Hypogonadism associated with muscle atrophy, physical inactivity and ESA hyporesponsiveness in men undergoing haemodialysis

AbstractBackgroundTestosterone deficiency (hypogonadism) is common among men undergoing haemodialysis, but its clinical implications are not well characterized. Testosterone is an anabolic hormone that induces erythrocytosis and muscle synthesis. We hypothesized that testosterone deficiency would be associated with low muscle mass, physical inactivity and higher dosages of erythropoietin-stimulating agents (ESA).MethodsSingle-center cross-sectional study of 57 male haemodialysis patients. None of the patients was undergoing testosterone replacement therapy. Total testosterone was measured in serum. Body composition (by bioelectrical impedance analysis) and physical activity (by the use of pedometers) were assessed. Patients with testosterone levels below the normal range were considered hypogonadal.ResultsMean testosterone level was 321±146ng/dL; 20 patients (35%) were hypogonadal. Hypogonadal patients were older and had lower mean arterial blood pressure, higher interleukin-6 levels, lower lean body mass and higher fat body mass. A negative association between testosterone and normalized ESA dose was found in uni- and multivariate regression analyses. Testosterone levels directly correlated with lean body mass regardless of confounders. Hypogonadal patients had lower physical activity than their counterparts [2753±1784 vs. 4291±3225steps/day (p=0.04)]. The relationship between testosterone and physical activity was independent of age, comorbidities and inflammatory markers, but dependent on the proportion of muscle mass.ConclusionHypogonadism is common in our male haemodialysis population and is associated with higher ESA doses, reduced muscle mass and lower physical activity. The link between low testosterone levels and physical inactivity may conceivably relate to reduced muscle mass due to inadequate muscle protein synthesis

Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses.

Natural killer (NK) cells recognize and kill target cells undergoing different types of stress. NK cells are also capable of modulating immune responses. In particular, they regulate T cell functions. Small RNA next-generation sequencing of resting and activated human NK cells and their secreted extracellular vesicles (EVs) led to the identification of a specific repertoire of NK-EV-associated microRNAs and their post-transcriptional modifications signature. Several microRNAs of NK-EVs, namely miR-10b-5p, miR-92a-3p, and miR-155-5p, specifically target molecules involved in Th1 responses. NK-EVs promote the downregulation of GATA3 mRNA in CD4+ T cells and subsequent TBX21 de-repression that leads to Th1 polarization and IFN-γ and IL-2 production. NK-EVs also have an effect on monocyte and moDCs (monocyte-derived dendritic cells) function, driving their activation and increased presentation and costimulatory functions. Nanoparticle-delivered NK-EV microRNAs partially recapitulate NK-EV effects in mice. Our results provide new insights on the immunomodulatory roles of NK-EVs that may help to improve their use as immunotherapeutic tools.This manuscript was funded by grants PDI-2020-120412RB-I00 and PDC2021- 121719-I00 (FS-M) and PID2020- 119352RB-I00 (AS) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD3671-INFLAMUNE-CM) from the Comunidad de Madrid (FS-M). CIBERCV (CB16/11/00272) and BIOIMID PIE13/041 from the Instituto de Salud Carlos. The current research has received funding from 'la Caixa' Foundation under the project code HR17-00016. Grants from Ramón Areces Foundation 'Ciencias de la Vida y de la Salud' (XIX Concurso-2018) and from Ayuda Fundación BBVA y Equipo de Investigación Científica (BIOMEDICINA-2018) (to FSM). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015–0505). IMDEA Nanociencia acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, CEX2020-001039-S). SGD is supported by a grant from the Spanish Ministry of Universities. Authors thank Dr Miguel Vicente-Manzanares for critical review and editing. We also thank Dr Francisco Urbano and Dr Covadonga Aguado for their support with EM (TEM facilities, Universidad Autónoma de Madrid).S

Echocardiographic findings in haemodialysis patients according to their state of hydration

