renal transplant patients were on sodium supplementation and fludrocortisone reduced sodium supplementation without significant effects on renal function or blood pressure. Fludrocortisone appears to be safe and effective for tubulopathies in children post-transplantation.

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden.

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.

Exploring the limit of dislocation based plasticity in nanostructured metals.

A twofold decrease to an unexplored scale of 5 nm was produced in Cu by applying a large sliding load in liquid nitrogen. Statistical and universal scaling analyses of deformation induced high angle boundaries, dislocation boundaries, and individual dislocations observed by high resolution electron microscopy reveal that dislocation processes still dominate. Dislocation based plasticity continues far below the transition suggested by experiment and molecular dynamics simulations, with a limit below 5 nm. Very high strength metals may emerge based on this enhanced structural refinement.

Long-term effectiveness of enzyme replacement therapy in adults with Gaucher disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapies (ERT) for adults with Gaucher disease (GD). DESIGN: A longitudinal, multi-centre cohort study, including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 150, aged 16 to 83 years) with a diagnosis of GD who attended a specialist treatment centre in England. At recruitment, 131 patients were receiving ERT (mean treatment duration, 10.8 years; range 0-18 years). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin; absence/presence of bone pain; spleen and liver volumes and AST levels. RESULTS: One hundred and fifty adults were recruited. Duration of ERT was associated with statistically significant improvements in platelet count (p < 0.001), haemoglobin (p < 0.001), liver and spleen volumes (p < 0.001) and AST levels (p = 0.02). CONCLUSIONS: These data provide further evidence of the long-term effectiveness of ERT in adults with GD.

Long-term effectiveness of enzyme replacement therapy in children with Gaucher disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapies (ERT) for children with Gaucher disease (GD). DESIGN: A longitudinal cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Children on treatment contributed data before and during treatment. Children not on treatment contributed natural history data. PARTICIPANTS: Consenting children (N = 25, aged 1.1 to 15.6 years) with a diagnosis of GD (14 with GD1 and 11 with GD3) who attended a specialist treatment centre in England. At recruitment, 24 patients were receiving ERT (mean treatment duration, 5.57 years; range 0-13.7 years). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin and absence/presence of bone pain. RESULTS: Duration of ERT was associated with statistically significant improvements in platelet count (p < 0.001), haemoglobin (p < 0.001), and reported bone pain (p = 0.02). The magnitude of effect on haematological parameters was greater in children with GD3 than in those with GD1. CONCLUSIONS: These data provide further evidence of the long-term effectiveness of ERT in children with GD.

Effectiveness of enzyme replacement therapy in adults with late-onset Pompe disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapy (ERT) for adults with late-onset Pompe disease. DESIGN: A longitudinal cohort study including prospective and retrospective clinical outcome data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 62) with a diagnosis of late-onset Pompe disease who attended a specialist treatment centre in England. This cohort represented 83 % of all patients in the UK with a confirmed diagnosis of this rare condition. At study entry, all but three patients were receiving ERT (range of treatment duration, 0 to 3.1 years). OUTCOME MEASURES: Percent predicted forced vital capacity (%FVC); ventilation dependency; mobility; 6 min walk test (6MWT); muscle strength and body mass index (BMI). RESULTS: An association was found between time on ERT and significant increases in the distance walked in the 6MWT (p < 0.001) and muscle strength scores (p < 0.001). Improvements in both these measures were seen over the first 2 years of treatment with ERT. No statistically significant relationship was found between time on ERT and respiratory function or in BMI. CONCLUSIONS: These data provide some further evidence of the effectiveness of ERT in adults with late-onset Pompe disease. SYNOPSIS: The results of this longitudinal cohort study of 62 adults with late-onset Pompe disease, provide further evidence on the effectiveness of ERT in this rare condition.

Long-term effectiveness of enzyme replacement therapy in Fabry disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapy (ERT) for adults and children with Fabry disease. DESIGN: Cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment and untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 289) and children (N = 22) with a confirmed diagnosis of Fabry disease attending a specialist Lysosomal Storage Disorder treatment centre in England. At recruitment 211 adults and seven children were on ERT (range of treatment duration, 0 to 9.7 and 0 to 4.2 years respectively). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression included left ventricular mass index (LVMI); proteinuria; estimated glomerular filtration rate (eGFR); pain; hearing and transient ischaemic attacks (TIA)/stroke. RESULTS: We found evidence of a statistically significant association between time on ERT and a small linear decrease in LVMI (p = 0.01); a reduction in the risk of proteinuria after adjusting for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (p < 0.001) and a small increase in eGFR in men and women without pre-treatment proteinuria (p = 0.01 and p < 0.001 respectively). The same analyses in children provided no statistically significant results. No associations between time on ERT and pain, risk of needing a hearing aid, or risk of stroke or TIAs, were found. CONCLUSIONS: These data provide some further evidence on the long-term effectiveness of ERT in adults with Fabry disease, but evidence of effectiveness could not be demonstrated in children.

