Spanish cohort of VEXAS syndrome: clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism.

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.

The 2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Birefringent crystals deposition and inflammasome expression in human atheroma plaques by levels of uricemia.

OBJECTIVE: To verify the monosodium urate (MSU) crystal deposition in artery walls following a structure assessment and to assess NLRP3 inflammasome expression in human atheroma plaques by levels of uricemia. METHODS: Patients with peripheral arterial disease who were candidates for amputation were recruited and classified as normouricemic or hyperuricemic. During surgery, an artery segment from the amputated limb was sampled, divided and fixed separately by cryo-embedding, 100% ethanol or Glyo-fixx. Samples were assessed by compensated polarized-light microscopy to identify MSU crystals on the artery walls. Afterwards, macrophages, neutrophils and NLRP3 inflammasome components at the plaque were categorized by immunostaining and compared between normouricemics and hyperuricemics. RESULTS: Thirty artery samples from 27 patients were studied; 10 (37.0%) participants were hyperuricemic. Birefringent needle-shaped crystals were found in three samples (10.0%), all processed by frozen sectioning. Other methods showed no crystals. No accompanying inflammatory process was noted, and the presence of crystals was equally distributed across ranges of uricemia, making it unlikely they were MSU crystals. Regarding immunostaining, 28 artery samples were available for analysis, with similar infiltration of macrophages and neutrophils. NLRP3 and gasdermin-D expression were significantly greater in hyperuricemics compared to normouricemics (P=0.044 and P=0.017, respectively). ASC content was numerically larger in hyperuricemics as well, while caspase-1 and IL-1beta expression were similar between groups. CONCLUSIONS: The presence of MSU crystals on artery walls was not confirmed. Hyperuricemia was associated with greater NLRP3 and gasdermin-D expression on human atheroma plaques in patients with peripheral artery disease.

Dietary supplements for chronic gout.

BACKGROUND: Dietary supplements are frequently used for the treatment of several medical conditions, both prescribed by physicians or self administered. However, evidence of benefit and safety of these supplements is usually limited or absent. OBJECTIVES: To assess the efficacy and safety of dietary supplementation for people with chronic gout. SEARCH METHODS: We updated the original search by searching CENTRAL, MEDLINE, Embase, CINAHL, and four trials registers (August 2020). We applied no date or language restrictions. We also handsearched the abstracts from the 2010 to 2019 American College of Rheumatology and European League against Rheumatism conferences, and checked the references of all included studies. SELECTION CRITERIA: We considered all published randomised controlled trials (RCTs) or quasi-RCTs that compared dietary supplements with no supplements, placebo, another supplement, or pharmacological agents for adults with chronic gout for inclusion. Dietary supplements included, but were not limited to, amino acids, antioxidants, essential minerals, polyunsaturated fatty acids, prebiotic agents, probiotic agents, and vitamins. The major outcomes were acute gout flares, study withdrawal due to adverse events (AEs), serum uric acid (sUA) reduction, joint pain reduction, participant global assessment, total number of AEs, and tophus regression. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Two previously included RCTs (160 participants) met our inclusion criteria; we did not identify any new trials for this update. As these two trials evaluated different diet supplements (enriched skim milk powder (SMP) and vitamin C) with different outcomes (gout flare prevention for enriched SMP, and sUA reduction for vitamin C), we reported the results separately. One trial (120 participants), at unclear risk of selection and detection bias, compared SMP enriched with glycomacropeptides (GMP) with un-enriched SMP, and with lactose, over three months. Participants were predominantly men, aged in their 50s, who had severe gout. The results for all major outcomes were imprecise, except for pain. None of the results were clinically significant. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the three-month study period. The effects of enriched SMP (SMP/GMP/G600) compared with the combined control groups (SMP and lactose powder) at three months in terms of mean number of gout flares per month were not clinically significant (mean (standard deviation (SD)) flares per month: 0.49 (1.52) in SMP/GMP/G60 group versus 0.70 (1.28) in the control groups; absolute risk difference: mean difference (MD) -0.21 flares per month, 95% confidence interval (CI) -0.76 to 0.34; low-quality evidence). The number of withdrawals due to adverse effects was similar between groups (7/40 in SMP/GMP/G600 group versus 11/80 in control groups; (risk ratio (RR) 1.27, 95% CI 0.53 to 3.03); there were 4% more withdrawals in the SMP/lactose groups (10% fewer to 18% more; low-quality evidence). Serum uric acid reduction was similar across groups (mean (SD) -0.025 (0.067) mmol/L in SMP/GMP/G60 group versus -0.010 (0.069) in control groups; MD -0.01, 95% CI -0.04 to 0.01; low-quality evidence). Pain from self-reported gout flares (measured on a 10-point Likert scale) improved slightly more in the GMP/G600 SMP group compared with controls (mean (SD) -1.97 (2.28) in SMP/GMP/G600 group versus -0.94 (2.25) in control groups; MD -1.03, 95% CI -1.89 to -0.17). This was an absolute reduction of 10% (95% CI 20% to 1% reduction; low-quality evidence), which may not be of clinical relevance. The risk of adverse events was similar between groups (19/40 in SMP/GMP/G600 group versus 39/80 in control groups; RR 0.97, 95% CI 0.66 to 1.45); the absolute risk difference was 1% fewer adverse events (1% fewer to 2% more), low-quality evidence). Gastrointestinal events such as nausea, flatulence and diarrhoea were the most commonly reported adverse effects. Data for participant global assessment were not available for analysis; the study did not report tophus regression. One trial (40 participants), at high risk of selection, performance, and detection bias, compared vitamin C alone with allopurinol, and with allopurinol plus vitamin C, in a three-arm study. We only included data from the vitamin C versus allopurinol comparison in this review. Participants were predominantly middle-aged men, and their severity of gout was representative of gout in general. Allopurinol reduced sUA levels more than vitamin C (MD 0.10 mmol/L, 95% CI 0.06 to 0.15), low-quality evidence. The study reported no adverse events; none of the participants withdrew due to adverse events. The study did not assess the rate of gout attacks, joint pain reduction, participant global assessment, or tophus regression. AUTHORS' CONCLUSIONS: While dietary supplements may be widely used for gout, this review found no high-quality that supported or refuted the use of glycomacropeptide-enriched skim milk powder or vitamin C for adults with chronic gout.