AbstractBackgroundChronic fluid overload is frequent in hemodialysis patients (P) and it associates with hypertension, left ventricular hypertrophy (LVH) and higher mortality. Moreover, echocardiographic data assessing fluid overload is limited. Our aim was to evaluate the relationship between fluid overload measured by bioimpedance spectroscopy (BIS) and different echocardiographic parameters.MethodsCross-sectional observational study including 76 stable patients. Dry weight was clinically assessed. BIS and echocardiography were performed. Weekly time-averaged fluid overload (TAFO) and relative fluid overload (FO/ECW) were calculated using BIS measurements.ResultsBased on TAFO three groups were defined: A- dehydrated, TAFO <-0.25 L 32 P (42%); B- normohydrated, TAFO between -0.25 and 1.5 l: 26 (34%); C- overhydrated, TAFO>1.5 l: 18 (24%). We found significant correlation between TAFO and left atrial volume index (LAVI) (r: 0.29; p=0.013) but not with FO/ECW (r 0.06; p=0.61). TAFO, but not FO/ECW kept a significant relationship with LAVI (p=0.03) using One-Way ANOVA test and linear regression methods. LVH was present in 73.7% (concentric 63.2%, eccentric in 10.5%). No differences between groups in the presence of LVH or left ventricular mass index were found.ConclusionsWe found that left atrial volume index determined by echocardiographic Area-length method, but not left ventricle hypertrophy or dimensions of cavities, are related on hydration status based on bioimpedance measured time-averaged fluid overload (TAFO), and not with FO/ECW

Antibióticos empíricos para la neumonía adquirida en la comunidad en pacientes adultos: Una revisión sistemática y un metaanálisis en red

Objetivo: El objetivo principal de este metaanálisis en red es identificar el antibiótico empírico (Em-ATB) con mayor probabilidad de ser el mejor (HPBB) en términos de (1) tasa de curación y (2) tasa de mortalidad en pacientes hospitalizados con neumonía adquirida en la comunidad (NAC) . Método: Criterios de inclusión: (1) pacientes adultos (>16 años) diagnosticados de NAC que requirieron hospitalización; (2) aleatorizados a al menos dos Em-ATB diferentes, (3) que informen de la tasa de curación y (4) que estén escritos en inglés o español. Criterios de exclusión: (1) protocolo de antibióticos ambiguo y (2) publicados exclusivamente en formato resumen o carta. Fuentes de datos: Medline, Embase, Cochrane y revisiones de citas desde el 1 de enero de 2000 hasta el 31 de diciembre de 2018. Riesgo de sesgo: Herramienta de Cochrane. Calidad de la revisión sistemática (RS): A MeaSurement Tool to Assess systematic Reviews-2. Certeza de la evidencia: Grading of Recommendations Assessment, Development and Evaluation. Análisis estadísticos: método frecuentista realizado con la biblioteca 'netmeta', paquete R. Resultados: se incluyeron 27 ensayos controlados aleatorizados (ECA) de las 41.307 citas seleccionadas inicialmente. En cuanto al riesgo de sesgo, más de una cuarta parte de los estudios presentaron riesgo bajo y ningún estudio presentó riesgo alto en todos los dominios. La calidad de la RS es moderada. Para la curación, se construyeron dos redes. Así, dos Em-ATB tienen la HPBB: cetarolina 600 mg (dos veces al día) y piperacilina 2000 mg (dos veces al día). Para la mortalidad, se construyeron tres redes. Así, tres Em-ATB tienen la HPBB: ceftriaxona 2000 mg (una vez al día) más levofloxacino 500 (dos veces al día), ertapenem 1000 mg (dos veces al día) y amikacina 250 mg (dos veces al día) más claritromicina 500 mg (dos veces al día). La certeza de la evidencia para cada resultado es moderada. Conclusiones: Para la tasa de curación, ceftarolina y piperacilina son las opciones con la HPBB. Sin embargo, para la tasa de mortalidad, las opciones son ceftriaxona más levofloxacino, ertapenem y amikacina más claritromicina. Parece necesario realizar un ECA que compare los tratamientos con el HPBB para cada evento (curación o mortalidad) (CRD42017060692).Objective: The main aim of this network meta-analysis is to identify the empiric antibiotic (Em-ATB) with the highest probability of being the best (HPBB) in terms of (1) cure rate and (2) mortality rate in hospitalised patients with community acquired pneumonia (CAP) . Method: Inclusion criteria: (1) adult patients (>16 years old) diagnosed with CAP that required hospitalisation; (2) randomised to at least two different Em-ATBs, (3) that report cure rate and (4) are written in English or Spanish. Exclusion criteria: (1) ambiguous antibiotics protocol and (2) published exclusively in abstract or letter format. Data sources: Medline, Embase, Cochrane and citation reviews from 1 January 2000 to 31 December 2018. Risk of bias: Cochrane's tool. Quality of the systematic review (SR): A MeaSurement Tool to Assess systematic Reviews-2. Certainity of the evidence: Grading of Recommendations Assessment, Development and Evaluation. Statistical analyses: frequentist method performed with the 'netmeta' library, R package. Results: 27 randomised controlled trials (RCTs) from the initial 41 307 screened citations were included. Regarding the risk of bias, more than one quarter of the studies presented low risk and no study presented high risk in all domains. The SR quality is moderate. For cure, two networks were constructed. Thus, two Em-ATBs have the HPBB: cetaroline 600 mg (two times a day) and piperacillin 2000 mg (two times a day). For mortality, three networks were constructed. Thus, three Em-ATBs have the HPBB: ceftriaxone 2000 mg (once a day) plus levofloxacin 500 (two times a day), ertapenem 1000 mg (two times a day) and amikacin 250 mg (two times a day) plus clarithromycin 500 mg (two times a day). The certainity of evidence for each results is moderate. Conclusion: For cure rate, ceftaroline and piperaciline are the options with the HPBB. However, for mortality rate, the options are ceftriaxone plus levofloxacin, ertapenem and amikacin plus clarithromycin. It seems necessary to conduct an RCT that compares treatments with the HPBB for each event (cure or mortality) (CRD42017060692)

