Global Challenges After a Global Challenge: Lessons Learned from the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed. In this chapter, world-leading scientists from different backgrounds share collectively their views about the pandemic's footprint and discuss challenges that face the international community.

The Study of Geographical Distribution in the Analysis of Domestication as an Evolutionary Process: Tensions in Alphonse de Candolle's Approach.

Interest in the study of domesticated plants increased near the end of the 18th century, mainly because of their economic potential. In the 19th century, there was a new focus on the historical understanding of species, their origin, changes in their distribution, and their evolutionary history. Charles Darwin developed an extended interpretation of species domestication, considering variations, reproduction, inheritance, and modification as standard processes between wild and domesticated organisms. In this context, one relatively neglected aspect was the geographical distribution of domesticated species. Alphonse de Candolle addressed and developed in detail the question of the geographical origin of cultivated plants. Since 1836 Alphonse de Candolle had been studying the topic and obtained evidence that contributed to understanding aspects such as the center of origin, dispersion, competition, selection, and time of domestication. Although Darwin himself admitted that Géographie botanique raisonnée (de Candolle, Alphonse,de. Géographie botanique raisonnée; ou, exposition des faits principaux et des lois concernant la distribution géographique des plantes de l'epoque actuelle, 2ème tome. Paris: Masson.) was of great help to him in the development of his evolutionary theory, the importance of de Candolle's contribution is seldom recognized. Our purpose is to detail the dialogue between Alphonse de Candolle and Darwin on the geography of domesticated plants, to understand some of the most critical discussions that contributed to the reinterpretation of domestication under the Darwinian proposal of modified descent.

Impact of a comprehensive geriatric assessment to manage elderly patients with locally advanced non-small-cell lung cancers: a multicenter prospective study.

PURPOSE: Concurrent chemoradiotherapy (cCRT) is the standard treatment for locally advanced and unresectable non-small-cell lung cancer. Population is aging, and Geriatric assessment (GA) has demonstrated its paper to select fit patients for active treatment and vulnerable, frail patients for interventions and/or palliative care in many histologies. Its role in locally advanced, unresectable non-small-cell lung cancer has been less explored. METHODS: To assess the capability of GA to detect frail patients not suitable for active treatment, we developed this exploratory non-interventional prospective study. All patients ≥ 70 years diagnosed with stage locally advanced and unresectable non-small-cell lung cancer were invited to undergo geriatric assessment. Secondary aims were description of population, exploring GA as prognostic factor, determination of toxicity profile and look for a frailty biomarker. RESULTS: From June 2017 to June 2020, 51 patients were included, of whom 35% (n:18) were classified as frail. Frail patients had less overall survival and more grade 3-4 toxicity. Exploratory results for frailty phenotype are described in the text. CONCLUSIONS: With the results of our study, we confirm that GA can detect frail patients unsuitable for treatment, with a higher risk of toxicity and less overall survival. A trend toward blood-test results for phenotype frailty can be hypothesis generation.

Characterization of cardiac resynchronization therapy response through machine learning and personalized models.

INTRODUCTION: The characterization and selection of heart failure (HF) patients for cardiac resynchronization therapy (CRT) remain challenging, with around 30% non-responder rate despite following current guidelines. This study aims to propose a novel hybrid approach, integrating machine-learning and personalized models, to identify explainable phenogroups of HF patients and predict their CRT response. METHODS: The paper proposes the creation of a complete personalized model population based on preoperative CRT patient strain curves. Based on the parameters and features extracted from these personalized models, phenotypes of patients are identified thanks to a clustering algorithm and a random forest classification is provided. RESULTS: A close match was observed between the 162 experimental and simulated myocardial strain curves, with a mean RMSE of 4.48% (±1.08) for the 162 patients. Five phenogroups of personalized models were identified from the clustering, with response rates ranging from 52% to 94%. The classification results show a mean area under the curves (AUC) of 0.86 ± 0.06 and provided a feature importance analysis with 22 features selected. Results show both regional myocardial contractility (from 22.5% to 33.0%), tissue viability and electrical activation delays importance on CRT response for each HF patient (from 55.8 ms to 88.4 ms). DISCUSSION: The patient-specific model parameters' analysis provides an explainable interpretation of HF patient phenogroups in relation to physiological mechanisms that seem predictive of the CRT response. These novel combined approaches appear as promising tools to improve understanding of LV mechanical dyssynchrony for HF patient characterization and CRT selection.