Diagnosing Gaucher disease: an on-going need for increased awareness amongst haematologists.

Gaucher disease (GD) is an inherited enzyme deficiency characterised by progressive cytopenias, hepatosplenomegaly and destructive bone disease. It is diagnosed by demonstration of beta glucosidase deficiency but may be suspected in presence of abnormal storage cells on tissue biopsy. Specific treatment is available in the form of enzyme replacement (ERT) and is effective in reversing many disease features. Delayed treatment has been associated with increased disease complications. This retrospective review of a single centre cohort of 86 patients was undertaken to ascertain if the diagnostic journey had improved since the introduction of ERT and commissioning of services. Fifty-six percent of patients presented primarily with features related to thrombocytopenia or splenomegaly with a median time from symptom onset to diagnosis of 2years (range 0.5-26years), 19% experiencing delays of 5 or more years. Seventy-five percent of patients were diagnosed by haematologists, 68% following an abnormal bone marrow biopsy. Raised serum ACE levels, low HDL cholesterol and raised ferritin were identified as prevalent laboratory abnormalities at the time of diagnosis. These features, coupled with the relative preservation of haemoglobin and white cell counts compared to the platelet count, help identify patients presenting to haematologists with a possible diagnosis of GD earlier in the diagnostic pathway.

Enhanced differentiation of osteoclasts from mononuclear precursors in patients with Gaucher disease.

Gaucher disease (GD) is an autosomal recessive disorder caused by deficiency of ß-glucocerebrosidase. Storage of glucosylceramide in reticuloendothelial cells results in multiorgan pathology including bone disease. Established skeletal disease may remain problematic despite Gaucher-specific treatment. Both osteopenia and osteonecrosis have been described but the underlying pathophysiology, in particular the role of monocyte-derived osteoclasts is not well defined. The objective of this study was to explore the effect of glucocerebrosidase deficiency, inhibition and replacement on osteoclast development and function. In cultures derived from GD patients, or where GBA was chemically inhibited multinucleate giant cells expressing markers of osteoclast differentiation occurred earlier and in greater numbers compared to normal controls and the functional capacity of osteoclasts for bone resorption was enhanced. Increases in osteoclast number and activity correlated with radiological markers of active bone disease. Abnormalities were reversed by addition of specific therapies and were attenuated by co-culture with cells derived from healthy controls (HCs). Numbers of osteoblast lineage cells in the peripheral blood were mismatched to osteoclast precursors indicating uncoupling of osteoblast-osteoclast regulation which may further impact on bone remodelling. Elucidation of the underlying mechanisms of these changes will suggest rational therapies for the most disabling aspect of this condition.

A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule.

Interventions to improve osteoporosis medication adherence and persistence: a systematic review and literature appraisal by the ISPOR Medication Adherence & Persistence Special Interest Group.

This study aims to systematically review, critically appraise and identify from the published literature, the most effective interventions to improve medication adherence in osteoporosis. A literature search using Medline, EMBASE, Cochrane library, and Cumulative Index to Nursing and Allied Health Literature was undertaken to identify prospective studies published between January 1, 1999 and June 30, 2012. We included studies on adult users of osteoporosis medications that tested a patient adherence intervention (e.g., patient education, intensified patient care, different dosing regimens) and reported quantitative results of adherence. The Delphi list was modified to assess the quality of studies. Of 113 articles identified, 20 studies fulfilled the inclusion criteria. The most frequent intervention was education (n = 11) followed by monitoring/supervision (n = 4), drug regimens (n = 2), drug regimens and patient support (n = 1), pharmacist intervention (n = 1), and electronic prescription (n = 1). Although patient education improved medication adherence in four studies, two large-scale randomized studies reported no benefits. Simplification of dosing regimens (with and without patient support program) was found to have a significant clinical impact on medication adherence and persistence. Monitoring/supervision showed no impact on medication persistence while electronic prescription and pharmacist intervention increased medication adherence or persistence. In conclusion, this review found that simplification of dosing regimens, decision aids, electronic prescription, or patient education may help to improve adherence or persistence to osteoporosis medications. We identified wide variation of quality of studies in the osteoporosis area. The efficacy of patient education was variable across studies, while monitoring/supervision does not seem an effective way to enhance medication adherence or persistence.

Effectiveness of out-patient based acute heart failure care: a pilot randomised controlled trial.

