HSP47 expression in the hamster Sertoli cell: An immunohistochemical study.

HSP47, a chaperone whose main function is the maturation of collagen molecules, is considered a marker of fibrotic diseases. Increased collagen synthesis in the testis has been associated with various pathologies leading to testicular seminiferous tubule regression. Our aim was to study whether HSP47 is expressed in hamster Sertoli cells both in the adult and in two physiological situations of seminiferous tubule atrophy: irreversible testicular ageing and testicular regression due to short (reversible) photoperiod. Eighteen animals were divided as follows: a group of 6 young animals aged 6 months, a group of 6 animals aged 24 months, which were exposed to a long photoperiod, and a final group of 6 young animals subjected to a short photoperiod. Testicular samples were fixed in methacarn and an immunohistochemical technique was used to detect HSP47. A semiquantitative study of the expression of this protein was performed between tubular sections of aged animals with complete spermatogenesis and arrested spermatogenesis with tubular sections with arrest spermatogenesis of photoinhibited testes. Sertoli cells were positive for HSP47, the intensity being higher in tubular sections with arrested spermatogenesis in both aged and photoinhibited animals. Sertoli cells were positive for HSP47, the intensity being greater in tubular sections with arrested spermatogenesis in both aged and photoinhibited animals. Semiquantitative analysis corroborated this observation in the sense that the expression of this protein differed according to the functional state of the seminiferous tubules. Thus, the intensity index of immunoreactivity was significantly higher in tubular sections with arrested spermatogenesis in aged animals compared with regressed animals, and in the latter compared with those whose tubular sections showed complete spermatogenesis. In conclusion, HSP47 expression in Sertoli cells was found for the first time in mammals. Moreover, increased expression seemed to be related to the degree of atrophy of the seminiferous epithelium and to the reversible or non-reversible physiological state of the seminiferous epithelium.

No evidence for association between rs10191329 severity locus and longitudinal disease severity in 1813 relapse-onset multiple sclerosis patients from the MSBase registry.

BACKGROUND: The International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if these variants remain associated with more robust, longitudinal measures of disease severity. METHODS: We examined the top variant, rs10191329, from Harroud et al.'s study in 1813 relapse-onset MS patients from the MSBase Registry to assess association with longitudinal disease severity. RESULTS: Our analysis revealed no significant association between rs10191329 genotype and longitudinal binary disease severity (p > 0.05). CONCLUSION: These findings highlight the complexity of genetic factors mediating long-term MS outcomes and the need for further research.

Professional Perspectives on Children's Health Assets: A Delphi Study.

This study aims to describe a local community expert's perspective on the identification of and access to children's health assets and to gather proposals to promote children's health and well-being within their community. The health asset approach is essential for health promotion, and there is evidence of its benefits to individuals' or communities' health when this approach is observed. Children's health assets are gaining increasing interest, but the literature that captures the perception of professionals working with children is scarce. Qualitative research designed with Delphi methodology was carried out with the participation of 25 professionals working in a neighbourhood with children and families. The participants stated that this neighbourhood was a good environment for the healthy and happy growth of children but pointed out that there were inequities. They emphasised the importance of economic and physical security and feeling loved. The absolute best aspects of the neighbourhood according to these experts were its support networks, mutual help, educational and health services, and green spaces, and the most deficient aspects were the possibility of a hopeful future and emotional support within the family unit. Poverty and/or the scarcity of economic resources were identified as the main barriers to accessing health assets. Special difficulties in access to health for migrant and Roma children were also identified. The panel of experts made concrete action proposals. It was recommended to support resources and services that already exist in their community. The experts prioritised work with families, education, working in conjunction with vulnerable groups, community participation, and networking.

Consistent effects of independent domestication events on the plant microbiota.

