Outbreak of Fusarium solani Meningitis in Immunocompetent Persons Associated With Neuraxial Blockade in Durango, Mexico, 2022-2023.

Background: Fungal meningitis can be associated with epidural anesthesia procedures. Fusariosis is a rare infection typically affecting immunocompromised patients and rarely causes meningitis. During 2022-2023, public health officials responded to a large outbreak of Fusarium solani meningitis associated with epidural anesthesia in Durango, Mexico. Methods: The public health response and epidemiological and clinical features of patients affected by this outbreak were described. Coordinated actions were addressed to identify the etiological agent, determine its drug susceptibility, develop diagnostic tests, and implement clinical and epidemiological protocols. Retrospective analyses of clinical variables and outcomes were performed to determine association with better patient survival. Results: A total of 1801 persons exposed to epidural anesthesia were identified, of whom 80 developed meningitis. Fusarium solani was found in 3 brain biopsies and showed susceptibility to voriconazole and amphotericin B. After F solani polymerase chain reaction (PCR) implementation, 57 patients with meningitis were PCR-screened, and 31 (38.8%) had a positive result. Most patients were female (95%), and cesarean section was the most common surgical procedure (76.3%). The case fatality rate was 51.3% (41 patients) and the median hospitalization duration was 39.5 days (interquartile range, 18-86 days). Seventy-one patients (88.8%) received voriconazole/amphotericin B and 64 subjects (80%) additionally received steroids. Cox regression analysis showed an increased lethality risk in patients who received antifungal treatment after 5 days (hazard ratio, 2.1 [95% confidence interval, 1.01-4.48], P < .05). Conclusions: The F solani meningitis outbreak in Durango was an unprecedented medical challenge. Timely treatment and effective healthcare management were associated with better survival outcomes.

Strengthening the Pharmacovigilance System in Mexico: Implementation of VigiFlow and VigiLyze, as ICSR and Signal Detection Management Systems.

Pharmacovigilance (PV) activities aim to identify potential risks of medicines and vaccines after they have been authorised in the market by collecting and analysing information on suspected adverse events from different stakeholders. These can be captured and transmitted electronically in the form of Individual Case Safety Reports (ICSRs). Hence, up-to-date ICSRs management systems, like VigiFlow and signal detection and management systems as VigiLyze, have an important role in the PV system of a country. In 2019, after various attempts to establish a PV database that could fulfil the needs of the country, Mexico's National Regulatory Authority, COFEPRIS (Federal Commission for the Prevention against Sanitary Risks) decided to implement these tools. This has been a successful project that is still ongoing, it has involved national and international organisations, and has required the participation and integration of different components of the national PV system. The implementation of these tools has allowed COFEPRIS to increase its reporting trends and quality of reporting, while contributing to make more efficient interactions and processes with PV stakeholders, even during the COVID-19 pandemic. It has also allowed them to strengthen their commitment to the WHO-Programme for International Drug Monitoring, while highlighting opportunities for improvement in the national PV scenario and in the PV tools themselves. The aim of this article is to describe the implementation process, give an overview of current results regarding ICSR data and processes, and highlight the achievements, challenges, and opportunities for improvement after the three years since the beginning of the project.

Down-Regulation-Resistant STAT4 Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon-γ Production.

OBJECTIVE: Variants in STAT4 are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. We undertook this study to investigate how disease-associated variants affect STAT4 expression, in particular in CD4+ T cells where STAT4 plays an essential role. METHODS: We compared Th1 differentiation between naive CD4+ T cells from healthy donors homozygous for the risk (R/R) or nonrisk (NR/NR) alleles. We analyzed epigenetic marks in STAT4 and evaluated the relevance of its third intron, assessed the consequences of Stat4 overexpression in vivo in mice, and analyzed the effects of the STAT4 genotype in patients with lupus nephritis. RESULTS: Naive CD4+ T cells from NR/NR healthy donors down-regulated STAT4 in response to interleukin-12 (IL-12). In contrast, cells from R/R healthy donors maintained high levels. R/R cells exhibited a higher abundance of transcriptionally active STAT4 and increased interferon-γ production. Accordingly, R/R healthy donors exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the STAT4 third intron, where most of the SLE-associated STAT4 single-nucleotide polymorphisms (SNPs) are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis in mice. Accordingly, the R/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis. CONCLUSION: The SLE-associated STAT4 haplotype correlates with an abnormal IL-12-mediated STAT4 transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4+ proinflammatory capacities that, in the context of SLE, contribute to more severe disease. R/R patients may benefit from blockade of the IL-12/STAT4 pathway.