BRAF mutational status is associated with survival outcomes in locally advanced resectable and metastatic NSCLC.

BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.

Advanced non-squamous NSCLC with no actionable oncogenic driver in Spain: a cross-sectional descriptive analysis of data from the Thoracic Tumor Registry.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for the vast majority of all diagnosed lung cancers. According to their histology, most NSCLCs are considered non-squamous cell carcinoma (NSCC), and up to 85% of the latter may lack either one of the two main actionable oncogenic drivers (i.e., EGFR mutations and ALK rearrangements). OBJECTIVE: Our analysis aimed to describe the clinical and epidemiological characteristics of Spanish patients suffering from NSCC with no actionable oncogenic driver in daily clinical practice. DESIGN: A retrospective, cross-sectional, descriptive analysis. METHODS: We analyzed the records of all Spanish patients with advanced NSCC diagnosed between January 2011 and January 2020 and included in the Spanish Thoracic Tumor Registry database. We evaluated the presence of metastasis and molecular profiling at the time of diagnosis and treatments received. We also assessed overall survival (OS) and progression-free survival (PFS) according to first-line treatment. RESULTS: One thousand seven hundred ninety-seven Spanish patients with NSCC were included. They were mainly men (73.2%), smokers (current [44.4%] and former [44.4%]) and presented adenocarcinoma histology (97.6%). Most patients had at least one comorbidity (80.4%) and one metastatic site (96.8%), and a non-negligible number of those tested were PD-L1 positive (35.2%). Notably, the presence of liver metastasis indicated a shorter median OS and PFS than metastasis in other locations (p < 0.001). Chemotherapy was more often prescribed than immunotherapy as first-, second-, and third-line treatment in that period. In first-line, the OS rates were similar in patients receiving either regimen, but PFS rates significantly better in patients treated with immunotherapy (p = 0.026). Also, a high number of patients did not reach second- and third-line treatment, suggesting the failure of current early diagnostic measures and therapies. CONCLUSIONS: This analysis of the most lethal tumor in Spain could highlight the strengths and the weaknesses of its clinical management and set the ground for further advances and research.

Risk profiles for ventricular arrhythmias in hypertrophic cardiomyopathy through clustering analysis including left ventricular strain.

AIMS: The prediction of ventricular arrhythmia (VA) in hypertrophic cardiomyopathy (HCM) remains challenging. We sought to characterize the VA risk profile in HCM patients through clustering analysis combining clinical and conventional imaging parameters with information derived from left ventricular longitudinal strain analysis (LV-LS). METHODS: A total of 434 HCM patients (65% men, mean age 56 years) were included from two referral centers and followed longitudinally (mean duration 6 years). Mechanical and temporal parameters were automatically extracted from the LV-LS segmental curves of each patient in addition to conventional clinical and imaging data. A total of 287 features were analyzed using a clustering approach (k-means). The principal endpoint was VA. RESULTS: 4 clusters were identified with a higher rhythmic risk for clusters 1 and 4 (VA rates of 26%(28/108), 13%(13/97), 12%(14/120), and 31%(34/109) for cluster 1,2,3 and 4 respectively). These 4 clusters differed mainly by LV-mechanics with a severe and homogeneous decrease of myocardial deformation for cluster 4, a small decrease for clusters 2 and 3 and a marked deformation delay and temporal dispersion for cluster 1 associated with a moderate decrease of the GLS (p < 0.0001 for GLS comparison between clusters). Patients from cluster 4 had the most severe phenotype (mean LV mass index 123 vs. 112 g/m2; p = 0.0003) with LV and left atrium (LA) remodeling (LA-volume index (LAVI) 46.6 vs. 41.5 ml/m2, p = 0.04 and LVEF 59.7 vs. 66.3%, p < 0.001) and impaired exercise capacity (% predicted peak VO2 58.6 vs. 69.5%; p = 0.025). CONCLUSION: Processing LV-LS parameters in HCM patients 4 clusters with specific LV-strain patterns and different rhythmic risk levels are identified. Automatic extraction and analysis of LV strain parameters improves the risk stratification for VA in HCM patients.

