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Pedro J Marcos,1 Rosa Malo de Molina,2 Ricard Casamor3 1Servicio de Neumología, Instituto de investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña (CHUAC), Sergas Universidade da Coruña (UDC), A Coruña, 2Servicio de Neumología, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, 3Medical Department, Novartis Farmacéutica SA, Barcelona, Spain Background: The aim of this study was to identify the percentage of undiagnosed patients with COPD through the implementation of an active search strategy in a selected subject population. Methods: An observational, cross-sectional, multicenter study was conducted in a primary care setting in Spain. General practitioners gave their diagnostic impression of COPD (yes/no) on the basis of clinical criteria of subjects with respiratory symptoms and tobacco exposure. Subsequently, post-bronchodilator spirometry and quality-of-life tests were performed. Multivariate logistic regression techniques using receiver operating characteristic (ROC) curves were used to identify the combination of variables that best discriminates COPD. Results: A total of 2,758 patients were screened at 368 primary care centers, of which 1,725 patients were included in the study. Seven hundred and ninety-three patients (46%) were diagnosed with COPD. Clinical judgment resulted in suspected COPD in 1,393 (81%) of the subjects. The best variables to discriminate COPD were a history of lower respiratory tract infections, cough, and dyspnea. This combination identified COPD with a ROCAUC of 0.61 denoting a poor discriminative ability. Conclusion: Employing an active search strategy leads to a new COPD diagnosis in almost half of the subjects. Screening of COPD with post-bronchodilator spirometry should be considered mandatory for any high-risk subject visiting the general practitioner clinic for any reason. Keywords: COPD, post-bronchodilator spirometry, primary care, screening

Objective: Life expectancy and obesity prevalence are increasing worldwide, leading to an increase in the prevalence of cardiovascular disease. High-density lipoprotein (HDL) functionality and immunosenescence play key roles in cardiovascular disease, longevity, and quality of aging. Both molecular hallmarks of aging are impacted by obesity and metabolic syndrome and can be modulated by lifestyle. We aimed to evaluate the effect of a lifestyle intervention focused on an energy-reduced Mediterranean diet (erMedDiet), physical activity (PA), and behavioral support on HDL cholesterol efflux capacity (CEC) and immunosenescence., Method: CEC and immunosenescent T cells were determined in 60 participants from the control group (CG) and 56 from the intervention group (IG) of the PREDIMED-Plus trial at baseline and after 1 and 3 years of follow-up. PREDIMED-Plus is a randomized, controlled, parallel-group trial with an IG of erMedDiet, PA promotion, and behavioral support for weight loss and a CG of usual primary care advice. The sample included 116 volunteers from the PREDIMED-Plus-IMDEA subsample of the PREDIMED-Plus trial. Men aged 55 to 75 years and women aged 60 to 75 years with a body mass index between 27 and 40 kg/m 2 and metabolic syndrome were included., Results: Participants within the IG had significantly improved CEC (2.42% and 10.69% after 1 and 3 years of follow-up) and a decreased in senescent T cell profile (-3.32% ± 12.54% and -6.74% ± 11.2%, p  < 0.001, after 1 and 3 years of follow-up). Baseline obesity status impacted the response to the intervention., Conclusions: A weight loss intervention program with erMedDiet and PA ameliorated senescence markers.

Home Respiratory Therapies (HRT) encompass a variety of treatments for patients with chronic respiratory diseases, administered at home over extended periods. The Service Providers of HRT (SPHRT) collaborate with hospital resources to address chronic respiratory diseases, acting as strategic partners. The contracting of HRT in the public health system involves contests where the SPHRT present technical and economic offers. The purpose of this document is to provide a technical basis that can assist professionals, SPHRT, and the administration in making decisions when calling for, evaluating, and deciding on such contests., (© 2024 Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Published by Elsevier España, S.L.U.)