The impact of COVID-19 and access to health services in the Hispanic/Mexican population living in the United States.

Introduction: The United States is home to 10.5 million undocumented immigrants, of which 5 out of 10 are Mexican or Central American. Their immigration status is an obstacle to secure employment that provides labor benefits such as sick leave and health insurance. Living through the global pandemic in the U.S. had a negative impact on this vulnerable population's mental and physical health. They avoided seeking primary or hospital care fearful that they were undocumented and uninsured. The services provided by the Ventanillas de Salud (VDS) "Health Windows" mitigated this pandemic's negative impact and have become an important source to support and increase access to health services among the immigrant community. Methods: De-identified data from a database system called the Continuous Information System and Health Reports of Mexicans in the United States (SICRESAL-MX) to perform this secondary analysis. The descriptive analysis describes socio-demographic, epidemiological, and situational characteristics of COVID-19. Results: Between January 2020 and July 2021, the VDS and UMS provided 11.5 million individual services to just over 4.3 million people. The main health conditions are overweight and obesity, high blood pressure and elevated cholesterol and glucose levels. Between March 2020 to July 2021 a total of 2,481,834 specific services related to COVID-19 were offered. Discussion: The Mexican migrant community in the United States is in a vulnerable situation, largely due to its immigration status which limits their access to health and human services, including primary health care services. Many of them have suffered from chronic diseases since before the pandemic, generating difficulties in monitoring the ailments and exacerbating their conditions.

Comparison of the Impacts of a Dynamic Exercise Program vs. a Mediterranean Diet on Serum Cytokine Concentrations in Women With Rheumatoid Arthritis. A Secondary Analysis of a Randomized Clinical Trial.

Background: Rheumatoid arthritis (RA) is a disease characterized by a chronic inflammatory state. High pro-inflammatory cytokine levels are associated with disease activity. Exercise and the Mediterranean diet (MD) exert anti-inflammatory effects; however, their impacts on inflammation in RA patients remains unknown. This study aimed to compare the effects of six-months of dynamic exercise program (DEP) vs. MD on pro- and anti-inflammatory cytokine serum concentrations. Methods: Secondary analysis of a randomized clinical trial in which 90 women with RA were randomly assigned to the DEP (n = 30), MD (n = 30), or control group (n = 30). All patients received pharmacological treatment. Serum concentrations of pro-inflammatory (TNF-α, TNF-ß, IL-1ß, IL-6 pg/mL) and anti-inflammatory (IL-10, IL-Ra pg/mL) cytokines were measured at baseline and after 6 months using the Luminex technique. Results: After 6 months of follow-up, we found an improvement of the median percentages changes concentrations of TNF-α (DEP, -12.3; MD, -13.3; control, 73.2; p = 0.01), TNF-ß (DEP, -67.4; MD, -54.9; control, 0; p = 0.04), and IL-6 (DEP, -19.9; MD, -37.7; control, 45.5; p = 0.04) in the DEP and MED groups in comparison with control group. IL-1Ra concentrations increased only in the MD group (13.8) compared to levels in the control group (-31.7), p = 0.04. There were no statistically significant differences between DEP and MD groups. Only n = 27 participants in the DEP group, n = 26 in the MD group, and n = 21 in the control group completed the follow-up. Conclusion: The DEP and the MD have potential effects in the concentrations of pro-inflammatory cytokines compared with those in a control group. Only the MD elevated the concentration of IL-Ra. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02900898].

