Neonatal Fc receptor promoter gene polymorphism does not predict pharmacokinetics of IVIg or the clinical course of GBS

Treatment of Guillain-Barré syndrome with a standard course of high-dose intravenous immunoglobulin (IVIg) results in a variable clinical recovery which is associated with changes in serum IgG levels after treatment. The neonatal Fc-receptor protects IgG from degradation, and a genetic polymorphism in its promoter region that influences the expression of Fc-receptor, may in part explain the variation in IgG levels and outcome. This polymorphism was determined by polymerase chain reaction in a cohort of 257 patients with Guillain-Barré syndrome treated with IVIg. We could not demonstrate a relation between this polymorphism, the pharmacokinetics of IVIg, or the clinical course and outcome

<i>Campylobacter jejuni </i>infections and anti-GM1 antibodies in Guillain-Barré syndrome

The group of patients with Guillain-Barre syndrome (GBS) is very heterogenous with regard to antecedent infections, immunological parameters, clinical manifestations, and response to treatment. In this study, the presumed pathogenic factors anti-GM1 antibodies and Campylobacter jejuni infections were related to the clinical characteristics. Serum from 154 patients with GBS, 63 patients with other neurological diseases (OND), and 50 normal controls (NC) were tested for the presence of antibodies against GM1 and C. jejuni. Anti-GM1 antibodies were detected in 31 (20%) GBS patients, 5 (8%) OND patients, and in none of the NC. Evidence for a recent C. jejuni infection was found in 49 (32%) GBS patients and less often in OND patients (11%) or NC (8%). In GBS patients, the presence of anti-GM1 antibodies was significantly associated with C. jejuni infections. The subgroup of GBS patients with anti-GM1 antibodies suffered more often from a rapidly progressive and more severe neuropathy with predominandy distal distribution of weakness, without deficits of cranial nerves or sensory disturbances. The subgroup with C. jejuni infection also more often had a severe pure motor variant of GBS. Recovery of the patients with anti-GMl antibodies and C. jejuni infections was not as good after plasma exchange compared with intravenous immunoglobulins.</p

Engineering <i>Mycoplasma pneumoniae</i> to bypass the association with Guillain-Barré syndrome

A non-pathogenic Mycoplasma pneumoniae-based chassis is leading the development of live biotherapeutic products (LBPs) for respiratory diseases. However, reports connecting Guillain-Barré syndrome (GBS) cases to prior M. pneumoniae infections represent a concern for exploiting such a chassis. Galactolipids, especially galactocerebroside (GalCer), are considered the most likely M. pneumoniae antigens triggering autoimmune responses associated with GBS development. In this work, we generated different strains lacking genes involved in galactolipids biosynthesis. Glycolipid profiling of the strains demonstrated that some mutants show a complete lack of galactolipids. Cross-reactivity assays with sera from GBS patients with prior M. pneumoniae infection showed that certain engineered strains exhibit reduced antibody recognition. However, correlation analyses of these results with the glycolipid profile of the engineered strains suggest that other factors different from GalCer contribute to sera recognition, including total ceramide levels, dihexosylceramide (DHCer), and diglycosyldiacylglycerol (DGDAG). Finally, we discuss the best candidate strains as potential GBS-free Mycoplasma chassis.</p

Variations in childbirth interventions in high-income countries: protocol for a multinational cross-sectional study

Introduction There are growing concerns about the increase in rates of commonly used childbirth interventions. When indicated, childbirth interventions are crucial for preventing maternal and perinatal morbidity and mortality, but their routine use in healthy women and children leads to avoidable maternal and neonatal harm. Establishing ideal rates of interventions can be challenging. This study aims to describe the range of variations in the use of commonly used childbirth interventions in high-income countries around the world, and in outcomes in nulliparous and multiparous women. Methods and analysis This multinational cross-sectional study will use data from births in 2013 with national population data or representative samples of the population of pregnant women in high-income countries. Data from women who gave birth to a single child from 37 weeks gestation onwards will be included and the results will be presented for nulliparous and multiparous women separately. Anonymised individual level data will be analysed. Primary outcomes are rates of commonly used childbirth interventions, including induction and/or augmentation of labour, intrapartum antibiotics, epidural and pharmacological pain relief, episiotomy in vaginal births, instrument-assisted birth (vacuum or forceps), caesarean section and use of oxytocin postpartum. Secondary outcomes are maternal and perinatal mortality, Apgar score below 7 at 5 min, postpartum haemorrhage and obstetric anal sphincter injury. Univariable and multivariable logistic regression analyses will be conducted to investigate variations among countries, adjusted for maternal age, body mass index, gestational weight gain, ethnic background, socioeconomic status and infant birth weight. The overall mean rates will be considered as a reference category, weighted for the size of the study population per country. Ethics and dissemination The Medical Ethics Review Committee of VU University Medical Center Amsterdam confirmed that an official approval of this study was not required. Results will be disseminated at national and international conferences and published in peer-reviewed journals.The study was developed during a meeting with COST-members (European Cooperation in Science and Technology). These meetings are funded by the COST Action IS1405 ‘BIRTH’ (European Cooperation in Science and Technology). There is no other external funding for this study.Peer Reviewe