Human papilloma virus screening: evaluation of testing and surveillance in rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus.

BACKGROUND AND OBJECTIVES: Immunosuppression is a known risk factor for cervical cancer. Women with rheumatic conditions are immunosuppressed due to the disease and the treatments. One of the main risk factors for this neoplasm is the lack of adherence to early detection programmes for human papillomavirus. The objectives of this study were to evaluate the adherence to the screening programme of patients in the Rheumatology Clinic, as well as to evaluate the prevalence of cervical lesions and their association with the different disease characteristics and the treatments received. METHODS: A descriptive retrospective study. The electronic medical history of patients actively being followed up in a tertiary hospital with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and systemic lupus erythematosus (SLE) were reviewed. RESULTS: Finally, 307 patients were included. No data were found for screening programme attendance in up to 42.4% of the patients (39.6% in RA, 43.8% in PSA and 46% in SLE). Among the patients who attended the screening programme at least once (57.6%), the prevalence of cervical dysplasia was 5.1%. No cases of neoplasia were found. In the simple logistic regression analysis, there was no association between attending the screening programme and any variable. The study also showed no association between the variables collected and the presence of infection and dysplasia. CONCLUSION: These results are influenced by the absence of screening data in a significant percentage of patients and by the low prevalence of dysplasia found in this series of patients with rheumatic diseases.

Estimation of intracranial pressure by ultrasound of the optic nerve sheath in an animal model of intracranial hypertension.

BACKGROUND: Ultrasound of the optic nerve sheath diameter (ONSD) has been used as a non-invasive and cost-effective bedside alternative to invasive intracranial pressure (ICP) monitoring. However, ONSD time-lapse behavior in intracranial hypertension (ICH) and its relief by means of either saline infusion or surgery are still unknown. The objective of this study was to correlate intracranial pressure (ICP) and ultrasonography of the optic nerve sheath (ONS) in an experimental animal model of ICH and determine the interval needed for ONSD to return to baseline levels. METHODS: An experimental study was conducted on 30 pigs. ONSD was evaluated by ultrasound at different ICPs generated by intracranial balloon inflation, saline infusion, and balloon deflation, and measured using an intraventricular catheter. RESULTS: All variables obtained by ONS ultrasonography such as left, right, and average ONSD (AON) were statistically significant to estimate the ICP value. ONSD changed immediately after balloon inflation and returned to baseline after an average delay of 30 min after balloon deflation (p = 0.016). No statistical significance was observed in the ICP and ONSD values with hypertonic saline infusion. In this swine model, ICP and ONSD showed linear correlation and ICP could be estimated using the formula: -80.5 + 238.2 × AON. CONCLUSION: In the present study, ultrasound to measure ONSD showed a linear correlation with ICP, although a short delay in returning to baseline levels was observed in the case of sudden ICH relief.