Changes in hand grip strength and body weight after a dynamic exercise program and Mediterranean diet in women with rheumatoid arthritis: a randomized clinical trial.

BACKGROUND: In patients with rheumatoid arthritis (RA) exercise improves muscle strength and decreases fat mass, whereas the consumption of a Mediterranean diet (MD) also has been associated with higher grip strength. Therefore, it is important to explore the combined effects of these interventions on hand grip strength and weight in RA. OBJECTIVE: To determine the combined effect of an MD and a dynamic exercise program (DEP) on hand grip strength in women with RA. METHOD: In a randomized clinical trial, 106 women with RA were included and assigned to the DEP-MD, DEP and MD groups. Weight, body circumferences, Disease Activity Score-28, Health Assessment Questionnaire Disability Index [HAQ-DI], and hand grip strength were measured at baseline and 24 weeks after the interventions. RESULTS: After 24 weeks, hand grip strength showed a significant increase in the DEP group (median 2 kg) compared with DEP-MD (median 0.5 kg) and MD (median -0.5 kg) groups (p = 0.03). In the MD group weight and waist circumference showed a significant decrease (-2.2 kg and -4.3 cm) compared with DEP-MD (0.85 kg and 1.9 cm) and DEP (0.35 kg and 0.5 cm) groups (p < 0.01). Finally, a significant decrease was observed in the HAQ-DI after treatment in the DEP-MD group of -0.5 and the DEP group of -0.25 compared with the MD group with no change (p = 0.03). CONCLUSION: In women with RA, in addition to pharmacological treatment, DEP increases hand grip strength and an MD decreases weight and waist circumferences, while the combination of DEP and MD improves disability.

Low-Density Granulocytes and Neutrophil Extracellular Traps as Biomarkers of Disease Activity in Adult Inflammatory Myopathies.

BACKGROUND/OBJECTIVE: Biomarkers for disease activity and damage accrual in idiopathic inflammatory myopathies (IIMs) are currently lacking. The purpose of this cross-sectional study is to analyze the relationship among low-density granulocytes (LDGs), neutrophil extracellular traps (NETs), and clinical and immunological features of patients with IIM. METHODS: We assessed disease activity, damage accrual, amount of LDGs, NETs, expression of LL-37, and serum cytokines in 65 adult patients with IIM. Differences between groups and correlations were assessed by Kruskal-Wallis, Mann-Whitney U, and Spearman ρ tests. The association between LDGs, NETs, disease activity, calcinosis, and cutaneous ulcers was assessed by logistic regression. To address the capacity of LDGs and NETs to diagnose disease activity, we used receiving operating characteristic curves. RESULTS: Low-density granulocytes were higher in patients with active disease, ulcers, calcinosis, and anti-MDA5 antibodies, which correlated with serum levels of IL-17A and IL-18. Neutrophil extracellular traps were higher in patients with calcinosis, elevated titers of antinuclear antibodies, and positive anti-PM/Scl75 tests. The combination of a high proportion of both total LDGs and NETs was associated with the presence of calcinosis and cutaneous ulcers. LL-37 was higher in NETs originating from LDGs. Normal-density neutrophils were elevated in patients with active dermatomyositis. CONCLUSIONS: Low-density granulocytes and NETs containing LL-37 are increased in patients with IIM and active disease, and correlate with proinflammatory cytokines. Both total and CD10+ LDGs are potential biomarkers for disease activity and, in combination with NETs, have the potential to detect patients who are at risk for cutaneous ulcers and calcinosis.

Protein phosphatase 2A B55ß limits CD8+ T cell lifespan following cytokine withdrawal.

