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We showed previously that the ABL-mediated phosphorylation of SOS1 promotes RAC activation and contributes to BCR-ABL leukemogenesis, suggesting the relevant role of SOS1 in the pathogenesis of CML. To try and obtain direct experimental evidence of the specific mechanistic implication of SOS1 in CML development, here, we combined a murine model of CML driven by a p210BCR/ABL transgene with our tamoxifen-inducible SOS1/2-KO system in order to investigate the phenotypic impact of the direct genetic ablation of SOS1 or SOS2 on the pathogenesis of CML. Our observations showed that, in contrast to control animals expressing normal levels of SOS1 and SOS2 or to single SOS2-KO mice, p210BCR/ABL transgenic mice devoid of SOS1 presented significantly extended survival curves and also displayed an almost complete disappearance of the typical hematological alterations and splenomegaly constituting the hallmarks of CML. SOS1 ablation also resulted in a specific reduction in the proliferation and the total number of colony-forming units arising from the population of bone marrow stem/progenitor cells from p210BCR/ABL transgenic mice. The specific blockade of CML development caused by SOS1 ablation in p210BCR/ABL mice indicates that SOS1 is critically required for CML pathogenesis and supports the consideration of this cellular GEF as a novel, alternative bona fide therapeutic target for CML treatment in the clinic.

In the context of difficult-to-treat carbapenem-resistant Pseudomonas aeruginosa infections, we evaluated imipenem, meropenem, and doripenem combinations against eleven carbapenemase-producing P. aeruginosa isolates. According to the widespread global distribution of high-risk clones and carbapenemases, four representative isolates were selected: ST175 (OXA-2/VIM-20), ST175 (VIM-2), ST235 (GES-5), and ST111 (IMP-33), for efficacy studies using a sepsis murine model. Minimum inhibitory concentration (mg/L) ranges were 64–256 for imipenem and 16–128 for meropenem and doripenem. In vitro, imipenem plus meropenem was synergistic against 72% of isolates and doripenem plus meropenem or imipenem against 55% and 45%, respectively. All combinations were synergistic against the ST175, ST235, and ST155 clones. In vivo, meropenem diminished the spleen and blood bacterial concentrations of four and three isolates, respectively, with better efficacy than imipenem or doripenem. The combinations did not show efficacy compared with the more active monotherapies, except for imipenem plus meropenem, which reduced the ST235 bacterial spleen concentration. Mortality decreased with imipenem plus meropenem or doripenem for the ST175 isolate. Results suggest that carbapenem combinations are not an alternative for severe infections by carbapenemase-producing P. aeruginosa. Meropenem monotherapy showed in vivo efficacy despite its high MIC, probably because its dosage allowed a sufficient antimicrobial exposure at the infection sites.

Inborn errors of immunity are a heterogeneous group of genetically determined disorders that compromise the immune system, predisposing patients to infections, autoinflammatory/autoimmunity syndromes, atopy/allergies, lymphoproliferative disorders, and/or malignancies. An emerging manifestation is susceptibility to fungal disease, caused by yeasts or moulds, in a superficial or invasive fashion. In this review, we describe recent advances in the field of inborn errors of immunity associated with increased susceptibility to fungal disease.

With a high risk of relapse and death, and a poor or absent response to therapeutics, the triple-negative breast cancer (TNBC) subtype is particularly challenging, especially in patients who cannot achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Although the tumor microenvironment (TME) is known to influence disease progression and the effectiveness of therapeutics, its predictive and prognostic potential remains uncertain. This work aimed to define the residual TME profile after NAC of a retrospective cohort with 96 TNBC patients by immunohistochemical staining (cell markers) and chromogenic in situ hybridization (genetic markers). Kaplan–Meier curves were used to estimate the influence of the selected TME markers on five-year overall survival (OS) and relapse-free survival (RFS) probabilities. The risks of each variable being associated with relapse and death were determined through univariate and multivariate Cox analyses. We describe a unique tumor-infiltrating immune profile with high levels of lymphocytes (CD4, FOXP3) and dendritic cells (CD21, CD1a and CD83) that are valuable prognostic factors in post-NAC TNBC patients. Our study also demonstrates the value of considering not only cellular but also genetic TME markers such as MUC-1 and CXCL13 in routine clinical diagnosis to refine prognosis modelling.

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the best therapeutic option for many patients with acute myeloid leukemia (AML). However, relapse remains the main cause of mortality after transplantation. The detection of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in AML, before and after HSCT, has been described as a powerful predictor of outcome. Nevertheless, multicenter and standardized studies are lacking. A retrospective analysis was performed, including 295 AML patients undergoing HSCT in 4 centers that worked according to recommendations from the Euroflow consortium. Among patients in complete remission (CR), MRD levels prior to transplantation significantly influenced outcomes, with overall (OS) and leukemia free survival (LFS) at 2 years of 76.7% and 67.6% for MRD-negative patients, 68.5% and 49.7% for MRD-low patients (MRD < 0.1), and 50.5% and 36.6% for MRD-high patients (MRD ≥ 0.1) (p < 0.001), respectively. MRD level did influence the outcome, irrespective of the conditioning regimen. In our patient cohort, positive MRD on day +100 after transplantation was associated with an extremely poor prognosis, with a cumulative incidence of relapse of 93.3%. In conclusion, our multicenter study confirms the prognostic value of MRD performed in accordance with standardized recommendations.

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity

Next–Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross–validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS–AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co–occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia–related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.

