Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression.

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Automated Mapping of Land Cover Type within International Heterogenous Landscapes Using Sentinel-2 Imagery with Ancillary Geospatial Data.

A near-global framework for automated training data generation and land cover classification using shallow machine learning with low-density time series imagery does not exist. This study presents a methodology to map nine-class, six-class, and five-class land cover using two dates (winter and non-winter) of a Sentinel-2 granule across seven international sites. The approach uses a series of spectral, textural, and distance decision functions combined with modified ancillary layers (such as global impervious surface and global tree cover) to create binary masks from which to generate a balanced set of training data applied to a random forest classifier. For the land cover masks, stepwise threshold adjustments were applied to reflectance, spectral index values, and Euclidean distance layers, with 62 combinations evaluated. Global (all seven scenes) and regional (arid, tropics, and temperate) adaptive thresholds were computed. An annual 95th and 5th percentile NDVI composite was used to provide temporal corrections to the decision functions, and these corrections were compared against the original model. The accuracy assessment found that the regional adaptive thresholds for both the two-date land cover and the temporally corrected land cover could accurately map land cover type within nine-class (68.4% vs. 73.1%), six-class (79.8% vs. 82.8%), and five-class (80.1% vs. 85.1%) schemes. Lastly, the five-class and six-class models were compared with a manually labeled deep learning model (Esri), where they performed with similar accuracies (five classes: Esri 80.0 ± 3.4%, region corrected 85.1 ± 2.9%). The results highlight not only performance in line with an intensive deep learning approach, but also that reasonably accurate models can be created without a full annual time series of imagery.

Trigeminal neuropathy presenting secondary to SARS-CoV-2 infection.

Introduction: A 58-year-old woman presented to a multidisciplinary facial pain clinic in October 2021 complaining of a constant pain in the right side of her face since contracting coronavirus SARS-CoV-2 18 months earlier. The pain extending from the right temple down to her right cheek extraorally and including the maxillary teeth and right side of tongue intraorally. This was accompanied by anosmia, diplopia on lateral gaze, and dizziness. Methods: Clinical examination was supplemented with several neurophysiological tests to confirm the diagnosis including an MRI brain scan, quantitative sensory testing, electrophysiological blink reflex testing, corneal confocal microscopy, and pain and short-form anxiety and depression questionnaires. Results: Quantitative sensory testing showed unilateral loss of perception in thermal and mechanical sensibility and bilateral hyperalgesia indicating central sensitization. Bilateral corneal confocal microscopy showed an abnormally reduced corneal nerve fibre length on the right side. MRI, blink reflex, and masseter inhibitory testing findings were normal. Conclusion: This case study is the first case of trigeminal neuropathy related to SARS-CoV-2 infection reported in the literature. It also discusses the successful management of the patient's trigeminal neuropathic pain.

WWOM VII: Effectiveness of topical interventions in the management of burning mouth syndrome: A systematic review.

OBJECTIVES: To assess the effectiveness of topical interventions in the management of burning mouth syndrome (BMS), based on the core outcome domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). METHODS: A systematic literature review of RCTs on topical interventions for the management of BMS, published in PubMed, Web of Science, PsycInfo, Cochrane Database/Central, and Google Scholar through May 2021 was performed. RESULTS: Eight RCTs (n = 358 study participants) were included in this study. Due to underreporting of IMMPACT domains, publication bias, high degree of heterogeneity between studies, meta-analysis was not undertaken. Based on changes in visual analogue pain scores (ΔVAS), the most reported outcome, the effectiveness of the topical interventions was demonstrated; however, it is low level of evidence. CONCLUSIONS: High levels of variability (interventions, outcomes, outcome measurement tools, and intervention effects evaluated), heterogeneity, publication bias, and underreporting of IMMPACT domains were observed across the RCTs. This systematic review highlights the need for application of standardized outcome measures to future RCTs. At the present time, there is lack of moderate-strong evidence on short- and long-term outcomes to support or refute the use of any particular topical intervention in managing BMS. Future RCTs with standardized outcome measures are needed.

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium.

INTRODUCTION: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. METHODS: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. RESULTS: Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). IMPLICATIONS: Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

Implementation of personalised medicine policies in mental healthcare: results from a stated preference study in the UK.

