Longitudinal multi-omics analysis of host microbiome architecture and immune responses during short-term spaceflight.

Maintenance of astronaut health during spaceflight will require monitoring and potentially modulating their microbiomes. However, documenting microbial shifts during spaceflight has been difficult due to mission constraints that lead to limited sampling and profiling. Here we executed a six-month longitudinal study to quantify the high-resolution human microbiome response to three days in orbit for four individuals. Using paired metagenomics and metatranscriptomics alongside single-nuclei immune cell profiling, we characterized time-dependent, multikingdom microbiome changes across 750 samples and 10 body sites before, during and after spaceflight at eight timepoints. We found that most alterations were transient across body sites; for example, viruses increased in skin sites mostly during flight. However, longer-term shifts were observed in the oral microbiome, including increased plaque-associated bacteria (for example, Fusobacteriota), which correlated with immune cell gene expression. Further, microbial genes associated with phage activity, toxin-antitoxin systems and stress response were enriched across multiple body sites. In total, this study reveals in-depth characterization of microbiome and immune response shifts experienced by astronauts during short-term spaceflight and the associated changes to the living environment, which can help guide future missions, spacecraft design and space habitat planning.

Biorefinery of waste activated sludge: Nutrient recovery and microbial lipid production by Yarrowia lipolytica.

The rising generation of waste activated sludge (WAS) demands a fundamental shift towards resource reuse and recovery. The conventional methodologies used to manage this by-product derived from wastewater treatment plants are increasingly constrained due to stringent regulatory measures aimed at mitigating its adverse impacts on the environment and public health. Therefore, this work evaluated a promising strategy for the efficient management of WAS, transforming it into a valuable renewable source to produce high-value-added compounds, such as lipids and a slow-release fertilizer (struvite). Wet oxidation (WO) was identified as a suitable technique for solubilising WAS while generating short-chain fatty acids (primarily acetic acid). It was found that conducting WO at 200 °C for 120 min resulted in a 65% reduction of the total suspended solids (TSS) content and 87% of the volatile suspended solids (VSS) content. Additionally, under these conditions, 4440 ± 105 mg/L and 593 ± 21 mg/L of acetic and propionic acid were obtained, respectively, which were assimilated by Yarrowia lipolytica to produce biolipids. Furthermore, the rupture of WAS flocs also led to the solubilisation of 980 ± 8 mg/L of ammonium. During the struvite precipitation stage, a NH4:PO4:Mg ratio of 1:1.5:1.5 was found to be the most effective for removing soluble ammonium (97.4 ± 0.8%), resulting in a high-purity struvite formation, and enhancing the carbon/nitrogen (C/N) ratio of the oxidised WAS from 3 to 105. This improvement in the C/N ratio raised the lipid content from 36 ± 1% to 49 ± 1% during the cultivation of Y. lipolytica. The application of the sequencing batch culture strategy further increased lipid content to 59 ± 1%, with 6.0 ± 0.3 g/L as the final concentration after the fifth cycle. The lipids produced, mainly monounsaturated fatty acids with 40% of oleic acid, offer potential as biodiesel feedstock. This lipid composition led to biodiesel properties, including cetane number, iodine value, kinematic viscosity and density that met international standards. Therefore, this research presents a promising alternative not only for WAS management but also for harnessing valuable resources, thereby establishing a basis for large-scale studies.

Modulation of neuronal activity in human centromedian nucleus during an auditory attention and working memory task.

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5-45 Hz). Average peri­stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13-45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.

Kloos Syndrome (Paralysis of Time). A Psychopathological Rare Case.

A case of Kloos syndrome is presented, a rare psychopathological manifestation in psychiatry characterized by the experience of "time paralysis" related to an epileptic focus in the left temporoparietal areas. This syndrome was identified through a detailed psychopathological analysis and detected by an electroencephalographic record. The patient's symptoms disappeared after receiving antiepileptic treatment with Carbamazepine. In this case report we highlight the detailed phenomenological and clinical analysis, as well as the importance of carrying out complementary tests when we are faced with unusual or sudden-onset symptoms without any trigger, as took place in the case exposed.

Iron promoted end-on dinitrogen-bridging in heterobimetallic complexes of uranium and lanthanides.