Background and objective: There are barriers to deprescription that hinder its implementation in clinical practice. The objective of this study was to analyse the main barriers and limitations of the deprescription process perceived by physicians who care for multipathological patients. Materials and methods: The “deprescription questionnaire of elderly patients” was adapted to an online format and sent to physicians in geriatrics. Question 1 is a reference to establish agreement or disagreement with this practice. The influence of different aspects of deprescription was analysed via the demographic characteristics of the clinicians and perceptions of the various barriers (questions 2–9) by means of bivariate analysis. Based on the latter, a multivariate model was carried out to demonstrate the relationship between barriers and the degree of deprescription agreement among respondents. Results: Of the 72 respondents, 72.2% were in favour of deprescribing. Regarding the analyses, the demographic characteristics did not influence rankings. The deprescription of preventive drugs and consensus with patients were associated with a positive attitude towards deprescribing, while withdrawing drugs prescribed by other professionals, time constraints and patient reluctance emerged as possible barriers. The only factor independently associated with deprescribing was lack of time. Conclusions: Time was found to be the main barrier to deprescription. Training, the creation of multidisciplinary teams and integrated health systems are key facilitators.

Leishmania infantum is one of the causative agents of visceral leishmaniases, the most severe form of leishmaniasis. An improved assembly for the L. infantum genome was published five years ago, yet delineation of its transcriptome remained to be accomplished. In this work, the transcriptome annotation was attained by a combination of both short and long RNA-seq reads. The good agreement between the results derived from both methodologies confirmed that transcript assembly based on Illumina RNA-seq and further delimitation according to the positions of spliced leader (SAS) and poly-A (PAS) addition sites is an adequate strategy to annotate the transcriptomes of Leishmania, a procedure previously used for transcriptome annotation in other Leishmania species and related trypanosomatids. These analyses also confirmed that the Leishmania transcripts boundaries are relatively slippery, showing extensive heterogeneity at the 5′- and 3′-ends. However, the use of RNA-seq reads derived from the PacBio technology (referred to as Iso-Seq) allowed the authors to uncover some complex transcription patterns occurring at particular loci that would be unnoticed by the use of short RNA-seq reads alone. Thus, Iso-Seq analysis provided evidence that transcript processing at particular loci would be more dynamic than expected. Another noticeable finding was the observation of a case of allelic heterozygosity based on the existence of chimeric Iso-Seq reads that might be generated by an event of intrachromosomal recombination. In addition, we are providing the L. infantum gene models, including both UTRs and CDS regions, that would be helpful for undertaking whole-genome expression studies. Moreover, we have built the foundations of a communal database for the active curation of both gene/transcript models and functional annotations for genes and proteins.

Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by progressive accumulation of a rare population of CD5+ B-lymphocytes in peripheral blood, bone marrow, and lymphoid tissues. CLL exhibits remarkable clinical heterogeneity, with some patients presenting with indolent disease and others progressing rapidly to aggressive CLL. The significant heterogeneity of CLL underscores the importance of identifying novel prognostic markers. Recently, the RAS-related gene RRAS2 has emerged as both a driver oncogene and a potential marker for CLL progression, with higher RRAS2 expression associated with poorer disease prognosis. Although missense somatic mutations in the coding sequence of RRAS2 have not been described in CLL, this study reports the frequent detection of three somatic mutations in the 3′ untranslated region (3′UTR) affecting positions +26, +53, and +180 downstream of the stop codon in the mRNA. An inverse relationship was observed between these three somatic mutations and RRAS2 mRNA expression, which correlated with lower blood lymphocytosis. These findings highlight the importance of RRAS2 overexpression in CLL development and prognosis and point to somatic mutations in its 3′UTR as novel mechanistic clues. Our results may contribute to the development of targeted therapeutic strategies and improved risk stratification for CLL patients.

Risk of suicidal behaviour (SB) in schizophrenia spectrum disorders (SSD) is a major concern, particularly in early stages of the illness, when suicide accounts for a high number of premature deaths. Although some risk factors for SB in SSD are well understood, the extent to which personality traits may affect this risk remains unclear, which may have implications for prevention. We conducted a systematic review of previous studies indexed in MEDLINE, PsycINFO and Embase examining the relationship between personality traits and SB in samples of patients with SSD. Seven studies fulfilled predetermined selection criteria. Harm avoidance, passive-dependent, schizoid and schizotypal personality traits increased the risk of SB, while self-directedness, cooperativeness, excluding persistence and self-transcendence acted as protective factors. Although only seven studies were retrieved from three major databases after applying predetermined selection criteria, we found some evidence to support that personality issues may contribute to SB in patients with SSD. Personality traits may therefore become part of routine suicide risk assessment and interventions targeting these personality-related factors may contribute to prevention of SB in SSD.

Elderly people confined to chronic care facilities face an increased risk of acquiring infections by multidrug-resistant organisms (MDROs). This review presents the current knowledge of the prevalence and risk factors for colonization by MDROs in long-term care facilities (LTCF), thereby providing a useful reference to establish objectives for implementing successful antimicrobial stewardship programs (ASPs). We searched in PubMed and Scopus for studies examining the prevalence of MDROs and/or risk factors for the acquisition of MDROs in LTCF. One hundred and thirty-four studies published from 1987 to 2020 were included. The prevalence of MDROs in LTCF varies between the different continents, where Asia reported the highest prevalence of extended-spectrum ß-lactamase (ESBL) Enterobacterales (71.6%), carbapenem resistant (CR) Enterobacterales (6.9%) and methicillin-resistant Staphylococcus aureus (MRSA) (25.6%) and North America the highest prevalence to MDR Pseudomonas aeruginosa (5.4%), MDR Acinetobacter baumannii (15.0%), vancomycin-resistant Enterococcus spp. (VRE) (4.0%), and Clostridioides difficile (26.1%). Furthermore, MDRO prevalence has experienced changes over time, with increases in MDR P. aeruginosa and extended spectrum ß-lactamase producing Enterobacterales observed starting in 2015 and decreases of CR Enterobacterales, MDR A. baumannii, VRE, MRSA and C. difficile. Several risk factors have been found, such as male sex, chronic wounds, the use of medical devices, and previous antibiotic use. The last of these aspects represents one of the most important modifiable factors for reducing colonization with MDROs through implementing ASPs in LTCF.