Correction : variations in childbirth interventions in high-income countries : protocol for a multinational cross-sectional study

Original article can be fount at: https://www.um.edu.mt/library/oar/handle/123456789/58714Correction issued for the article Variations in childbirth interventions in highincome countries: protocol for a multinational cross-sectional study (10.1136/bmjopen-2017-017993)peer-reviewe

The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1

Engineering Mycoplasma pneumoniae to bypass the association with Guillain-Barré syndrome

A non-pathogenic Mycoplasma pneumoniae-based chassis is leading the development of live biotherapeutic products (LBPs) for respiratory diseases. However, reports connecting Guillain-Barré syndrome (GBS) cases to prior M. pneumoniae infections represent a concern for exploiting such a chassis. Galactolipids, especially galactocerebroside (GalCer), are considered the most likely M. pneumoniae antigens triggering autoimmune responses associated with GBS development. In this work, we generated different strains lacking genes involved in galactolipids biosynthesis. Glycolipid profiling of the strains demonstrated that some mutants show a complete lack of galactolipids. Cross-reactivity assays with sera from GBS patients with prior M. pneumoniae infection showed that certain engineered strains exhibit reduced antibody recognition. However, correlation analyses of these results with the glycolipid profile of the engineered strains suggest that other factors different from GalCer contribute to sera recognition, including total ceramide levels, dihexosylceramide (DHCer), and diglycosyldiacylglycerol (DGDAG). Finally, we discuss the best candidate strains as potential GBS-free Mycoplasma chassis.This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme ERC LUNG-BIOREPAIR (101020135). We also acknowledge the support of the Spanish Ministry of Science and Innovation through the Plan Nacional PID2021-122341NB-I00 and the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033), the Generalitat de Catalunya through the CERCA programme, the Center for Industrial Technology Development (CDTI) through the Neotec programme (SNEO 20211019) and to the EMBL partnership. C.P.-L. acknowledges the support of ‘Programa Torres Quevedo’ grant [PTQ2020-011048] funded by MCIN/AEI/10.13039/501100011033; European Union ‘NextGenerationEU/PRTR’. The proteomics analyses were performed in the CRG/UPF Proteomics Unit which is part of the Spanish National Infrastructure for Omics Technologies (ICTS OmicsTech). We thank T. Hoogenboezem and C. Gago da Graça (Department of Pediatrics, Erasmus MC–Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands) for excellent technical assistance.Peer reviewe

Regional variation in colorectal cancer testing and geographic availability of care in a publicly insured population

Despite its demonstrated effectiveness, colorectal cancer (CRC) testing is suboptimal, particularly in vulnerable populations such as those who are publicly insured. Prior studies provide an incomplete picture of the importance of the intersection of multilevel factors affecting CRC testing across heterogeneous geographic regions where vulnerable populations live. We examined CRC testing across regions of North Carolina by using population-based Medicare and Medicaid claims data from disabled individuals who turned 50 years of age during 2003–2008. We estimated multilevel models to examine predictors of CRC testing, including distance to the nearest endoscopy facility, county-level endoscopy procedural rates, and demographic and community contextual factors. Less than 50% of eligible individuals had evidence of CRC testing; men, African-Americans, Medicaid beneficiaries, and those living furthest away from endoscopy facilities had significantly lower odds of CRC testing, with significant regional variation. These results can help prioritize intervention strategies to improve CRC testing among publicly insured, disabled populations

IVIg-induced plasmablasts in patients with Guillain-Barré syndrome

Objective: The Guillain–Barré syndrome (GBS) is an acute, immune-mediated disease of peripheral nerves. Plasmablasts and plasma cells play a central role in GBS by producing neurotoxic antibodies. The standard treatment for GBS is high-dose intravenous immunoglobulins (IVIg), however the working mechanism is unknown and the response to treatment is highly variable. We aimed to determine whether IVIg changes the frequency of B-cell subsets in patients with GBS. Methods: Peripheral blood mononuclear cells were isolated from 67 patients with GBS before and/or 1, 2, 4, and 12 weeks after treatment with high-dose IVIg. B-cell subset frequencies were determined by flow cytometry and related to serum immunoglobulin levels. Immunoglobulin transcripts before and after IVIg treatment were examined by next-generation sequencing. Antiglycolipid antibodies were determined by ELISA. Results: Patients treated with IVIg demonstrated a strong increase in plasmablasts, which peaked 1 week after treatment. Flow cytometry identified a relative increase in IgG2 plasmablasts posttreatment. Within IGG sequences, dominant clones were identified which were also IGG2 and had different immunoglobulin sequences compared to pretreatment samples. High plasmablast frequencies after treatment correlated with an increase in serum IgG and IgM, suggesting endogenous production. Patients with a high number of plasmablasts started to improve earlier (P = 0.015) and were treated with a higher dose of IVIg. Interpretation: High-dose IVIg treatment alters the distribution of B-cell subsets in the peripheral blood of GBS patients, suggesting de novo (oligo-)clonal B-cell activation. Very high numbers of plasmablasts after IVIg therapy may be a potential biomarker for fast clinical recovery