How T cells integrate environmental cues into signals that limit the magnitude and length of immune responses is poorly understood. Here, we provide data that demonstrate that B55ß, a regulatory subunit of protein phosphatase 2A, represents a molecular link between cytokine concentration and apoptosis in activated CD8+ T cells. Through the modulation of AKT, B55ß induced the expression of the proapoptotic molecule Hrk in response to cytokine withdrawal. Accordingly, B55ß and Hrk were both required for in vivo and in vitro contraction of activated CD8+ lymphocytes. We show that this process plays a role during clonal contraction, establishment of immune memory, and preservation of peripheral tolerance. This regulatory pathway may represent an unexplored opportunity to end unwanted immune responses or to promote immune memory.

Effect of a Dynamic Exercise Program in Combination With Mediterranean Diet on Quality of Life in Women With Rheumatoid Arthritis.

OBJECTIVE: To assess the effect of a dynamic exercise program (DEP) in combination with a Mediterranean diet (MD) on health-related quality of life in women with rheumatoid arthritis (RA). METHOD: A randomized clinical trial including 144 women with RA diagnosis was performed. Patients were randomized into 4 groups: (1) MD + DEP (n = 36), (2) DEP (n = 37), (3) MD (n = 40), and (4) control (n = 31). All patients received conventional disease-modifying antirheumatic drugs. Health-related quality of life was assessed with 36-item Short Form Health Survey v2 (0-100 score) and disability with Health Assessment Questionnaire Disability Index at enrollment and after 24 weeks. Between-groups comparisons of the change in the quality of life scores from baseline to follow-up were performed using analysis of covariance in which baseline-to-follow-up was the dependent variable, and the intervention group was the independent variable. RESULTS: All patients had low disease activity at the time of enrollment, with a mean 28-joint Disease Activity Score of less than 3.2. Patients who were included in the MD + DEP and DEP groups showed 15 points of increase in health-related quality of life global punctuation versus 3.5 in the MD group and -4.6 in the control group (p = 0.01). Also the scores in the physical component after 24 weeks of intervention in the MD + DEP group improved (15.5), in the DEP group (12) and MD group as well (5.1), whereas the control group showed a decrease of the score (-1.7) (p = 0.03 between groups). CONCLUSIONS: The combination of MD + DEP could improve the quality of life in RA patients with low disease activity receiving conventional disease-modifying antirheumatic drugs.

The role of low density granulocytes and NETosis in the pathogenesis of adult-onset Still's Disease.

OBJECTIVES: To analyse the potential contribution of low-density granulocytes (LDGs) and NETosis, as well as the differential protein cargo of neutrophil extracellular traps (NETs), as physiopathogenic mechanisms of adult-onset Still's disease (AOSD). METHODS: We recruited 30 patients with AOSD according to the Yamaguchi diagnostic criteria. LDGs were addressed by multiparametric flow cytometry as those CD14-, CD15+, CD10+ cells in the peripheral blood mononuclear cells fraction. NETs were quantified by ELISA, immunofluorescence and fluorescence spectrometry. The expression of LL-37 and high mobility group box 1 (HMGB-1) in NETs was measured by immunofluorescence and confocal microscopy. Additionally, normal density neutrophils from healthy controls were stimulated with serum from patients with AOSD and NET induction was assessed by immunofluorescence. RESULTS: Patients with active disease as well as those with arthritis, cutaneous manifestations and fever had a higher amount of NETs and LDGs. Serum NETs from AOSD patients correlated with the number of swollen joints (r=0.41, p=0.032), absolute number of monocytes (r=0.529, p=0.005). The spontaneous NETs from patients with cutaneous manifestations and fever had higher cargo of HMGB-1 compared with patients in remission. CONCLUSIONS: LDGs and NETs are increased in patients with active AOSD and correlate with particular clinical features. Patients with cutaneous lesions and fever present a higher cargo of HMGB1 in their spontaneous NETs.

PPP2R2B hypermethylation causes acquired apoptosis deficiency in systemic autoimmune diseases.

Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55ß), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases. Altered expression of B55ß conditioned resistance to cytokine withdrawal-induced death (CWID) in patients with autoimmune diseases. The impaired upregulation of B55ß was caused by inflammation-driven hypermethylation of specific cytosines located within a regulatory element of PPP2R2B preventing CTCF binding. This phenotype could be induced in healthy T cells by exposure to TNF-α. Our results reveal a gene whose expression is affected by an acquired defect, through an epigenetic mechanism, in the setting of systemic autoimmunity. Because failure to remove activated T cells through CWID could contribute to autoimmune pathology, this mechanism illustrates a vicious cycle through which autoimmune inflammation contributes to its own perpetuation.

Epidemiologic Profile of Erectile Dysfunction in Patients with Systemic Lupus Erythematosus: The Latin American Landscape.

OBJECTIVE: The aim of this study was to describe the prevalence of erectile dysfunction (ED), as well as associated demographic and clinical features, in men with systemic lupus erythematosus (SLE), by means of a systematic, standardized evaluation. METHODS: We performed a transversal study in 8 tertiary care centers in Latin America. We included male patients ≥ 16 years who fulfilled ≥ 4 American College of Rheumatology criteria for SLE and had regular sexual activity, and evaluated them with the International Index of Erectile Function-5 questionnaire. Relevant demographic, clinical, and serological characteristics were recorded. We included 2 control groups: the first was made up of healthy men and the second of men with autoimmune diseases other than SLE (non-SLE group). RESULTS: We included 590 subjects (174 SLE, 55 non-SLE, and 361 healthy controls). The prevalence of ED in the SLE group was 69%. Mean age in that group was 36.3 ± 1.03 years. Among SLE patients with and without ED, these factors were significantly different: the presence of persistent lymphopenia (p = 0.006), prednisone dose (9.3 ± 1.2 vs 5.3 ± 1.3 mg, p = 0.026), and the Systemic Lupus International Collaborating Clinics damage score (1.25 ± 0.14 vs 0.8 ± 0.16 points, p = 0.042). Independent risk factors for ED in patients with SLE were persistent lymphopenia (OR 2.79, 95% CI 1.37-5.70, p = 0.001) and corticosteroid use in the previous year (OR 2.15, 95% CI 1.37-3.37, p = 0.001). CONCLUSION: Regardless of comorbidities, treatment (excluding steroids), and type of disease activity, patients with SLE have a high prevalence of ED, especially considering that most patients are young. Recent corticosteroid use and persistent lymphopenia, which could be related to endothelial dysfunction, are risk factors for this complication in men with SLE.

Factors associated with remission in patients with systemic lupus erythematosus: new insights into a desirable state.

The primary aim of this study was to assess demographic, clinical, and serological factors associated with remission in systemic lupus erythematosus (SLE). A retrospective cohort study was performed. We examined relevant features in patients with SLE with a follow-up of at least 8 years from active disease (SLE Disease Activity Index-2000 [SLEDAI-2K] ≥6). The primary outcome was to assess various remission states in SLE according to disease activity and treatment. Differences between groups were assessed by Student's t test and chi-square test for continuous and categorical variables, respectively. Multivariate Cox proportional hazard analysis was used to assess association between variables, and we performed a Kaplan-Meier analysis with log rank test to evaluate time to remission. One hundred twenty-four patients fulfilled our inclusion criteria: 116 (93.54%) were women with a mean age of 30.23 ± 8.52 years. Twenty-four patients (19.35%), 25 patients (20.16%), and 16 patients (12.9%) achieved complete remission, clinical remission on corticosteroids, and clinical remission off corticosteroids, respectively. SLEDAI-2K at 3rd month of follow-up (HR = 0.85, 95% CI = 0.73-0.98, p = 0.029) and total number of disease flares (HR = 0.73, 95% CI = 0.56-0.95, p = 0.024) were associated with complete remission, and total number of disease flares (HR = 0.80, 95% CI = 0.67-0.95, p = 0.011) was associated with clinical remission on corticosteroids. Our findings are clinically relevant to encourage an intensive immunosuppressive treatment and close monitoring early after active disease.