OBJECTIVES: Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). METHODS: We randomised patients with AHF, considered to need IV diuretic treatment for ≥2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days. RESULTS: Eleven patients were randomised to IPM and 13 to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p = .86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p = .13}. Two patients randomised to IPM (vs 6 OPM) were readmitted [p = .31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p = .04). OPM was associated with mean cost savings of £2658 (95% CR 460-4857) per patient. CONCLUSIONS: Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings.

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression.

The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.

Fabry disease in unselected patients with TIA or stroke: population-based study.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. In recent years, the prevalence of FD has been reported to be up to 4% in cryptogenic young stroke patients. However, there have been no population-based studies in unselected patients with transient ischaemic attack (TIA) or stroke across the full range of ages. METHODS: We determined the prevalence of FD mutations in consecutive patients from a population-based study of acute TIA or ischaemic stroke (Oxford Vascular Study). Analysis included amplifying of the α-galactosidase A gene by polymerase chain reaction, denaturing high-performance liquid chromatography (dHPLC) analysis and sequencing using standard automated sequencing protocols [Mutation Surveyor software (Softgenetics)] where the dHPLC indicated a possible mutation. RESULTS: Samples of 1046 consecutive patients (52% women; mean age 73.2 years; 15% age <60 years; 572 stroke; 474 TIA) were tested. No patient had a known gene mutation causing FD, giving an upper 95% confidence interval around the estimated frequency of 0.35% overall and 2.37% in the 154 patients aged under 60 years. However, in 5 (0.48%) samples, a known polymorphism or sequence variation in the gene was identified that can be associated with lower than normal enzyme activity in plasma without causing the full clinical manifestation of FD. CONCLUSIONS: Fabry disease is rare in an unselected group of UK patients with TIA or stroke. Larger studies in unselected younger patients with cryptogenic stroke are required to determine whether routine screening is justified in this group.

Using routinely recorded data in a UK RCT: a comparison to standard prospective data collection methods.

BACKGROUND: Routinely recorded data held in electronic health records can be used to inform the conduct of randomised controlled trials (RCTs). However, limitations with access and accuracy have been identified. OBJECTIVE: Using epilepsy as an exemplar condition, we assessed the attributes and agreement of routinely recorded data compared to data collected using case report forms in a UK RCT assessing antiepileptic drug treatments for individuals newly diagnosed with epilepsy. METHODS: The case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK multicentre RCT assessing the clinical and cost-effectiveness of antiepileptic drugs as treatments for epilepsy. Ninety-eight of 470 eligible participants provided consent for access to routinely recorded secondary care data that were retrieved from NHS Digital Hospital Episode Statistics (N=71) and primary and secondary care data from The Secure Anonymised Information Linkage Databank (N=27). We assessed data items relevant to the identification of individuals eligible for inclusion in SANAD II, baseline and follow-up visits. The attributes of routinely recorded data were assessed including the degree of missing data. The agreement between routinely recorded data and data collected on case report forms in SANAD II was assessed using calculation of Cohen's kappa for categorical data and construction of Bland-Altman plots for continuous data. RESULTS: There was a significant degree of missing data in the routine record for 15 of the 20 variables assessed, including all clinical variables. Agreement was poor for the majority of comparisons, including the assessments of seizure occurrence and adverse events. For example, only 23/62 (37%) participants had a date of first-ever seizure identified in routine datasets. Agreement was satisfactory for the date of prescription of antiepileptic drugs and episodes of healthcare resource use. CONCLUSIONS: There are currently significant limitations preventing the use of routinely recorded data for participant identification and assessment of clinical outcomes in epilepsy, and potentially other chronic conditions. Further research is urgently required to assess the attributes, agreement, additional benefits, cost-effectiveness and 'optimal mix' of routinely recorded data compared to data collected using standard methods such as case report forms at clinic visits for people with epilepsy. TRIAL REGISTRATION: Standard and New Antiepileptic Drugs II (SANAD II (EudraCT No: 2012-001884-64, registered 05/09/2012; ISRCTN Number: ISRCTN30294119 , registered 03/07/2012)).

Macrophage-colony-stimulating factor selectively enhances macrophage scavenger receptor expression and function.

Regulation of macrophage scavenger receptor (MSR) activity may be an important determinant of the extent of atherogenesis. The effect of macrophage-colony-stimulating factor (M-CSF) on this pathway was studied using a recently developed monoclonal antibody to murine MSR. M-CSF markedly and selectively increased MSR synthesis in murine macrophages: posttranslationally, the receptor appeared more stable and shifted to a predominantly surface distribution. Functionally, M-CSF enhanced modified lipoprotein uptake and increased divalent cation-independent adhesion in vitro. These results suggest a plausible mechanism whereby M-CSF production in the atheromatous plaque microenvironment could promote the recruitment and retention of mononuclear phagocytes and subsequent foam cell formation.