BACKGROUND: Public support for the implementation of personalised medicine policies (PMPs) within routine care is important owing to the high financial costs involved and the potential for redirection of resources from other services. AIMS: We aimed to determine the attributes of a PMP most likely to elicit public support for implementation. We also aimed to determine whether such support differed between a depression PMP and one for cystic fibrosis. METHOD: In a discrete-choice experiment, paired vignettes illustrating both the current model of care (CMoC) and a hypothetical PMP for either depression or cystic fibrosis were presented to a representative sample of the UK public (n = 2804). Each vignette integrated varying attributes, including anticipated therapeutic benefit over CMoC, and the annual cost to the taxpayer. Respondents were invited to express their preference for either the PMP or CMoC within each pair. RESULTS: The financial cost was the most important attribute influencing public support for PMPs. Respondents favoured PMP implementation where it benefited a higher proportion of patients or was anticipated to be more effective than CMoC. A reduction in services for non-eligible patients reduced the likelihood of support for PMPs. Respondents were more willing to fund PMPs for cystic fibrosis than for depression. CONCLUSIONS: Cost is a significant factor in the public's support for PMPs, but essential caveats, such as protection for services available to PMP-ineligible patients, may also apply. Further research should explore the factors contributing to condition-specific nuances in public support for PMPs.

Electrical stimulation to clinically identify position of the lingual nerve: results of 50 subjects with reliability and correlation with MRI.

PURPOSE: Recently we described mapping of the lingual nerve clinically in patients using electrical nerve stimulation. This paper reports results of a larger study with inter- and intra-observer reliability and comparison with positional measurements from magnetic resonance imaging (MRI). METHODS: In 50 healthy participants, measurements were taken when subjects felt a tingling sensation in the tongue induced by a stimulation probe over the lingual nerve. Three positions were measured in relation to the third molar. Measurement reliability was tested for both inter-observer and intra-observer agreement and positional data of the lingual nerve measured clinically was also compared with nerve position as measured from MRI scans. RESULTS: Out of 50 participants, 96 nerves (49 = left/47 = right) were included in the study. The lingual nerve was identified in 90% (87) of this sample. The mean of height of the nerve in points A, B and C were 9.64 mm, 10.77 mm and 12.34 respectively. Inter-and intra-observer agreement was considered to be good to excellent (ICC = 0.8-0.96). Agreement between nerve mapping measured values and MRI measured values was good (ICC < 0.6). CONCLUSION: This technique may prove useful for the clinical determination of lingual nerve position prior to procedures in the third molar region.

Orofacial pain in 1916 patients with early or moderate Parkinson disease.

INTRODUCTION: Several studies have reported that some types of orofacial pain are more common in patients with Parkinson disease (PD) than the general population. OBJECTIVES: In this study, we aimed to investigate the prevalence of self-reported orofacial pain in a larger group of patients with PD than has been previously studied. METHODS: We analysed data from 1916 participants with PD in a cross-sectional study recruited to the UK Parkinson's Pain Study who had detailed assessments of pain, motor, and nonmotor symptoms. The King's Parkinson's Pain scale was used to quantify different subtypes of pain. RESULTS: A total of 139 (7.3%) patients reported the presence of some form of orofacial pain. Burning mouth syndrome was reported in 32 (1.7%), whereas chewing pain was found in 38 (2.0%) and grinding pain in 78 (4.0%). Orofacial pain was significantly more common in females (10.4%) than males (5.9%). Multiple logistic regression analysis showed a significant association between orofacial pain and pain severity, neuropathic pain, and oral motor and nonmotor dysfunction. CONCLUSION: In our study, population cohort of early patients with PD found prevalence of orofacial pain conditions similar to that in the general population.

Formulation and optimisation of novel transfersomes for sustained release of local anaesthetic.

OBJECTIVE: To investigate the effect of formulation parameters on the preparation of transfersomes as sustained-release delivery systems for lidocaine and to develop and validate a new high-performance liquid chromatography (HPLC) method for analysis. METHOD: Taguchi design of experiment (DOE) was used to optimise lidocaine-loaded transfersomes in terms of phospholipid, edge activator (EA) and phospholipid : EA ratio. Transfersomes were characterised for size, polydispersity index (PDI), charge and entrapment efficiency (%EE). A HPLC method for lidocaine quantification was optimised and validated using a mobile phase of 30%v/v PBS (0.01 m) : 70%v/v Acetonitrile at a flow rate of 1 ml/min, detected at 255 nm with retention time of 2.84 min. The release of lidocaine from selected samples was assessed in vitro. KEY FINDINGS: Transfersomes were 200 nm in size, with PDI ~ 0.3. HPLC method was valid for linearity (0.1-2 mg/ml, R2 0.9999), accuracy, intermediate precision and repeatability according to ICH guidelines. The %EE was between 44% and 56% and dependent on the formulation parameters. Taguchi DOE showed the effect of factors was in the rank order : lipid : EA ratio Ëƒ EA type Ëƒ lipid type. Optimised transfersomes sustained the release of lidocaine over 24 h. CONCLUSION: Sustained-release, lidocaine-loaded transfersomes were successfully formulated and optimised using a DOE approach, and a new HPLC method for lidocaine analysis was developed and validated.