Recent reports have identified rare, biallelic damaging variants of the AGTPBP1 gene that cause a novel and documented human disease known as childhood-onset neurodegeneration with cerebellar atrophy (CONDCA), linking loss of function of the AGTPBP1 protein to human neurodegenerative diseases. CONDCA patients exhibit progressive cognitive decline, ataxia, hypotonia or muscle weakness among other clinical features that may be fatal. Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene. In particular, in the Purkinje cell degeneration (pcd) mouse model, mutations in AGTPBP1 lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells. In addition, neurodegeneration in the olfactory bulb, retina, thalamus and spinal cord were also reported. In addition to neurodegeneration, pcd mice show behavioural deficits such as cognitive decline. Here, we provide an overview of what is currently known about the structure and functional role of AGTPBP1 and discuss the various alterations in AGTPBP1 that cause neurodegeneration in the pcd mutant mouse and humans with CONDCA. The sequence of neuropathological events that occur in pcd mice and the mechanisms governing these neurodegenerative processes are also reported. Finally, we describe the therapeutic strategies that were applied in pcd mice and focus on the potential usefulness of pcd mice as a promising model for the development of new therapeutic strategies for clinical trials in humans, which may offer potential beneficial options for patients with AGTPBP1 mutation-related CONDCA.

Currently, brachytherapy is the most commonly used therapeutic approach for uveal melanomas. Surgical resection by means of endoresection or exoresection is an alternative approach. The present report recounts our experience over 15 years in the treatment of uveal melanoma using a combined approach of resection surgery with brachytherapy. This is a single-center observational retrospective cohort study in which we describe clinical outcomes, complications and survival in 35 cases of melanoma of the iris or the ciliary body after a combination of surgery and brachytherapy or brachytherapy alone. Local treatment of the tumor was successful in all cases with surgery and brachytherapy. The most frequent complications were scleromalacia, bullous keratopathy, retinal toxicity, cataracts, hypotonia, and photophobia. There were three cases of recurrence, all of which were found in the group of patients who had received brachytherapy alone, and in one case we had to perform a secondary enucleation due to tumor growth after brachytherapy. At present, only one patient has died during follow-up due to liver metastases six years after the start of treatment. In carefully selected patients, this approach can be effective and safe, as long as a close follow-up is carried out after surgery.

Nivolumab (anti-PD-1 antibody) and atezolizumab (anti-PD-L1 antibody) have shown superior survival outcomes and improved adverse effects compared to standard chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. However, the efficacy of both treatments has not been directly compared in clinical trials. This retrospective, single-centre study was performed from June 2015 to December 2020 and included a cohort of 158 previously treated patients with stage IV or recurrent NSCLC who received PD-1 (nivolumab) (n = 89) or PD-L1 (atezolizumab) (n = 69) inhibitors at the Virgen del Rocío Hospital in Seville. The objective response rate (ORR) was 22.5% in the nivolumab group and 14.5% in the atezolizumab group (p = 0.140). Multivariate analysis did not show significant differences between the two groups for PFS and OS (PFS hazard ratio (HR): 0.80, 95% confidence interval (CI): 0.55–1.17, p = 0.260; OS HR: 0.79, 95% CI: 0.52–1.21, p = 0.281). Adverse events of all grades occurred in 68 patients in the nivolumab group (76.4%) and in 34 patients in the atezolizumab group (49.3%) (p < 0.001). Atezolizumab and nivolumab did not show statistically significant differences in survival outcomes in patients with NSCLC, even when stratified by histological subtype (squamous versus nonsquamous). However, the safety analysis suggested a more favourable toxicity profile for atezolizumab.

To assess the effect of combination antibiotic empirical therapy on 30-day case-fatality rate in neutropenic cancer patients with Pseudomonas aeruginosa (PA) bacteremic pneumonia. This was a multinational, retrospective cohort study of neutropenic onco-hematological patients with PA blood stream infection (BSI) (2006–2018). The effect of appropriate empirical combination therapy, appropri ate monotherapy and inappropriate empirical antibiotic therapy [IEAT] on 30-day case-fatality was assessed only in patients with PA bacteremic pneumonia. Among 1017 PA BSI episodes, pneumonia was the source of BSI in 294 (28.9%). Among those, 52 (17.7%) were caused by a multidrug-resistant (MDR) strain and 68 (23.1%) received IEAT, mainly when the infection was caused by an MDR strain [38/52 (73.1%) vs. 30/242 (12.4%); p < 0.001]. The 30-day case-fatality rate was higher in patients with PA bacteremic pneumonia than in those with PA BSI from other sources (55.1% vs. 31.4%; p < 0.001). IEAT was associated with increased 30-day case-fatality (aHR 1.44 [95%CI 1.01–2.03]; p = 0.042), whereas the use of appropriate combination empirical treatment was independently associated with improved survival (aHR 0.46 [95%CI 0.27–0.78]; p = 0.004). Appropriate empiri cal monotherapy was not associated with improved overall survival (aHR 1.25 [95%CI 0.76–2.05]; p = 0.39). Combination antibiotic empirical therapy should be administered promptly in febrile neutropenic patients with suspected pneumonia as the source of infection.

Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. Conclusions: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response.