End-on binding of dinitrogen to low valent metal centres is common in transition metal chemistry but remains extremely rare in f-elements chemistry. In particular, heterobimetallic end-on N2 bridged complexes of lanthanides are unprecedented despite their potential relevance in catalytic reduction of dinitrogen. Here we report the synthesis and characterization of a series of N2 bridged heterobimetallic complexes of U(iii), Ln(iii) and Ln(ii) which were prepared by reacting the Fe dinitrogen complex [Fe(depe)2(N2)] (depe = 1,2-bis(diethylphosphino)-ethane), complex A with [MIII{N(SiMe3)2}3] (M = U, Ce, Sm, Dy, Tm) and [LnII{N(SiMe3)2}2], (Ln = Sm, Yb). Despite the lack of reactivity of the U(iii), Ln(iii) and Ln(ii) amide complexes with dinitrogen, the end-on dinitrogen bridged heterobimetallic complexes [{Fe(depe)2}(µ-η1:η1-N2)(M{N(SiMe3)2}3)], 1-M (M = U(iii), Ce(iii), Sm(iii), Dy(iii) and Tm(iii)), [{Fe(depe)2}(µ-η1:η1-N2)(Ln{N(SiMe3)2}2)], 1*-Ln (Ln = Sm(ii), Yb(ii)) and [{Fe(depe)2(µ-η1:η1-N2)}2{SmII{N(SiMe3)2}2}], 3 could be prepared. The synthetic method used here allowed to isolate unprecedented end-on bridging N2 complexes of divalent lanthanides which provide relevant structural models for the species involved in the catalytic reduction of dinitrogen by Fe/Sm(ii) systems. Computational studies showed an essentially electrostatic interaction of the end-on bridging N2 with both Ln(iii) and Ln(ii) complexes with the degree of N2 activation correlating with their Lewis acidity. In contrast, a back-bonding covalent contribution to the U(iii)-N2Fe bond was identified by computational studies. Computational studies also suggest that end-on binding of N2 to U(iii) and Ln(ii) complexes is favoured for the iron-bound N2 compared to free N2 due to the higher N2 polarization.

Acute Kidney Injury in the Context of COVID-19: An Analysis in Hospitalized Mexican Patients.

During the COVID-19 pandemic, a considerable proportion of patients developed a severe condition that included respiratory failure, shock, or multiple organ dysfunction. Acute Kidney Injury (AKI) has been recognized as a possible cause of severe COVID-19 development. Given this, this study investigates the occurrence and consequences of AKI in Mexican patients to contribute to better knowledge and management of this problem. Methods: Using a retrospective observational cohort methodology, we investigated 313 cases from a cohort of 1019 patients diagnosed with COVID-19 at the IMSS Zacatecas General Hospital of Zone No. 1 in 2020. The prevalence of AKI was determined using the AKIN criteria based on serum creatinine levels and a detailed review of demographic characteristics, medical history, comorbidities, and clinical development. Results: The data showed a 25.30% prevalence of AKI among patients infected with severe COVID-19. Remarkably, these patients with AKI exhibited an advanced age (>65 years), arterial hypertension, a higher number of white blood cells during admission and the hospital stay, and elevated levels of C-reactive protein, serum creatinine, and blood urea nitrogen (BUN). Clinically, patients with AKI had signs of prostration, pneumonia, and the requirement for ventilatory assistance when compared to those without AKI. Finally, those diagnosed with AKI and COVID-19 had a 74% death rate. Relative risk analyses indicated that age (>65 years), arterial hypertension, high creatinine levels, endotracheal intubation, and pneumonia are associated with the development of AKI. On the other hand, among the protective factors against AKI, high hemoglobin levels and the consumption of statins during COVID-19 were found. Conclusions: The findings of this study underscore the significance of promptly identifying and effectively managing AKI to potentially alleviate the negative consequences of this complication within the Mexican population during COVID-19.

SEOM-GEM clinical guidelines for cutaneous melanoma (2023).

Cutaneous melanoma incidence is rising. Early diagnosis and treatment administration are key for increasing the chances of survival. For patients with locoregional advanced melanoma that can be treated with complete resection, adjuvant-and more recently neoadjuvant-with targeted therapy-BRAF and MEK inhibitors-and immunotherapy-anti-PD-1-based therapies-offer opportunities to reduce the risk of relapse and distant metastases. For patients with advanced disease not amenable to radical treatment, these treatments offer an unprecedented increase in overall survival. A group of medical oncologists from the Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines, based on a thorough review of the best evidence available. The following guidelines try to cover all the aspects from the diagnosis-clinical, pathological, and molecular-staging, risk stratification, adjuvant therapy, advanced disease therapy, and survivor follow-up, including special situations, such as brain metastases, refractory disease, and treatment sequencing. We aim help clinicians in the decision-making process.