Non-alcoholic steatohepatitis (NASH) is one of the fastest growing liver diseases worldwide, and oxidative stress is one of NASH main key drivers. Nicotinamide adenine dinucleotide phosphate (NADPH) is the ultimate donor of reductive power to a number of antioxidant defences. Here, we explored the potential of increasing NADPH levels to prevent NASH progression. We used nicotinamide riboside (NR) supplementation or a G6PD-tg mouse line harbouring an additional copy of the human G6PD gene. In a NASH mouse model induced by feeding mice a methionine-choline deficient (MCD) diet for three weeks, both tools increased the hepatic levels of NADPH and ameliorated the NASH phenotype induced by the MCD intervention, but only in female mice. Boosting NADPH levels in females increased the liver expression of the antioxidant genes Gsta3, Sod1 and Txnrd1 in NR-treated mice, or of Gsr for G6PD-tg mice. Both strategies significantly reduced hepatic lipid peroxidation. NR-treated female mice showed a reduction of steatosis accompanied by a drop of the hepatic triglyceride levels, that was not observed in G6PD-tg mice. NR-treated mice tended to reduce their lobular inflammation, showed a reduction of the NK cell population and diminished transcription of the damage marker Lcn2. G6PD-tg female mice exhibited a reduction of their lobular inflammation and hepatocyte ballooning induced by the MCD diet, that was related to a reduction of the monocyte-derived macrophage population and the Tnfa, Ccl2 and Lcn2 gene expression. As conclusion, boosting hepatic NADPH levels attenuated the oxidative lipid damage and the exhausted antioxidant gene expression specifically in female mice in two different models of NASH, preventing the progression of the inflammatory process and hepatic injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

COVID-19 is a global threat for the healthcare systems due to the rapid spread of the pathogen that causes it. In such situation, the clinicians must take important decisions, in an environment where medical resources can be insufficient. In this task, the computer-aided diagnosis systems can be very useful not only in the task of supporting the clinical decisions but also to perform relevant analyses, allowing them to understand better the disease and the factors that can identify the high risk patients. For those purposes, in this work, we use several machine learning algorithms to estimate the outcome of COVID-19 patients given their clinical information. Particularly, we perform 2 different studies: the first one estimates whether the patient is at low or at high risk of death whereas the second estimates if the patient needs hospitalization or not. The results of the analyses of this work show the most relevant features for each studied scenario, as well as the classification performance of the considered machine learning models. In particular, the XGBoost algorithm is able to estimate the need for hospitalization of a patient with an AUC-ROC of 0 . 8415 ± 0 . 0217 while it can also estimate the risk of death with an AUC-ROC of 0 . 7992 ± 0 . 0104 . Results have demonstrated the great potential of the proposal to determine those patients that need a greater amount of medical resources for being at a higher risk. This provides the healthcare services with a tool to better manage their resources., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis., (© 2023. The Author(s).)

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Introduction: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP., Methods: We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population., Results: We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7-35.2]), hospitalization in the past 12 months (OR 3.7 [1.5-9.2]), and bronchiectasis (OR 3.2 [1.4-7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%., Conclusions: COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy., (Published by Elsevier España, S.L.U.)

Background: Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway., Results: We identify and validate rs2291007 within a conserved region in the 3'UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction., Conclusions: We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels., (© 2022. The Author(s).)

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity., (© 2022. The Author(s).)

Obesity is associated to a low grade of chronic inflammation leading to metabolic stress, insulin resistance, metabolic syndrome, dislipidemia, cardiovascular disease, and even cancer. A Mediterranean diet has been shown to reduce systemic inflammatory factors, insulin resistance, and metabolic syndrome. In this scenario, precision nutrition may provide complementary approaches to target the metabolic alterations associated to "unhealthy obesity". In a previous work, we described a pomegranate extract (PomE) rich in punicalagines to augment markers of browning and thermogenesis in human differentiated adipocytes and to augment the oxidative respiratory capacity in human differentiated myocytes. Herein, we have conducted a preclinical study of high-fat-diet (HFD)-induced obesity where PomE augments the systemic energy expenditure (EE) contributing to a reduction in the low grade of chronic inflammation and insulin resistance associated to obesity. At the molecular level, PomE promotes browning and thermogenesis in adipose tissue, reducing inflammatory markers and augmenting the reductive potential to control the oxidative stress associated to the HFD. PomE merits further investigation as a complementary approach to alleviate obesity, reducing the low grade of chronic inflammation and metabolic stress.

