Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

Autoimmune; Multiple sclerosisAutoinmune; Esclerosis múltipleAutoimmune; Esclerosi múltipleIntronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.This research was supported by grants to KV from MINECO (SAF2016-74891-R), Instituto de Salud Carlos III (FIS-PI20/00123), Gobierno Vasco RIS3 (Ref. 2019222043), and Red Española de Esclerosis Múltiple (REEM; RD16/0015/0005). NV and LMV were supported by ISCIII (FIS-PI18/00572) and REEM (RD16/0015/0001). RTN is a recipient of a fellowship from the Secretaría Nacional de Ciencia y Tecnología e Innovación (SENACYT; Convocatoria Doctorado de Investigación Ronda III, 2018; Ref. BIDP-III-2018-12) of the Gobierno Nacional, República de Panamá

Factors Associated With Peripheral Nerve Injury After Pelvic Laparoscopy: The Importance of Surgical Positioning

BACKGROUND: Nerve damage after abdominal and pelvic surgery is rare but potentially serious. The incidence of peripheral nerve injury is difficult to assess, and rates of between 0.02% and 21% have been cited in the literature. Signs and symptoms of this type of injury may appear immediately after surgery or a few days later. PURPOSE: This study was developed to assess the rate of peripheral nerve injury after pelvic laparoscopy and to identify associated risk factors. METHODS: A pilot prospective cohort study was conducted between March 2018 and April 2019 on 101 patients with a 1-month follow-up using two semistructured clinical interviews. We carried out a descriptive analysis followed by univariable and multivariable logistic regression analyses. RESULTS: Thirteen patients were found to have peripheral nerve injuries, representing a rate of 12.9%. Overall, 14 injuries (five severe and nine mild) were detected. One patient had two mild injuries. In this study, the risk of injury was found to increase 1.77-fold (OR = 1.77, 95% CI [1.13, 2.76], p = .007) for each hour the patient was in the Trendelenburg position. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The longer the patient is in the Trendelenburg position, the greater the risk of peripheral nerve damage. Patients aged 60 years or less also face a higher risk of nerve injury.This study was supported by a 600-euro grant from the Basque Foundation for Health Innovation and Research

Bacillus thuringiensis Cyt proteins as enablers of activity of Cry and Tpp toxins against Aedes albopictus

Aedes albopictus is a species of mosquito, originally from Southeast Asia, that belongs to the Culicidae family and the Dipteran insect order. The distribution of this vector has rapidly changed over the past decade, making most of the temperate territories in the world vulnerable to important human vector-borne diseases such as dengue, yellow fever, zika or chikungunya. Bacillus thuringiensis var. israeliensis (Bti)-based insecticides represent a realistic alternative to the most common synthetic insecticides for the control of mosquito larvae. However, several studies have revealed emerging resistances to the major Bti Crystal proteins such as Cry4Aa, Cry4Ba and Cry11Aa, making the finding of new toxins necessary to diminish the exposure to the same toxicity factors overtime. Here, we characterized the individual activity of Cyt1Aa, Cry4Aa, Cry4Ba and Cry11Aa against A. albopictus and found a new protein, Cyt1A-like, that increases the activity of Cry11Aa more than 20-fold. Additionally, we demonstrated that Cyt1A-like facilitates the activity three new Bti toxins: Cry53-like, Cry56A-like and Tpp36-like. All in all, these results provide alternatives to the currently available Bti products for the control of mosquito populations and position Cyt proteins as enablers of activity for otherwise non-active crystal proteins.This research was funded by Gobierno de Navarra with grant numbers 0011-1365-2020-000297 to C.J.C. and 0011-1365-2020-000033 to A.T.-A. L.L. received a doctoral grant from the European Union’s H2020 research and innovation programme under Marie Sklodowska-Curiegrant agreement Nº801586. A.M.-G. was supported by a FPU PhD grant from the Spanish Ministry of Science and Innovation (FPU20/05496). A.B. Fernández’s contract was cofounded by the Program Torres Quevedo (Ministerio de Ciencia, Innovación y Universidades, Gobierno de España) (PTQ-2018-010091) and Bioinsectis SL