Non-Classical Effects of FGF23: Molecular and Clinical Features.

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.

Bitter taste receptors: Key target to understand the effects of polyphenols on glucose and body weight homeostasis. Pathophysiological and pharmacological implications.

Experimental and clinical research has reported beneficial effects of polyphenol intake on high prevalent diseases such as type 2 diabetes and obesity. These phytochemicals are ligands of taste 2 receptors (T2Rs) that have been recently located in a variety of organs and extra-oral tissues. Therefore, the interaction between polyphenol and T2Rs in brain structures can play a direct effect on appetite/satiety regulation and food intake. T2Rs are also expressed along the digestive tract, and their interaction with polyphenols can induce the release of gastrointestinal hormones (e.g., ghrelin, GLP-1, CCK) influencing appetite, gastrointestinal functionally, and glycemia control. Intestinal microbiota can also influence on network effects of polyphenols-T2Rs interaction and vice versa, impacting innate immune responses and consequently on gut functionally. Furthermore, polyphenols binding to T2Rs present important effects on adipose tissue metabolism. Interestingly, T2R polymorphism could, at least partially, explain the inter-individual variability of the effects of polyphenols on glucose and body weight homeostasis. Together, these factors can contribute to understand the beneficial effects of polyphenol-rich diets but also might aid in identifying new pharmacological pathway targets for the treatment of diabetes and obesity.

[Strategies and recommendations to face respiratory syncytial virus disease in 2024]. / Estrategias y recomendaciones para enfrentar la enfermedad por virus respiratorio sincicial el año 2024.

During the winter of 2023, Chile faced a complex situation related to the respiratory syncytial virus (RSV). After experiencing a decline in RSV circulation during the years of the SARS-CoV-2 pandemic, a late outbreak was observed in the spring of 2022 and an early onset of the outbreak in 2023, with a significant increase in the number of serious cases. The ineffectiveness of strategic planning and risk communication contributed to the complexity of the situation. To avoid the above next winter, measures such as active surveillance, unification of definitions for acute respiratory infections, identification of RSV variants, public education about infections and advance preparation regarding hospital beds and health personnel are suggested. The importance of immunization and intersectoral collaboration to acquire new preventive alternatives is highlighted, as well as the need for early communication about the importance of immunization and identification of high-risk groups, improvement in training of medical personnel and strategic planning of the Ministry of Health. seeking a proactive and collaborative approach to address the complex RSV situation in future winters. The Chilean Immunization Advisory Committee has already carried out an analysis and recommendation on a new prevention alternative. This working group will support any decision of the Ministry of Health in public policies that attempt a change in the paradigm of control of this disease for the health of the children of our country.

Enhancing adaptive proton therapy through CBCT images: Synthetic head and neck CT generation based on 3D vision transformers.

BACKGROUND: Proton therapy is a form of radiotherapy commonly used to treat various cancers. Due to its high conformality, minor variations in patient anatomy can lead to significant alterations in dose distribution, making adaptation crucial. While cone-beam computed tomography (CBCT) is a well-established technique for adaptive radiation therapy (ART), it cannot be directly used for adaptive proton therapy (APT) treatments because the stopping power ratio (SPR) cannot be estimated from CBCT images. PURPOSE: To address this limitation, Deep Learning methods have been suggested for converting pseudo-CT (pCT) images from CBCT images. In spite of convolutional neural networks (CNNs) have shown consistent improvement in pCT literature, there is still a need for further enhancements to make them suitable for clinical applications. METHODS: The authors introduce the 3D vision transformer (ViT) block, studying its performance at various stages of the proposed architectures. Additionally, they conduct a retrospective analysis of a dataset that includes 259 image pairs from 59 patients who underwent treatment for head and neck cancer. The dataset is partitioned into 80% for training, 10% for validation, and 10% for testing purposes. RESULTS: The SPR maps obtained from the pCT using the proposed method present an absolute relative error of less than 5% from those computed from the planning CT, thus improving the results of CBCT. CONCLUSIONS: We introduce an enhanced ViT3D architecture for pCT image generation from CBCT images, reducing SPR error within clinical margins for APT workflows. The new method minimizes bias compared to CT-based SPR estimation and dose calculation, signaling a promising direction for future research in this field. However, further research is needed to assess the robustness and generalizability across different medical imaging applications.

Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer.

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure. Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

Analysis and Simulation of the Compressive Strength of Bioinspired Lightweight Structures Manufactured by a Stereolithography 3D Printer.

The use of metamaterials is a good alternative when looking for structures that can withstand compression forces without increasing their weight. In this sense, using nature as a reference can be an appropriate option to design this type of material. Therefore, in this work, a comparative study of a selection of eight representative models of a wide variety of existing solutions, both bioinspired and proposed by various researchers, is presented. These models have been manufactured using stereolithography (SLA) printing, which allows complex geometries to be obtained in a simple way that would be more complicated to achieve by other procedures. Additionally, the manufacturing cost of each model has been determined. The compression tests of the different models have made it possible to evaluate the breaking force and its corresponding deformation. Likewise, a finite element analysis of the manufactured models has been carried out to simulate their behavior under compression, achieving results very similar to those obtained in the experimental tests. In this way, it has been concluded that, among the three-dimensional patterns, the structure called "3D auxetic" is the one that supports the greatest breaking force due to the topographic characteristics of its bar structure. Similarly, among the two-dimensional patterns, the structure called "Auxetic 1", with a topography based on curves, is capable of supporting the greatest deformation in the compression direction before breaking. Moreover, the highest resistance-force-to-cost ratio has been obtained with a "3D auxetic" structure.

Lifileucel, an Autologous Tumor-infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non-small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors.

In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy.

Pharmacokinetics and pharmacodynamics of dextroketamine alone or combined with midazolam in Caiman crocodilus.

Pharmacokinetics studies of anesthetic agents are important for understanding of the pharmacology and metabolism of anesthetic agents in reptilians. This study was designed to examine the pharmacokinetic and pharmacodynamic properties of intravenous dextroketamine alone or combined with midazolam in Caiman crocodilus. Eight caimans were anesthetized with dextroketamine (10 mg/kg; group D) or dextroketamine and midazolam (10 and 0.5 mg/kg respectively; group DM) into the occipital venous sinus. The pharmacokinetic parameters were calculated by HPLC using a non-compartmental modeling. Serial blood samples were collected at baseline and within 15 and 30 min, and 11.5, 2, 4, 8, 12, 24 and 48 h of drug administration. Sedation status over time differed between groups. All animals in group D (8/8; 100%) showed signs of light sedation at t10. Half (4/8; 50%) of these caimans did not progress to deeper levels of sedation. In spite of light sedation at t10, animals in group DM were deeply sedated within 13.13 ± 7.04 min of anesthetic agent injection. The area under the plasma concentration-time curve (AUC0-48) and half-life of dextroketamine changed significantly after combination with midazolam. Even without significant changes in clearance, the almost two-fold increase in the half-life of dextroketamine suggests a slower rate of elimination.

Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy.

INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.

Assessing the social impacts of the COVID-19 crisis using phone helplines. The case of the Balearic Islands, Spain.

Background: Crises and health policies to tackle them can increase health inequalities. We explored the scope and usefulness of helplines set up during the COVID-19 crisis and characterised the vulnerability of their users. This study explored the geographic and socioeconomic effects of the telephone helplines set up by the Balearic Islands Government and aimed to characterise the vulnerability of their users. Methods: Telephonic survey combined with a geographical analysis of a sample of calls made between 15th of March and 30th of June of 2020 to five helplines: COVID-19 general information; psychological, social (minimum vital income), labour (temporary employment regulation), and housing (rental assistance) helps. The questionnaire included sociodemographic and housing characteristics, type of problem, and if it was solved or not. We used multinomial regression to explore factors associated with having solved the problem. We calculated the standardised rate of calls by municipality using Chi-squared and z-test to test differences. Results: 1,321 interviews from 2,678 selected (231 excluded, 608 untraceable, and 518 refusals). 63.8% of women, 48.7% were born in another country. They had no internet at home in 3.1%, only on the phone in 17.3%. The 23.5% had no income at home. The Problem was solved in 25.4%, and partly in 30.9%. Factors associated with not solving the problem were not having income at home (p = 0.021), labour (p = 0.008), economic (p = 0.000) or housing (p = 0.000) problems. People from 55 of 67 municipalities did at least one call. The highest rates of calls were from coastal tourist municipalities. Conclusion: Helplines reached most of the territory of the Balearic Islands and were used mainly in tourist municipalities. It probably has not been helpful for families with more significant deprivation. Digital inequalities have emerged.