Introduction: Currently there is lack of data regarding the impact of a home telehealth program on readmissions and mortality rate after a COPD exacerbation-related hospitalization., Objective: To demonstrate if a tele-monitoring system after a COPD exacerbation admission could have a favorable effect in 1-year readmissions and mortality in a real-world setting., Methods: This is an observational study where we compared an intervention group of COPD patients treated after hospitalization that conveyed a telehealth program with a followance period of 1 year with a control group of patients evaluated during one year before the intervention began. A propensity-score analyses was developed to control for confounders. The main clinical outcome was 1-year all-cause mortality or COPD-related readmission., Results: The analysis comprised 351 telemonitoring patients and 495 patients in the control group. The intervention resulted in less mortality or readmission after 12 months (35.2% vs. 45.2%; hazard ratio [HR] 0.71 [95% CI=0.56-0.91]; p=0.007). This benefit was maintained after the propensity score analysis (HR=0.66 [95% CI=0.51-0.84]). This benefit, which was seen from the first month of the study and during its whole duration, is maintained when mortality (HR=0.54; 95% CI=[0.36-0.82]) or readmission (subdistribution hazard ratio [SHR] 0.66; 95% CI=[0.50-0.86]) are analyzed separately., Conclusion: Telemonitoring after a severe COPD exacerbation is associated with less mortality or readmissions at 12 months in a real world clinical setting., (Copyright © 2020 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD). The G6PD-overexpressing mouse (G6PD-Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty., Methods: Old wild-type (WT) and G6PD-Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated., Results: The percentage of frail mice was significantly lower in the G6PD-Tg than in the WT genotype, especially in 26-month-old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01)., Conclusions: Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Introduction: Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients., Methods: A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months., Results: Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81)., Conclusion: Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression., (Copyright © 2021 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Phaeodactylum tricornutum is a rich source of fucoxanthin, a carotenoid with several health benefits. In the present study, high performance countercurrent chromatography (HPCCC) was used to isolate fucoxanthin from an extract of P. tricornutum . A multiple sequential injection HPCCC method was developed combining two elution modes (reverse phase and extrusion). The lower phase of a biphasic solvent system ( n -heptane, ethyl acetate, ethanol and water, ratio 5/5/6/3, v / v/v/v ) was used as the mobile phase, while the upper phase was the stationary phase. Ten consecutive sample injections (240 mg of extract each) were performed leading to the separation of 38 mg fucoxanthin with purity of 97% and a recovery of 98%. The process throughput was 0.189 g/h, while the efficiency per gram of fucoxanthin was 0.003 g/h. Environmental risk and general process evaluation factors were used for assessment of the developed separation method and compared with existing fucoxanthin liquid-liquid isolation methods. The isolated fucoxanthin retained its well-described ability to induce nuclear translocation of transcription factor FOXO3. Overall, the developed isolation method may represent a useful model to produce biologically active fucoxanthin from diatom biomass.

Introduction: The prevalence of COPD phenotypes that are referred for assessment for lung transplantation is unknown, as well as whether specific phenotype influences post-transplant evolution in those patients who receive it., Material and Methods: Ambispective observational study without intervention. The main objective was to know the prevalence of the different COPD phenotypes of the patients referred for the evaluation of a lung transplant. Secondary objective were to compare their clinical characteristics, to perform an analysis of post-transplant survival or complications according to their phenotype., Results: 502 patients were evaluated for lung transplantation, of which 173 met the study criteria. 31.21% of the patients were discarded for transplantation on a first visit. The final cohort of potential transplant candidates who completed the pre-transplant study was 119 (69%) and 47 finally received a lung transplant (39.5%). The most frequent COPD phenotype evaluated for lung transplantation was the exacerbator (59%), followed by the non-exacerbator (38%) and the Asthma COPD Overlap [ACO] (3%). 59.8% of the exacerbator-phenotype patients assessed did not complete the pre-transplant study. Exacerbator-phenotype patients have a lower post-transplant survival (1115.1 days [standard deviation-DE-587]) vs. ACO: 1432 days [DE 507.5] and Non-exacerbators: 1317.8 days [DE 544.7] p  = 0.16), although this difference has not been statistically significant., Conclusions: The most frequent COPD phenotype assessed for lung transplantation is the exacerbator, although more than half of these patients fail to complete the pre-transplant study., (© 2021 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Neumología y Cirugía Torácica (SEPAR).)

Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. Although many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are significant as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and nontumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally, we integrated our data to study interspecies DNA methylation levels at orthologous CpG sites. Globally, we found considerable differences between the characteristics of DNA methylation alterations in cancer and aging in both species. Moreover, we describe robust evidence for the conservation of the specific cancer and aging epigenomic signatures in human and mouse. Our observations point toward the preservation of the functional consequences of these alterations at multiple levels of genomic regulation. Finally, our analyses reveal a role for the genomic context in explaining disease- and species-specific epigenetic traits., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir and/or ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an antiapoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: This study was aimed to identify risk factors associated with unfavorable outcomes (composite outcome variable: mortality and need for mechanical ventilation) in patients hospitalized in Galicia with COVID-19 pneumonia., Methods: Retrospective, multicenter, observational study carried out in the 8 Galician tertiary hospitals. All Patients admitted with confirmed COVID-19 pneumonia from 1st of March to April 24th, 2020 were included. A multivariable logistic regression analysis was performed in order to identify the relationship between risk factors, therapeutic interventions and the composite outcome variable., Results: A total of 1292 patients (56.1% male) were included. Two hundred and twenty-five (17.4%) died and 327 (25.3%) reached the main outcome variable. Age [odds ratio (OR) = 1.03 (95% confidence interval (CI): 1.01-1.04)], CRP quartiles 3 and 4 [OR = 2.24 (95% CI: 1.39-3.63)] and [OR = 3.04 (95% CI: 1.88-4.92)], respectively, Charlson index [OR = 1.16 (95%CI: 1.06-1.26)], SaO2 upon admission [OR = 0.93 (95% CI: 0.91-0.95)], hydroxychloroquine prescription [OR = 0.22 (95%CI: 0.12-0.37)], systemic corticosteroids prescription [OR = 1.99 (95%CI: 1.45-2.75)], and tocilizumab prescription [OR = 3.39 (95%CI: 2.15-5.36)], significantly impacted the outcome. Sensitivity analysis using different alternative logistic regression models identified consistently the ratio admissions/hospital beds as a predictor of the outcome [OR = 1.06 (95% CI: 1.02-1.11)]., Conclusion: These findings may help to identify patients at hospital admission with a higher risk of death and may urge healthcare authorities to implement policies aimed at reducing deaths by increasing the availability of hospital beds., Competing Interests: The authors have declared that no competing interests exist.

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD + -dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13 C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD + synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

In this work we look at the past in order to analyze four key variables after one year of the COVID-19 pandemic in Galicia (NW Spain): new infected, hospital admissions, intensive care unit admissions and deceased. The analysis is presented by age group, comparing at each stage the percentage of the corresponding group with its representation in the society. The time period analyzed covers 1 March 2020 to 1 April 2021, and includes the influence of the B.1.1.7 lineage of COVID-19 which in April 2021 was behind 90% of new cases in Galicia. It is numerically shown how the pandemic affects the age groups 80+, 70+ and 60+, and therefore we give information about how the vaccination process could be scheduled and hints at why the pandemic had different effects in different territories.

Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis. As a proof of concept of the role of cholesterol homeostasis on DFTD proliferation, we show that atorvastatin, an FDA-approved statin-drug subtype used against human cardiovascular diseases that inhibits cholesterol synthesis, shuts down DFTD energy metabolism and prevents tumor growth in an in vivo DFTD-xenograft model. In conclusion, we show that intervention against cholesterol homeostasis and carbohydrate-dependent energy metabolism by atorvastatin constitutes a feasible biochemical treatment against DFTD, which may assist in the conservation of the Tasmanian devil., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Senescent cells accumulate with obesity in the white adipose tissue of mice and humans. These senescent cells enhance the pro-inflammatory environment that, with time, contributes to the onset of glucose intolerance and type 2 diabetes. Glucose intolerance in mouse models of obesity has been successfully reversed by the elimination of senescent cells with the senolytic compounds navitoclax or the combination of dasatinib and quercetin (D/Q). In this work, we generated obese mice by high-fat diet feeding, and treated them with five consecutive cycles of navitoclax or D/Q during 16 weeks. We observed an efficient reduction in the white adipose tissue of the senescence markers senescence-associated β-galactosidase activity, Cdkn2a-p16 and Cdkn2a-p19 at the end of the 5 cycles. Mice treated with both navitoclax and D/Q showed an improvement of their insulin sensitivity and glucose tolerance during a short period of time (cycles 3 and 4), that disappeared at the fifth cycle. Also, these mice tended to increase the expression at their adipose tissue of the adipogenic genes Pparg and, Cebpa , as well as their plasma adiponectin levels. Together, our work shows that two different senolytic treatments, acting through independent pathways, are transiently effective in the treatment of obesity-induced metabolic disorders.