The effect of plant domestication on plant-microbe interactions remains difficult to prove. In this study, we provide evidence of a domestication effect on the composition and abundance of the plant microbiota. We focused on the genus Phaseolus, which underwent four independent domestication events within two species (P. vulgaris and P. lunatus), providing multiple replicates of a process spanning thousands of years. We targeted Phaseolus seeds to identify a link between domesticated traits and bacterial community composition as Phaseolus seeds have been subject to large and consistent phenotypic changes during these independent domestication events. The seed bacterial communities of representative plant accessions from subpopulations descended from each domestication event were analyzed under controlled and field conditions. The results showed that independent domestication events led to similar seed bacterial community signatures in independently domesticated plant populations, which could be partially explained by selection for common domesticated plant phenotypes. Our results therefore provide evidence of a consistent effect of plant domestication on seed microbial community composition and abundance and offer avenues for applying knowledge of the impact of plant domestication on the plant microbiota to improve microbial applications in agriculture.

Clinical Relevance of RSV and SARS-CoV-2 Coinfections in Infants and Young Children.

We analyzed the frequency, clinical impact and severity of respiratory syncytial virus (RSV) and SARS-CoV-2 coinfections in a single pediatric center between March 2020 and January 2023. Compared to single RSV infections, RSV/SARS-CoV-2 coinfections were uncommon (2.1%), occurred more frequently during circulation of omicron, and were associated with increased disease severity as defined by longer hospitalization and increased need for high-flow nasal cannula.

Selection signatures and population dynamics of transposable elements in lima bean.

The domestication process in lima bean (Phaseolus lunatus L.) involves two independent events, within the Mesoamerican and Andean gene pools. This makes lima bean an excellent model to understand convergent evolution. The mechanisms of adaptation followed by Mesoamerican and Andean landraces are largely unknown. Genes related to these adaptations can be selected by identification of selective sweeps within gene pools. Previous genetic analyses in lima bean have relied on Single Nucleotide Polymorphism (SNP) loci, and have ignored transposable elements (TEs). Here we show the analysis of whole-genome sequencing data from 61 lima bean accessions to characterize a genomic variation database including TEs and SNPs, to associate selective sweeps with variable TEs and to predict candidate domestication genes. A small percentage of genes under selection are shared among gene pools, suggesting that domestication followed different genetic avenues in both gene pools. About 75% of TEs are located close to genes, which shows their potential to affect gene functions. The genetic structure inferred from variable TEs is consistent with that obtained from SNP markers, suggesting that TE dynamics can be related to the demographic history of wild and domesticated lima bean and its adaptive processes, in particular selection processes during domestication.

Association of Serum Neurofilament Light Chain Levels at Disease Onset With Disability Worsening in Patients With a First Demyelinating Multiple Sclerosis Event Not Treated With High-Efficacy Drugs.

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial. Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event. Design, Setting, and Participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022). Exposures: Clinical evaluations at least every 6 months. Main Outcomes and Measures: The main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes. Results: Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values. Conclusions and Relevance: This cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Multifaceted Analysis of Cerebrospinal Fluid and Serum from Progressive Multiple Sclerosis Patients: Potential Role of Vitamin C and Metal Ion Imbalance in the Divergence of Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis.

The progressive forms of multiple sclerosis (MS) primary progressive MS (PPMS) and secondary progressive MS (SPMS) are clinically distinguished by the rate at which symptoms worsen. Little is however known about the pathological mechanisms underlying the differential rate of accumulation of pathological changes. In this study, 1H NMR spectroscopy was used to measure low-molecular-weight metabolites in paired cerebrospinal fluid (CSF) and serum of PPMS, SPMS, and control patients, as well as to determine lipoproteins and glycoproteins in serum samples. Additionally, neurodegenerative and inflammatory markers, neurofilament light (NFL) and chitinase-3-like protein 1 (CHI3L1), and the concentration of seven metal elements, Mg, Mn, Cu, Fe, Pb, Zn, and Ca, were also determined in both CSF and serum. The results indicate that the pathological changes associated with progressive MS are mainly localized in the central nervous system (CNS). More so, PPMS and SPMS patients with comparable disability status are pathologically similar in relation to neurodegeneration, neuroinflammation, and some metabolites that distinguish them from controls. However, the rapid progression of PPMS from the onset may be driven by a combination of neurotoxicity induced by heavy metals coupled with diminished CNS antioxidative capacity associated with differential intrathecal ascorbate retention and imbalance of Mg and Cu.

