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.

A comparison of foot fractures relative to other fragility fractures: a review and analysis of the American Orthopaedic Association's Own the Bone Database.

Evidence regarding the risk factors and characteristics of those with foot fragility fractures compared to non-foot fragility fractures is limited. Foot fragility fracture patients are more likely to be younger female with a higher BMI. A foot fragility fracture is strongly predictive of a subsequent foot fragility fracture. PURPOSE: Osteoporosis can clinically result in fragility fractures. Evidence regarding the risk factors and characteristics of foot fragility fractures compared to non-foot fragility fractures is limited. The American Orthopaedic Association's Own the Bone (OTB) is a bone health initiative with a substantial dataset. The purpose of this study was to examine and compare characteristics of patients presenting with isolated foot fragility fracture to those with a non-foot fragility fracture. METHODS: Between January 2009 and March of 2022, 58,001 fragility fractures occurred that were included in this cohort. A total of 750 patients had foot fragility fracture(s) and 57,251 patients had a non-foot fragility fracture that included shoulder, arm, elbow, forearm, wrist, spine, ribs, pelvis, hip, thigh, knee, tibia/fibula, and ankle. Demographics, fracture history, bone health factors, medication history, and medication use for each patient were reported in the OTB database. This data was utilized in our secondary cohort comparative analysis of characteristics and the risk of future fractures between foot fragility fracture and non-foot fragility fracture groups. RESULTS: Foot fragility fracture patients have a significantly higher probability to be younger (66.9 years old), female (91.5%), and have a higher BMI (28.3 kg/m2) compared to non-foot fragility fracture (p < 0.0001) patients. Patients with a foot fragility fracture are nine times (OR = 9.119, CI = 7.44-11.18, p < 0.001) more likely to have had a prior foot fragility fracture. Young, female patients with a prior foot fragility fracture are at higher risk of a future foot fragility fracture, and this risk increased as BMI increased. CONCLUSIONS: Foot fragility fracture patients are more likely to be female and younger compared to patients with a non-foot fragility fracture. A foot fragility fracture is a sentinel event considering that a prior foot fragility fracture is strongly predictive of a subsequent foot fragility fracture. LEVEL OF EVIDENCE: 3 (retrospective cohort).

Inspiration4 data access through the NASA Open Science Data Repository.

The increasing accessibility of commercial and private space travel necessitates a profound understanding of its impact on human health. The NASA Open Science Data Repository (OSDR) provides transparent and FAIR access to biological studies, notably the SpaceX Inspiration4 (I4) mission, which amassed extensive data from civilian astronauts. This dataset encompasses omics and clinical assays, facilitating comprehensive research on space-induced biological responses. These data allow for multi-modal, longitudinal assessments, bridging the gap between human and model organism studies. Crucially, community-driven data standards established by NASA's OSDR Analysis Working Groups empower artificial intelligence and machine learning to glean invaluable insights, guiding future mission planning and health risk mitigation. This article presents a concise guide to access and analyze I4 data in OSDR, including programmatic access through GLOpenAPI. This pioneering effort establishes a precedent for post-mission health monitoring programs within space agencies, propelling research in the burgeoning field of commercial space travel's impact on human physiology.

Stimulus awareness is necessary for both instrumental learning and instrumental responding to previously learned stimuli.

Instrumental conditioning is a crucial part of adaptive behaviour, allowing agents to selectively interact with stimuli in their environment. Recent evidence suggests that instrumental conditioning cannot proceed without stimulus awareness. However, whether accurate unconscious instrumental responding can emerge from consciously acquired knowledge of the stimulus-action-outcome contingencies is unknown. We studied this question using instrumental trace conditioning, where participants learned to make approach/avoid decisions in two within-subject modes: conscious (stimuli in plain view) and unconscious (visually masked). Both tasks were followed by an unconscious-only instrumental performance task. We show that even when the contingencies are reliably learned in the conscious mode, participants fail to act upon them in the unconscious responding task. We also replicate the previous results that no instrumental learning occurs in the unconscious mode. Consequently, the absence of stimulus awareness not only precludes instrumental conditioning, but also precludes any kind of instrumental responding to already known stimuli. This suggests that instrumental behaviour is entirely supported by conscious awareness of the world, and corroborates the proposals that consciousness may be necessary for adaptive behaviours requiring selective action.

Community-developed checklists for publishing images and image analyses.

Images document scientific discoveries and are prevalent in modern biomedical research. Microscopy imaging in particular is currently undergoing rapid technological advancements. However, for scientists wishing to publish obtained images and image-analysis results, there are currently no unified guidelines for best practices. Consequently, microscopy images and image data in publications may be unclear or difficult to interpret. Here, we present community-developed checklists for preparing light microscopy images and describing image analyses for publications. These checklists offer authors, readers and publishers key recommendations for image formatting and annotation, color selection, data availability and reporting image-analysis workflows. The goal of our guidelines is to increase the clarity and reproducibility of image figures and thereby to heighten the quality and explanatory power of microscopy data.

Spatiotemporal Observation of Quasi-Ballistic Transport of Electrons in Graphene.

We report spatiotemporal observations of room-temperature quasi-ballistic electron transport in graphene, which is achieved by utilizing a four-layer van der Waals heterostructure to generate free charge carriers. The heterostructure is formed by sandwiching a MoS2 and MoSe2 heterobilayer between two graphene monolayers. Transient absorption measurements reveal that the electrons and holes separated by the type-II interface between MoS2 and MoSe2 can transfer to the two graphene layers, respectively. Transient absorption microscopy measurements, with high spatial and temporal resolution, reveal that while the holes in one graphene layer undergo a classical diffusion process with a large diffusion coefficient of 65 cm2 s-1 and a charge mobility of 5000 cm2 V-1 s-1, the electrons in the other graphene layer exhibit a quasi-ballistic transport feature, with a ballistic transport time of 20 ps and a speed of 22 km s-1, respectively. The different in-plane transport properties confirm that electrons and holes move independently of each other as charge carriers. The optical generation of ballistic charge carriers suggests potential applications for such van der Waals heterostructures as optoelectronic materials.

Explainable machine learning identifies multi-omics signatures of muscle response to spaceflight in mice.

The adverse effects of microgravity exposure on mammalian physiology during spaceflight necessitate a deep understanding of the underlying mechanisms to develop effective countermeasures. One such concern is muscle atrophy, which is partly attributed to the dysregulation of calcium levels due to abnormalities in SERCA pump functioning. To identify potential biomarkers for this condition, multi-omics data and physiological data available on the NASA Open Science Data Repository (osdr.nasa.gov) were used, and machine learning methods were employed. Specifically, we used multi-omics (transcriptomic, proteomic, and DNA methylation) data and calcium reuptake data collected from C57BL/6 J mouse soleus and tibialis anterior tissues during several 30+ day-long missions on the international space station. The QLattice symbolic regression algorithm was introduced to generate highly explainable models that predict either experimental conditions or calcium reuptake levels based on multi-omics features. The list of candidate models established by QLattice was used to identify key features contributing to the predictive capability of these models, with Acyp1 and Rps7 proteins found to be the most predictive biomarkers related to the resilience of the tibialis anterior muscle in space. These findings could serve as targets for future interventions aiming to reduce the extent of muscle atrophy during space travel.

Viral activation and ecological restructuring characterize a microbiome axis of spaceflight-associated immune activation.

Maintenance of astronaut health during spaceflight will require monitoring and potentially modulating their microbiomes, which play a role in some space-derived health disorders. However, documenting the response of microbiota to spaceflight has been difficult thus far due to mission constraints that lead to limited sampling. Here, we executed a six-month longitudinal study centered on a three-day flight to quantify the high-resolution microbiome response to spaceflight. Via paired metagenomics and metatranscriptomics alongside single immune profiling, we resolved a microbiome "architecture" of spaceflight characterized by time-dependent and taxonomically divergent microbiome alterations across 750 samples and ten body sites. We observed pan-phyletic viral activation and signs of persistent changes that, in the oral microbiome, yielded plaque-associated pathobionts with strong associations to immune cell gene expression. Further, we found enrichments of microbial genes associated with antibiotic production, toxin-antitoxin systems, and stress response enriched universally across the body sites. We also used strain-level tracking to measure the potential propagation of microbial species from the crew members to each other and the environment, identifying microbes that were prone to seed the capsule surface and move between the crew. Finally, we identified associations between microbiome and host immune cell shifts, proposing both a microbiome axis of immune changes during flight as well as the sources of some of those changes. In summary, these datasets and methods reveal connections between crew immunology, the microbiome, and their likely drivers and lay the groundwork for future microbiome studies of spaceflight.