Body composition evaluated by body mass index and bioelectrical impedance vector analysis in women with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a complex inflammatory disease that modifies body composition. Although body mass index (BMI) is one of the clinical nutrition tools widely used to assess indirectly nutritional status, it is not able to identify these body alterations. Bioelectrical Vector Analysis (BIVA) is an alternative method to assess hydration and body cell mass of patients with wasting conditions. OBJECTIVE: To investigate the differences in nutrition status according to BMI groups (normal, overweight and obesity) and BIVA classification (cachectic and non-cachectic) in women with RA. METHODS: Women with confirmed diagnosis of RA were included from January 2015 to June 2016. Whole-body bioelectrical impedance was measured using a tetrapolar and mono-frequency equipment. Patients were classified according to BMI as: low body weight (n = 6, 2.7%), normal (n = 59, 26.3%), overweight (n = 88, 39.3%) and obese (n = 71, 31.7%), and each group was divided into BIVA groups (cachectic 51.8% and non-cachectic 48.2%). RESULTS: A total of 224 RA patients were included, with mean age 52.7 years and median disease duration of 12 years. Significant differences were found in weight, arm circumference, waist, hip, resistance/height, reactance/height and erythrocyte sedimentation rate among all BMI groups. However, serum albumin levels were significantly different between cachectic and non-cachectic patients independently of BMI. In all BMI categories, cachectic groups had lower reactance and phase angle than non-cachectic subjects. CONCLUSION: RA patients with normal or even high BMI have a significantly lower muscle component. Evaluation of body composition with BIVA in RA patients could be an option for cachexia detection.

Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus.

OBJECTIVES: To assess if ubiquitinated proteins potentially present in neutrophil extracellular traps (NETs) can modify cellular responses and induce inflammatory mechanisms in patients with systemic lupus erythematosus (SLE) and healthy subjects. MATERIALS AND METHODS: We studied 74 subjects with SLE and 77 healthy controls. Neutrophils and low-density granulocytes were isolated, and NETs were induced. Ubiquitin content was quantified in NETs by western blot analysis, ELISA and immunofluorescence microscopy, while ubiquitination of NET proteins was assessed by immunoprecipitation. Monocyte-derived macrophages from SLE and controls were isolated and stimulated with NETs or ubiquitin. Calcium flux and cytokine synthesis were measured following these stimuli. RESULTS: NETs contain ubiquitinated proteins, with a lower expression of polyubiquitinated proteins in subjects with SLE than in controls. Myeloperoxidase (MPO) is present in ubiquitinated form in NETs. Patients with SLE develop antiubiquitinated MPO antibodies, and titres positively correlate with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (P<0.01), and negatively correlate with complement components (P<0.01). Stimulation of monocyte-derived macrophages with NETs or with ubiquitin led to enhanced calcium flux. In addition, stimulation with NETs led to enhanced cytokine (tumour necrosis factor-α and interleukin-10) production in macrophages from patients with SLE when compared with controls, which was hampered by inhibition of NET internalisation by macrophages. CONCLUSION: This is the first study to find ubiquitinated proteins in NETs, and evidence for adaptive immune responses directed towards ubiquitinated NET proteins in SLE. The distinct differences in ubiquitin species profile in NETs compared with healthy controls may contribute to dampened anti-inflammatory responses observed in SLE. These results also support a role for extracellular ubiquitin in inflammation in SLE.

The Systemic Lupus Erythematosus Infection Predictive Index (LIPI): A Clinical-Immunological Tool to Predict Infections in Lupus Patients.