Not all roads lead to the immune system: the genetic basis of multiple sclerosis severity.

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; ßmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.

Clinical Phenotype of Respiratory Syncytial Virus Bronchiolitis before and during the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: The main objective of this report was to comprehensively analyze the clinical characteristics of children hospitalized with respiratory syncytial virus (RSV) infections in 2021 during the coronavirus disease 2019 (COVID-19) pandemic and to compare them with those in the five previous RSV seasons. We hypothesized that the clinical and demographic features of children hospitalized with RSV infection in 2021 were different from those hospitalized in previous respiratory seasons. STUDY DESIGN: In this retrospective observational study, children younger than 2 years hospitalized with RSV bronchiolitis from January 1, 2015, to December 31, 2021, at the Department of Pediatrics of the Hospital Gregorio Marañón, Madrid, Spain, were included. We compared the clinical characteristics of children hospitalized with RSV bronchiolitis in the five seasons before the COVID-19 pandemic and during the subsequent off-seasonal surge of RSV infections. RESULTS: We found a significant reduction in hospitalizations for RSV bronchiolitis during the usual winter epidemic period due to the COVID-19 pandemic. Children hospitalized with RSV infection in 2021, during the COVID-19 pandemic, were older than children hospitalized in the prepandemic period (2015-2020; 4.0 [1.6-9.2] vs. 3 [1.5-6.5] months; p < 0.01). We also found shorter duration of oxygen days during the COVID-19 period compared with previous respiratory seasons (3 [2-5] vs. 4 [2-6] days; p = 0.02). CONCLUSION: The COVID-19 pandemic modified the RSV seasonality with a significant reduction in RSV hospitalizations during the expected 2020-2021 season and a reappearance of RSV 7 months later than expected. We also found changes in the median age of children with RSV bronchiolitis during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic compared with the prepandemic RSV seasons and shorter duration of oxygen days suggesting a modest reduction in disease severity. We hypothesize that this observation reflects the lack of RSV circulation in the previous months (April 2020-March 2021), with a larger pool of vulnerable infants that had not been previously infected. KEY POINTS: · The COVID-19 pandemic shifted RSV seasonality.. · RSV children hospitalized during the pandemic were older.. · Modest reduction in disease severity was observed during the pandemic..

Effectiveness and safety of tocilizumab in monotherapy in biologic-naïve and non-naïve patients with rheumatoid arthritis in a real-world setting.

OBJECTIVE: To evaluate the effectiveness and safety of tocilizumab (TCZ) monotherapy in biologic-naïve patients with rheumatoid arthritis (RA) versus patients with previous biologic exposure in a real-world setting. MATERIALS AND METHODS: Non-controlled clinical-trial, 32-week prospective multicenter study including RA patients with moderate-severe disease activity starting TCZ in monotherapy who had a prior inadequate response or were intolerant to methotrexate (MTX). Effectiveness according to EULAR response evaluated at 24-week and safety at 32-weekwere assessed. RESULTS: Of the 93 were enrolled of whom 84 (90%) were eligible for the effectiveness analysis. Biologic-naïve patients (n=46, 54.8%) were younger (51.5 versus 57.9) with shorter disease duration (6.4 versus 13.3) but presented similar comorbidities in comparison with non-naïve patients. DAS28 remission was achieved in a higher percentage in the group of patients with prior biological treatment. 89 adverse events (AE) were recorded in 50 patients, most of them non-serious AE (non-SAE) (86.3%). CONCLUSIONS: In a real world setting, TCZ exhibit similar effectiveness and safety in monotherapy in patients with RA regardless previous exposure to other biologic therapies. This study provides additional and valuable real-world findings on the use of TCZ in patients with RA.