Background and objective: Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, which leads to subfertility. PCOS is the most frequent metabolic disorder in women and the major cause of infertility. Susceptibility to developing PCOS is determined by a complex interaction between environmental and genetic factors. Although different mechanisms have been proposed to explain PCOS manifestations, defects in insulin actions or in the insulin signaling pathways are central in the pathogenesis of the syndrome. However, the mechanisms (molecular players and signaling pathways) underlying its primary origin still remain an unsolved issue. Current research is increasingly focusing on the discovery of novel biomarkers to further elucidate the complex pathophysiology of PCOS. Sam68, an RNA-binding protein, is recruited to insulin signaling, mediating different insulin actions. We aimed to investigate the role of Sam68 in insulin signaling and the possible implications of Sam68 in the insulin resistance in PCOS. Materials and methods: Granulosa cells were taken from women with PCOS (n = 25) and healthy donors (n = 25) and, within the age range of 20 to 42 years, from GINEMED, Assisted Reproduction Centre, Seville, Spain. The Sam68 expression level was analyzed both by qPCR and immunoblot. Statistical significance was assessed by one-way ANOVA, followed by a post-hoc test. A p value of < 0.05 was considered statistically significant. Results: We found that insulin stimulation increases the phosphorylation and expression level of Sam68 in granulosa cells from normal donors. The downregulation of Sam68 expression resulted in a lower activation of both the MAPK and the PI3K pathways in response to insulin. Moreover, the granulosa cells from the women with PCOS presented a lower expression of Sam68, as well as insulin receptor and insulin receptor substrate-1 (IRS-1). In these cells

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

Scant information is available concerning the characteristics that may favour the acquisition of COVID-19 in patients with inflammatory bowel disease (IBD). Therefore, the aim of this study was to assess these differences between infected and noninfected patients with IBD. (2) This nationwide case–control study evaluated patients with inflammatory bowel disease with COVID-19 (cases) and without COVID-19 (controls) during the period March–July 2020 included in the ENEIDA of GETECCU. (3) A total of 496 cases and 964 controls from 73 Spanish centres were included. No differences were found in the basal characteristics between cases and controls. Cases had higher comorbidity Charlson scores (24% vs. 19%; p = 0.02) and occupational risk (28% vs. 10.5%; p < 0.0001) more frequently than did controls. Lockdown was the only protective measure against COVID-19 (50% vs. 70%; p < 0.0001). No differences were found in the use of systemic steroids, immunosuppressants or biologics between cases and controls. Cases were more often treated with 5-aminosalicylates (42% vs. 34%; p = 0.003). Having a moderate Charlson score (OR: 2.7; 95%CI: 1.3–5.9), occupational risk (OR: 2.9; 95%CI: 1.8–4.4) and the use of 5-aminosalicylates (OR: 1.7; 95%CI: 1.2–2.5) were factors for COVID-19. The strict lockdown was the only protective factor (OR: 0.1; 95%CI: 0.09–0.2). (4) Comorbidities and occupational exposure are the most relevant factors for COVID-19 in patients with IBD. The risk of COVID-19 seems not to be increased by immunosuppressants or biologics, with a potential effect of 5-aminosalicylates, which should be investigated further and interpreted with caution.

Extracellular vesicles (EVs) are membrane-derived vesicles released by a variety of cell types, including hepatocytes, hepatic stellate cells, and immune cells in normal and pathological conditions. Depending on their biogenesis, there is a complex repertoire of EVs that differ in size and origin. EVs can carry lipids, proteins, coding and non-coding RNAs, and mitochondrial DNA causing alterations to the recipient cells, functioning as intercellular mediators of cell–cell communication (auto-, para-, juxta-, or even endocrine). Nevertheless, many questions remain unanswered in relation to the function of EVs under physiological and pathological conditions. The development and optimization of methods for EV isolation are crucial for characterizing their biological functions, as well as their potential as a treatment option in the clinic. In this manuscript, we will comprehensively review the results from different studies that investigated the role of hepatic EVs during liver diseases, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, fibrosis, and hepatocellular carcinoma. In general, the identification of patients with early-stage liver disease leads to better therapeutic interventions and optimal management. Although more light needs to be shed on the mechanisms of EVs, their use for early diagnosis, follow-up, and prognosis has come into the focus of research as a high-potential source of ‘liquid biopsies’, since they can be found in almost all biological fluids. The use of EVs as new targets or nanovectors in drug delivery systems for liver disease therapy is also summarized.

Recent studies in mice and humans demonstrated the relevance of H2S synthesising enzymes, such as CTH, CBS, and MPST, in the physiology of adipose tissue and the differentiation of preadipocyte into adipocytes. Here, our objective was to investigate the combined role of CTH, CBS, and MPST in the preservation of adipocyte protein persulfidation and adipogenesis. Combined partial CTH, CBS, and MPST gene knockdown was achieved treating fully human adipocytes with siRNAs against these transcripts (siRNA_MIX). Adipocyte protein persulfidation was analyzed using label-free quantitative mass spectrometry coupled with a dimedone-switch method for protein labeling and purification. Proteomic analysis quantified 216 proteins with statistically different levels of persulfidation in KD cells compared to control adipocytes. In fully differentiated adipocytes, CBS and MPST mRNA and protein levels were abundant, while CTH expression was very low. It is noteworthy that siRNA_MIX administration resulted in a significant decrease in CBS and MPST expression, without impacting on CTH. The combined partial knockdown of the CBS and MPST genes resulted in reduced cellular sulfide levels in parallel to decreased expression of relevant genes for adipocyte biology, including adipogenesis, mitochondrial biogenesis, and lipogenesis, but increased proinflammatory- and senescence-related genes. It should be noted that the combined partial knockdown of CBS and MPST genes also led to a significant disruption in the persulfidation pattern of the adipocyte proteins. Although among the less persulfidated proteins, we identified several relevant proteins for adipocyte adipogenesis and function, among the most persulfidated, key mediators of adipocyte inflammation and dysfunction as well as some proteins that might play a positive role in adipogenesis were found. In conclusion, the current study indicates that the combined partial elimination of CBS and MPST (but not CTH) in adipocytes affects the expr

Objectives: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain. Methods: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis. Results: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins. Conclusions: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.

FLT3–ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3–ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3–ITD mutations. In multivariate analyses, patients with an FLT3–ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3–ITD-mutated patients, median OS gradually decreased according to FLT3–ITD status and ratio (34.3 months FLT3–ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3–ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3–ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3–ITD status in all patients, and we found that the group of FLT3–ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3–ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3–ITD mutations.

Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvi ronment and its clinical significance, we quantified several relevant immune biomarkers. Design: We studied 76 primary (non-recurrent) GBMs with sufficient clinical follow-up, including a subgroup of patients treated with a dendritic cell vaccine. The IDH-mutation, EGFR-amplification, and MGMT methylation statuses were determined. Several relevant immune biomarkers, including CD163, CD8, PD1, and PDL1, were quantified in representative selected areas by digital image analysis and semi quantitative evaluation. The percentage of each immune expression was calculated with respect to the total number of tumor cells. Results: All GBMs were wild-type IDH, with a subgroup of classical GBMs according to the EGFR amplification (44%). Morphologically, CD163 immunostained microglia and intratumor clusters of macrophages were observed. A significant direct correlation was found between the expression of CD8 and the mechanisms of lymphocyte immunosuppression, in such a way that higher values of CD8 were directly associated with higher values of CD163 (p < 0.001), PDL1 (0.026), and PD1 (0.007). In a multivariate analysis, high expressions of CD8+ (HR = 2.05, 95%CI (1.02–4.13), p = 0.034) and CD163+ cells (HR 2.50, 95%CI (1.29–4.85), p = 0.007), were associated with shorter survival durations. The expression of immune biomarkers was higher in the non-classical (non-EGFR amplified tumors) GBMs. Other relevant prognostic factors were age, receipt of the dendritic cell vaccine, and MGMT methylation status. Conclusions: In accordance with the inverse correlation between CD8 and survival and the direct correlation between effector cells and CD163 macrophages and immune-checkpoint expression, we postulate that

Ustekinumab has shown efficacy in Crohn’s Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients’ data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index ≤ 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission..

Morphological embryo quality is an accurate prognostic tool for the success of assisted reproduction implantation, although complete certainty cannot be guaranteed. The transcriptome of the cumulus cells could be monitored as a faithful reflex of the physiological state of the oocytes, given the molecular crosstalk between both types of cells. Here, we compare the expression of specific genes related to oocyte competence, such as hyaluronic acid synthase 2 (HAS2), cell division control protein 42 (CDC42), connexin 43 (CX43), and glutathione peroxidase 3 (GPX3), in cumulus cells from implanted versus non-implanted embryos in 25 women, using RT-qPCR. After embryo transfer, two cohorts were differentiated: the pregnant group (women with the implantation of 100% of embryos transferred) versus the non-pregnant group (with an absence of embryo implantation), aiming to compare the possible differential expression of the selected genes in the cumulus cells of embryos from each group. HAS2, CDC42 and CX43 did not reveal differential expression between the two cohorts. However, GPX3 showed significantly reduced expression in the cumulus belonging to the pregnant group. Interestingly, even cumulus cells belonging only to morphotype A embryos showed a significantly lower expression of GPX3 in the pregnancy group. GPX3 overexpression in cumulus cells could be a poor prognostic indicator of implantation, discriminating beyond the capacity of the morphokinetic score. Unveiling the cumulus transcriptome could improve successful implantation in assisted reproduction treatments.

Morphological embryo quality is an accurate prognostic tool for the success of assisted reproduction implantation, although complete certainty cannot be guaranteed. The transcriptome of the cumulus cells could be monitored as a faithful reflex of the physiological state of the oocytes, given the molecular crosstalk between both types of cells. Here, we compare the expression of specific genes related to oocyte competence, such as hyaluronic acid synthase 2 (HAS2), cell division control protein 42 (CDC42), connexin 43 (CX43), and glutathione peroxidase 3 (GPX3), in cumulus cells from implanted versus non-implanted embryos in 25 women, using RT-qPCR. After embryo transfer, two cohorts were differentiated: the pregnant group (women with the implantation of 100% of embryos transferred) versus the non-pregnant group (with an absence of embryo implantation), aiming to compare the possible differential expression of the selected genes in the cumulus cells of embryos from each group. HAS2, CDC42 and CX43 did not reveal differential expression between the two cohorts. However, GPX3 showed significantly reduced expression in the cumulus belonging to the pregnant group. Interestingly, even cumulus cells belonging only to morphotype A embryos showed a significantly lower expression of GPX3 in the pregnancy group. GPX3 overexpression in cumulus cells could be a poor prognostic indicator of implantation, discriminating beyond the capacity of the morphokinetic score. Unveiling the cumulus transcriptome could improve successful implantation in assisted reproduction treatments.

Liver fibrosis can be caused by non-alcoholic steatohepatitis (NASH), among other conditions. We performed a study to analyze the effects of a nontoxic, water-soluble extract of the edible mushroom Agaricus bisporus (AB) as a potential inhibitor of fibrosis progression in vitro using human hepatic stellate cell (LX2) cultures and in vivo in LDLR-/- mice. Treatment of LX2 cells with the AB extract reduced the levels of fibrotic and oxidative-related markers and increased the levels of GATA4 expression. In LDLR-/- mice with high-fat diet (HFD)-induced liver fibrosis and inflammation, the progression of fibrosis, oxidative stress, inflammation, and apoptosis were prevented by AB extract treatment. Moreover, in the mouse model, AB extract could exert an antiatherogenic effect. These data suggest that AB mushroom extract seems to exert protective effects by alleviating inflammation and oxidative stress during the progression of liver fibrosis, possibly due to a decrease in Toll-like receptor 4 (TLR4) expression and a reduction in Nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we observed a potential atheroprotective effect in our mouse model.

Bacteriophages are ubiquitous in nature and their use is a current promising alternative in biological control. Multidrug resistant (MDR) bacterial strains are present in the livestock industry and phages are attractive candidates to eliminate them and their biofilms. This alternative therapy also reduces the non-desirable effects produced by chemicals on food. The World Health Organization (WHO) estimates that around 420,000 people die due to a foodborne illness annually, suggesting that an improvement in food biocontrol is desirable. This review summarizes relevant studies of phage use in biocontrol focusing on treatments in live animals, plants, surfaces, foods, wastewaters and bioremediation.