The Posttraumatic Tarsometatarsal Joints.

Tarsometatarsal joint injuries can be painful and debilitating and are most commonly due to direct or indirect trauma. Posttraumatic arthritis is a well-known long-term complication, with incidence as high as 58%. Conservative treatment options include shoe modifications, orthotic inserts, topical or oral anti-inflammatories, and intra-articular corticosteroid injections. There are various joint prep and fixation techniques reported in the literature, many with positive clinical and radiographic outcomes. This article discusses nonoperative and operative management of posttraumatic tarsometatarsal joint arthritis, reviews available literature, and includes the authors' tips and techniques.

A Comparison of Ankle Fractures Relative to Other Fragility Fractures: A Review and Analysis of the American Orthopaedic Association's Own the Bone Database.

BACKGROUND: Ankle fragility fractures (AFX) continue to increase in the elderly population. There is limited knowledge of AFX characteristics compared to nonankle fragility fractures (NAFX). The American Orthopaedic Association's Own the Bone (OTB) is a fragility fracture initiative. This robust data set was used to examine and compare characteristics of patients presenting with AFX to those with NAFX. METHODS: The OTB database contained 72,617 fragility fractures between January 2009 and March of 2022 and were reviewed in our secondary cohort comparative analysis. After exclusions, AFX accounted for 3229 patients and 54,772 patients were in the NAFX cohort. Bivariate analysis and logistic regression compared the AFX and NAFX groups concerning demographics, bone health factors, medication use, and prior fragility fracture. RESULTS: AFX patients were found to have a higher likelihood to be younger (67.6 years old), female (81.4%), non-Caucasian (11.7%) and have a higher BMI (30.6) compared to NAFX. Prior AFX predicted the risk of a future AFX. The probability of an AFX increased with increased age and BMI. CONCLUSION: A prior AFX is independently predictive of subsequent AFX. Therefore, these fractures should be considered a sentinel event. These patients are more likely to have higher BMI, to be of female gender, non-Caucasian race, and are younger compared to patients with NAFX. LEVEL OF EVIDENCE: Level III, retrospective cohort.

Management of Subchondral Lesions in the Foot and Ankle.

The treatment of subchondral lesions is an area with limited focus within the foot and ankle literature. The literature has shown an association between disruption of the subchondral bone plate and the formation of subchondral cysts. The primary causes of subchondral lesions are acute trauma, repetitive microtrauma, as well as idiopathic means. Evaluation of these injuries should be done carefully and often requires advanced imaging including MRI and computed tomography. Treatment does vary depending on the presentation of the subchondral lesion with or without the presence of an osteochondral lesion.

Community-developed checklists for publishing images and image analyses.

Images document scientific discoveries and are prevalent in modern biomedical research. Microscopy imaging in particular is currently undergoing rapid technological advancements. However for scientists wishing to publish the obtained images and image analyses results, there are to date no unified guidelines. Consequently, microscopy images and image data in publications may be unclear or difficult to interpret. Here we present community-developed checklists for preparing light microscopy images and image analysis for publications. These checklists offer authors, readers, and publishers key recommendations for image formatting and annotation, color selection, data availability, and for reporting image analysis workflows. The goal of our guidelines is to increase the clarity and reproducibility of image figures and thereby heighten the quality and explanatory power of microscopy data is in publications.

Feasibility of unconscious instrumental conditioning: A registered replication.

The extent to which high-level, complex functions can proceed unconsciously has been a topic of considerable debate. While unconscious processing has been demonstrated for a range of low-level processes, from feature integration to simple forms of conditioning and learning, theoretical contributions suggest that increasing complexity requires conscious access. Here, we focus our attention on instrumental conditioning, which has been previously shown to proceed without stimulus awareness. Yet, instrumental conditioning also involves integrating information over a large temporal scale and distinct modalities in order to deploy selective action, constituting a process of substantial complexity. With this in mind, we revisit the question of feasibility of instrumental conditioning in the unconscious domain. Firstly, we address the theoretical and practical considerations relevant to unconscious learning in general. Secondly, we aim to replicate the first study to show instrumental conditioning in the absence of stimulus awareness (Pessiglione et al., 2008), following the original design and supplementing the original crucial analyses with a Bayesian approach (Experiment 1). We found that apparent unconscious learning took place when replicating the original methods directly and according to the tests of awareness used. However, we could not establish that the full sample was unaware in a separate awareness check. We therefore attempted to replicate the effect yet again with improved methods to address the issues related to sensitivity and immediacy (Experiment 2), including an individual threshold-setting task and a trial-by-trial awareness check permitting exclusion of individual aware trials. Here, we found evidence for absence of unconscious learning. This result provides evidence that instrumental conditioning did not occur without stimulus awareness in this paradigm, supporting the view that complex forms of learning may rely on conscious access. Our results provides support for the proposal that perceptual consciousness may be necessary for complex, flexible processes, especially where selective action and behavioural adaptation are required.

CMOS Time-to-Digital Converters for Biomedical Imaging Applications.

Time-to-digital converters (TDCs) are high-performance mixed-signal circuits capable of timestamping events with sub-gate delay resolution. As a result of their high-performance, in recent years TDCs were integrated in complementary metal-oxide-semiconductor (CMOS) technology with highly sensitive photodetectors known as single-photon avalanche diodes (SPADs), to form digital silicon photomultipliers (dSiPMs) and SPAD imagers. Time-resolved SPAD-based sensors are capable of detecting the absorption of a single photon and timestamping it with picosecond resolution. As such, SPAD-based sensors are very useful in the field of biomedical imaging, using time-of-flight (ToF) information to produce data that can be used to reconstruct high-quality biological images. Additionally, the capability of integration in standard CMOS technologies, allows SPAD-based sensors to provide high-performance, while maintaining low cost. In this paper, we present an overview of fundamental TDC principles, and an analysis of state-of-the-art TDCs. Furthermore, the integration of TDCs into dSiPMs and SPAD imagers will be discussed, with an analysis of the current results of TDCs in different biomedical imaging applications. Finally, several important research challenges for TDCs in biomedical imaging applications are presented.

Concise or comprehensive? Predictors of impact assessment choices for electric transmission line projects.

Environmental impact assessment (EIA) procedures required in the United States and many other countries are often highlighted as a major hindrance to timely and efficient deployment of critical infrastructure projects. Under the U.S. National Environmental Policy Act, a more extensive environmental impact statement (EIS) review can take several more years and cost much more than a succinct environmental assessment (EA). This not only affects the project in question, but also likely informs how-or whether-additional projects are pursued. Thus, understanding key predictors of the EA versus EIS choice sheds light on supply-side considerations affecting infrastructure deficits. Using the case of NEPA reviews conducted for 244 transmission line projects between 2005 and 2018 by two U.S. federal agencies in the western United States, the Bureau of Land Management (BLM) and Department of Energy (DOE), this addresses the following question: What project features most predict whether EA or an EIS is used to assess a transmission line project? Drawing upon NEPA assessment guidance and agency NEPA records, we use a regression classification tree to analyze how protocols and project attributes relate to assessment choice. The result is essentially a null finding: transmission line length is by far the most important predictor of whether a project receives an extensive EIS or a shorter EA, with little predictive value provided by other attributes. While absolute project size undoubtedly influences impacts, the lack of further differentiation in what predicts use of EISs versus EAs suggests assessment does not simply respond to project details but also shapes proposal and design choices beforehand.

Challenges and considerations for single-cell and spatially resolved transcriptomics sample collection during spaceflight.

Single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (SRT) have experienced rapid development in recent years. The findings of spaceflight-based scRNA-seq and SRT investigations are likely to improve our understanding of life in space and our comprehension of gene expression in various cell systems and tissue dynamics. However, compared to their Earth-based counterparts, gene expression experiments conducted in spaceflight have not experienced the same pace of development. Out of the hundreds of spaceflight gene expression datasets available, only a few used scRNA-seq and SRT. In this perspective piece, we explore the growing importance of scRNA-seq and SRT in space biology and discuss the challenges and considerations relevant to robust experimental design to enable growth of these methods in the field.

Intraductal fully covered self-expanding metal stents in the management of post-liver transplant anastomotic strictures: a UK wide experience.

Background: Fully covered intraductal self-expanding metal stents (IDSEMS) have been well described in the management of post-liver transplant (LT) anastomotic strictures (ASs). Their antimigration waists and intraductal nature make them suited for deployment across the biliary anastomosis. Objectives: We conducted a multicentre study to analyse their use and efficacy in the management of AS. Design: This was a retrospective, multicentre observational study across nine tertiary centres in the United Kingdom. Methods: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography with IDSEMS insertion were analysed retrospectively. Recorded variables included patient demographics, procedural characteristics, response to therapy and follow-up data. Results: In all, 162 patients (100 males, 62%) underwent 176 episodes of IDSEMS insertion for AS. Aetiology of liver disease in this cohort included hepatocellular carcinoma (n = 35, 22%), followed by alcohol-related liver disease (n = 29, 18%), non-alcoholic steatohepatitis (n = 20, 12%), primary biliary cholangitis (n = 15, 9%), acute liver failure (n = 13, 8%), viral hepatitis (n = 13, 8%) and autoimmune hepatitis (n = 12, 7%). Early AS occurred in 25 (15%) cases, delayed in 32 (20%) cases and late in 95 (59%) cases. Age at transplant was 54 years (range, 12-74), and stent duration was 15 weeks (range, 3 days-78 weeks). In total, 131 (81%) had complete resolution of stricture at endoscopic re-evaluation. Stricture recurrence was observed in 13 (10%) cases, with a median of 19 weeks (range, 4-88 weeks) after stent removal. At removal, there were 21 (12%) adverse events, 5 (3%) episodes of cholangitis and 2 (1%) of pancreatitis. In 11 (6%) cases, the removal wires unravelled, and 3 (2%) stents migrated. All were removed endoscopically. Conclusion: IDSEMS appears to be safe and highly efficacious in the management of post-LT AS, with low rates of AS recurrence.

Validating Causal Diagrams of Human Health Risks for Spaceflight: An Example Using Bone Data from Rodents.

As part of the risk management plan for human system risks at the US National Aeronautics and Space Administration (NASA), the NASA Human Systems Risk Board uses causal diagrams (in the form of directed, acyclic graphs, or DAGs) to communicate the complex web of events that leads from exposure to the spaceflight environment to performance and health outcomes. However, the use of DAGs in this way is relatively new at NASA, and thus far, no method has been articulated for testing their veracity using empirical data. In this paper, we demonstrate a set of procedures for doing so, using (a) a DAG related to the risk of bone fracture after exposure to spaceflight; and (b) four datasets originally generated to investigate this phenomenon in rodents. Tests of expected marginal correlation and conditional independencies derived from the DAG indicate that the rodent data largely agree with the structure of the diagram. Incongruencies between tests and the expected relationships in one of the datasets are likely explained by inadequate representation of a key DAG variable in the dataset. Future directions include greater tie-in with human data sources, including multiomics data, which may allow for more robust characterization and measurement of DAG variables.

Contrast Enhanced Mammography in Routine Clinical Practice: Frequency and Malignancy Rates of Enhancing Otherwise Occult Findings.

BACKGROUND: In routine clinical practice, contrast-enhanced mammography (CEM) examinations identify enhancing findings seen only on subtraction images that have no low-energy mammographic or sonographic correlate. The purpose of this study is to report the frequency and malignancy rates of enhancing findings seen only on subtraction images in a tertiary care breast imaging practice. MATERIALS AND METHODS: Consecutive review of CEM exams from December 2015 to May 2020. Chi square tests were used to determine associations between cancer diagnosis and clinical characteristics of enhancing findings seen only on subtraction images, P < .05 indicating a statistically significant difference. RESULTS: Four percent (100/2464) of CEM examinations identified 108 enhancing findings seen only on subtraction images. Twenty of those CEM enhancing findings were directly managed as a multifocal disease. Of those further evaluated with MR, 23% (19/78) with associated MR correlates were treated surgically as presumed multicentric or multifocal disease following multidisciplinary review. The remaining 76% (59/78) of enhancing findings were seen only on subtraction images, these included: 20% (12/59) and downgraded to benign on MR 80% (47/59) with suspicious findings which underwent MR vacuum assisted breast biopsy yielding: 26% (12/47) malignancy, 9% (4/47) high risk, and 66% (31/47) benign diagnoses. CONCLUSION: Enhancing findings seen on subtraction only CEM images are seen in 4% of cases in clinical practice. MR correlation can help characterize CEM findings to: (1) avoid unnecessary biopsy for benign findings, and (2) guide tissue sampling or empiric surgical planning for suspicious findings.