Bacteraemic pneumococcal pneumonia and SARS-CoV-2 pneumonia: differences and similarities

OBJECTIVE: To analyse differences in clinical presentation and outcome between bacteraemic pneumococcal community-acquired pneumonia (B-PCAP) and sSvere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pneumonia. METHODS: This observational multi-centre study was conducted on patients hospitalized with B-PCAP between 2000 and 2020 and SARS-CoV-2 pneumonia in 2020. Thirty-day survival, predictors of mortality, and intensive care unit (ICU) admission were compared. RESULTS: In total, 663 patients with B-PCAP and 1561 patients with SARS-CoV-2 pneumonia were included in this study. Patients with B-PCAP had more severe disease, a higher ICU admission rate and more complications. Patients with SARS-CoV-2 pneumonia had higher in-hospital mortality (10.8% vs 6.8%; P=0.004). Among patients admitted to the ICU, the need for invasive mechanical ventilation (69.7% vs 36.2%; P<0.001) and mortality were higher in patients with SARS-CoV-2 pneumonia. In patients with B-PCAP, the predictive model found associations between mortality and systemic complications (hyponatraemia, septic shock and neurological complications), lower respiratory reserve and tachypnoea; chest pain and purulent sputum were protective factors in these patients. In patients with SARS-CoV-2 pneumonia, mortality was associated with previous liver and cardiac disease, advanced age, altered mental status, tachypnoea, hypoxaemia, bilateral involvement, pleural effusion, septic shock, neutrophilia and high blood urea nitrogen; in contrast, ≥7 days of symptoms was a protective factor in these patients. In-hospital mortality occurred earlier in patients with B-PCAP. CONCLUSIONS: Although B-PCAP was associated with more severe disease and a higher ICU admission rate, the mortality rate was higher for SARS-CoV-2 pneumonia and deaths occurred later. New prognostic scales and more effective treatments are needed for patients with SARS-CoV-2 pneumonia

Mural Endocarditis: The GAMES Registry Series and Review of the Literature

Introduction: Mural infective endocarditis (MIE) is a rare type of endovascular infection. We present a comprehensive series of patients with mural endocarditis. Methods: Patients with infectious endocarditis (IE) from 35 Spanish hospitals were prospectively included in the GAMES registry between 2008 and 2017. MIEs were compared to non-MIEs. We also performed a literature search for cases of MIE published between 1979 and 2019 and compared them to the GAMEs series. Results: Twenty-seven MIEs out of 3676 IEs were included. When compared to valvular IE (VIE) or device-associated IE (DIE), patients with MIE were younger (median age 59 years, p \0.01). Transplantation (18.5% versus 1.6% VIE and 2% DIE, p \ 0.01), hemodialysis (18.5% versus 4.3% VIE and 4.4% DIE, p = 0.006), catheter source (59.3% versus 9.7% VIE and 8.8% DIE, p \ 0.01) and Candida etiology (22.2% versus 2% DIE and 1.2% VIE, p \ 0.01) were more common in MIE, whereas the Charlson Index was lower (4 versus 5 in non MIE, p = 0.006). Mortality was similar.MIE from the literature shared many characteristics with MIE from GAMES, although patients were younger (45 years vs. 56 years, p \ 0.001), the Charlson Index was lower (1.3 vs. 4.3, p = 0.0001), catheter source was less common (13.9% vs. 59.3%) and there were more IVDUs (25% vs. 3.7%). S. aureus was the most frequent microorganism (50%, p = 0.035). Systemic complications were more common but mortality was similar. Conclusion: MIE is a rare entity. It is often a complication of catheter use, particularly in immunocompromised and hemodialysis patients. Fungal etiology is common. Mortality is similar to other IEs