An ultrafast system for signaling mechanical pain in human skin.

The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.

Corneal Confocal Microscopy Detects Small-Fiber Neuropathy in Burning Mouth Syndrome: A Cross-Sectional Study.

AIMS: To assess the utility of corneal confocal microscopy in identifying small fiber damage in patients with burning mouth syndrome (BMS). METHODS: A prospective cross-sectional cohort study was conducted at two United Kingdom dental hospitals between 2014 and 2017. A total of 17 consecutive patients with idiopathic BMS aged between 18 and 85 years and 14 healthy age-matched control subjects were enrolled in this study. Corneal subbasal nerve plexus measures were quantified in images acquired using a laser-scanning in vivo corneal confocal microscope. The main outcome measures were corneal nerve fiber density, nerve branch density, nerve fiber length, and Langerhans cell density. RESULTS: Of the 17 patients with BMS, 15 (88%) were women, and the mean (standard deviation) age of the sample was 61.7 (6.5) years. Of the healthy controls, 7 (50%) were women, and the mean (standard deviation) age was 59.3 (8.68) years. Corneal nerve fiber density (no./mm2) (BMS: 29.27 ± 6.22 vs controls: 36.19 ± 5.9; median difference = 6.71; 95% CI: 1.56 to 11.56; P = .007) and corneal nerve fiber length (mm/mm2) (BMS: 21.06 ± 4.77 vs controls: 25.39 ± 3.91; median difference = 4.5; 95% CI: 1.22 to 6.81; P = .007) were significantly lower in BMS patients compared to controls, and Langerhans cell density (no./mm2) (BMS: 74.04 ± 83.37 vs controls: 29.17 ± 45.14; median difference = -21.27; 95% CI: -65.35 to -2.91; P = .02) was significantly higher. CONCLUSION: Using a rapid noninvasive ophthalmic imaging technique, this study provides further evidence for small fiber damage in BMS and has potential utility for monitoring disease progression and/or response. Furthermore, this technique shows a hitherto undocumented increased density of immune cells in this group of patients.

The longitudinal relationship of alcohol problems and depressive symptoms and the impact of externalising symptoms: findings from the Belfast Youth Developmental Study.

PURPOSE: The aim of the present study was to contribute to the inconsistent literature on the comorbid relationship of alcohol problems and depressive symptoms from late adolescent to emerging adulthood by accounting for their trajectories and their conjoint relationship while controlling for the influence of externalising symptoms. METHODS: We utilised data, from a longitudinal school cohort from Northern Ireland (Belfast Youth Developmental Study), over three time points where the participants were 16, 17 and 21 years of age. A total of 3118 participants were included, 1713 females and 1405 males. Second-order latent growth models were applied to examine growth trajectories. Parallel process growth models were used to assess whether growth trajectories of the symptoms were associated. Externalising symptoms were subsequently added as a covariate. RESULTS: Alcohol problems among males significantly increased over time but decreased in females. Depressive symptoms initially increased then decreased in both genders. Results indicated associations of the alcohol problems and depression, both initially and with time. Accounting for externalising symptoms only somewhat diminished this effect in males but not in females. An increase of initial levels of depression was associated with a decrease in alcohol problems over time. This association was only true among females. After controlling for externalising symptoms, the relationship was no longer observed. CONCLUSIONS: The present study provides further evidence of a significant relationship of alcohol problems and depression in adolescents and further supports a small literature indicating that depression may have protective effects of alcohol problems. Finally, the study shows the importance of accounting for externalising symptoms.

Dynamic changes of functional segregation and integration in vulnerability and resilience to schizophrenia.

