26 research outputs found
VAV1 and BAFF, via NFÎșB pathway, are genetic risk factors for myasthenia gravis
Objective To identify novel genetic loci that predispose to earlyâonset myasthenia gravis (EOMG) applying a twoâstage association study, exploration, and replication strategy. Methods Thirtyâfour loci and one confirmation loci, human leukocyte antigen (HLA)âDRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, Bâcell activating factor (BAFF), and tumor necrosis factorâalpha (TNFâα), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLAâDRA and TNFâα loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for Tâ and Bâcell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of Bâcells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factorâkappaB (NFÎșB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG
Clinical presentation and survival of smear-positive pulmonary tuberculosis patients of a University General Hospital in a developing country
Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension
OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo
The impact of human expert visual inspection on the discovery of strong gravitational lenses
We investigate the ability of human âexpertâ classifiers to identify strong gravitational lens candidates in Dark Energy Survey like imaging. We recruited a total of 55 people that completed more than 25% of the project. During the classification task, we present to the participants 1489 images. The sample contains a variety of data including lens simulations, real lenses, non-lens examples, and unlabeled data. We find that experts are extremely good at finding bright, well-resolved Einstein rings, whilst arcs with g-band signal-to-noise less than âŒ25 or Einstein radii less than âŒ1.2 times the seeing are rarely recovered. Very few non-lenses are scored highly. There is substantial variation in the performance of individual classifiers, but they do not appear to depend on the classifierâs experience, confidence or academic position. These variations can be mitigated with a team of 6 or more independent classifiers. Our results give confidence that humans are a reliable pruning step for lens candidates, providing pure and quantifiably complete samples for follow-up studies
Biomarkers of Environmental Enteropathy, Inflammation, Stunting, and Impaired Growth in Children in Northeast Brazil
Critical to the design and assessment of interventions for enteropathy and its developmental consequences in children living in impoverished conditions are non-invasive biomarkers that can detect intestinal damage and predict its effects on growth and development. We therefore assessed fecal, urinary and systemic biomarkers of enteropathy and growth predictors in 375 6â26 month-old children with varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301 of these children returned for followup anthropometry after 2-6m. Biomarkers that correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin (if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption); and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggesting impaired defenses). In contrast, subsequent growth was predicted in those with higher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP and SAA (showing intestinal barrier disruption and inflammation). Better growth was predicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin in predicting subsequent growth impairment. Biomarkers clustered into markers of 1) functional intestinal barrier disruption and translocation, 2) structural intestinal barrier disruption and inflammation and 3) systemic inflammation. Principle components pathway analyses also showed that L/M with %L, I-FABP and MPO associate with impaired growth, while also (like MPO) associating with a systemic inflammation cluster of kynurenine, LBP, sCD14, SAA and K/T. Systemic evidence of LPS translocation associated with stunting, while markers of barrier disruption or repair (A1AT and Reg1 with low zonulin) associated with fecal MPO and neopterin. We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPS translocation and of intestinal and systemic inflammation can help elucidate how we recognize, understand, and assess effective interventions for enteropathy and its growth and developmental consequences in children in impoverished settings
VAV1 and BAFF, via NFÎșB pathway, are genetic risk factors for myasthenia gravis
Objective To identify novel genetic loci that predispose to earlyâonset myasthenia gravis (EOMG) applying a twoâstage association study, exploration, and replication strategy. Methods Thirtyâfour loci and one confirmation loci, human leukocyte antigen (HLA)âDRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, Bâcell activating factor (BAFF), and tumor necrosis factorâalpha (TNFâα), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLAâDRA and TNFâα loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for Tâ and Bâcell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of Bâcells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factorâkappaB (NFÎșB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG
Predicting SARS-CoV-2 Variant Spread in a Completely Seropositive Population Using Semi-Quantitative Antibody Measurements in Blood Donors
SARS-CoV-2 serologic surveys estimate the proportion of the population with antibodies against historical variants, which nears 100% in many settings. New approaches are required to fully exploit serosurvey data. Using a SARS-CoV-2 anti-Spike (S) protein chemiluminescent microparticle assay, we attained a semi-quantitative measurement of population IgG titers in serial cross-sectional monthly samples of blood donations across seven Brazilian state capitals (March 2021–November 2021). Using an ecological analysis, we assessed the contributions of prior attack rate and vaccination to antibody titer. We compared anti-S titer across the seven cities during the growth phase of the Delta variant and used this to predict the resulting age-standardized incidence of severe COVID-19 cases. We tested ~780 samples per month, per location. Seroprevalence rose to >95% across all seven capitals by November 2021. Driven by vaccination, mean antibody titer increased 16-fold over the study, with the greatest increases occurring in cities with the highest prior attack rates. Mean anti-S IgG was strongly correlated (adjusted R2 = 0.89) with the number of severe cases caused by Delta. Semi-quantitative anti-S antibody titers are informative about prior exposure and vaccination coverage and may also indicate the potential impact of future SARS-CoV-2 variants
Different Host Complement Systems and Their Interactions with Saliva from Lutzomyia longipalpis (Diptera, Psychodidae) and Leishmania infantum Promastigotes
Fecal MPO, Fecal alpha-1-antitrypsin (A1AT), and plasma LPS, FABP and SAA each predicts subsequent growth impairment.
<p>a: For MPO, <i>p</i> = 0.028; n = 266 when correcting for age and gender, and independent of breastfeeding status (that showed no correlation in these 6-26m old children) and of age. b: For A1AT, n = 237; <i>p</i> = 0.042; and A1AT also correlates with âcatchup WAZâ as well, <i>p</i> = 0.035 after correcting for age and gender. c: For urine L/M, higher values correlated (controlling for age and gender) with impaired growth (delta HAZ) (<i>r</i> = -0.173; <i>p</i> = 0.009; n = 230). d: For plasma LPS (ie lower LUM), higher values correlated with impaired growth (delta HAZ) (<i>r</i> = 0.151; <i>p</i> = 0.017; n = 251). e: For plasma FABP, higher values correlated with impaired growth (delta HAZ) (r = -0.134; <i>p</i> = 0.042; n = 231). f: For plasma SAA, higher values correlated with impaired growth (delta HAZ) (r = -0.132; p = 0.046; n = 231).</p
Path model, using Principle Components Analyses (Equamax rotation solution maximizing independence of groups) showing associations among 1) Barrier (green), 2) Local Gut (orange) and 3) Systemic (pink) sets of biomarkers, as well as their predictive utility regarding linear growth.
<p>Path model, using Principle Components Analyses (Equamax rotation solution maximizing independence of groups) showing associations among 1) Barrier (green), 2) Local Gut (orange) and 3) Systemic (pink) sets of biomarkers, as well as their predictive utility regarding linear growth.</p