Experimental Study of a Sequential Membrane Process of Ultrafiltration and Nanofiltration for Efficient Polyphenol Extraction from Wine Lees.

The wine industry is a sector of great importance in the Spanish economy, contributing substantial annual revenues. However, one challenge facing the industry is the amount of waste generated, reaching millions of tons annually. These residues consist of organic matter of industrial interest, such as polyphenols. These substances are characterised by their excellent antioxidant properties, making them ideal for use in the food, cosmetic, and pharmaceutical industries. Modern techniques, such as membrane technology, are explored for their extraction based on separating compounds according to size. This work studies a sequential filtration process using ultrafiltration (UF) and nanofiltration (NF) membranes at different operating conditions (2 bar and 9.5 bar for UF and NF, respectively, at 20 °C) to extract polyphenols from wine lees. The results show a total polyphenols rejection rate for each process of 54% for UF and 90% for NF. Pore blocking models have been studied for the UF process and an intermediate pore blocking of the membrane upon wine lees filtration has been identified. A mathematical model that justifies the behavior of a polymeric NF membrane with the filtration of pre-treated vinasse residues has been validated. This study shows a viable process for extracting polyphenols from wine lees with sequential membrane technology.

Attitudes, Behaviors, and Perceptions of Students Vaping in Three Mexican Universities.

The increase in the popularity and use of electronic cigarettes (e-cigarettes) has consistently risen worldwide and has become associated with adverse health outcomes. This study has identified the attitudes and perceptions of undergraduate students who vape in three universities in Mexico. A cross-sectional study involving 495 participants was conducted using a survey from October to December 2023. Three universities in different states in Mexico collaborated with colleges in Yucatan, Durango, and Nuevo Leon, Mexico. Descriptive statistics include frequencies and percentages, and four logistic regression models were employed. In the sample, 31% and 17.54% of participants reported smoking and vaping, respectively. Students who reported vaping in the last month reported that their first experience with vaping was at an average of 17.3 years of age, and of those, 71.26% (n = 62) reported having vaped for over 100 days, while the remaining 38% reported vaping for between 2 and 100 days. Students from Veracruz and Yucatan began vaping at a younger age than in the central and northern regions. There is a need to educate students about the dangers of the chemicals in the liquids they use, the secondary exposure vapers, and the health dangers they pose.

Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy.

BACKGROUND AND AIMS: The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients. APPROACH AND RESULTS: Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score-matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06-0.73]) and AST (OR 0.97 [95% CI: 0.95-0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95-0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08-0.64]), diabetes (sHR 5.62 [95% CI: 2.02-15.68]), albumin (sHR 0.34 [95% CI: 0.13-0.89]), and platelets (sHR 0.99 [95% CI: 0.98-1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14-0.95]), albumin (sHR 0.36 (95% CI: 0.16-0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17-11.70]) were associated with decompensated cirrhosis. CONCLUSIONS: Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation.

Systematic review of the utility and limits of 3D printing in spine surgery.

OBJECTIVE: The main objective of this study has been to demonstrate why additive printing allows to make complex surgical pathological processes that affect the spine more visible and understandable, increasing precision, safety and reliability of the surgical procedure. METHODS: A systematic review of the articles published in the last 10 years on 3D printing-assisted spinal surgery was carried out, in accordance with PRISMA 2020 declaration. Keywords "3D printing" and "spine surgery" were searched in Pubmed, Embase, Cochrane Database of Systematic Reviews, Google Scholar and Opengrey databases, which was completed with a manual search through the list of bibliographic references of the articles that were selected following the defined inclusion and exclusion criteria. RESULTS: From the analysis of the 38 selected studies, it results that 3D printing is useful in surgical planning, medical teaching, doctor-patient relationship, design of navigation templates and spinal implants, and research, optimizing the surgical process by focusing on the patient, offering magnificent support during the surgical procedure. CONCLUSIONS: The use of three-dimensional printing biomodels allows: making complex surgical pathological processes that affect the spine more visible and understandable; increase the accuracy, precision and safety of the surgical procedure, and open up the possibility of implementing personalized treatments, mainly in tumor surgery.