Background and Objective: Enterobacteriaceae (EB) spp. family is known to include potentially multidrug-resistant (MDR) microorganisms, and remains as an important cause of community-acquired pneumonia (CAP) associated with high mortality. The aim of this study was to determine the prevalence and specific risk factors associated with EB and MDR-EB in a cohort of hospitalized adults with CAP., Methods: We performed a multinational, point-prevalence study of adult patients hospitalized with CAP. MDR-EB was defined when ≥3 antimicrobial classes were identified as non-susceptible. Risk factors assessment was also performed for patients with EB and MDR-EB infection., Results: Of the 3193 patients enrolled with CAP, 197 (6%) had a positive culture with EB. Fifty-one percent (n = 100) of EB were resistant to at least one antibiotic and 19% (n = 38) had MDR-EB. The most commonly EB identified were Klebsiella pneumoniae (n = 111, 56%) and Escherichia coli (n = 56, 28%). The risk factors that were independently associated with EB CAP were male gender, severe CAP, underweight (body mass index (BMI) < 18.5) and prior extended-spectrum beta-lactamase (ESBL) infection. Additionally, prior ESBL infection, being underweight, cardiovascular diseases and hospitalization in the last 12 months were independently associated with MDR-EB CAP., Conclusion: This study of adults hospitalized with CAP found a prevalence of EB of 6% and MDR-EB of 1.2%, respectively. The presence of specific risk factors, such as prior ESBL infection and being underweight, should raise the clinical suspicion for EB and MDR-EB in patients hospitalized with CAP., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

: Colorectal cancer has the second highest cancer-related mortality rate, with an estimated 881,000 deaths worldwide in 2018. The urgent need to reduce the incidence and mortality rate requires innovative strategies to improve prevention, early diagnosis, prognostic biomarkers, and treatment effectiveness. Caloric restriction (CR) is known as the most robust nutritional intervention that extends lifespan and delays the progression of age-related diseases, with remarkable results for cancer protection. Other forms of energy restriction, such as periodic fasting, intermittent fasting, or fasting-mimicking diets, with or without reduction of total calorie intake, recapitulate the effects of chronic CR and confer a wide range of beneficial effects towards health and survival, including anti-cancer properties. In this review, the known molecular, cellular, and organismal effects of energy restriction in oncology will be discussed. Energy-restriction-based strategies implemented in colorectal models and clinical trials will be also revised. While energy restriction constitutes a promising intervention for the prevention and treatment of several malignant neoplasms, further investigations are essential to dissect the interplay between fundamental aspects of energy intake, such as feeding patterns, fasting length, or diet composition, with all of them influencing health and disease or cancer effects. Currently, effectiveness, safety, and practicability of different forms of fasting to fight cancer, particularly colorectal cancer, should still be contemplated with caution., Competing Interests: The authors declare no conflicts of interests.

Nowadays, obesity and its associated metabolic disorders, including diabetes, metabolic syndrome, cardiovascular disease, or cancer, continue to be a health epidemic in westernized societies, and there is an increased necessity to explore anti-obesity therapies including pharmaceutical and nutraceutical compounds. Considerable attention has been placed on the identification of bioactive compounds from natural sources to manage the metabolic stress associated with obesity. In a previous work, we have demonstrated that a CO 2 supercritical fluid extract from yarrow (Yarrow SFE), downregulates the expression of the lipogenic master regulator SREBF1 and its downstream molecular targets FASN and SCD in a tumoral context. Since obesity and diabetes are strongly considered high-risk factors for cancer development, herein, we aimed to investigate the potential therapeutic role of Yarrow SFE in the metabolic stress induced after a high-fat diet in mice. For this purpose, 32 C57BL/6 mice were distributed in four groups according to their diets: standard diet (SD); SD supplemented with Yarrow SFE (SD + Yarrow); high-fat diet (HFD); and HFD supplemented with Yarrow SFE (HFD + Yarrow). Fasting glycemia, insulin levels, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile, gene expression, and lipid content of liver and adipose tissues were analyzed after three months of treatment. Results indicate improved fasting glucose levels in plasma, enhanced insulin sensitivity, and diminished hypercholesterolemia in the HFD + Yarrow group compared to the HFD group. Mechanistically, Yarrow SFE protects liver from steatosis after the HFD challenge by augmenting the adipose tissue buffering capacity of the circulating plasma glucose.

Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.

Sirtuins are a family of protein deacylases and ADP-ribosyl-transferases, homologs to the yeast SIR2 protein. Seven sirtuin paralogs have been described in mammals, with different subcellular locations, targets, enzymatic activities, and regulatory mechanisms. All sirtuins share NAD + as substrate, placing them as central metabolic hubs with strong relevance in lifespan, metabolism, and cancer development. Much effort has been devoted to studying the roles of sirtuins in cancer, providing a wealth of data on sirtuins roles in mouse models and humans. Also, extensive data are available on the effects of pharmacological modulation of sirtuins in cancer development. Here, we present a comprehensive and organized resume of all the existing evidence linking every sirtuin with cancer development. From our analysis, we conclude that sirtuin modulation after tumor initiation results in unpredictable outcomes in most tumor types. On the contrary, all genetic and pharmacological models indicate that sirtuins activation prior to tumor initiation can constitute a powerful preventive strategy.

Introduction: Influenza A H1N1 community-acquired pneumonia (CAP) is a quite frequent respiratory disease. Despite being considered more serious than other CAPs, there are very few studies comparing its characteristics with noninfluenza CAP. We aim to establish the differences between pneumonia due to H1N1 virus and pneumonia not caused by H1N1 influenza virus and to determine the probability that a pneumonia is due to an H1N1 virus infection based on the most relevant variables., Methods: We used a case-control study where cases were H1N1 CAP patients with confirmed microbiological diagnosis and controls were patients with CAP admitted to hospital. H1N1 and other influenza types were discarded among controls. We calculated the probability of being a case or control using multivariate logistic regression., Results: We included 99 cases and 270 controls. Cases were younger than controls (53 vs 71 years, respectively). Mortality was much higher for H1N1 patients (13% vs 0.3%), and admission to intensive care unit was more frequent for H1N1 cases. The variables most associated with presenting H1N1 CAP were bilateral affectation on chest X-rays (OR: 5.70; 95% CI 2.69-10.40), followed by presence of arthromyalgias, with cases presenting close to three times more arthromyalgias compared to controls. Low leukocytes count and high AST values were also significantly associated with H1N1 CAP. H1N1 CAPs are characterized by bilateral affectation, low leukocyte count, presence of arthromyalgias, and high AST., Conclusions: A few and easy to obtain clinical parameters might be extremely useful to distinguish H1N1 CAP from CAPs of other origin.

Background: Who should be tested for viruses in patients with community acquired pneumonia (CAP), prevalence and risk factors for viral CAP are still debated. We evaluated the frequency of viral testing, virus prevalence, risk factors and treatment coverage with oseltamivir in patients admitted for CAP., Methods: Secondary analysis of GLIMP, an international, multicenter, point-prevalence study of hospitalized adults with CAP. Testing frequency, prevalence of viral CAP and treatment with oseltamivir were assessed among patients who underwent a viral swab. Univariate and multivariate analysis was used to evaluate risk factors., Results: 553 (14.9%) patients with CAP underwent nasal swab. Viral CAP was diagnosed in 157 (28.4%) patients. Influenza virus was isolated in 80.9% of cases. Testing frequency and viral CAP prevalence were inhomogeneous across the participating centers. Obesity (OR 1.59, 95%CI: 1.01-2.48; p = 0.043) and need for invasive mechanical ventilation (OR 1.62, 95%CI: 1.02-2.56; p = 0.040) were independently associated with viral CAP. Prevalence of empirical treatment with oseltamivir was 5.1%., Conclusion: In an international scenario, testing frequency for viruses in CAP is very low. The most common cause of viral CAP is Influenza virus. Obesity and need for invasive ventilation represent independent risk factors for viral CAP. Adherence to recommendations for treatment with oseltamivir is poor., (Copyright © 2018 European Federation of Internal Medicine. All rights reserved.)