Pregnant women are particularly vulnerable to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In addition to unfavorable perinatal outcomes, there has been an increase in obstetric interventions. With this study, we aimed to clarify the reasons, using Robson’s classification model, and risk factors for cesarean section (C-section) in SARS-CoV-2-infected mothers and their perinatal results. This was a prospective observational study that was carried out in 79 hospitals (Spanish Obstetric Emergency Group) with a cohort of 1704 SARS-CoV-2 PCR-positive pregnant women that were registered consecutively between 26 February and 5 November 2020. The data from 1248 pregnant women who delivered vaginally (vaginal + operative vaginal) was compared with those from 456 (26.8%) who underwent a C-section. C-section patients were older with higher rates of comorbidities, in vitro fertilization and multiple pregnancies (p < 0.05) compared with women who delivered vaginally. Moreover, C-section risk was associated with the presence of pneumonia (p < 0.001) and 41.1% of C-sections in patients with pneumonia were preterm (Robson’s 10th category). However, delivery care was similar between asymptomatic and mild–moderate symptomatic patients (p = 0.228) and their predisposing factors to C-section were the presence of uterine scarring (due to a previous C-section) and the induction of labor or programmed C-section for unspecified obstetric reasons. On the other hand, higher rates of hemorrhagic events, hypertensive disorders and thrombotic events were observed in the C-section group (p < 0.001 for all three outcomes), as well as for ICU admission. These findings suggest that this type of delivery was associated with the mother’s clinical conditions that required a rapid and early termination of pregnancy.

The association between ultra-processed food (UPF) and risk of cardiometabolic disorders is an ongoing concern. Different food processing-based classification systems have originated discrepancies in the conclusions among studies. To test whether the association between UPF consumption and cardiometabolic markers changes with the classification system, we used baseline data from 5636 participants (48.5% female and 51.5% male, mean age 65.1 ± 4.9) of the PREDIMED Plus (“PREvention with MEDiterranean DIet”) trial. Subjects presented with overweight or obesity and met at least three metabolic syndrome (MetS) criteria. Food consumption was classified using a 143-item food frequency questionnaire according to four food processing-based classifications: NOVA, International Agency for Research on Cancer (IARC), International Food Information Council (IFIC) and University of North Carolina (UNC). Mean changes in nutritional and cardiometabolic markers were assessed according to quintiles of UPF consumption for each system. The association between UPF consumption and cardiometabolic markers was assessed using linear regression analysis. The concordance of the different classifications was assessed with intra-class correlation coefficients (ICC3, overall = 0.51). The highest UPF consumption was obtained with the IARC classification (45.9%) and the lowest with NOVA (7.9%). Subjects with high UPF consumption showed a poor dietary profile. We detected a direct association between UPF consumption and BMI (p = 0.001) when using the NOVA system, and with systolic (p = 0.018) and diastolic (p = 0.042) blood pressure when using the UNC system. Food classification methodologies markedly influenced the association between UPF consumption and cardiometabolic risk markers.

The SOS family of Ras-GEFs encompasses two highly homologous and widely expressed members, SOS1 and SOS2. Despite their similar structures and expression patterns, early studies of constitutive KO mice showing that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable led to initially viewing SOS1 as the main Ras-GEF linking external stimuli to downstream RAS signaling, while obviating the functional significance of SOS2. Subsequently, different genetic and/or pharmacological ablation tools defined more precisely the functional specificity/redundancy of the SOS1/2 GEFs. Interestingly, the defective phenotypes observed in concomitantly ablated SOS1/2-DKO contexts are frequently much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells, demonstrating functional redundancy between them and suggesting an ancillary role of SOS2 in the absence of SOS1. Preferential SOS1 role was also demonstrated in different RASopathies and tumors. Conversely, specific SOS2 functions, including a critical role in regulation of the RAS–PI3K/AKT signaling axis in keratinocytes and KRAS-driven tumor lines or in control of epidermal stem cell homeostasis, were also reported. Specific SOS2 mutations were also identified in some RASopathies and cancer forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for consideration as a relevant biomarker/therapy target.

Background: The Mediterranean diet (MD) could be involved in the regulation of different miRNAs related to metabolic syndrome (MS). Methods: We analyzed the serum level of mir-let7a-5p, mir-21, mir-590, mir-107 and mir-192 in patients with morbid obesity and its association with the MD and MS. Results: There is an association between the adherence to MD and higher serum levels of mir-590. Mir-590 was lower in those patients who consumed >2 commercial pastries/week. Mir-let7a was lower in those who consumed ≥1 sweetened drinks, in those who consumed ≥3 pieces of fruit/day and in those who consumed less red than white meat. A lower mir-590 and mir-let7a, and a higher mir-192 level, were found in patients who met the high-density lipoprotein cholesterol (HDL) criterion of MS. A higher mir-192 was found in those patients who met the triglyceride criterion of MS and in those with type 2 diabetes (T2DM). Conclusions: There is an association between specific serum levels of miRNAs and the amount and kind of food intake related to MD. Mir-590 was positively associated with a healthy metabolic profile and type of diet, while mir-192 was positively associated with a worse metabolic profile. These associations could be suggestive of a possible modulation of these miRNAs by food.

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect −83.51%; 95% CI −87.23 to −79.79). The incidence density of CR-GNB decreased by −0.915 cases per 1000 occupied bed days (95% CI −1.743 to −0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of −91.15% (95% CI −105.53 to −76.76) and −89.93% (95% CI −107.03 to −72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates.

Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.

Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate directly or indirectly nitric oxide synthase (NOS) expression and NO production, impacting all hallmarks of the oncogenic process. Among lncRNA, HEIH and UCA1 develop their oncogenic functions by inhibiting their target miRNAs and consequently reversing the inhibition of NOS and promoting tumor proliferation. The connection between miRNAs and NO is also involved in two important features in cancer, such as the tumor microenvironment that includes key cellular components such as tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs) and cancer stem cells (CSCs).