Validation of the inverse method for the determination of the access flow with thermodilution.

INTRODUCTION: Thermodiluction is a widely used method for measuring vascular access flow (QA). Among the possibilities of TD, the reverse method (MI) can be beneficial in the execution time, without impact on the dialysis efficacy (Kt). However, it is not a sufficiently studied technique. METHOD: Transversal study of 117 arteriovenous fistulas (AVF). Two QA measurements were taken with the method described by the manufacturer (MR) and another with MI. MI is bases in the obtention of an inverted recirculation registry at the beginning of the session and a single subsequent recirculation measurement with the lines in normal position. In the concordance analysis, the Bland-Altman method and Cohen's Kappa index were used. RESULTS: Very good concordance between MR and MI was evidenced for QA below 700 ml/min, but it worsens as flow increases. The median variability between the MR measurements (intra-method variability) was 3.4% (-17.13). This value did not differ from the median variability generated between MR and MI (inter-method variability), which was 2% (-14, 12) (P = 0.287). The degree of agreement between the two to identify AVFs susceptible to intervention was very good (K = 0.834). The time spent using the MI was significantly shorter (P = 0.000) without evidence of variations in the Kt of the measurement sessions (P = 0.201). CONCLUSIONS: The thermodiluction MI is valid to determine the flow of the vascular access, especially in Qa lower than 700 ml/min, with great time savings, simplification of the procedure and without modifying the dialysis efficiency. The variability between the measurement by MR and MI is similar to that of MR. The concordance between methods in identifying potentially pathological AVFs is very good.

Consequences of introgression and gene flow on the genetic structure and diversity of Lima bean (Phaseolus lunatus L.) in its Mesoamerican diversity area.

We evaluated the role of gene flow and wild-crop introgression on the structure and genetic diversity of Lima bean (Phaseolus lunatus) in the Yucatan Peninsula, an important Mesoamerican diversity area for this crop, using a genotyping-by-sequencing approach (15,168 SNP markers) and two scales. At the local scale, STRUCTURE and NGSEP analyses showed predominantly crop-to-wild introgression, but also evidence of a bidirectional gene flow in the two wild-weedy-crop complexes studied (Itzinté and Dzitnup). The ABBA-BABA tests showed a higher introgression in Itzinté (the older complex) than in Dzitnup (the younger one); at the allelic level, the wild-crop introgression in Itzinté was similar in both directions, in Dzitnup it was higher from crop-to-wild; and at the chromosomal level, introgression in Itzinté was from wild-to-crop, whereas in Dzitnup it occured in the opposite direction. Also, we found H E values slightly higher in the domesticated accessions than in the wild ones, in both complexes (Itzinté: wild = 0.31, domesticated = 0.34; Dzinup: wild = 0.27, domesticated = 0.36), but %P and π estimators were higher in the wild accessions than in the domesticated ones. At a regional scale, STRUCTURE and MIGRATE showed a low gene flow, predominantly from crop-to-wild; and STRUCTURE, Neighbor-Joining and PCoA analyses indicated the existence of two wild groups and one domesticated group, with a marked genetic structure based in the existence of domesticated MI and wild MII gene pools. Also, at the regional scale, we found a higher genetic diversity in the wild accessions than in the domesticated ones, in all estimators used (e.g., H E = 0.27 and H E = 0.17, respectively). Our results indicate that gene flow and introgression are playing an important role at the local scale, but its consequences on the structure and genetic diversity of the Lima bean are not clearly reflected at the regional scale, where diversity patterns between wild and domesticated populations could be reflecting historical events.

Cellular Modifications in Spermatogenesis during Seasonal Testicular Regression: An Update Review in Mammals.