Mural Endocarditis: The GAMES Registry Series and Review of the Literature

Introduction: Mural infective endocarditis (MIE) is a rare type of endovascular infection. We present a comprehensive series of patients with mural endocarditis. Methods: Patients with infectious endocarditis (IE) from 35 Spanish hospitals were prospectively included in the GAMES registry between 2008 and 2017. MIEs were compared to non-MIEs. We also performed a literature search for cases of MIE published between 1979 and 2019 and compared them to the GAMEs series. Results: Twenty-seven MIEs out of 3676 IEs were included. When compared to valvular IE (VIE) or device-associated IE (DIE), patients with MIE were younger (median age 59 years, p < 0.01). Transplantation (18.5% versus 1.6% VIE and 2% DIE, p < 0.01), hemodialysis (18.5% versus 4.3% VIE and 4.4% DIE, p = 0.006), catheter source (59.3% versus 9.7% VIE and 8.8% DIE, p < 0.01) and Candida etiology (22.2% versus 2% DIE and 1.2% VIE, p < 0.01) were more common in MIE, whereas the Charlson Index was lower (4 versus 5 in non-MIE, p = 0.006). Mortality was similar. MIE from the literature shared many characteristics with MIE from GAMES, although patients were younger (45 years vs. 56 years, p < 0.001), the Charlson Index was lower (1.3 vs. 4.3, p = 0.0001), catheter source was less common (13.9% vs. 59.3%) and there were more IVDUs (25% vs. 3.7%). S. aureus was the most frequent microorganism (50%, p = 0.035). Systemic complications were more common but mortality was similar. Conclusion: MIE is a rare entity. It is often a complication of catheter use, particularly in immunocompromised and hemodialysis patients. Fungal etiology is common. Mortality is similar to other IEs

Effectiveness and safety of anti-CGRP monoclonal antibodies in patients over 65 years: a real-life multicentre analysis of 162 patients

Background Anti-CGRP monoclonal antibodies have shown notable effectiveness and tolerability in migraine patients; however, data on their use in elderly patients is still lacking, as clinical trials have implicit age restrictions and real-world evidence is scarce. In this study, we aimed to describe the safety and effectiveness of erenumab, galcanezumab and fremanezumab in migraine patients over 65 years old in real-life. Methods In this observational real-life study, a retrospective analysis of prospectively collected data from 18 different headache units in Spain was performed. Migraine patients who started treatment with any anti-CGRP monoclonal antibody after the age of 65 years were included. Primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and medication intake frequencies by months 3 and 6, response rates, changes in patient-reported outcomes and reasons for discontinuation. As a subanalysis, reduction in monthly migraine days and proportion of adverse effects were also compared among the three monoclonal antibodies. Results A total of 162 patients were included, median age 68 years (range 65-87), 74.1% women. 42% had dyslipidaemia, 40.3% hypertension, 8% diabetes, and 6.2% previous cardiovascular ischaemic disease. The reduction in monthly migraine days at month 6 was 10.17.3 days. A total of 25.3% of patients presented adverse effects, all of them mild, with only two cases of blood pressure increase. Headache and medication intake frequencies were significantly reduced, and patient-reported outcomes were improved. The proportions of responders were 68%, 57%, 33% and 9% for reductions in monthly migraine days >= 30%,>= 50%,>= 75% and 100%, respectively. A total of 72.8% of patients continued with the treatment after 6 months. The reduction in migraine days was similar for the different anti-CGRP treatments, but fewer adverse effects were detected with fremanezumab (7.7%). Conclusions Anti-CGRP mAbs are safe and effective treatments in migraine patients over 65 years old in real-life clinical practice

Microsatellite based genetic diversity and population structure of the endangered Spanish Guadarrama goat breed