Gout Is Prevalent but Under-Registered Among Patients With Cardiovascular Events: A Field Study.

Objectives: Gout is an independent cardiovascular (CV) risk factor with significant morbidity and mortality. We aimed to estimate the prevalence of gout, characteristics and management in a hospitalized population for CV disease, a topic that remains to be defined. Methods: An observational, descriptive, cross-sectional study was carried out in patients admitted for CV events in the Cardiology, Neurology, and Vascular Surgery units of a tertiary center. Patients were selected following a non-consecutive, systematic sampling. Data about CV disease and gout were obtained from face-to-face interviews and patients' records. Gout diagnosis was established using the 2015 ACR/EULAR clinical classification criteria. The registration rate of gout was assessed by auditing patients' records and hospital discharge reports of CV events from the units of interest in the previous 2 years. To predict the presence of gout, multivariate logistic regression models were built to study the possible explanatory variables. Results: Two hundred and sixty six participants were recruited, predominantly males (69.9%) and Caucasians (96.6%) with a mean age of 68 years. Gout was identified in 40 individuals; thus, the prevalence was 15.0% (95% CI 10.9-19.2%). In 35% of cases, the diagnosis was absent from patients' records. Gout was found in 1.4-2.6% of hospital discharge reports of CV events, also indicating under-registration. The disease was long-standing, but with low reported rates of flares, involved joints, and tophi. At admission, only half of the gout patients were on urate-lowering therapy, being 38.5% of them on serum urate <6 mg/dl. The only independent predictor of gout was the existence of previous hyperuricemia (median serum urate in previous 5 years ≥7 mg/dl), with an odds ratio of 2.9 (95% CI 1.2-7.1); if hyperuricemia is not included in the model, the only independent predictor was chronic kidney disease (odds ratio 3.0; 95% CI 1.4-6.6). Conclusion: Gout is highly prevalent among patients admitted for CV events, with significant lack of awareness and suboptimal management, despite being a well-established independent CV risk factor.

Human Papiloma Virus Screening: Evaluation Of Testing And Surveillance In Rheumatoid Arthritis, Psoriatic Arthritis And Systemic Lupus Erythematosus. / Cribado del virus de papiloma humano: evaluación de grado de vigilancia en artritis reumatoide, artritis psoriásica y lupus eritematoso sistémico.

BACKGROUND AND OBJECTIVES: Immunosuppression is a known risk factor for cervical cancer. Women with rheumatic conditions are immunosuppressed due to the disease and the treatments. One of the main risk factors for this neoplasm is the lack of adherence to early detection programmes for human papillomavirus. The objectives of this study were to evaluate the adherence to the screening programme of patients in the Rheumatology Clinic, as well as to evaluate the prevalence of cervical lesions and their association with the different disease characteristics and the treatments received. MATERIAL AND METHODS: A descriptive retrospective study. The electronic medical history of patients actively being followed up in a tertiary hospital with rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus were reviewed. RESULTS: Finally, 307 patients were included. No data were found for screening programme attendance in up to 42.4% of the patients (39.6% in rheumatoid arthritis, 43.8% in psoriatic arthritis and 46% in systemic lupus erythematosus). Among the patients who attended the screening programme at least once (57.6%), the prevalence of cervical dysplasia was 5.1%. No cases of neoplasia were found. In the simple logistic regression analysis, there was no association between attending the screening programme and any variable. The study also showed no association between the variables collected and the presence of infection and dysplasia. CONCLUSION: These results are influenced by the absence of screening data in a significant percentage of patients and by the low prevalence of dysplasia found in this series of patients with rheumatic diseases.

Experience with tocilizumab in severe COVID-19 pneumonia after 80 days of follow-up: A retrospective cohort study.

OBJECTIVES: To describe the clinical characteristics and predictors of major outcomes in patients treated with tocilizumab (TCZ) for severe COVID-19 pneumonia. PATIENTS AND METHODS: Case series of all sequential patients with severe COVID-19 pneumonia treated with TCZ at an Academic Spanish hospital (March 12 - May 2, 2020). Clinical outcomes: death, length of hospital stay. An early clinical response to TCZ (48-72 h after the administration) was assessed by variations in respiratory function markers, Brescia COVID Respiratory Severity Scale (BCRSS), inflammatory parameters, and patients' and physicians' opinion. Associations were tested by multiple logistic regression. RESULTS: From a cohort of 236 patients, 77 patients treated with TCZ were included (median age 62 years (IQR 53.0-72.0), 64.9% were males), 42.9% had Charlson index ≥3; hypertension (41.6%), obesity (34.7%), and diabetes (20.8%). Median follow-up was 83.0 days (78.0-86.5), no patient was readmitted. ICU admission was required for 42 (54.5%), invasive mechanical ventilation in 38 (49.4%) and 10 patients died (12.9% global, 23.8% at ICU admitted). After multivariate adjustment, TCZ response by BCRSS (OR 0.03 (0.01-0.68), p = 0.028), and Charlson index (OR 3.54 (1.20-10.44), p = 0.022) has been identified as independent factors associated with mortality. Median of hospital stay was 16.0 days (11.0-23.0); BCRSS, physician subjective and D-dimer response were associated with shorter hospitalization stay. CONCLUSIONS: In a Mediterranean cohort, use of tocilizumab for severe COVID-19 show 12.9% of mortality. Early TCZ-response by BCRSS and low comorbidity were associated with increased survival. Early TCZ-response was related to shorter median hospital stay.

Complex regional pain syndrome secondary to sacrococcygeal dislocation following trauma to the lumbosacral region. case report

ABSTRACT Introduction: The complex regional pain syndrome (CRPS) is a rare condition characterized by inflammatory, vasomotor and central nervous system (CNS) involvement. Its clinical presentation can be subacute, acute or chronic, and may have severe effects on the patient's quality of life. Case description: 21-year-old female patient with trauma in the lumbosacral region associated with pain and functional limitation. Diagnostic imaging showed sacrococcygeal dislocation with subsequent inflammatory and acute and chronic autonomic symptoms that were treated medically and surgically. The patient responded to treatment with long-term improvement of the symptoms. Discussion: In this case, CRPS occurred after trauma and caused subacute symptoms that became even more acute until reaching a chronic presentation. Inflammation, vasomotor dysfunction and CNS involvement made this case a multidisciplinary diagnostic and therapeutic challenge. Conclusion: CRPS is a rare disease that is difficult to diagnose. However, diagnosis should be timely in order to initiate personalized treatment, since this disease considerably affects the patient's quality of life.

RESUMEN Introducción. El síndrome doloroso regional complejo (SDRC) es una patología poco frecuente que se caracteriza por causar compromiso a nivel inflamatorio, vasomotor y del sistema nervioso central (SNC). Su presentación clínica puede ser subaguda, aguda o crónica y puede afectar considerablemente la calidad de vida del paciente. Presentación del caso. Paciente femenina de 21 años con trauma en región lumbosacra asociado a dolor y limitación funcional, a quien se le practicaron imágenes diagnosticas que evidenciaron luxofractura sacrococcígea con posterior presencia de síntomas inflamatorios y autonómicos (agudos y crónicos) que se trataron con medicamentos y cirugía. La paciente respondió al tratamiento con mejoría de la sintomatología a largo plazo. Discusión. El SDRC se presentó posterior a un traumatismo y ocasionó sintomatología subaguda que se agudizó hasta llegar a la presentación crónica de la enfermedad. La inflamación, la disfunción vasomotora y el compromiso del SNC hacen de este caso un reto diagnóstico y terapéutico multidisciplinario. Conclusión. El SDRC es una patología poco frecuente y de difícil diagnóstico; sin embrago, es necesario diagnosticarlo de forma oportuna para poder iniciar un tratamiento personalizado, ya que es una enfermedad que compromete considerablemente la calidad de vida del paciente.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Role of Carotid Ultrasound and Systematic Coronary Risk Evaluation Charts for the Cardiovascular Risk Stratification of Patients with Psoriatic Arthritis.

OBJECTIVE: The assessment of the cardiovascular (CV) risk is recommended in patients with chronic inflammatory rheumatic diseases. The objectives of this study were to assess the CV risk profile in a cohort of patients with psoriatic arthritis (PsA), to determine the presence of subclinical cardiovascular disease by carotid ultrasound (US), and to study the association of CV disease to PsA characteristics. METHODS: This was a cross-sectional multicentric descriptive study. The clinical CV risk was calculated with Systematic Coronary Risk Evaluation (SCORE) charts. Common carotid US was conducted to evaluate the carotid wall intima-media thickness and the presence of atheroma plaques. Patients were reclassified upon US results. Multivariate analyses were performed to identify associations of US carotid abnormalities with the classical CV risk factors and PsA characteristics. RESULTS: The study included 176 patients with PsA. The SCORE-estimated CV risk was intermediate in 65.3% of the patients. In the US study, 32% of the patients had abnormalities, and 30.8% of the patients were upgraded and reclassified as very high risk owing to the presence of atheroma. Subclinical CV disease was associated with age and dyslipidemia but not with other risk factors. It was associated with axial disease in the subgroup with intermediate risk, and with C-reactive protein levels in patients with high risk. CONCLUSION: Many patients with PsA have clinical estimated intermediate or high risk of a fatal CV event. A carotid US study detects subclinical vascular disease and may be useful to depict the real risk. The presence of atheroma is only partially explained by the classic CV risk factors.

Trypanosoma cruzi Virulence Factors for the Diagnosis of Chagas' Disease.

trans-Sialidase and cruzipain are important virulence factors from Trypanosoma cruzi, the etiological agent of Chagas disease, that have highly antigenic domains in their structure and were reported as potential tools for diagnosis of the illness. The aim of the present study is to assess the possibility of using cruzipain and the catalytic domain of trans-sialidase in a Surface Plasmon Resonance-based immunosensor for the diagnosis of chronic Chagas disease. Immunoassays carried out with canine sera verified that cruzipain allows the detection of anti-Trypanosoma cruzi antibodies whereas recombinant trans-sialidase did not yield specific detections, due to the high dilutions of serum used in the immunoassays that hinder the possibility to sense the specific low titer antibodies. The developed cruzipain-based biosensor, whose price per assay is comparable to a commercial enzyme-linked immunosorbent assay (ELISA), was successfully applied for the rapid quantification of specific antibodies against Trypanosoma cruzi in fresh human sera showing an excellent agreement with ELISA.

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI.

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including "The Lancet Neurology Commission" and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus.

OBJECTIVES: To estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort. METHODS: All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities, and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection. RESULTS: A total of 3658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7), and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥1 severe infection. Total severe infections recorded in these patients numbered 1227. The incidence rate was 29.2 (95% CI: 27.6-30.9) infections per 1000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p < 0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR = 1.016, 95% CI: 1.009-1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR = 2.151, 95% CI: 1.539-3.005), corticosteroids (≥10mg/day) (HR = 1.271, 95% CI: 1.034-1.561), immunosuppressors (HR = 1.348, 95% CI: 1.079-1.684), hospitalization by SLE (HR = 2.567, 95% CI: 1.905-3.459), Katz severity index (HR = 1.160, 95% CI: 1.105-1.217), SLICC/ACR damage index (HR = 1.069, 95% CI: 1.031-1.108), and smoking (HR = 1.332, 95% CI: 1.121-1.583). Duration of antimalarial use (months) proved protective (HR = 0.998, 95% CI: 0.997-0.999). CONCLUSIONS: Severe infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin-Americans and is associated with age, previous infection, and smoking. Antimalarials exerted a protective effect.

Primary tuberculosis infection in patients treated with tumor necrosis factor-alpha antagonists and a negative initial screening.

INTRODUCTION: Despite screening for latent tuberculosis (TB), new cases of TB infection are detected in patients treated with anti-TNF-α and negative initial screening, some of them after long treatment, which points more to a new infection. OBJECTIVES: To describe the cases that have presumably developed a primary tuberculous infection during treatment with anti-TNF-α drugs. METHODS: Retrospective audit (1999-2012). Inclusion criteria were: a) anti-TNF-α treatment; b) initial latent TB screening negative; c) TB diagnosed during anti-TNF-α treatment; d) suspected primary TB infection (diagnosis after at least 12 months on anti-TNF-α). Clinical, epidemiological, therapeutic and outcome variables were reviewed. RESULTS: Two cases of primary TB infection were found out of of 771 anti-TNF-α treated patients (0.2%). One woman aged 41 suffered TB pneumonia after 35 months of treatment with adalimumab, and a male aged 37 who developed disseminated TB after 107 months of treatment with infliximab. CONCLUSIONS: Although uncommon, during TNF antagonist therapy, TB risk persists despite negative initial screening, so clinicians should be aware of TB during the entire treatment.