Breast Cancer Tissue Explants: An Approach to Develop Personalized Therapy in Public Health Services.

Breast cancer is one of the main causes of death worldwide. Lately, there is great interest in developing methods that assess individual sensitivity and/or resistance of tumors to antineoplastics to provide personalized therapy for patients. In this study we used organotypic culture of human breast tumor slices to predict the experimental effect of antineoplastics on the viability of tumoral tissue. Samples of breast tumor were taken from 27 patients with clinically advanced breast cancer; slices were obtained and incubated separately for 48 h with paclitaxel, docetaxel, epirubicin, 5-fluorouracil, cyclophosphamide, and cell culture media (control). We determined an experimental tumor sensitivity/resistance (S/R) profile by evaluating tissue viability using the Alamar Blue® metabolic test, and by structural viability (histopathological analyses, necrosis, and inflammation). These parameters were related to immunohistochemical expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The predominant histological type found was infiltrating ductal carcinoma (85.2%), followed by lobular carcinoma (7.4%) and mixed carcinoma (7.4%). Experimental drug resistance was related to positive hormone receptor status in 83% of samples treated with cyclophosphamide (p = 0.027). Results suggest that the tumor S/R profile can help to predict personalized therapy or optimize chemotherapeutic treatments in breast cancer.

Thioredoxin regulates the redox state and the activity of the human tRNA ligase complex.

The mammalian tRNA ligase complex (tRNA-LC) catalyzes the splicing of intron-containing pre-tRNAs in the nucleus and the splicing of XBP1 mRNA during the unfolded protein response (UPR) in the cytoplasm. We recently reported that the tRNA-LC coevolved with PYROXD1, an essential oxidoreductase that protects the catalytic cysteine of RTCB, the catalytic subunit of the tRNA-LC, against aerobic oxidation. In this study, we show that the oxidoreductase Thioredoxin (TRX) preserves the enzymatic activity of RTCB under otherwise inhibiting concentrations of oxidants. TRX physically interacts with oxidized RTCB, and reduces and reactivates RTCB through the action of its redox-active cysteine pair. We further show that TRX interacts with RTCB at late stages of UPR. Since the interaction requires oxidative conditions, our findings suggest that prolonged UPR generates reactive oxygen species. Thus, our results support a functional role for TRX in securing and repairing the active site of the tRNA-LC, thereby allowing pre-tRNA splicing and UPR to occur when cells encounter mild, but still inhibitory levels of reactive oxygen species.

Aspen plus simulation of sargassum for quality synthesis gas.

Biomass is widely considered as a raw material for the production of biochemicals and biofuels and among all the options for its use, the gasification process is the most popular due to its environmental advantages. The great arrival of sargassum to the coasts of the State of Quintana Roo, Mexico, which has taken place for several years, forces us to study its energy use. In this study, the experimental results of the gasification of four biomasses (pine sawdust, bamboo dust, rice husk, and cane bagasse) from three different bibliographical references were simulated and validated, using the Aspen Plus computer software. The simulation model used considers the combustion of 30% of the biomass and therefore an energy balance, in addition to an estimate of the tar generated in the process. Based on the comparison of the percentage molar composition and the heating value of the syngas obtained the performance of the process was evaluated, where the lowest error per difference was for the validation of rice husk (RH) with an ER of 0.35. Subsequently, the sargassum gasification simulation was carried out with information on the properties of this biomass from five bibliographic references, obtaining as a result a syngas with a lower heating value (LHV) that varies between 2.6 and 4.8 MJ/Nm3 for ER of 0.3 and 0.35, respectively.

One-year follow-up of a multifocal intraocular lens with optimized elevated phase shift.

PURPOSE: To evaluate the standard outcomes of a multifocal intraocular lens (mIOL) with optimized elevated phase shift (EPS). SETTING: Qvision, Ophthalmology Department, VITHAS Almería, Spain. DESIGN: Retrospective observational. METHODS: 41 patients, consecutively operated on cataracts or refractive lens exchange with the implantation of the Liberty 640PM (EPS 2.0) and followed during 12 months, were included in the analysis. Retrieved variables were visual acuities at far, intermediate, and near distances; defocus curves (VADC); and prediction error of 4 formulas optimized for IOLMaster 500 and Pentacam AXL Wave. Patient-reported outcomes were also obtained for assessing spectacle independence, satisfaction, bothersome to dysphotopsia, difficulties in daily life tasks, and decision to be operated with the same mIOL. RESULTS: The median monocular efficacy with best distance correction was 0, 0.1, and 0.1 logMAR at far, intermediate, and near distances, respectively, with patients achieving binocularly a median of 0 logMAR at the 3 distances. VADC showed a depth of field of 3 diopters (D) above 0.2 logMAR with a median increase of 0.07 logMAR from -1.5 to -2.5 D. Complete spectacle independence was achieved at far distance, whereas 97.6% and 85.4% was achieved at intermediate and near distances, respectively. 7.3% of patients were bothered by dysphotopsia, and 92.6% of patients were likely to be operated again. CONCLUSIONS: EPS 2.0 restored patients' vision in the full range of the depth of field with a nearly monotone decrease of visual performance from far to near, achieving high rates of spectacle independence at all distances and with low positive dysphotopsia rates ( ClinicalTrials.gov Identifier: NCT05735990).

Frank's sign associated with the severity of ischemic heart disease in patients under 65 years old.

BACKGROUND AND OBJECTIVE: Frank's sign is the diagonal ear fold which has been associated with ischemic heart disease. The objective of this work was to evaluate the relationship of Frank's sign with severity of ischemic heart disease in adults ≤ 65 years old in the northeast of Mexico. PATIENTS AND METHODS: A cross-sectional study was conducted in patients ≤ 65 years old who underwent coronary angiography consecutively over a period of 5 months in 2022. Severe coronary artery disease (CAD) was associated with Frank's sign and other common cardiovascular risks. To determine the association, bivariate and multivariate analysis was performed using logistic regression that included variables with a value of p<0.05. Statistical analysis was performed with SPSS version 22. RESULTS: We included 311 patients ≤ 65 years, of whom 80% were men. The median age was 57 years (range 28-65). Frank's sign was positive in 62% of the population. The main clinical characteristics in patients with Frank's sign were type 2 diabetes mellitus (55%), p=0.003, dyslipidemia (53%), p=0.026 and smoking (68%), p=0.002. In the multivariate analysis, the independent variables associated with severe CAD were Frank's Sign OR 3.26; 95% CI (1.98-5.38), p≤0.001, male gender OR 2.28; 95% CI (1.20-4.35), p=0.012, and dyslipidemia OR 1.81; 95% CI (1.11-2.97), p=0.017. CONCLUSIONS: There is an independent association between Frank's sign with the presence of severe CAD in patients ≤ 65 years old, which may be useful for screening and prevention.

Real-world treatment outcomes of medicines used in special situations (off-label and compassionate use) in oncology and hematology: A retrospective study from a comprehensive cancer institution.

PURPOSE: Medicines in special situations (MSS) refer to off-label or to unlicensed drugs under investigation (compassionate use). Our objectives were to evaluate characteristics and to estimate overall survival (OS), event-free survival (EFS), and the duration of treatment (DT) of MSS used for cancer treatment at a multicentre comprehensive cancer institution. METHODS: Retrospective cohort study on adult cancer patients for whom an MSS treatment was requested (January 2011-December 2020). A descriptive analysis was performed and median OS and EFS and 95% confidence intervals (CIs) were estimated. Survival curves were stratified by type of tumor, ECOG (Eastern Cooperative Oncology Group) performance status (PS), age, sex, treatment stage and type of drug (mechanism of action and target). RESULTS: Treatment was initiated in 2092 episodes (1930 patients) out of 2377 MSS episodes (2189 patients) requested, 33% for hematological treatment and 87% for advanced stage cancer. Median OS (months) was 21.1 (95% CI 19.4-22.7), median EFS was 5.6 (95% CI 5.1-6.0) months, and median DT was 4.5 [0.0; 115.3] months. OS and EFS statistically significantly favored female patients, ECOG PS ≥2 episodes showed worse OS and EFS outcomes (p < 0.0001). Statistically significant differences in survival were found within solid and hematological cancer, disease stage, drug mechanism of action, and type of cancer (p < 0.001) but not for age. Survival outcomes by tumor subtype and drug are presented both globally and separately based on disease stage. CONCLUSION: MSS uses are practiced across almost all cancer types, mostly for advanced disease. ECOG PS ≥2, along with advanced disease, was related to worse survival. Information about real-world outcomes is valuable and contributes to better decision-making regarding MSS and our experience in this field could be of interest for other colleagues.