Influence of occlusal thickness on the fracture resistance of chairside milled lithium disilicate posterior full-coverage single-unit prostheses containing virgilite: A comparative in vitro study.

PURPOSE: To evaluate the fracture resistance of chairside computer-aided design and computer-aided manufacturing (CAD-CAM) lithium disilicate mandibular posterior crowns with virgilite of different occlusal thicknesses and compare them to traditional lithium disilicate crowns. MATERIALS AND METHODS: Seventy-five chairside CAD-CAM crowns were fabricated for mandibular right first molars, 60 from novel lithium disilicate with virgilite (CEREC Tessera, Dentsply Sirona), and 15 from traditional lithium disilicate (e.max CAD, Ivoclar Vivadent). These crowns were distributed across five groups based on occlusal thickness and material: Group 1 featured CEREC Tessera crowns with 0.8 mm thickness, Group 2 had 1.0 mm thickness, Group 3 had 1.2 mm thickness, Group 4 with 1.5 mm thickness, and Group 5 included e.max CAD crowns with 1.0 mm thickness. These crowns were luted onto 3D-printed resin dies using Multilink Automix resin cement (Ivoclar Vivadent). Subsequently, they underwent cyclic loading (2,000,000 cycles at 1 Hz with a 275 N force) and loading until fracture. Scanning electron microscopy (SEM) assessed the fractured specimens. Statistical analysis involved one-way ANOVA and the Kruskal-Wallis Test (α = 0.05). RESULTS: Fracture resistance varied significantly (<0.001) across mandibular molar crowns fabricated from chairside CAD-CAM lithium disilicate containing virgilite, particularly between crowns with 0.8 mm and those with 1.2 and 1.5 mm occlusal thickness. However, no significant differences were found when comparing crowns with 1, 1.2, and 1.5 mm thicknesses. CEREC Tessera crowns with 1.5 mm thickness exhibited the highest resistance (2119 N/mm2), followed by those with 1.2 mm (1982 N/mm2), 1.0 mm (1763 N/mm2), and 0.8 mm (1144 N/mm2) thickness, whereas e.max CAD crowns with 1.0 mm occlusal thickness displayed the lowest resistance (814 N/mm2). CONCLUSIONS: The relationship between thickness and fracture resistance in the virgilite lithium disilicate full-coverage crowns was directly proportional, indicating that increased thickness corresponded to higher fracture resistance. No significant differences were noted among crowns with thicknesses ranging from 1 to 1.5 mm. This novel ceramic exhibited superior fracture resistance compared to traditional lithium disilicate.

Corrosion Induced on Aluminum by Biodiesel Components in Non-Oxygen Environments.

Biodiesel is a mixture of saturated and unsaturated Fatty Acid Methyl Esters (FAMEs) whose composition affects the corrosion behavior of metal containers during storage. This study examines the effect of the C=C bond present in selected FAMEs (Methyl Stearate, Methyl Oleate, and Methyl Linoleate) in aluminum corrosion in the absence of oxygen. First, mass loss assays were carried out at 100, 200, and 280 °C for 1000 h using pure Methyl Stearate (MS), 5% Methyl Oleate in Methyl Stearate (MS-5% MO), and 5% Methyl Linoleate in Methyl Stearate (MS-5% ML). Next, chemical changes in FAMEs were studied using FTIR, TGA, and GC/MS. SEM/EDS analysis allowed us to inspect the aluminum surfaces and their chemical characterization. We estimated higher corrosion rates for MS assays than those of unsaturated methyl ester mixtures. In a separate set of experiments, we used electrochemical techniques (potentiodynamic polarization, linear polarization resistance, and electrochemical impedance spectroscopy) to investigate aluminum corrosion induced by thermal-degraded products from FAMEs at 100, 200, and 280 °C for 300 h able to dissolve in aqueous extracts. These electrochemical experiments revealed that the products in the aqueous extracts from the unsaturated methyl ester mixture form a passive layer on the Al surface thicker than pure MS at the corresponding degradation temperatures.