Testicular regression occurs during the non-breeding season in many mammals. This affects spermatogenesis, resulting in decreased or arrested activity. Both lead to a decrease or cessation in sperm production. In recent years, the cellular mechanisms that lead to infertility in males in non-reproductive periods have been studied in very different species of mammals. At the start of the present century, the main mechanism involved was considered as an increase in the apoptotic activity of germ cells during the regression period. The loss of spermatogonia and spermatocytes causes not only a decrease in spermatogenesis, but an arrest of the seminiferous epithelium activity at the end of regression. Recently, in some mammal species, it was found that apoptosis is the usual mechanism involved in epithelium activity arrest, although it is firstly atrophied by massive desquamation of the germ cells that are released from their binding with the Sertoli cells, and which are shed into the lumen of the seminiferous tubule. In other species, it has been shown that not only germ cell apoptosis, but also Sertoli cell apoptosis, including decreased proliferative activity, spermatophagy or autophagy, are involved in testicular regression. Furthermore, the most recent studies indicate that there are multiple patterns of seminiferous epithelium regression in seasonally breeding animals, which may not only be used by different species, but also by the same ones to reproduce in the best conditions, ensuring their survival. In conclusion, at this time, it is not possible to consider the existence of a paradigmatic cellular mechanism in the involution of the seminiferous epithelium applicable to all male mammals with seasonal reproduction, rather the existence of several mechanisms which participate to a greater or lesser extent in each of the species that have been studied to date.

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration.

There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Usefulness of Impella support in different clinical settings in cardiogenic shock.

BACKGROUND: The Impella pump has emerged as a promising tool in patients with cardiogenic shock (CS). Despite its attractive properties, there are scarce data on the specific clinical setting and the potential role of Impella devices in CS patients from routine clinical practice. METHODS: This is an observational, retrospective, single center, cohort study. All consecutive patients with diagnosis of CS and undergoing support with Impella 2.5®, Impella CP® or Impella 5.0® from April 2015 to December 2020 were included. Baseline characteristics, management and outcomes were assessed according to CS severity, age and cause of CS. Main outcome measured was in-hospital mortality. RESULTS: A total of 50 patients were included (median age: 59.3 ± 10 years). The most common cause of CS was acute coronary syndrome (ACS) (68%), followed by decompensation of previous cardiomyopathy (22%). A total of 13 patients (26%) had profound CS. Most patients (54%) improved pulmonary congestion at 48 h after Impella support. A total of 19 patients (38%) presented significant bleeding. In-hospital mortality was 42%. Among patients with profound CS (n = 13), five patients were previously supported with venoarterial extracorporeal membrane oxygenation. A total of eight patients (61.5%) died during the admission, and no patient achieved ventricular recovery. Older patients (≥ 67 years, n = 10) had more comorbidities and the highest mortality (70%). Among patients with ACS (n = 34), 35.3% of patients had profound CS; and in most cases (52.9%), Impella support was performed as a bridge to recovery. In contrast, only one patient from the decompensated cardiomyopathy group (n = 11) presented with profound CS. In 90.9% of these cases, Impella support was used as a bridge to cardiac transplantation. There were no cases of death. CONCLUSIONS: In this cohort of real-life CS patients, Impella devices were used in different settings, with different clinical profiles and management. Despite a significant rate of complications, mortality was acceptable and lower than those observed in other series.

High prevalence of intrathecal IgA synthesis in multiple sclerosis patients.

The detection of intrathecal IgA synthesis (IAS) in multiple sclerosis (MS) could be underestimated. To assess it, we develop a highly sensitive assay based on isoelectric focusing (IEF). 151 MS patients and 53 controls with different neurological diseases were recruited. IgA concentration was analyzed using a newly developed in house ELISA. IgA oligoclonal bands to detect IAS were determined by IEF. Most individuals showed an IgA concentration within normal range in serum samples (90.69%) but 31.37% of individuals had a IgA concentration below the normal range in the cerebrospinal fluid (CSF). No significant differences were observed between MS and control groups, neither in CSF nor in serum. The new IEF was more sensitive than those previously described (0.01 mg/dl of IgA), and clearly identified patients with and without IAS, that was not related with IgA concentration. Using IEF, MS patients showed higher percentage of IAS-IEF (43.00%) than the control group (16.98) (p = 0.001). The incidence was especially higher in patients with clinically isolated syndrome (66.00%). The new IFE demonstrated a higher percentage of IAS in MS patients than assumed in the past. The presence of IAS-IEF in MS is higher than in other neurological diseases.

Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis.

Multiple sclerosis (MS) is a complex and demyelinating disease of the central nervous system. One of the challenges of the post-genome-wide association studies (GWAS) era is to understand the molecular basis of statistical associations to reveal gene networks and potential therapeutic targets. The L3MBTL3 locus has been associated with MS risk by GWAS. To identify the causal variant of the locus, we performed fine mapping in a cohort of 3440 MS patients and 1688 healthy controls. The variant that best explained the association was rs6569648 (P = 4.13E-10, odds ratio = 0.71, 95% confidence interval (CI) = 0.64-0.79), which tagged rs7740107, located in intron 7 of L3MBTL3. The rs7740107 (A/T) variant has been reported to be the best expression and splice quantitative trait locus (eQTL and sQTL) of the region in up to 35 human genotype-tissue expression (GTEx) tissues. By sequencing RNA from blood of 17 MS patients and quantification by digital qPCR, we determined that this eQTL/sQTL originated from the expression of a novel short transcript starting in intron 7 near rs7740107. The short transcript was translated into three proteins starting at different translation initiation codons. These N-terminal truncated proteins lacked the region where L3MBTL3 interacts with the transcriptional regulator Recombination Signal Binding Protein for Immunoglobulin Kappa J Region which, in turn, regulates the Notch signalling pathway. Our data and other functional studies suggest that the genetic mechanism underlying the MS association of rs7740107 affects not only the expression of L3MBTL3 isoforms, but might also involve the Notch signalling pathway.

Age and respiratory syncytial virus etiology in bronchiolitis clinical outcomes.

Background: Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis. Precise and updated information about demographic characteristics, clinical manifestations, and risk factors for severe disease are needed for optimal implementation of upcoming new therapeutic and preventive interventions. Objectives: The main goals of this study were to define the epidemiology of acute bronchiolitis in hospitalized young children during 5 calendar years in Spain; evaluate the differences in clinical manifestations between children hospitalized with RSV infection and those hospitalized with non-RSV infection; and identify demographic characteristics, clinical parameters, and risk factors associated with disease severity. Methods: We performed a retrospective review of the medical records of children younger than 2 years who were hospitalized with bronchiolitis between January 2015 and December 2019. We constructed multivariable models to identify independent predictors of disease severity defined as length of hospital stay (LOS), pediatric intensive care unit (PICU) admission, and need for a high-flow-nasal canula (HFNC). Results: From January 2015 to December 2019, 1437 children were hospitalized with bronchiolitis and met the inclusion criteria. The proportion of children hospitalized with bronchiolitis caused by RSV increased significantly during the study period, from 60% to 65% (P = .03). The children with RSV bronchiolitis were younger than those with non-RSV bronchiolitis (median age = 3 months [interquartile range = 1.5-6.5 months] vs 4 months [interquartile range = 2-7.5 months], respectively (P < .01). The children younger than 6 months with RSV bronchiolitis had enhanced disease severity compared with those with non-RSV bronchiolitis, as defined by an LOS of more than 4 days, severity scores, need for an HFNC, intravenous fluids, enteral feeding, and PICU admissions (P < .01). Age younger than 6 months and RSV-positive etiology were independently associated with greater odds of PICU admission, need for an HFNC, and longer LOS. Conclusion: This study identified differences in disease severity between young children with RSV bronchiolitis and those with non-RSV bronchiolitis. These differences are particularly significant in children younger than 6 months, who comprise a group of infants with suboptimal innate immunity to RSV and may benefit from new preventive strategies.