<p>Abstract</p> <p>Background</p> <p>Assessing genetic biodiversity and population structure of minor breeds through the information provided by neutral molecular markers, allows determination of their extinction risk and to design strategies for their management and conservation. Analysis of microsatellite loci is known to be highly informative in the reconstruction of the historical processes underlying the evolution and differentiation of animal populations. Guadarrama goat is a threatened Spanish breed which actual census (2008) consists of 3057 females and 203 males distributed in 22 populations more or less isolated. The aim of this work is to study the genetic status of this breed through the analysis of molecular data from 10 microsatellites typed in historic and actual live animals.</p> <p>Results</p> <p>The mean expected heterozygosity across loci within populations ranged from 0.62 to 0.77. Genetic differentiation measures were moderate, with a mean F_STof 0.074, G_STof 0.081 and R_STof 0.085. Percentages of variation among and within populations were 7.5 and 92.5, respectively. Bayesian clustering analyses pointed out a population subdivision in 16 clusters, however, no correlation between geographical distances and genetic differences was found. Management factors such as the limited exchange of animals between farmers (estimated gene flow Nm = 3.08) mostly due to sanitary and social constraints could be the major causes affecting Guadarrama goat population subdivision.</p> <p>Conclusion</p> <p>Genetic diversity measures revealed a good status of biodiversity in the Guadarrama goat breed. Since diseases are the first cause affecting the census in this breed, population subdivision would be an advantage for its conservation. However, to maintain private alleles present at low frequencies in such small populations minimizing the inbreeding rate, it would necessitate some mating designs of animals carrying such alleles among populations. The systematic use of molecular markers will facilitate the comprehensive management of these populations, which in combination with the actual breeding program to increase milk yield, will constitute a good strategy to preserve the breed.</p

Working group on cephalopod fisheries and life history (Wgceph; outputs from 2022 meeting)

Rapports Scientifiques du CIEM. Volume 5, nº 1WGCEPH worked on six Terms of Reference. These involved reporting on the status of stocks; reviewing advances in stock identification, assessment for fisheries management and for the Ma- rine Strategy Framework Directive (MSFD), including some exploratory stock assessments; re- viewing impacts of human activities on cephalopods; developing identification guides and rec- ommendations for fishery data collection; describing the value chain and evaluating market driv- ers; and reviewing advances in research on environmental tolerance of cephalopods. ToR A is supported by an annual data call for fishery and survey data. During 2019–2021, com- pared to 1990–2020, cuttlefish remained the most important cephalopod group in terms of weight landed along the European North Atlantic coast, while loliginid squid overtook octopus as the second most important group. Short-finned squid remained the least important group in land- ings although their relative importance was almost double in 2019–2022 compared to 1992–2020. Total cephalopod landings have been fairly stable since 1992. Cuttlefish landings are towards the low end of the recent range, part of a general downward trend since 2004. Loliginid squid landings in 2019 were close to the maximum seen during the last 20 years but totals for 2020 and 2021 were lower. Annual ommastrephid squid landings are more variable than those of the other two groups and close to the maximum seen during 1992– 2021. Octopod landings have generally declined since 2002 but the amount landed in 2021 was higher than in the previous four years. Under ToR B we illustrate that the combination of genetic analysis and statolith shape analysis is a promising method to provide some stock structure information for L. forbsii. With the sum- mary of cephalopod assessments, we could illustrate that many cephalopod species could al- ready be included into the MSFD. We further provide material from two reviews in preparation, covering stock assessment methods and challenges faced for cephalopod fisheries management. Finally, we summarise trends in abundance indices, noting evidence of recent declines in cuttle- fish and some octopuses of the genus Eledone. Under ToR C, we describe progress on the reviews of (i) anthropogenic impacts on cephalopods and (ii) life history and ecology. In relation to life history, new information on Eledone cirrhosa from Portugal is included. Under ToR D we provide an update on identification guides, discuss best practice in fishery data collection in relation to maturity determination and sampling intensity for fishery monitoring. Among others, we recommend i) to include the sampling of cephalopods in any fishery that (a) targets cephalopods, (b) targets both cephalopods and demersal fishes or (c) takes cephalopods as an important bycatch, ii) Size-distribution sampling, iii) the use of standardized sampling pro- tocols, iv) an increased sampling effort in cephalopod. Work under ToR E on value chains and market drivers, in conjunction with the Cephs & Chefs INTERREG project, has resulted in two papers being submitted. Abstracts of these are in the report. Finally, progress under ToR F on environmental tolerance limits of cephalopods and climate en- velope models is discussed, noting the need to continue this work during the next cycle.info:eu-repo/semantics/publishedVersio

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation