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.

Collection of biospecimens from the inspiration4 mission establishes the standards for the space omics and medical atlas (SOMA).

The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from four crew members longitudinally before (Launch: L-92, L-44, L-3 days), during (Flight Day: FD1, FD2, FD3), and after (Return: R + 1, R + 45, R + 82, R + 194 days) spaceflight, spanning a total of 289 days across 2021-2022. The collection process included venous whole blood, capillary dried blood spot cards, saliva, urine, stool, body swabs, capsule swabs, SpaceX Dragon capsule HEPA filter, and skin biopsies. Venous whole blood was further processed to obtain aliquots of serum, plasma, extracellular vesicles and particles, and peripheral blood mononuclear cells. In total, 2,911 sample aliquots were shipped to our central lab at Weill Cornell Medicine for downstream assays and biobanking. This paper provides an overview of the extensive biospecimen collection and highlights their processing procedures and long-term biobanking techniques, facilitating future molecular tests and evaluations.As such, this study details a robust framework for obtaining and preserving high-quality human, microbial, and environmental samples for aerospace medicine in the Space Omics and Medical Atlas (SOMA) initiative, which can aid future human spaceflight and space biology experiments.

A Second Space Age Spanning Omics, Platforms, and Medicine Across Orbits.

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, countries, and space-related entities has enabled a"Second Space Age." This new era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, encompassing multi-omic, single-cell, and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring, and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics (PGx), as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this review, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration (NASA), Japan Aerospace Exploration Agency (JAXA), European Space Agency (ESA), and other space agencies, and also detail the commercial spaceflight sector's (e.g. SpaceX, Blue Origin, Axiom, Sierra Space) entrance into aerospace medicine and space biology, the first aerospace medicine biobank, and the myriad upcoming missions that will utilize these tools to ensure a permanent human presence beyond LEO, venturing out to other planets and moons.

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.

Impaired Cognitive Performance in Mice Exposed to Prolonged Hyperoxia.

Supplementation of oxygen at concentrations significantly above environmental level for prolonged periods may lead to hyperoxia and tissue toxicity. The mammalian brain undergoes structural and functional changes during adaptation to hypoxia and hyperoxia. In this study we investigated the effect of prolonged hyperoxic exposure on cognitive and motor performance in mice. Two-month-old male mice were placed in either hyperoxic (50% O2) or normoxic conditions for 3 weeks. Cognitive function was measured using the Y-maze test. High alteration rate between the three arms of the maze is indicative of sustained memory and cognitive function. Motor function was measured using the grip strength and rotarod tests. In the rotarod test high speed and long latency are indicative of coordination and resistance. After 3 weeks of exposure, hematocrit levels were significantly decreased in the hyperoxia group compared to normoxic control littermates (%, mean ± SD, 37.8 ± 1.3, n = 15 vs. 49.9 ± 5.1, n = 15, p < 0.05). In the Y-maze test, chronic hyperoxic exposure resulted in a statistically significant decrease in alteration rate compared to normoxic control (%, mean ± SD, 53.4 ± 9.9, n = 30 vs. 61.2 ± 9.5, n = 15, p < 0.05). The rotarod and grip strength tests did not show statistically significant changes between the two groups. Our data suggest that chronic hyperoxia may lead to decreased cognitive performance in adult mice, which may be secondary to structural and functional changes in the brain.

Pan-cancer analysis reveals molecular patterns associated with age.

Older age is a strong risk factor for several diseases, including cancer. The etiology and biology of age-associated differences among cancers are poorly understood. To address this knowledge gap, we aim to delineate differences in tumor molecular characteristics between younger and older patients across a variety of tumor types from The Cancer Genome Atlas. We show that these groups exhibit widespread molecular differences in select tumor types. Our work shows that tumors in younger individuals exhibit a dysregulated molecular aging phenotype and are associated with hallmarks of premature senescence. Additionally, we find that these tumors are enriched for driver gene mutations, resulting in homologous recombination defects. Lastly, we observe a trend toward decreased immune infiltration and function in older patients and find that, immunologically, young tumor tissue resembles aged healthy tissue. Taken together, we find that tumors from young individuals possess unique characteristics that may be leveraged for therapy.

Altered Behavioral Performance in the Neuron-Specific HIF-1- and HIF-2-Deficient Mice Following Chronic Hypoxic Exposure.

Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate in mice for HIF-1 and HIF-2. The objective of this study was to investigate the effect of neuronal deletion of HIF-1 and HIF-2 in hypoxic adaptation by using the neuron-specific knockout (KO) mice. The floxed control and KO mice were used. Hypoxic mice were kept in a hypobaric chamber at a pressure of 300 torr (0.4 ATM, which was equivalent to 8% oxygen under normobaric condition) for 3 weeks. The littermate, normoxic control mice were housed in the same room next to the chamber to match ambient conditions. Body weights were monitored throughout the 3-week course. Cognitive function was measured using a Y-maze test; motor functions were measured using the rotarod test and the grip strength test. The hematocrit increased significantly at the end of 3-week hypoxic exposure in both control and KO mice. In the Y-maze test, the alternation rate (indicative of sustained cognition) trended lower in the KO mice compared to the controls following hypoxia (%, 51.3 ± 13.1, n = 6 vs. 63.2 ± 12.0, n = 8). In the rotarod test, the latency (seconds) in the KO mice was significantly lower compared to the controls (50.4 ± 5.7 vs. 77.1 ± 5.0, n = 3 each before hypoxia and 66.4 ± 3.4, n = 6 vs. 98.1 ± 15.4 after hypoxia, n = 3). The grip strength in the KO mice was similar compared to the control mice before hypoxia, but the strength of KO mice trended higher after hypoxic exposure. Our data suggest that deficiency of neuronal HIF-1 and HIF-2 may result in changes in behavioral performance and other adaptative responses to hypoxia.

Chronic Achilles tendon rupture associated with rupture of the peroneus brevis tendon. A clinical case. / Rotura crónica del tendón de Aquiles asociada a rotura del tendón peroneus brevis. Caso clínico.

The treatment of a chronic rupture of the Achilles tendon remains difficult. Different techniques such as augmentation or plasties are used for restoring the gap in these ruptures. The combination of Achilles tendon rupture with other tendon ruptures may increase the difficulty in their treatment. We present a rare combination of a delayed Achilles tendon rupture and a peroneus brevis tendon rupture and its management. The importance of the presented case is the combination of both ruptures that adds difficulty to the surgical technique. A thorough analysis should be made of the magnetic resonance findings when planning a tendon transposition. To our knowledge, there are no reports of a simultaneous combination of an Achilles tendon rupture and a peroneus brevis tendon rupture.

Patency rates of dysfunctional central hemodialysis venous catheter: Comparison between catheter exchange alone and catheter exchange with fibrin sheath angioplasty.

PURPOSE: The purpose of this study was to compare patency rates and risk of obstruction of catheter exchange (CE) with that of CE with fibrin sheath angioplasty (CE+FSA) in dysfunctional tunneled central hemodialysis venous catheter (CHVC). MATERIALS AND METHODS: A total of 107 consecutive patients with dysfunctional CHVC were retrospectively included. There were 66 men and 41 women with a mean age of 67.8±12.5 (SD) years (range: 23.0-86.0 years). Seventy-three of 107 patients (68.2%) underwent CE procedure and 34 of 107 (31.8%) underwent CE+FSA. Kaplan-Meier log-rank test and multivariate Cox regression analyses were performed to determine patency rates and risk of obstruction according to type of endovascular procedure. RESULTS: Patency rates after endovascular procedures at 3, 6, 12, 24 and 36 months follow up were 75%, 75%, 65%, 65% and 65% in CE+FSA group and 70%, 65%, 62%, 30% and 0% in CE group. Mean time until obstruction of CHVC was 778.4 days after CE+FSA and 497 days after CE (P=0.211). Endovascular procedure was unrelated to risk of obstruction in adjusted model (HR=1.34; P=0.515). CONCLUSIONS: Our findings suggest that both techniques are equivalent in terms of patency and safety results, so other aspects as cost assessment should be considered when choosing between both techniques.

Mapping the thickness changes on retinal layers segmented by spectral-domain optical coherence tomography using the posterior pole program in glaucoma. / Mapeo de los cambios de grosor en el glaucoma de las capas retinianas maculares segmentadas usando el programa de polo posterior de la tomografía de coherencia óptica de dominio espectral.

OBJECTIVES: To evaluate changes in retinal layers of the macula (mRLs) using OCT posterior pole program (PPP) in primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study included 128 patients with POAG and 103 healthy controls who had PPP maps (macular grid 8×8) drawn by SD-OCT. Only one eye per patient was studied. The 9 mRLs were automatically segmented by prototype software, obtaining: a macular retinal nerve fibre layer (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform+nuclear layer, photoreceptor layer, retinal pigment epithelium (RPE), outer retina and RPE+outer retina. Thickness values were obtained on 64 cells of the grid for each mRL, and mean thickness of superior and inferior hemispheres were calculated. Comparisons of mean thickness of these hemispheres and thickness of each cell between groups were determined. Differences in the cell by cell comparisons were represented quantitatively by heat maps for each mRL. RESULTS: Photoreceptors and RPE were found in POAG group when comparing thickness of hemispheres, thinning of mRNFL, GCL, IPL, and thickening of INL. Heat maps showed symmetrical thinning patters between superior and inferior hemispheres in inner retinal layers (except for INL) and asymmetrical thickening patters in outer retinal layers in GPAA group. CONCLUSIONS: There are thickness changes in all mRLs in POAG, when studied by PPP. Thinning of inner layers (except for INL), and thickening of outer layers in POAG show different symmetry patterns in relation to horizontal meridian.

Identification of new candidate genes for retinopathy in type 2 diabetics. Valencia Study on Diabetic Retinopathy (VSDR). Report number 3. / Identificación de nuevos genes candidatos para la retinopatía en diabéticos tipo 2. Estudio Valencia sobre Retinopatía Diabética (EVRD). Informe n.° 3.

OBJECTIVE: To identify genes involved in the pathogenic mechanisms of non-proliferative diabetic retinopathy (NPDR), among which include oxidative stress, extracellular matrix changes, and/or apoptosis, in order to evaluate the risk of developing this retinal disease in a type2 diabetic (DM2) population. MATERIAL AND METHODS: A case-control study was carried out on 81 participants from the Valencia Study on Diabetic Retinopathy (VSDR) of both genders, with ages 25-85years. They were classified into: (i)DM2 group (n=49), with DR (+DR; n=14) and without DR (-DR; n=35), and (ii)control group (GC; n=32). The protocols included a personal interview, standardised ophthalmological examination, and blood collection (to analyse the DNA for determining the gene expression (TP53, MMP9, and SLC23A2) in the study groups. Statistical analyses were performed using the SPSS v22.0 program. RESULTS: The TP53 and MMP9 genes showed a higher expression in the DM2 group compared to the GC, although the difference was only significant for the MMP9 gene (TP53: 10.40±1.20 vs. 8.23±1.36, P=.084; MMP9: 1.45±0.16 vs. 0.95±0.16, P=.036), and the SLC23A2 gene showed a significant lower expression in the DM2 vs CG (5.58±0.64 vs. 11.66±1.90, P=.026). When sub-dividing the DM2 group according to the presence of retinopathy, the expression of the TP53, MMP9 and SLC23A2 genes showed significant differences between the DM2-RD, DM2+RD and GC groups (TP53: 9.95±1.47 vs. 11.52±2.05 vs. 8.23±1.36, P=.038; MMP9: 1.47±0.20 vs. 1.41±0.27 vs. 0.95±0.16, P=.021; SLC23A2: 5.61±0.77 vs. 5.51±1.21 vs. 11.66±1.90, P=.018). CONCLUSIONS: Genes involved in extracellular matrix integrity (MMP9) and/or apoptosis (TP53), could be considered potential markers of susceptibility to the development/progression of NPDR. Interestingly, the SLC232A2 gene (ascorbic acid transporter) can be considered a protector of the risk of the development/progression of the retinopathy.

Ultrasound-Guided Angioplasty of Dysfunctional Vascular Access for Haemodialysis. The Pros and Cons.

PURPOSE: To describe the benefits and the disadvantages of angioplasty in dialysis fistulas using only ultrasound guidance. MATERIALS AND METHODS: This is a prospective study in 132 failing or non-maturing arteriovenous accesses that underwent 189 ultrasound-guided balloon angioplasties. The technical success was defined as non-use of X-ray fluoroscopy during the procedure. RESULTS: 127 procedures (67%) were successfully completed without fluoroscopy. Most failures were due to difficulty to traverse aneurismal segments, as well as anastomotic stenoses. Including initial failures, the primary patency rates at 6, 12 months and 2 years were 75 ± 3, 41 ± 3 and 14 ± 2%, respectively. CONCLUSION: Endovascular repair of the dysfunctional vascular access for haemodialysis under ultrasound guidance is feasible and safe in roughly two-thirds of cases.

Biomarkers of lipid peroxidation in the aqueous humor of primary open-angle glaucoma patients. / Biomarcadores de peroxidación lipídica en el humor acuoso de pacientes con glaucoma primario de ángulo abierto.

OBJECTIVE: To investigate the lipid peroxidation (PEROX) processes in primary open-angle glaucoma (POAG) patients, and whether this mechanism may be related to disease progression. MATERIAL AND METHODS: A prospective, observational, cross-sectional, non-experimental, and analytical study was conducted on a case and a comparison group, consisting of 175 surgical patients divided into: 1) POAG group (GG; n=88) and 2) comparison group of patients with cataracts (CG; n=87). Demographic data, patient characteristics, lifestyle data, as well as ophthalmological examination were registered in an Excel spreadsheet. Biochemical data were obtained by processing the aqueous humor collected at the beginning of surgery. Determination of malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS) and total antioxidant activity (AAO) was assayed using enzymatic-colorimetric methods in the aqueous humor samples. Statistical analysis was performed using SPSS 15.0 software. RESULTS: Aqueous humor MDA/TBARS levels were significantly higher (P<.001) and the AAO significantly lower (P<.001) in the GG than in the GC. The MDA/TBARS directly correlated with intraocular pressure (IOP) values and the cup-to-disc ratio (CDR). Decreased AAO activity correlated inversely with IOP and CDR. Differences between groups were noticeably higher in the GG as regards obesity, alcohol consumption, anxiety, depression, and sedentary lifestyle. In the multivariate analysis, the variables that showed a better predictive ability were: MDA/TBARS, PIO, AAO, CDR, and depression. CONCLUSIONS: The POAG patients have a PEROX background that is reflected in the aqueous humor by variations in MDA/TBARS and AAO. Moreover, both the MDA/TBARS and AAO correlated with IOP values and the CDR. We propose that determination of MDA/TBARS and AAO in the aqueous humor of POAG patients can be used as biomarkers for monitoring the disease, as well the changes in lifestyle and other related risk factors.

Genetic systems for a new approach to risk of progression of diabetic retinopathy. / Sistemas genéticos para un nuevo abordaje del riesgo de progresión de la retinopatía diabética.

OBJECTIVE: To evaluate the risk of progression of diabetic retinopathy (DR) using new strategies to obtain genetic information in type 2 diabetes (T2D) based on interfering ribonucleic acid (RNA). MATERIAL AND METHODS: A prospective multicentre case-control study of 132 participants was distributed into: T2D with (+DR) or without (-DR) (T2DG; n=77), and a control group (CG; n=55). After an eye examination and personal interview, tears were collected for molecular analysis (expression of microRNAs [miRNAs] (miRCURY ™ ARN Isolation Kit, Qiagen)]. Libraries, 137 vs. 140bp (GeneMapper, Applied Biosystems), were obtained in 18 samples (T2DG+DR=6; T2DG-DR=6; CG=6) by performing next-generation sequencing (NGS). SPSS 15.0 statistical program was used to perform data analysis. RESULTS: The mean age was 67±12 years in the T2DG vs. 55±21 years in the CG. Distribution men/women: 25/30 in T2DG vs. 51/28 in CG. A family history of DM, diet compliance, smoking, drinking and exercise, showed significant differences between groups (P<.001). A 20-25 microlitre sample of tears contained a mean of 9.42±3.30 ng/mL of purified ARN, with significant differences between T2DG/CG (P=.002) and T2DG+RD/CG (P=.004). Tear expression of miARNs in T2DG directly correlated with age/obesity/T2D duration (P<.05), and indirectly with visual acuity (P<.05). A total of 14 miRNAs related to the presence, pathogenic mechanisms and risk factors for the progression of diabetic retinopathy, were identified. CONCLUSIONS: We propose to use tears as a source of genetic information for DM. Specific miRNAs involved in DR development and/or progression can be used as molecular biomarkers, and based on these, for developing future biotherapies.

Anesthetic considerations in HELLP syndrome.

BACKGROUND: HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) is an obstetric complication with heterogonous presentation and multisystemic involvement. It is characterized by microangiopathic hemolytic anemia, elevated liver enzymes by intravascular breakdown of fibrin in hepatic sinusoids and reduction of platelet circulation by its increased consumption. METHODS: In terms of these patients' anesthetic management, it is essential to consider some details: (1) effective, safe perioperative management by a multidisciplinary approach, and quick, good communication among clinical specialists to achieve correct patient management; (2) neuroaxial block, particularly spinal anesthesia, is the first choice to do the cesarean if there is only moderate, but not progressive thrombocytopenia; (3) if a general anesthesia is required, it is necessary to control the response to stress produced by intubation, especially in patients with either severe high blood pressure or neurological signs, or to prevent major cerebral complications; (4) invasive techniques, e.g., as tracheostomy, arterial, and deep-vein canalization, should be considered; (5) if contraindication for neuroaxial anesthesia exists, rapid sequence intubation with general anesthesia should be regarded as an emergency in patients with full stomach; (6) increased risk of difficult airways should be taken into account. RESULTS: Optimal patient management can be chosen after considering the risks and benefits of each anesthetic technique, and based on good knowledge of these patients' pathophysiological conditions. CONCLUSION: Later, close patient monitoring is recommended for potential development of hemorrhagic complications, disseminated intravascular coagulation (DIC), or eclampsia.

Manejo radiológico invasivo de las fístulas de hemodiálisis midiendo el flujo con un catéter endovascular / Invasive radiologic management of hemodialysis fistulas: Measuring flow with an endovascular catheter

Objetivos: Analizar los valores del flujo obtenidos con un catéter endovascular y demostrar que son más fiables que los hallazgos angiográficos y clínicos para planificar y determinar el resultado del tratamiento radiológico invasivo de las fístulas de hemodiálisis, así como demostrar su seguridad durante los procedimientos intervencionistas. Material y métodos: Medimos con el catéter 341 fístulas de hemodiálisis en 598 procedimientos. En total, se hicieron 3.051 medidas de flujo. Fueron 162 fístulas distales (47,6%), 132 humerales (38,4%) y 47 injertos protésicos (14%). Los motivos de disfunción más frecuentes fueron las presiones elevadas y el déficit de flujo. Resultados: El catéter se utilizó para medir el resultado del tratamiento radiológico en 419 casos (70%) y solo para medir el control del flujo del acceso en 179 casos (30%). En los casos en los que se trataron radiológicamente las lesiones del acceso, el flujo mejoró en 312 ml/min de media. Los casos no tratados presentaron un flujo medio de 1.232 ml/min. En 2 casos (0,35%) la punta del catéter perforó la pared de la vena, que se resolvió inflando un balón a pocas atmósferas. Conclusiones: El catéter endovascular medidor de flujos es una herramienta útil en los procedimientos invasivos de radiología vascular para hemodiálisis. Al valorar el estado hemodinámico del acceso vascular, su mayor utilidad es que ayuda a tomar la decisión de tratar o no una estenosis (AU)

Objectives: To analyze the values of flow obtained with an endovascular catheter, and to determine whether they are more reliable than angiographic and clinical findings for planning and for determining the outcome of invasive radiologic treatment of hemodialysis fistulas, as well as to determine the safety of this technique during interventional radiology procedures. Material and methods: We used endovascular catheters to measure flow in 341 vascular accesses for hemodialysis (162 [47.6%] distal fistulas, 132 [38.4%] humeral fistulas, and 47 [14%] arteriovenous grafts) in 598 procedures (a total of 3,051 flow measurements). Dysfunction was most commonly due to high pressures and flow deficits. Results: The catheter was used to measure the results of radiologic treatment in 419 (70%) cases and only to measure the control of flow in the hemodialysis access in 179 (30%) cases. In the cases where lesions of the access had been treated radiologically, the flow improved by a mean of 1,232 ml/min. In 2 (0.35%) cases, the tip of the catheter perforated the wall of the vein; this complication was resolved by inflating a low pressure balloon. Conclusions: Endovascular catheters are useful for measuring flow in invasive vascular radiology procedures for hemodialysis. In assessing the hemodynamic status of a vascular access, they are most helpful in determining whether stenosis is present (AU)