Schizophrenia (SZ) is a highly heritable disease with neurodevelopmental origins and significant functional brain network dysfunction. Functional network is heavily influenced by neurodevelopment processes and can be characterized by the degree of segregation and integration. This study examines functional segregation and integration in SZ and their first-degree relatives (high risk [HR]) to better understand the dynamic changes in vulnerability and resiliency, and disease markers. Resting-state functional magnetic resonance imaging data acquired from 137 SZ, 89 HR, and 210 healthy controls (HCs). Small-worldness σ was computed at voxel level to quantify balance between segregation and integration. Interregional functional associations were examined based on Euclidean distance between regions and reflect degree of segregation and integration. Distance strength maps were used to localize regions of altered distance-based functional connectivity. σ was significantly decreased in SZ compared to HC, with no differences in high risk (HR). In three-group comparison, significant differences were noted in short-range connectivity (primarily in the primary sensory, motor and their association cortices, and the thalamus) and medium/long-range connectivity (in the prefrontal cortices [PFCs]). Decreased short- and increased medium/long-range connectivity was found in SZ. Decreased short-range connectivity was seen in SZ and HR, while HR had decreased medium/long-range connectivity. We observed disrupted balance between segregation and integration in SZ, whereas relatively preserved in HR. Similarities and differences between SZ and HR, specific changes of SZ were found. These might reflect dynamic changes of segregation in primary cortices and integration in PFCs in vulnerability and resilience, and disease markers in SZ.

Patient-delivered tDCS on chronic neuropathic pain in prior responders to TMS (a randomized controlled pilot study).

BACKGROUND: Successful response to repetitive transcranial magnetic stimulation (rTMS) of the motor cortex requires continued maintenance treatments. Transcranial Direct Current Stimulation (tDCS) may provide a more convenient alternative. METHODS: This pilot study aimed to examine the feasibility of a randomized, double-blind, double-crossover pilot study for patients to self-administer tDCS motor cortex stimulation for 20 minutes/day over five consecutive days. Primary outcomes were as follows: usability of patient-administered tDCS, compliance with device, recruitment, and retention rates. Secondary outcomes were as follows: effect on overall pain levels and quality of life via Short Form-36 anxiety and depression via Hospital Anxiety and Depression Scale, and Mini-Mental State scores. RESULTS: A total of 24 subjects with neuropathic pain, who had previously experienced rTMS motor cortex stimulation (13 with reduction in pain scores, 11 nonresponders) were recruited at the Pain Research Institute, Fazakerley, UK. A total of 21 subjects completed the study. Recruitment rate was 100% but retention rate was only 87.5%. All patients reported satisfactory usability of the tDCS device. No significant difference was shown between Sham vs Anodal (-0.16, 95% CI: -0.43 to 0.11) P=0.43, Sham vs Cathodal (0.11, 95% CI: -0.16 to 0.37) P=0.94, or Cathodal vs Anodal (-0.27, 95% CI: -0.54 to 0.00) P=0.053 treatments. Furthermore, no significant changes were demonstrated in anxiety, depression, or quality of life measurements. The data collected to estimate sample size for a definitive study suggested that the study's sample size was already large enough to detect a change of 15% in pain levels at 90% power for the overall group of 21 patients. CONCLUSION: This study did not show a beneficial effect of tDCS in this group of patients and does not support the need for a larger definitive study using the same experimental paradigm. TRIAL REGISTRATION: ISRCTN56839387.

Physician-Specific Maximum Acceptable Risk in Personalized Medicine: Implications for Medical Decision Making.

BACKGROUND: In discrete-choice experiments (DCEs), respondents are presented with a series of scenarios and asked to select their preferred choice. In clinical decision making, DCEs allow one to calculate the maximum acceptable risk (MAR) that a respondent is willing to accept for a one-unit increase in treatment efficacy. Most published studies report the average MAR for the whole sample, without conveying any information about heterogeneity. For a sample of psychiatrists prescribing drugs for a series of hypothetical patients with schizophrenia, this article demonstrates how heterogeneity accounted for in the DCE modeling can be incorporated in the derivation of the MAR. METHODS: Psychiatrists were given information about a group of patients' responses to treatment on the Positive and Negative Syndrome Scale (PANSS) and the weight gain associated with the treatment observed in a series of 26 vignettes. We estimated a random parameters logit (RPL) model with treatment choice as the dependent variable. RESULTS: Results from the RPL were used to compute the MAR for the overall sample. This was found to be equal to 4%, implying that, overall, psychiatrists were willing to accept a 4% increase in the risk of an adverse event to obtain a one-unit improvement of symptoms - measured on the PANSS. Heterogeneity was then incorporated in the MAR calculation, finding that MARs ranged between 0.5 and 9.5 across the sample of psychiatrists. LIMITATIONS: We provided psychiatrists with hypothetical scenarios, and their MAR may change when making decisions for actual patients. CONCLUSIONS: This analysis aimed to show how it is possible to calculate physician-specific MARs and to discuss how MAR heterogeneity could have implications for medical practice.