Liver stiffness (LS) at sustained virological response (SVR) after direct-acting antivirals (DAA)-based therapy is a predictor of liver events in hepatitis C virus (HCV)-infected patients. The study aim was to identify genetic factors associated with LS changes from the moment of starting anti-HCV therapy to SVR. This prospective study included HCV-infected patients from the GEHEP 011 cohort who achieved SVR with DAA-based therapy, with LS pre-treatment ≥9.5 kPa and LS measurement available at SVR. Plink and Magma software were used to carry out genome-wide single-nucleotide polymorphism (SNP)-based and gene-based association analyses, respectively. The ShinyGO application was used for exploring enrichment in Gene Ontology (GO) categories for biological processes. Overall, 242 patients were included. Median (quartile 1, quartile 3) LS values at pre-treatment and at SVR were 16.8 (12, 28) kPa and 12.0 (8.5, 19.3) kPa, respectively. Thirty-five SNPs and three genes reached suggestive association with LS changes from the moment of starting anti HCV therapy to SVR. GO categories related to DNA packaging complex, DNA conformation change, chromosome organization and chromatin organization were significantly enriched. Our study reports possible genetic factors associated with LS changes during HCV-infection cure. In addition, our results suggest that processes related to DNA conformation are also involved in these changes.

Non-oncologic chronic pain is a common high-morbidity impairment worldwide and acknowledged as a condition with significant incidence on quality of life. Pain intensity is largely perceived as a subjective experience, what makes challenging its objective measurement. However, the physiological traces of pain make possible its correlation with vital signs, such as heart rate variability, skin conductance, electromyogram, etc., or health performance metrics derived from daily activity monitoring or facial expressions, which can be acquired with diverse sensor technologies and multisensory approaches. As the assessment and management of pain are essential issues for a wide range of clinical disorders and treatments, this paper reviews different sensor-based approaches applied to the objective evaluation of non-oncological chronic pain. The space of available technologies and resources aimed at pain assessment represent a diversified set of alternatives that can be exploited to address the multidimensional nature of pain.

Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tanglesare prime features of Alzheimer’s disease (AD). The pathology of AD is very complex and still notfully understood, since different neural cell types are involved in the disease. Although neuronalfunction is clearly deteriorated in AD patients, recently, an increasing number of evidences havepointed towards glial cell dysfunction as one of the main causative phenomena implicated in ADpathogenesis. The complex disease pathology together with the lack of reliable disease models haveprecluded the development of effective therapies able to counteract disease progression. The discoveryand implementation of human pluripotent stem cell technology represents an important opportunityin this field, as this system allows the generation of patient-derived cells to be used for diseasemodeling and therapeutic target identification and as a platform to be employed in drug discoveryprograms. In this review, we discuss the current studies using human pluripotent stem cells focusedon AD, providing convincing evidences that this system is an excellent opportunity to advance inthe comprehension of AD pathology, which will be translated to the development of the still missingeffective therapies.

Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.

Dietary polyphenol intake is associated with improvement of metabolic disturbances. The aims of the present study are to describe dietary polyphenol intake in a population with metabolic syndrome (MetS) and to examine the association between polyphenol intake and the components of MetS. This cross-sectional analysis involved 6633 men and women included in the PREDIMED (PREvención con DIeta MEDiterranea-Plus) study. The polyphenol content of foods was estimated from the Phenol-Explorer 3.6 database. The mean of total polyphenol intake was 846 ± 318 mg/day. Except for stilbenes, women had higher polyphenol intake than men. Total polyphenol intake was higher in older participants (>70 years of age) compared to their younger counterparts. Participants with body mass index (BMI) >35 kg/m2 reported lower total polyphenol, flavonoid, and stilbene intake than those with lower BMI. Total polyphenol intake was not associated with a better profile concerning MetS components, except for high-density lipoprotein cholesterol (HDL-c), although stilbenes, lignans, and other polyphenols showed an inverse association with blood pressure, fasting plasma glucose, and triglycerides. A direct association with HDL-c was found for all subclasses except lignans and phenolic acids. To conclude, in participants with MetS, higher intake of several polyphenol subclasses was associated with a better profile of MetS components, especially HDL-c.

OBJECTIVES: To know the frequency and causes of low value surgical practices, according to the opinion of surgeons and anesthetists, and to determine their degree of knowledge about the Spanish "Choosing wisely" initiative. METHODS: Cross-sectional observational study, based on a self-administered online questionnaire through an opportunistic sample of 370 surgeons and anesthetists from three Spanish regions, contacted through Scientific Societies. The survey took part between July and December 2017. RESULTS: A patient profile requesting unnecessary practices was identified (female, 51-65 years old and unaffiliated disease). The frequency of requests was weekly or daily for 50.0% of the professionals, of whom 15.1% acknowledged succumbing to these pressures. To dissuade the patient, clinical reasons (47%) were considered the most effective. To increase control and safety in the case was the main reason to indicate them. The greatest responsibility for overuse was attributed to physicians, defensive medicine and mass media. Assessing professionals' knowledge on unnecessary practices, an average of 5 correct answers out of 7 was obtained. Some 64.1% of the respondents were unaware of the Spanish "Choosing wisely" initiative. CONCLUSIONS: Low value surgical practices are perceived as a frequent problem, which requires an approach entailing intervention with patients and the media as well as professiona

Around a 20–30% of inflammatory bowel disease (IBD) patients are diagnosed before they are 18 years old. Anti-TNF drugs can induce and maintain remission in IBD, however, up to 30% of patients do not respond. The aim of the work was to identify markers that would predict an early response to anti-TNF drugs in pediatric patients with IBD. The study population included 43 patients aged <18 years with IBD who started treatment with infliximab or adalimumab. Patients were classified into primary responders (n = 27) and non-responders to anti-TNF therapy (n = 6). Response to treatment could not be analyzed in 10 patients. Response was defined as a decrease in over 15 points in the disease activity indexes from week 0 to week 10 of infliximab treatment or from week 0 to week 26 of adalimumab treatment. The expression profiles of nine genes in total RNA isolated from the whole-blood of pediatric IBD patients taken before biologic administration and after 2 weeks were analyzed using qPCR and the 2−∆∆Ct method. Before initiation and after 2 weeks of treatment the expression of SMAD7 was decreased in patients who were considered as non-responders (p value < 0.05). Changes in expression were also observed for TLR2 at T0 and T2, although that did not reach the level of statistical significance. In addition, the expression of DEFA5 decreased 1.75-fold during the first 2 weeks of anti-TNF treatment in responders, whereas no changes were observed in non-responders. Expression of the SMAD7 gene is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD. TLR2 and DEFA5 need to be validated in larger studies.

Background: Overuse reduces the efficiency of healthcare systems and compromises patient safety. Different institutions have issued recommendations on the indication of preoperative chest X-rays, but the degree of compliance with these recommendations is unknown. This study investigates the frequency and characteristics of the inappropriateness of this practice. Methods: This is a descriptive observational study with analytical components, performed in a tertiary hospital in the Community of Madrid (Spain) between July 2018 and June 2019. The inappropriateness of preoperative chest X-ray tests was analyzed according to “Choosing Wisely”, “No Hacer” and “Essencial” initiatives and the cost associated with this practice was estimated in Relative Value and Monetary Units. Results: A total of 3449 preoperative chest X-ray tests were performed during the period of study. In total, 5.4% of them were unjustified according to the “No Hacer” recommendation and 73.3% according to “Choosing Wisely” and “Essencial” criteria, which would be equivalent to 5.6% and 11.8% of the interventions in which this test was unnecessary, respectively. One or more preoperative chest X-ray(s) were indicated in more than 20% of the interventions in which another chest X-ray had already been performed in the previous 3 months. A higher inappropriateness score was also recorded for interventions with an American Society of Anesthesiologists (ASA) grade ≥ III (16.5%). The Anesthesiology service obtained a lower inappropriateness score than other Petitioning Surgical Services (57.5% according to “Choosing Wisely” and “Essencial”; 4.1% according to “No Hacer”). Inappropriate indication of chest X-rays represents an annual cost of EUR 52,122.69 (170.1 Relative Value Units) according to “No Hacer” and EUR 3895.29 (2276.1 Relative Value Units) according to “Choosing Wisely” or “Essencial” criteria. Conclusions: There was wide variability between the recommendations that directly affected the degree of

The purpose of this work is to describe a first approach to a smart bioimpedance spectroscopy device for its application to the estimation of body composition. The proposed device is capable of carrying out bioimpedance measurements in multiple configurable frequencies, processing the data to obtain the modulus and the bioimpedance phase in each of the frequencies, and transmitting the processed information wirelessly. Another novelty of this work is a new algorithm for the identification of Cole model parameters, which is the basis of body composition estimation through bioimpedance spectroscopy analysis. Against other proposals, the main advantages of the proposed method are its robustness against parasitic effects by employing an extended version of Cole model with phase delay and three dispersions, its simplicity and low computational load. The results obtained in a validation study with respiratory patients show the accuracy and feasibility of the proposed technology for bioimpedance measurements. The precision and validity of the algorithm was also proven in a validation study with peritoneal dialysis patients. The proposed method was the most accurate compared with other existing algorithms. Moreover, in those cases affected by parasitic effects the proposed algorithm provided better approximations to the bioimpedance values than a reference device.

This work addresses the design and experimental characterization of on-body antennas, which play an essential role within Body Sensor Networks. Four antenna designs were selected from a set of eighteen antenna choices and finally implemented for both passive and active measurements. The issues raised during the process of this work (requirements study, technology selection, development and optimization of antennas, impedance matching, unbalanced to balanced transformation, passive and active characterization, off-body and on-body configurations, etc.) were studied and solved, driving a methodology for the characterization of on-body antennas, including transceiver effects. Despite the influence of the body, the antennas showed appropriate results for an in-door environment. Another novelty is the proposal and validation of a phantom to emulate human experimentation. The differences between experimental and simulated results highlight a set of circumstances to be taken into account during the design process of an on-body antenna: more comprehensive simulation schemes to take into account the hardware effects and a custom design process that considers the application for which the device will be used, as well as the effects that can be caused by the human body.

Background: Quantification of T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) from dried blood spots (DBS) allows detection of neonates with severe T-cell and/or B-cell lymphopenia that are potentially affected by severe combined immunodeficiency (SCID), as well as X-linked agammaglobulinemia (XLA). Methods: Determination of TRECs and KRECs using a triplex RT-PCR (TRECS-KRECS-β-actin) assay from prospectively collected DBS between February 2014 and December 2016 in three hospitals in Seville, Spain. Cut-off levels were TRECs < 6/punch, KRECs < 4/punch and b-actin > 700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (CDC) were included. Results: A total of 8943 DBS samples obtained from 8814 neonates were analysed. Re-punching was necessary in 124 samples (1.4%) due to insufficient β-actin values (<700 copies/punch). Preterm neonates (GA < 37 weeks) and neonates with a BW < 2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeated pathological results, ten neonates were re-sampled (0.11%), of which five neonates (0.055%) confirmed the pathological results: one case was a fatal chromosomopathy (TRECs 1/KRECs 4); two were extreme premature newborns (TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); and 2 neonates were born to mothers receiving azathioprine during pregnancy (TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All controls were correctly identified. Conclusions: Severe T- and B-cell lymphopenias were correctly identified by the TRECS-KRECS-β-actin assay. Prematurity and low BW are associated with lower TREC and KREC levels. Extreme prematurity and maternal immune suppressive therapy can cause false positive results of TRECs and KRECs values.