Among autoimmune diseases, systemic lupus erythematosus (SLE) patients have a unique predisposition to develop infections, which represents one of their main causes of morbidity and mortality. Many infections occur at disease diagnosis in the absence of immunosuppressive therapy, suggesting that the immunological abnormalities in SLE patients might be fundamental for the development of this complication. The aim of this study was to address the main clinical and immunological features associated with the development of infection and to create and validate a compound clinical-immunological infection predictive index in a cohort of SLE patients. We included 55 SLE patients with < 5 years since diagnosis. The clinical and immunological features were evaluated periodically and patients were followed-up during 1 year, searching for the development of infection. Immunophenotyping was performed by multiparametric flow cytometry and neutrophil extracellular traps (NETs) were assessed by confocal microscopy. Eighteen patients (32.7%) presented 19 infectious events, 5 (26.3%) were severe. For the construction of the index, we performed a logistic regression analysis and the cutoff points were determined with ROC curves. Increased numbers of peripheral Th17 cells, B cell lymphopenia, and lower TLR2 expression in monocytes, as well as the use of cyclophosphamide were the major risk factors for the development of infection and thus were included in the index. Besides, patients that developed infection were characterized by increased numbers of low-density granulocytes (LDGs) and higher expression of LL-37 in NETs upon infection. Finally, we validated the index retrospectively in a nested case-control study. A score >1.5 points was able to predict infection in the following year (AUC = 0.97; LR- = 0.001, specificity 100%, P = 0.0003). Our index encompasses novel immunological features able to prospectively predict the risk of infection in SLE patients.

Add-on Pyridostigmine Enhances CD4+ T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study.

BACKGROUND: In human immunodeficiency virus (HIV)-infection, persistent T-cell activation leads to rapid turnover and increased cell death, leading to immune exhaustion and increased susceptibility to opportunistic infections. Stimulation of the vagus nerve increases acetylcholine (ACh) release and modulates inflammation in chronic inflammatory conditions, a neural mechanism known as the cholinergic anti-inflammatory pathway (CAP). Pyridostigmine (PDG), an ACh-esterase inhibitor, increases the half-life of endogenous ACh, therefore mimicking the CAP. We have previously observed that PDG reduces ex vivo activation and proliferation of T-cells obtained from people living with HIV. METHODS: We conducted a 16-week proof-of-concept open trial using PDG as add-on therapy in seven HIV-infected patients with discordant immune response receiving combined antiretroviral therapy, to determine whether PDG would promote an increase in total CD4+ T-cells. The trial was approved by the Institutional Research and Ethics Board and registered in ClinicalTrials.gov (NCT00518154). RESULTS: Seven patients were enrolled after signing informed consent forms. We observed that addition of PDG induced a significant increase in total CD4+ T-cells (baseline = 153.1 ± 43.1 vs. week-12 = 211.9 ± 61.1 cells/µL; p = 0.02). Post hoc analysis showed that in response to PDG, four patients (57%) significantly increased CD4+ T-cell counts (responders = 257.8 ± 26.6 vs. non-responders = 150.6 ± 18.0 cells/µL; p = 0.002), and the effect persisted for at least 1 year after discontinuation of PDG. CONCLUSION: Our data indicate that in patients with HIV, add-on PDG results in a significant and persistent increase in circulating CD4+ T-cells.

Differential T cell subsets and cytokine profile between steady-state and G-CSF-primed bone marrow and its association with graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). At our Institution, patients transplanted using G-CSF-primed bone marrow (G-BM), have a lower incidence of GVHD when compared to other sources. The objective of this study was to analyze and compare T cell subsets and cytokines in donor G-BM and steady-state BM (SS-BM). A prospective study was performed in 48 donor samples. Mononuclear cells were isolated by gradient density. T cell subsets and cytokine production in supernatants were analyzed by multiparametric flow cytometry. Six and 16 patients developed acute and chronic GVHD, respectively. Patients who developed GVHD were characterized by a predominant pro-inflammatory response (IL-17A (10.02 vs 0.43pg/mL, p=0.006), TNF-α (54.57 vs 0.81pg/mL, p=0.001)), in contrast to a deficient suppressor profile (IL-10 (7.87 vs 41.37pg/mL, p=0.003)) and Tregs (0.95% vs 1.52%, p=0.004). G-BM showed an enhanced suppressive phenotype (increased Th2 and Tregs) in comparison to SS-BM. GVHD is associated with an imbalance between pro-inflammatory and suppressor immune responses. G-BM showed a more favorable immunologic profile characterized by diminished pro-inflammatory cytokine production, which was associated with a lower frequency of GVHD in our cohort.