Eficacia de la técnica sostener relajar en comparación con el estiramiento dinámico sobre la flexibilidad de los isquiotibiales / Efficacy of the hold-relax technique compared to dynamic stretching on hamstring flexibility / Eficácia da técnica segurar-relaxar comparada ao alongamento dinâmico na flexibilidade dos isquiotibiais

Objetivo: el estiramiento muscular se aplica con el propósito de aumentar el arco de movimiento. Para este propósito se usan diferentes técnicas, entre ellas: la facilitación neuromuscular propioceptiva (FNP) y el estiramiento dinámico, pero aún no se conoce cuál de ellas es más efectiva. El objetivo de esta investigación fue estimar la eficacia de la técnica sostener relajar en comparación con el estiramiento dinámico sobre la flexibilidad de los isquiotibiales en adultos jóvenes sanos. Metodología: ensayo clínico controlado aleatorizado, con enmascaramiento de dos brazos. En el estudio participaron un total de 32 voluntarios adultos jóvenes con edades entre los 18 y 30 años y fueron aleatorizados a dos grupos de intervención FNP (n = 16), dinámico (n = 16). La flexibilidad de la articulación de la rodilla se evaluó mediante el ángulo poplíteo a través de la goniometría. Resultados: los resultados de las medias edad, peso, talla e índice masa corporal son equivalentes, lo que indica grupos comparables entre sí. No se hallaron diferencias entre los grupos de estiramiento en los promedios ajustados -2.09 (IC95% -7.05 a 2.87). Conclusiones: tanto la técnica dinámica como la FNP aumentaron el arco de movimiento de rodilla, ambas técnicas de estiramiento mostraron diferencias con la línea de base. No se encontraron diferencias entre los grupos de estiramiento.

Objective: Muscle stretching is applied with the purpose of increasing range of motion. Different techniques are used for this purpose, including proprioceptive neuromuscular facilitation (PNF) and dynamic stretching, but it is still unclear which one is more effective. The objective of this research was to estimate the efficacy of the hold-relax technique compared to dynamic stretching on hamstring flexibility in healthy young adults. Methodology: Randomized controlled trial with blinding, consisting of two intervention arms. The study included a total of 32 young adult volunteers aged 18 to 30 years, who were randomized into two intervention groups: PNF (n = 16) and dynamic stretching (n = 16). Knee joint flexibility was assessed using the popliteal angle measured with a goniometer. Results: The mean age, weight, height, and body mass index were found to be equivalent, indicating comparable groups. No significant differences were found between the stretching groups in the adjusted means, with a mean difference of -2.09 (95 % CI -7.05 to 2.87). Conclusions: Both dynamic stretching and PNF demonstrated an increase in knee range of motion, with both stretching techniques showing differences from the baseline. No significant differences were found between the stretching groups.