Potential group B Streptococcus interspecies transmission between cattle and people in Colombian dairy farms

Group B Streptococcus (GBS), is a leading cause of neonatal death and an emerging pathogen in adults. Additionally, GBS is a bovine pathogen causing intramammary infections. The likelihood of GBS interspecies transmission is largely unknown. We explored the potential transmission of GBS between cattle and people on dairy farms in Colombia and compared the antimicrobial resistance (AMR) profiles of isolates from both host species. Across 33 farms, throat swabs and rectal swabs were collected from 191 people, and rectal swabs and composite milk samples from 2092 cattle, yielding 60 human isolates and 301 bovine isolates. The majority (64%) of isolates belonged to shared sequence types (ST). Sequence type (ST) 1 was the most common strain in both host species, suggesting that interspecies transmission may be possible. Two members of the bovine-specific clonal complex 61/67 were detected in human samples (ST718 and ST1175), providing evidence for the lack of genuine species barriers. Apparent prevalence of penicillin resistance was surprisingly high in human and bovine isolates. Further investigation of this phenomenon is needed and could lead to modification of standard testing and treatment recommendations in human and veterinary medicine

Determination of essential biomarkers in lung cancer: a real-world data study in Spain.

Background: The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. Patients and Methods: The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. Results: 9,239 patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value <0.001). The global testing of EGFR, ALK, and ROS1 was 78.9%, 64.7%, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. Conclusions: Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer

A single-dose strategy for immunization with live attenuated vaccines is an effective option before treatment initiation in multiple sclerosis patients

Multiple sclerosis; Infections; VaccinationEsclerosi múltiple; Infeccions; VacunacióEsclerosis múltiple; Infecciones; VacunaciónBackground: Mumps-Measles-Rubella (MMR) and Varicella zoster vaccines (VAR) are live attenuated vaccines, usually administered in a two-dose scheme at least 4 weeks apart. However, single-dose immunization schemes may also be effective and can reduce delays in immunosuppressive treatment initiation in patients with multiple sclerosis (pwMS) who need to be immunized. Objectives: To evaluate the immunogenicity of a single-dose attempt (SDA) versus the standard immunization scheme (SIS) with VAR and/or MMR in pwMS. Methods: Retrospective observational study in pwMS vaccinated against VAR and/or MMR. We compared seroprotection rates and antibody geometric mean titers (GMTs) between the two strategies. Results: Ninety-six patients were included. Thirty-one patients received VAR and 67 MMR. In the SDA group, the seroprotection rate was 66.7% (95% confidence interval (CI): 53.3–78.3) versus 97.2% (95% CI: 85.5–99.9) in the SIS (p < 0.001). For the seroprotected patients, GMTs were similar for both schemes. Conclusion: An SDA of VAR and/or MMR vaccines could be sufficient to protect almost two-thirds of patients. Testing immunogenicity after a single dose of VZ and/or MMR could be included in routine clinical practice to achieve rapid immunization.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI19/01606 and co-funded by the European Union and ECTRIMS clinical fellowship awarded to René Carvajal from 2021 to 2022

Determination of essential biomarkers in lung cancer : a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics

Background The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. Patients and methods The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. Results Nine thousand two hundred thirty-nine patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value < 0.001). The global testing of EGFR, ALK, and ROS1 was 78.9, 64.7, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. Conclusions Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI

Deep learning; Disability; Structural MRIAprendizaje profundo; Discapacidad; Resonancia magnética estructuralAprenentatge profund; Discapacitat; Ressonància magnètica estructuralThe application of convolutional neural networks (CNNs) to MRI data has emerged as a promising approach to achieving unprecedented levels of accuracy when predicting the course of neurological conditions, including multiple sclerosis, by means of extracting image features not detectable through conventional methods. Additionally, the study of CNN-derived attention maps, which indicate the most relevant anatomical features for CNN-based decisions, has the potential to uncover key disease mechanisms leading to disability accumulation. From a cohort of patients prospectively followed up after a first demyelinating attack, we selected those with T1-weighted and T2-FLAIR brain MRI sequences available for image analysis and a clinical assessment performed within the following six months (N = 319). Patients were divided into two groups according to expanded disability status scale (EDSS) score: ≥3.0 and < 3.0. A 3D-CNN model predicted the class using whole-brain MRI scans as input. A comparison with a logistic regression (LR) model using volumetric measurements as explanatory variables and a validation of the CNN model on an independent dataset with similar characteristics (N = 440) were also performed. The layer-wise relevance propagation method was used to obtain individual attention maps. The CNN model achieved a mean accuracy of 79% and proved to be superior to the equivalent LR-model (77%). Additionally, the model was successfully validated in the independent external cohort without any re-training (accuracy = 71%). Attention-map analyses revealed the predominant role of frontotemporal cortex and cerebellum for CNN decisions, suggesting that the mechanisms leading to disability accrual exceed the mere presence of brain lesions or atrophy and probably involve how damage is distributed in the central nervous system.MS PATHS is funded by Biogen. This study has been possible thanks to a Junior Leader La Caixa Fellowship awarded to C. Tur (fellowship code is LCF/BQ/PI20/11760008) by “la Caixa” Foundation (ID 100010434). The salaries of C. Tur and Ll. Coll are covered by this award

Bioactive characterization of Persea americana Mill. by-products: A rich source of inherent antioxidants

[EN] Avocado (Persea americana Mill.) is a worldwide consumed fruit, with great interest for cosmetic and pharmaceutical industries; however, 30% of avocado fruits are bio-wastes (peels and kernels), converting them into a potential source of bioactive compounds, such as phenolic compounds. Therefore, the hydroethanolic extracts of peels and kernels of Persea america Mill. var. Hass were analysed regarding their individual phenolic profile by HPLC-DAD/ESI-MS and correlated with their antioxidant, antimicrobial and cytotoxic activities. Avocado by-products presented a very distinct phenolic profile, presenting higher concentration in peels (227.9 mg/g of extract for total phenolic content), mainly in (epi)catechin derivatives (175 mg/g of extract), followed by chlorogenic derivatives (42.9 mg/g of extract). In this study hydrophilic and lipophilic antioxidant assays were performed together for the first time in P. americana by-products, and although kernels showed a great antioxidant potential (EC50 values ranging from 18.1 to 276 mu g/mL), peels presented the highest potential (EC50 ranging from 11.7 to 152 mu g/mL), mainly due to the presence of phenolic compounds, and an overall better performance in the antibacterial assays. Further studies needs to be conducted to better understand the correlation between the presence of phenolic compounds and bioactivities, however, the main objective is to implement these biocompounds in different products and industries, due to results obtained, P. americana peels could be a great alternative in the substitution of synthetic antioxidants.The authors are grateful to the Foundation for Science and Technology(FCT, Portugal) and FEDER under Program PT2020 for financial support to CIMO (UID/AGR/00690/2013) and L. Barros contract. The authors would like to thank the Interreg Espana-Portugal for financial support through the project 0377_Iberphenol_6_E. B. Melgar thanks CONACyT for his grant (No. 329930). The authors are also grateful to the Serbian Ministry of Education, Science and Technological Development, grant number 173032 for financial support.Melgar-Castañeda, B.; Dias, MI.; Ciric, A.; Sokovic, M.; Garcia-Castello, EM.; Rodríguez López, AD.; Barros, L.... (2018). Bioactive characterization of Persea americana Mill. by-products: A rich source of inherent antioxidants. Industrial Crops and Products. 111:212-218. https://doi.org/10.1016/j.indcrop.2017.10.024S21221811