Describing differences among populations of thoracic tumors patients under and over 80 years: Data analysis from the SLCG thoracic tumor registry.

OBJECTIVES: Cancer is a disease of old age; however, most studies usually included minority of patients fit elderly. The purpose is to investigate the clinical characteristics and genetic information of patients with thoracic tumors who are 80 years old or older compared to those under 80 years old. STUDY DESIGN AND METHODS: The Thoracic Tumor Registry (TTR) is a Spanish observational, prospective cohort study that included patients diagnosed with thoracic tumors. Data were collected from medical records related to sociodemographic, epidemiological, clinical, molecular/genetic, and treatment outcome variables. RESULTS: The total number of patients, recruited from August 2016 to April 2023, was 26.193 (93,1 % were younger than 80 years and 6,9 % were 80 years or older). In the group of older patients: the male ratio increased (72,9 % vs. 80 %); the number of elderly people who had never smoked or were ex-smokers increased (9,9 % vs. 21,1 % and 44,8 % vs. 61,3 %, respectively) and the number of current smokers decreased (43,3 % vs. 17,5 %); had higher ECOG performance status at diagnosis (for ECOG ≥ 2, 15 % vs. 32,9 %), and there were more patients with previous cancer (17,3 % vs. 28 %). The proportion of men is higher than that of women (73 % vs. 27 % in <80 years and 80 % vs. 20 % in ≥80 years). For all biomarkers, the proportion of patients who had a molecular determination was lower in older patients. There were no differences in terms of alterations in the biomarkers tested; except for EGFR, for which the positivity rate was higher in patients aged 80 years and older (25 % vs. 15,3 %). CONCLUSION: The proportion of older patients with targeted mutations is higher. So, at least at diagnosis, it should be proceeded in a standard way. Then, when it comes to treatment, comorbidities and patient's baseline situation should be considered. CLINICAL TRIAL REGISTRATION: NCT02941458.

Age-Dependent Changes in the Occurrence and Segregation of GABA and Acetylcholine in the Rat Superior Cervical Ganglia.

The occurrence, inhibitory modulation, and trophic effects of GABA have been identified in the peripheral sympathetic nervous system. We have demonstrated that GABA and acetylcholine (ACh) may colocalize in the same axonal varicosities or be segregated into separate ones in the rat superior cervical ganglia (SCG). Neurotransmitter segregation varies with age and the presence of neurotrophic factors. Here, we explored age-dependent changes in the occurrence and segregation of GABA and ACh in rats ranging from 2 weeks old (wo) to 12 months old or older. Using immunohistochemistry, we characterized the expression of L-glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular acetylcholine transporter (VAChT) in the rat SCG at 2, 4, 8, 12 wo and 12 months old or older. Our findings revealed that GAD67 was greater at 2 wo compared with the other ages, whereas VAChT levels were greater at 4 wo than at 12 wo and 12 months old or older. The segregation of these neurotransmitters was more pronounced at 2 and 4 wo. We observed a caudo-rostral gradient of segregation degree at 8 and 12 wo. Data point out that the occurrence and segregation of GABA and ACh exhibit developmental adaptative changes throughout the lifetime of rats. We hypothesize that during the early postnatal period, the increase in GABA and GABA-ACh segregation promotes the release of GABA alone which might play a role in trophic actions.

Parametric analysis of an integrated cardio-respiratory model in preterm newborns during apnea.

The analysis of the complex interactions involved in the acute physiological response to apnea-bradycardia events in preterm newborns remains a challenging task. This paper presents a novel integrated model of cardio-respiratory interactions, adapted to preterm newborns. A sensitivity analysis, based Morris' screening method, was applied to study the effects of physiological parameters on heart rate and desaturation, during the simulation of a 15-seconds apnea-bradycardia episode. The most sensitive parameters are associated with fundamental, integrative physiological mechanisms involving: (i) respiratory mechanics (intermediate airways and lung compliance), (ii) fraction of inspired oxygen, (iii) metabolic rates (oxygen consumption rate), (iv) heart rate regulation and (v) chemoreflex (gain). Results highlight the relevant influence of physiological variables, involved in preterm apnea-bradycardia events.

Pathogenic CANVAS (AAGGG)n repeats stall DNA replication due to the formation of alternative DNA structures.

CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A2G3)n repeat in the RFC1 gene. There are a multitude of repeat motifs found in the human population at this locus, some of which are pathogenic and others benign. In this study, we conducted structure-functional analyses of the pathogenic (A2G3)n and nonpathogenic (A4G)n repeats. We found that the pathogenic, but not the nonpathogenic, repeat presents a potent, orientation-dependent impediment to DNA polymerization in vitro. The pattern of the polymerization blockage is consistent with triplex or quadruplex formation in the presence of magnesium or potassium ions, respectively. Chemical probing of both repeats in vitro reveals triplex H-DNA formation by only the pathogenic repeat. Consistently, bioinformatic analysis of S1-END-seq data from human cell lines shows preferential H-DNA formation genome-wide by (A2G3)n motifs over (A4G)n motifs. Finally, the pathogenic, but not the nonpathogenic, repeat stalls replication fork progression in yeast and human cells. We hypothesize that the CANVAS-causing (A2G3)n repeat represents a challenge to genome stability by folding into alternative DNA structures that stall DNA replication.

Comparison of Clinical and Genetic Characteristics Between Younger and Older Lung Cancer Patients.

INTRODUCTION: The aim of this study was to analyze the clinical and genetic characteristics of young lung cancer cases, and to compare them with those of older cases. METHODS: We used the Thoracic Tumors Registry (TTR) as a data source representative of lung cancer cases diagnosed in Spain, and included all cases registered until 9/01/2023 which had information on age at diagnosis or the data needed to calculate it. We performed a descriptive statistical analysis and fitted logistic regressions to analyze how different characteristics influenced being a younger lung cancer patient. RESULTS: A total of 26,336 subjects were included. Lung cancer cases <50 years old had a higher probability of being women (OR: 1.38; 95% CI: 1.21-1.57), being in stage III or IV (OR: 1.32; 95% CI: 1.08-1.62), not having comorbidities (OR: 5.21; 95% CI: 4.59-5.91), presenting with symptoms at diagnosis (OR: 1.53; 95% CI: 1.29-1.81), and having ALK translocation (OR: 7.61; 95% CI: 1.25-46.32) and HER2 mutation (OR: 5.71; 95% CI: 1.34-24.33), compared with subjects ≥50 years. Among subjects <35 years old (n=61), our study observed a higher proportion of women (59.0% vs. 26.6%; p<0.001), never smokers (45.8% vs. 10.3%; p<0.001), no comorbidities (21.3% vs. 74.0%; p<0.001); ALK translocation (33.3% vs. 4.4%; p<0.001) and ROS1 mutation (14.3% vs. 2.3%; p=0.01), compared with subjects ≥35 years. CONCLUSIONS: Lung cancer displays differences by age at diagnosis which may have important implications for its clinical management.

Addressing lung cancer screening eligibility in Spain using 2013 and 2021 US Preventive Service Task Force criteria: cross-sectional study.

Objectives: The aim of the study was to ascertain the percentage of Spanish lung cancer cases that would fulfil the lung cancer screening inclusion criteria recommended by the United States Preventive Service Task Force (USPSTF) in 2013 and 2021. Methods: A cross-sectional study was carried out. All lung cancer cases registered in the Thoracic Tumor Registry with data on date of birth, date of diagnosis, smoking habit, number of pack-years and time elapsed since smoking cessation were included. Results: The study included 15 006 patients diagnosed with lung cancer in Spain between 2016 and 2022. Eligibility to participate in screening increased from 53.7% to 63.5% (an increase of 9.8%) according to the 2013 and 2021 recommendations, respectively. The percentage of eligible men rose by 9.2 percentage points with the 2021 versus 2013 recommendations, whereas this rise was 11.5 percentage points in women. Under the 2021 recommendations, 36.6% of women and 5.3% of men would not have fulfilled the screening inclusion criteria due to being never-smokers; 14.9% of women and 11.0% of men would not have fulfilled the age criterion; and 27.0% of ex-smokers among women compared to 35.6% among men would not have been eligible due to >15 years having elapsed since smoking cessation. Conclusions: In Spain, over one-third of lung cancer cases could not be detected through screening, by virtue of not meeting the most recent inclusion criteria stated by the USPSTF. The degree of fulfilment in a potential nationwide screening programme should be analysed, with the aim of establishing inclusion criteria in line with each country's context.

Fracture Resistance of Chairside CAD/CAM Molar Crowns Fabricated with Different Lithium Disilicate Ceramic Materials

PURPOSE: To compare the fracture resistance of five different groups of chairside CAD/CAM molar crowns fabricated from various lithium disilicate ceramic materials (LDC): one conventional precrystallized CAD/CAM LDC, two novel precrystallized LDCs, and one fully crystallized LDC tested both with and without optional sintering. MATERIALS AND METHODS: A total of 60 chairside CAD/CAM lithium disilicate molar crowns (n = 12 per group) with 1.5-mm occlusal thickness and a 1.0-mm chamfer finish were designed and fabricated with a chairside CAD/CAM system (CEREC, Dentsply Sirona). The restorations were divided into five groups: (1) IPS e.max CAD; (2) Amber Mill; (3) Straumann n!ce; (4) Straumann n!ce with optional sintering; and (5) Supreme CAD. Restorations were cemented using conventional resin luting cement and primer system to 3D-printed resin dies. Bonded restorations were loaded for 100,000 cycles with 275-N force, and the load at break (LB) and peak load (PL) until fracture were measured. SEM images of fracture surfaces on the printed dies were obtained. RESULTS: Fracture resistance was significantly different depending on the material. Supreme CAD showed the highest fracture resistance (LB: 1,557.2 N; PL: 1,785.8 N), followed by Amber Mill (LB: 1,393.0 N; PL: 1,604.2 N) and IPS e.max CAD (LB: 1,315.7 N; PL: 1,461.9 N). Straumann n!ce without (LB: 862.4 N; PL: 942.9 N) and with the optional sintering (LB: 490.4 N; PL: 541.0 N) showed significantly lower fracture resistance than the others. CONCLUSION: The fracture resistance of chairside CAD/CAM lithium disilicate molar crowns varied depending on the material, and the novel materials did not perform as well as the conventional equivalents. Fully crystallized lithium disilicate ceramic block materials showed lower fracture resistance than precrystallized counterparts and should be used with caution in the clinic, especially with optional sintering.

A reduced complexity ECG imaging model for regularized inversion optimization.

The resolution of the inverse problem of electrocardiography represents a major interest in the diagnosis and catheter-based therapy of cardiac arrhythmia. In this context, the ability to simulate several cardiac electrical behaviors was crucial for evaluating and comparing the performance of inversion methods. For this application, existing models are either too complex or do not produce realistic cardiac patterns. In this work, a low-resolution heart-torso model generating realistic whole heart cardiac mappings and electrocardiograms in healthy and pathological cases is designed. This model was built upon a simplified heart-torso geometry and implements the monodomain formalism by using the finite element method. In addition, a model reduction step through a sensitivity analysis was proposed where parameters were identified using an evolutionary optimization approach. Finally, the study illustrates the usefulness of the proposed model by comparing the performance of different variants of Tikhonov-based inversion methods for the determination of the regularization parameter in healthy, ischemic and ventricular tachycardia scenarios. First, results of the sensitivity analysis show that among 58 parameters only 25 are influent. Note also that the level of influence of the parameters depends on the heart region. Besides, the synthesized electrocardiograms globally present the same characteristic shape compared to the reference once with a correlation value that reaches 88%. Regarding inverse problem, results highlight that only Robust Generalized Cross Validation and Discrepancy Principle provide best performance, with a quasi-perfect success rate for both, and a respective relative error, between the generated electrocardiograms to the reference one, of 0.75 and 0.62.

Pathogenic CANVAS (AAGGG)n repeats stall DNA replication due to the formation of alternative DNA structures.

CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A2G3)n repeat in the RFC1 gene. There are a multitude of repeat motifs found in the human population at this locus, some of which are pathogenic and others benign. In this study, we conducted structure-functional analyses of the main pathogenic (A2G3)n and the main nonpathogenic (A4G)n repeats. We found that the pathogenic, but not the nonpathogenic, repeat presents a potent, orientation-dependent impediment to DNA polymerization in vitro. The pattern of the polymerization blockage is consistent with triplex or quadruplex formation in the presence of magnesium or potassium ions, respectively. Chemical probing of both repeats in supercoiled DNA reveals triplex H-DNA formation by the pathogenic repeat. Consistently, bioinformatic analysis of the S1-END-seq data from human cell lines shows preferential H-DNA formation genome-wide by (A2G3)n motifs over (A4G)n motifs in vivo. Finally, the pathogenic, but not the non-pathogenic, repeat stalls replication fork progression in yeast and human cells. We hypothesize that CANVAS-causing (A2G3)n repeat represents a challenge to genome stability by folding into alternative DNA structures that stall DNA replication.

Historiographical approaches to biogeography: a critical review.

We performed a critical review of the historiographical studies on biogeography. We began with the pioneering works of Augustin and Alphonse de Candolle. Then, we analyzed the historical accounts of biogeography developed by (1) Martin Fichman and his history on the extensionism-permanentism debate; (2) Gareth Nelson and his critique of the Neo-Darwinian historiography of biogeography; (3) Ernst Mayr, with his dispersalist viewpoint; (4) Alan Richardson, who wrote a microhistory on the biogeographic model constructed by Darwin; (5) Michael Paul Kinch and the ideas discussed in the 19th century about the geographical distribution of living beings; (6) Janet Browne, who highlighted the importance of the pre-Darwinian naturalists; (7) Peter Bowler, who focused mainly on the influence of paleontology on biogeography; (8) James Larson, who looked into the practices of the naturalists of Northern Europe in the late 18th century; and (9) Malte Ebach, who like Larson, was more interested in analysing the practices rather than the ideas of naturalists who studied the geographical distribution of organisms. Finally, these works are compared with each other. There has not been a dominant paradigm in the construction of historical narratives of biogeography; however, they provide a useful context for understanding problems of biogeography that continue to be debated to this day.

Tratamiento de la dermatochalasis con cirugía de ondas de radio / Dermatochalasis Treatment with Radiowave Surgery

Objetivo: Describir los resultados de la blefaroplastia de los párpados superiores realizada con radiocirugía a pacientes con dermatochalasis del párpado superior. Métodos: Se realizó un estudio descriptivo longitudinal con pacientes del servicio de Oftalmología en el Hospital Clínico Quirúrgico Hermanos Ameijeiras en el período entre enero de 2021 a diciembre de 2022. Después de aplicar los criterios de selección la muestra quedó constituida por los primeros 50 pacientes que asistieron de forma consecutiva. Resultados: Predominaron los pacientes entre los 60 a 79 años de edad, el sexo femenino y los de color de piel blanca (p > 0,05). Se logró una reducción completa de la piel redundante en más de un 50 por ciento. El tiempo quirúrgico promedio con radiofrecuencia fue de 35.9 min. La satisfacción de los pacientes fue buena en un 96 por ciento. Las complicaciones posoperatorias se manifestaron en un 32 por ciento de los pacientes, solo en dos pacientes fueron serias, las cuales no dejaron secuelas. Conclusiones: La cirugía con ondas de radios para el tratamiento de la dermatochalasis permite alcanzar el resultado estético que se desea, con satisfacción tanto para el médico, como para los pacientes quienes logran mejorar su calidad de vida(AU)

Objective: To describe the results of upper eyelid blepharoplasty performed with radiosurgery in patients with upper eyelid dermatochalasis. Methods: A longitudinal descriptive study was carried out with patients from the ophthalmology service at Hospital Clínico Quirúrgico Hermanos Ameijeiras, from January 2021 to December 2022. After applying the selection criteria, the sample was made up of the first 50 patients who attended consecutively. Results: Patients aged 60-79 years predominated, as well as the female sex and the white skin color (p > 0.05). A complete reduction of redundant skin was achieved in more than 50 percent. The average surgical time with radiofrequency was 35.9 min. Patient satisfaction was good in 96 percent. Postoperative complications were present in 32 percent of patients, only in two patients were they serious, but did not leave any sequelae. Conclusions: Radiowave surgery for treating dermatochalasis allows to achieve the desired aesthetic outcome, with satisfaction for both the physician and the patients, who achieve an improvement in their quality of life(AU)