Finalidade: O alongamento muscular é aplicado com a finalidade de aumentar a ampli-tude de movimento. Para tanto, diversas técnicas são utilizadas, dentre elas: facilitação neuromuscular proprioceptiva (FNP) e alongamento dinâmico, mas ainda não se sabe qual delas é mais eficaz. O objetivo desta investigação foi estimar a eficáciada técnica segurar-relaxar em comparação com o alongamento dinâmico na flexibilidade dos isquiotibiais em adultos jovens saudáveis. Metodologia: Ensaio clínico randomizado, cego, controlado por dois braços. Um total de 32 voluntários adultos jovens com idades entre 18 e 30 anos participaram do estudo e foram randomizados para dois grupos de intervenção FNP (n = 16), dinâmico (n = 16). A flexibilidade da articulação do joelho foi avaliada por meio do ângulo poplíteo por goniometria. Resultados: os resultados das médias de idade, peso, altura e índice de massa corporal são equivalentes, o que indica grupos comparáveis entre si. Não foram encontradas dife-renças entre os grupos de alongamento nas médias ajustadas - 2,09 (IC 95 % -7,05 a 2,87). Conclusões: tanto a técnica dinâmica quanto o PNF aumentaram a amplitude de mo-vimento do joelho, ambas as técnicas de alongamento apresentaram diferenças com a linha de base. Não foram encontradas diferenças entre os grupos de alongamento.

Approach to Circular Chemistry Preparing New Polyesters from Olive Oil.

The transformation of cooking oils and their waste into polyesters is a challenge for circular chemistry. Herein, we have used epoxidized olive oil (EOO), obtained from cooking olive oil (COO), and various cyclic anhydrides (such as phthalic anhydride PA, maleic anhydride MA, and succinic anhydride SA) as raw materials for the preparation of new bio-based polyesters. For the synthesis of these materials, we have used the bis(guanidine) organocatalyst 1 and tetrabutylammonium iodide (Bu4NI) as cocatalyst. The optimal reaction conditions for the preparation of poly(EOO-co-PA) and poly(EOO-co-MA) were 80 °C for 5 h using toluene as solvent; however, the synthesis of poly(EOO-co-SA) required more extreme reaction conditions. Furthermore, we have exclusively succeeded in obtaining the trans isomer for MA-polyester. The obtained biopolyesters were characterized by NMR, Fourier transform infrared, thermogravimetric analysis, and scanning electron microscopy analyses. Since there are few examples of functionalized and defined compounds based on olive oil, it is innovative and challenging to transform these natural-based compounds into products with high added value.

Adjuvant dabrafenib and trametinib for patients with resected BRAF -mutated melanoma: DESCRIBE-AD real-world retrospective observational study.

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF - V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF -mutated melanoma patients aged ≥18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations.

Engineered flavoproteins as bioorthogonal photo-triggers for the activation of metal-based anticancer prodrugs.

A multifunctional hybrid constructed for controlling the delivery and activation of Pt anticancer agents in vitro is described herein. We employed consensus tetratricopeptide repeat protein (CTPR) for the covalent co-anchoring of riboflavin (photocatalyst) and a Pt(IV) prodrug complex. The Pt-loaded flavoprotein induced a 40% reduction in PANC-1 cell viability as a result of the photocatalytic formation of cisplatin.

Jasmonate-deficient mutant lox3a reveals crosstalk between jasmonate and ethylene in the differential regulation of male and female flower opening and early fruit development in Cucurbita pepo.

Jasmonate (JA) has been found to be a relevant hormone in floral development in numerous species, but its function in cucurbit floral development and sex determination is unknown. Crosstalk between JA and ethylene (ET) in the differential regulation of male and female floral development was investigated by using the novel JA-deficient mutant lox3a, and the ET-deficient and -insensitive mutants, aco1a and etr2b, respectively, of Cucurbita pepo. The lox3a mutation suppresses male and female flower opening and induces the development of parthenocarpic fruit. A bulked-segregant analysis coupled with whole genome sequencing and fine mapping approach allowed the identification of lox3a mutation in CpLOX3A, a LIPOXYGENASE gene involved in JA biosynthesis. The reduced JA content and expression of JA-signalling genes in male and female flowers of lox3a, and the rescue of lox3a phenotype by external application of methyl jasmonate (MeJA), demonstrated that JA controls petal elongation and flower opening, as well as fruit abortion in the absence of fertilization. JA also rescued the phenotype of ET mutants aco1a and etr2b, which are both specifically defective in female flower opening and fruit abortion. ET, the sex determining hormone of cucurbits, is induced in female flowers towards anthesis, activating JA production and promoting the aperture of the female flower, and the abortion of the unfertilized ovary. Given the close association between flower closure and parthenocarpic fruit development, we propose that flower opening can act as a switch that triggers fruit set and development in fertilized ovaries, but may alternatively induce the abortion of the unfertilized ovary. Both ET and JA from mature and senescent petals can serve as remote signals that determine the alternative development of the ovary and fruit.