FOXO proteins are transcription factors with important roles in the regulation of the expression of genes involved in cell growth, proliferation, differentiation, and longevity. FOXO proteins are active in the nucleus but, upon post-translational modification they form a docking site for 14-3-3 proteins and are translocated to the cytoplasm where they are inactive.We make use of this regulatory mechanism of FOXO proteins to develop an image-based high-throughput screening platform to detect compounds that regulate FOXO3 subcellular localization. This system has proven a powerful tool to isolate inhibitors of proteins upstream of FOXO, such as PI3K inhibitors.

The NAD + -dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-Ras G12V -driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-Ras G12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs., (© 2018 The Authors.)

The employment of systemic corticosteroids in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD) has been shown to improve airway limitation, decrease treatment failure and risk of relapse, and may improve symptoms in addition to decreasing the length of hospital stay. Nowadays, all clinical guidelines recommend systemic corticosteroids to treat moderate or severe COPD exacerbations. However, their use is associated with potential side effects, mainly hyperglycemia. In the era of precision medicine, the possibility of employing blood eosinophil count has emerged as a potential way of optimizing therapy. Issues regarding the intra-individual variability of blood eosinophil count determination, a lack of clear data regarding the real prevalence of eosinophilic acute exacerbations, the fact that previously published studies have demonstrated the benefit of systemic corticosteroids irrespective of eosinophil levels, and especially the fact that there is only one well-designed study justifying this approach have led us to think that we are not ready to use eosinophil count to guide treatment with systemic corticosteroids during acute exacerbations of COPD., Competing Interests: The authors declare no conflict of interest.

Diabetes refers to a group of metabolic diseases characterized by impaired insulin signalling and high blood glucose. A growing body of epidemiological evidence links diabetes to several types of cancer but the underlying molecular mechanisms are poorly understood. The signalling cascade connecting insulin and FOXO proteins provides a compelling example for a conserved pathway at the interface between insulin signalling and cancer. FOXOs are transcription factors that orchestrate programs of gene expression known to control a variety of processes in response to cellular stress. Genes regulated by this family of proteins are involved in the regulation of cellular energy production, oxidative stress resistance and cell viability and proliferation. Accordingly, FOXO factors have been shown to play an important role in the suppression of tumour growth and in the regulation of metabolic homeostasis. There is emerging evidence that deregulation of FOXO factors might account for the association between insulin resistance-related metabolic disorders and cancer., (© 2017 UICC.)

Introduction: It is not known whether clinical practice guidelines for the treatment of COPD exacerbations with short coursesofsystemic corticosteroids(SC-SCS) are followed in clinical practice., Method: Prospective, observational cohort study in patients admitted due to severe COPD exacerbation. The primary endpoint was the percentage of patients who received SC-SCS as treatment for severe exacerbation (doses of 200-300mg for 5-6 days). Secondary variables were percentageof patients with duration or reduced dose, dose in the first 24hours, days of intravenous systemic corticosteroids (SCS), and duration of hospital length of stay (LOS). Simple linear regression was performed with LOS as a dependent variable and multivariate analysis with factors associated with LOS., Results: 158 patients were evaluated. 4.4% (7) patients received SC-SCS, 8.7% received a reduced dose and duration was reduced in 15.8%. The median dose and duration of SCS were 602.5mg (200-1625) and 14 (4-36) days, respectively. We observed an association between days of SCSand LOS (P<.001) and doses of intrahospitalSCSand LOS (P<.001). Factors associated with LOS were doses of intrahospitalSCS received (.01 [95% CI:.007-.013]; P<0.001), days of steroid treatment (.14 [95% CI .03-.25], P=.009) and PAFI (pO2/FiO 2 ratio) at admission (-.012 [95% CI: -.012 to -.002], P=.015)., Conclusions: The SCS schedules used in routine clinical practice are longer and administered at a higher dose than recommended, leading toa longer hospital stay., (Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)