Total Hip Arthroplasty Outcomes: An 18-Year Experience in a Single Center: Is Systemic Lupus Erythematosus a Potential Risk Factor for Adverse Outcomes?

BACKGROUND: In patients with systemic lupus erythematosus (SLE), persistent joint activity and treatment with glucocorticoids are associated with musculoskeletal complications. About 30% of these patients become candidates for surgical treatment. The aim of this study was to evaluate postoperative outcomes after total hip arthroplasty (THA) in SLE patients. METHODS: We performed a retrospective cohort study at a tertiary care center in Mexico City between 1995 and 2013. All patients with SLE who underwent THA during that period were included (n = 58). They were compared with 2 control groups, one from another inflammatory arthropathy (rheumatoid arthritis, n = 58) and other noninflammatory (osteoarthritis, n = 58), matched by gender and date of surgery. The primary outcome was the frequency of postoperative complications during follow-up. RESULTS: We included 174 patients who underwent THA during the study period. Patients with SLE were younger (P < .0001), had a longer hospitalization stay (P = .001), and required more transfusions (P = .004). Global complications in THA in patients with SLE were more prevalent than rheumatoid arthritis (36.2% vs 15.5%, P = .029) and osteoarthritis (36.2% vs 5.1%, P < .0001) patients. After multivariate analysis, risk factors for THA complications were: SLE (hazard ratio 2.8, 95% confidence interval 1.2-6.8; P = .018) and low postoperative hemoglobin (hazard ratio 0.77, 95% confidence interval 0.73-0.83; P < .0001). Long-term complications after THA were similar among groups. CONCLUSION: This is the largest single-center study regarding clinical outcomes after THA in SLE patients. Our data suggest that SLE is an independent risk factor for adverse postoperative outcomes, mainly immediate complications, but the long-term outcome is good enough to offer surgical treatment that will improve quality of life.

Renal Thrombotic Microangiopathy in Proliferative Lupus Nephritis: Risk Factors and Clinical Outcomes: A Case-Control Study.

BACKGROUND: Renal thrombotic microangiopathy (TMA) may be associated with lupus nephritis. Its relationship to other disease factors and its specific effect on prognosis are not precisely known. Evidence regarding these aspects is controversial, and information focusing on kidney-limited TMA in systemic lupus erythematosus (SLE) patients is scarce. OBJECTIVES: The aims of this study were to identify risk factors for renal TMA in patients with lupus nephritis and to determine its impact on clinical outcomes. METHODS: A case-control study was performed. We studied 245 renal biopsies from SLE patients. We included patients with renal TMA, as well as control subjects adjusted for glomerulonephritis class, estimated glomerular filtration rate, activity and chronicity indices, and follow-up time. Serological and clinical features were measured at the time of the biopsy and during follow-up. RESULTS: Twenty-three patients with renal TMA and 21 control subjects were included. There were no differences in Systemic Lupus Erythematosus Disease Activity Index score, end-stage renal disease, or mortality between groups during follow-up. After multivariate analysis, lymphopenia (odds ratio, 10.69; 95% CI, 1.35-84.74) and anti-Ro antibody positivity (odds ratio, 8.96; 95% CI, 1.49-53.57) remained significantly associated with renal TMA. CONCLUSIONS: Lymphopenia and anti-Ro positivity are independent risk factors for renal TMA in SLE patients. This increased risk could be a consequence of the potential role of these factors in endothelial dysfunction and damage. Outcomes were similar for patients with the same estimated glomerular filtration rate and biopsy characteristics, regardless of the presence of TMA.