Evolving Concepts on Inflammatory Biomarkers and Malnutrition in Chronic Kidney Disease.

While patient care, kidney replacement therapy, and transplantation techniques for chronic kidney disease (CKD) have continued to progress, the incidence of malnutrition disorders in CKD appears to have remained unchanged over time. However, there is now a better understanding of the underlying pathophysiology according to the disease background, disease stage, and the treatment received. In CKD patients, the increased production of proinflammatory cytokines and oxidative stress lead to a proinflammatory milieu that is at least partially responsible for the increased morbidity and mortality in this patient population. New insights into the pathogenic role of innate immunity and the proinflammatory cytokine profile, characterized, for instance, by higher levels of IL-6 and TNF-α, explain some of the clinical and laboratory abnormalities observed in these patients. In this article, we will explore currently available nutritional-inflammatory biomarkers in distinct CKD populations (hemodialysis, peritoneal dialysis, transplantation) with a view to evaluating their efficacy as predictors of malnutrition and their involvement in the common proinflammatory process. Although there is a direct relationship between inflammatory-nutritional status, signs and symptoms [e.g., protein-energy wasting (PEW), anorexia], and comorbidities (e.g., atheromatosis, atherosclerosis), we are in need of clearly standardized markers for nutritional-inflammatory assessment to improve their performance and design appropriate bidirectional interventions.

Patients awaiting surgery for neurosurgical diseases during the first wave of the COVID-19 pandemic in Spain: a multicentre cohort study.

OBJECTIVES: The large number of infected patients requiring mechanical ventilation has led to the postponement of scheduled neurosurgical procedures during the first wave of the COVID-19 pandemic. The aims of this study were to investigate the factors that influence the decision to postpone scheduled neurosurgical procedures and to evaluate the effect of the restriction in scheduled surgery adopted to deal with the first outbreak of the COVID-19 pandemic in Spain on the outcome of patients awaiting surgery. DESIGN: This was an observational retrospective study. SETTINGS: A tertiary-level multicentre study of neurosurgery activity between 1 March and 30 June 2020. PARTICIPANTS: A total of 680 patients awaiting any scheduled neurosurgical procedure were enrolled. 470 patients (69.1%) were awaiting surgery because of spine degenerative disease, 86 patients (12.6%) due to functional disorders, 58 patients (8.5%) due to brain or spine tumours, 25 patients (3.7%) due to cerebrospinal fluid (CSF) disorders and 17 patients (2.5%) due to cerebrovascular disease. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was mortality due to any reason and any deterioration of the specific neurosurgical condition. Second, we analysed the rate of confirmed SARS-CoV-2 infection. RESULTS: More than one-quarter of patients experienced clinical or radiological deterioration. The rate of worsening was higher among patients with functional (39.5%) or CSF disorders (40%). Two patients died (0.4%) during the waiting period, both because of a concurrent disease. We performed a multivariate logistic regression analysis to determine independent covariates associated with maintaining the surgical indication. We found that community SARS-CoV-2 incidence (OR=1.011, p<0.001), degenerative spine (OR=0.296, p=0.027) and expedited indications (OR=6.095, p<0.001) were independent factors for being operated on during the pandemic. CONCLUSIONS: Patients awaiting neurosurgery experienced significant collateral damage even when they were considered for scheduled procedures.

LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes.

Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that LINE-1 (Long Interspersed Nuclear Element-1; L1) RNA accumulation was an early event in both typical and atypical human progeroid syndromes. L1 RNA negatively regulated the enzymatic activity of the histone-lysine N-methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of L1 RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as p16, p21, activating transcription factor 3 (ATF3), matrix metallopeptidase 13 (MMP13), interleukin 1a (IL1a), BTG anti-proliferation factor 2 (BTG2), and growth arrest and DNA damage inducible beta (GADD45b). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after L1 RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of L1 RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.