Surfactant Effects on Lipid-Based Vesicles Properties.

Understanding the effect of surfactant properties is critical when designing vesicular delivery systems. This review evaluates previous studies to explain the influence of surfactant properties on the behavior of lipid vesicular systems, specifically their size, charge, stability, entrapment efficiency, pharmacokinetics, and pharmacodynamics. Generally, the size of vesicles decreases by increasing the surfactant concentration, carbon chain length, the hydrophilicity of the surfactant head group, and the hydrophilic-lipophilic balance. Increasing surfactant concentration can also lead to an increase in charge, which in turn reduces vesicle aggregation and enhances the stability of the system. The vesicles' entrapment efficiency not only depends on the surfactant properties but also on the encapsulated drug. For example, the encapsulation of a lipophilic drug could be enhanced by using a surfactant with a low hydrophilic-lipophilic balance value. Moreover, the membrane permeability of vesicles depends on the surfactant's carbon chain length and transition temperature. In addition, surfactants have a clear influence on pharmacokinetics and pharmacodynamics such as sustaining drug release, enhancing the circulation time of vesicles, improving targeting and cellular uptake.

The Influence of Genotype Information on Psychiatrists' Treatment Recommendations: More Experienced Clinicians Know Better What to Ignore.

BACKGROUND: This study applies attribute nonattendance to medical decision making. We aimed to demonstrate how this type of analysis can be used in medical decision making to assess whether psychiatrists were influenced in their treatment recommendations by information on the genotype of a patient, despite knowing the patient's response to treatment as measured by the Positive and Negative Syndrome Scale. A patient's genetic information may be used to predict their response to therapy; such information, however, becomes redundant, and should not influence decisions, once a clinician knows the patient's actual response to treatment. METHODS: Sixty-seven psychiatrists were presented with patients' pre- or post-treatment scores on the Positive and Negative Syndrome Scale for two hypothetical treatments for schizophrenia. Psychiatrists were also informed whether the patient possessed a genotype linked to hyper-responsiveness to one of the treatments, and were asked to recommend one of these two treatments. Attribute nonattendance assessed whether the information on genotype influenced psychiatrists' treatment recommendations. RESULTS: Years of experience predicted whether psychiatrists were influenced by the genetic information. Psychiatrists with 1 year or less of experience had a 46% probability of considering genetic information, whereas psychiatrists with at least 15 years of experience had a lower probability (7%). CONCLUSIONS: Psychiatrists and other clinicians should be cautious about allowing a patient's genetic information to carry unnecessary weight in their clinical decision making.

Other facial neuralgias.

Premise In this article we review some lesser known cranial neuralgias that are distinct from trigeminal neuralgia, trigeminal autonomic cephalalgias, or trigeminal neuropathies. Included are occipital neuralgia, superior laryngeal neuralgia, auriculotemporal neuralgia, glossopharyngeal and nervus intermedius neuralgia, and pain from acute herpes zoster and postherpetic neuralgia of the trigeminal and intermedius nerves. Problem Facial neuralgias are rare and many physicians do not see such cases in their lifetime, so patients with a suspected diagnosis within this group should be referred to a specialized center where multidisciplinary team diagnosis may be available. Potential solution Each facial neuralgia can be identified on the basis of clinical presentation, allowing for precision diagnosis and planning of treatment. Treatment remains conservative with oral or topical medication recommended for neuropathic pain to be tried before more invasive procedures are undertaken. However, evidence for efficacy of current treatments remains weak.

Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known. METHODS: We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54 weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110 weeks), enabling assessment of the impact of 1 year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54 weeks and 110 weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux. RESULTS: All HDL vascular assays were impaired in patients compared with controls. After 54 weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110 weeks. No significant trend was noted for cholesterol efflux. CONCLUSIONS: HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties.