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ABSTRACT We investigated the effects of Candida albicans colonization on inflammatory responses in the murine glandular stomach, which is similar to the glandular mucosa of the human stomach. We also explored whether the presence of a food allergy could exacerbate C. albicans-induced inflammation or if C. albicans would amplify allergic inflammation in the glandular stomach. C. albicans successfully colonized the stomach of amoxicillin-pre-treated BALB/c mice and induced gastritis in the limiting ridge with minimal inflammation in the glandular stomach. There was significant upregulation of Il18, calprotectin (S100a8 and S100a9), and several antimicrobial peptides, but minimal induction of type 1, 2, or 3 responses in the glandular stomach. A robust type 2 response, inflammatory cell recruitment, and tissue remodeling occurred in the glandular stomach following oral ovalbumin challenges in sensitized mice. The type 2 response was not augmented by C. albicans colonization, but there was significant upregulation of Il1b, Il12a, Tnf, and Il17a in C. albicans-colonized food allergic mice. The presence of C. albicans did not affect the expression of genes involved in barrier integrity and signaling, many of which were upregulated during food allergy. Overall, our data indicate that C. albicans colonization induces minimal inflammation in the glandular stomach but augments antimicrobial peptide expression. Induction of a food allergy results in robust type 2 inflammation in the glandular stomach, and while C. albicans colonization does not exacerbate type 2 inflammation, it does activate a number of innate and type 3 immune responses amid the backdrop of allergic inflammation.IMPORTANCEFood allergy continues to be a growing public health concern, affecting at least 1 in 10 individuals in the United States alone. However, little is known about the involvement of the gastric mucosa in food allergy. Gastrointestinal Candida albicans colonization has been reported to promote gastrointestinal inflammation in a number of chronic diseases. Using a mouse model of food allergy to egg white protein, we demonstrate regionalization of the inflammatory response to C. albicans colonization, induction of robust type 2 (allergic) inflammation in the stomach, and augmentation of innate and type 3 responses by C. albicans colonization during food allergy.

Abstract Background Sepsis from infection is a global health priority and clinical trials have failed to deliver effective therapeutic interventions. To address complicating heterogeneity in sepsis pathobiology, and improve outcomes, promising precision medicine approaches are helping identify disease endotypes, however, they require a more complete definition of sepsis subgroups. Methods Here, we use RNA sequencing from peripheral blood to interrogate the host response to sepsis from participants in a global observational study carried out in West Africa, Southeast Asia, and North America (N = 494). Results We identify four sepsis subtypes differentiated by 28-day mortality. A low mortality immunocompetent group is specified by features that describe the adaptive immune system. In contrast, the three high mortality groups show elevated clinical severity consistent with multiple organ dysfunction. The immunosuppressed group members show signs of a dysfunctional immune response, the acute-inflammation group is set apart by molecular features of the innate immune response, while the immunometabolic group is characterized by metabolic pathways such as heme biosynthesis. Conclusions Our analysis reveals details of molecular endotypes in sepsis that support immunotherapeutic interventions and identifies biomarkers that predict outcomes in these groups.

BackgroundBrain inflammation plays a key role in ischemia/reperfusion (I/R) injury and is the main cause of “ineffective or futile recanalization” after successful mechanical thrombectomy (MT) in acute ischemic stroke (AIS). One of the primary sources of inflammatory cells after AIS are derived from the spleen. As an innovative and potential neuroprotective strategy after stroke, Remote Administration of Hypothermia (RAH) temporarily suppresses immune activities in the spleen, reduces the release of inflammatory cells and cytokines into blood, and thus reversibly diminishes inflammatory injury in the brain.MethodsThis single-center, prospective, randomized controlled study (RCT) is proposed for AIS patients with anterior circulation large vessel occlusion (LVO). Subjects will be randomly assigned to either the control or intervention groups in a 1:1 ratio (n = 40). Participants allocated to the intervention group will receive RAH on the abdomen above the spleen prior to recanalization until 6 h after thrombectomy. All enrolled patients will receive standard stroke Guideline care. The main adverse events associated with RAH are focal cold intolerance and abdominal pain. The primary outcome will assess safety as it pertains to RAH application. The secondary outcomes include the efficacy of RAH on spleen, determined by spleen volumes, blood inflammatory factor (cells and cytokines), and on brain injury, determined by infarction volumes and poststroke functional outcomes.DiscussionThis study aims to examine the safety and preliminary effectiveness of RAH over the spleen during endovascular therapy in AIS patients. The results of this study are expected to facilitate larger randomized clinical trials and hopefully prove RAH administration confers adjuvant neuroprotective properties in AIS treated with MT.Clinical trial registrationhttps://www.chictr.org.cn/. Identifier ChiCTR 2300077052.

Background/Objectives: Neural processes involved in visual detection, decision-making, and motor plan execution are believed to play a key role in the avoidance of sport-related injuries, but very little evidence exists to guide the development of training activities for the optimization of brain function. Immersive virtual reality provides a means to precisely measure the amount of time that elapses from visual stimulus presentation to the initiation of a motor response (i.e., perceptual latency) or its completion (i.e., response time). Methods: The median value of a metric quantifying both the speed and accuracy (i.e., the rate correct per second of response time) of 50 high school female soccer players was used to assign those who exhibited suboptimal performance to a training program. Training sessions required less than 5 min and the number of sessions completed over a 7-week period ranged from 3 to 13 (median = 5). Results: Among 42 players available for follow-up assessment at 8 weeks after the first practice session (training n = 19; comparison n = 23), the results of regression-discontinuity analyses demonstrated statistically significant differences (p < 0.05) for metrics representing fast/accurate movement initiation (i.e., the rate correct score for perceptual latency, p = 0.016) and across-trial consistency (i.e., perceptual latency variability, p = 0.027). From the first practice session to the end of the soccer season, 12 injuries were sustained by 10 players (four concussions and eight musculoskeletal injuries). A time-to-event analysis demonstrated strong associations with perceptual latency variability ≥ 0.143 (Hazard Ratio = 15.43, p = 0.011) and a lifetime history of at least one concussion (Hazard Ratio = 8.84, p = 0.008). Conclusions: The strong association of movement initiation consistency with the avoidance of concussion or musculoskeletal injury suggests that the training program may have a highly beneficial far-transfer effect.

Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit).Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4–96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure.Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment.Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.

Background: We investigated 51 g-negative carbapenem-resistant Enterobacterales (CRE) isolates collected from 22 patients over a five-year period from six health care institutions in the Ochsner Health network in southeast Louisiana. Methods: Short genomic reads were generated using Illumina sequencing and assembled for each isolate. Isolates were classified as Enterobacter spp. (n = 20), Klebsiella spp. (n = 30), and Escherichia coli (n = 1) and grouped into 19 different multi-locus sequence types (MLST). Species and patient-specific core genomes were constructed representing ∼50% of the chromosomal genome. Results: We identified two sets of patients with genetically related infections; in both cases, the related isolates were collected > 6 months apart, and in one case, the isolates were collected in different locations. On the other hand, we identified four sets of patients with isolates of the same species collected within 21 days from the same location; however, none had genetically related infections. Genes associated with resistance to carbapenem drugs (blaKPC and/or blaCTX-M-15) were found in 76% of the isolates. We found three blaKPC variants (blaKPC-2, blaKPC-3, and blaKPC-4) associated with four different Enterobacter MLST variants, and two blaKPC variants (blaKPC-2, blaKPC-3) associated with seven different Klebsiella MLST variants. Conclusions: Molecular surveillance is increasingly becoming a powerful tool to understand bacterial spread in both community and clinical settings. This study provides evidence that genetically related infections in clinical settings do not necessarily reflect temporal associations, and vice versa. Our results also highlight the regional genomic and resistance diversity within related bacterial lineages.

Abstract Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.

Abstract Introduction Whole genome sequencing (WGS) of bacterial isolates can be used to identify antimicrobial resistance (AMR) genes. Previous studies have shown that genotype-based AMR has variable accuracy for predicting carbapenem resistance in carbapenem-resistant Enterobacterales (CRE); however, the majority of these studies used short-read platforms (e.g. Illumina) to generate sequence data. In this study, our objective was to determine whether Oxford Nanopore Technologies (ONT) long-read WGS would improve detection of carbapenem AMR genes with respect to short-read only WGS for nine clinical CRE samples. We measured the minimum inhibitory breakpoint (MIC) using two phenotype assays (MicroScan and ETEST) for six antibiotics, including two carbapenems (meropenem and ertapenem) and four non-carbapenems (gentamicin, ciprofloxacin, cefepime, and trimethoprim/sulfamethoxazole). We generated short-read data using the Illumina NextSeq and long-read data using the ONT MinION. Four assembly methods were compared: ONT-only assembly; ONT-only assembly plus short-read polish; ONT + short-read hybrid assembly plus short-read polish; short-read only assembly. Results Consistent with previous studies, our results suggest that the hybrid assembly produced the highest quality results as measured by gene completeness and contig circularization. However, ONT-only methods had minimal impact on the detection of AMR genes and plasmids compared to short-read methods, although, notably, differences in gene copy number differed between methods. All four assembly methods showed identical presence/absence of the blaKPC-2 carbapenemase gene for all samples. The two phenotype assays showed 100% concordant results for the non-carbapenems, but only 65% concordance for the two carbapenems. The presence/absence of AMR genes was 100% concordant with AMR phenotypes for all four non-carbapenem drugs, although only 22%—50% sensitivity for the carbapenems. Conclusions Overall, these findings suggest that the lack of complete correspondence between CRE AMR genotype and phenotype for carbapenems, while concerning, is independent of sequencing platform/assembly method.

IntroductionA history of concussion is recognized as a risk factor for musculoskeletal injury, which is likely associated with physiological effects that warrant better understanding. This study aimed to assess the potential of measurements obtained from an immersive virtual reality (VR) test to identify a subtle perceptual–motor impairment that may be prospectively associated with the occurrence of a core or lower extremity sprain or strain.MethodsA cohort of 68 high school athletes (41 female soccer players and 27 male football players) provided survey responses and completed an immersive VR test several days prior to the initiation of preseason practice sessions. Measurements of eye, neck, arm, and whole-body displacements were obtained during 40 successive lunging/reaching responses to visual stimuli moving horizontally across the VR headset display. Injury occurrences were electronically documented from the initial preseason practice session to the final game of the season.ResultsA statistically significant and intrinsically credible two-factor prediction model for core or lower extremity injury occurrence included an interaction between female sex and a self-reported history of two or more concussions, along with slow response time (RT) for arm reach (OR = 4.67; 95% CI, 1.51–14.43). Follow-up analyses identified sex-specific cut points for arm reach RT associated with elevated injury risk, which were ≥1.385 s for females and ≥1.257 s for males.DiscussionHigh school female soccer players who have sustained more than one concussion appear to be highly vulnerable to core or lower extremity sprain or strain, with the risk of injury compounded by a slow arm reach RT. Male football players as a group demonstrated significantly faster arm reach RT than that of female soccer players, but slow perceptual–motor RT for arm reach was also identified as a potentially important injury risk factor for male players. Immersive VR appears to provide precise measurements of behavioral performance characteristics that depend on brain processing efficiency. Given that the speed, accuracy, and consistency of perceptual–motor responses may be modifiable, future research should explore the potential benefits of VR training for reducing the risk of sport-related injuries.

Lactobacillus johnsonii is a commensal bacterium that has been isolated from vaginal and gastrointestinal (GI) tracts of vertebrate hosts, including humans, rodents, swine, and poultry. Lactobacillus-based probiotic supplements are popular because of the health advantages they offer. Species such as L. johnsonii are particularly interesting due to their potential health-promoting properties. Here, we reviewed the research on specific strains of L. johnsonii that have been studied in the context of health and disease and delved into the underlying mechanisms that aid in preserving host homeostasis. The utilization of L. johnsonii strains has been widely linked to numerous health benefits in the host. These include pathogen antagonism, control of mucosal and systemic immune responses, reduction of chronic inflammation, modulation of metabolic disorders, and enhanced epithelial barrier. These findings suggest that L. johnsonii plays a critical role in maintaining host homeostasis, highlighting its potential as a probiotic.

Ostreid herpesvirus 1 (OsHV-1) is one of the most economically important pathogens of Pacific oysters. Understanding the pathogenesis of this virus is critical to developing tools to control outbreaks on shellfish farms. OsHV-1 is genetically related to vertebrate herpesviruses, which have a lytic and a latent stage, with the latent stage capable of being reactivated to the lytic stage. Here, OsHV-1 latency in Pacific oysters was investigated in experimentally and naturally infected oysters. Lytic infection in one-year-old oysters injected with the Tomales Bay strain of OsHV-1 was detectable between 1 and 4 days post-injection (dpi) but was not detectable after 5 dpi. The injected oysters shed 1 × 102 to 1 × 104 DNA copies/ml into the water during the 4-day acute phase. Lytic shedding was not detectable in two-year-old oysters injected similarly with the same strain of OsHV-1; however, the OsHV-1 genome was detectable by qPCR in the adductor muscle, gill, mantle, and hemocytes within the first 3 dpi, after which it became undetectable. No OsHV-1 was detectable in the adductor muscle, gill, or mantle from experimentally infected oysters on days 15 and 21 post-injection or from oysters sampled 9 months after surviving an OsHV-1 mortality event; however, OsHV-1 DNA could be detected in hemocytes of both experimentally infected oysters at 21 dpi and naturally infected oysters using nested PCR. In addition, lytic viral gene transcription was detectable in hemocytes of experimentally infected oysters between 1 and 21 dpi and in hemocytes of naturally infected oysters. Furthermore, OsHV-1 reactivation from latency was induced in experimentally infected oysters at 21 dpi and in naturally infected oysters 12 months after an OsHV-1 outbreak.

Opioid use disorder is characterized by excessive use of opioids, inability to control its use, a withdrawal syndrome upon discontinuation of opioids, and long-term likelihood of relapse. The behavioral stages of opioid addiction correspond with affective experiences that characterize the opponent process view of motivation. In this framework, active involvement is accompanied by positive affective experiences which gives rise to “reward craving,” whereas the opponent process, abstinence, is associated with the negative affective experiences that produce “relief craving.” Relief craving develops along with a hypersensitization to the negatively reinforcing aspects of withdrawal during abstinence from opioids. These negative affective experiences are hypothesized to stem from neuroadaptations to a network of affective processing called the “extended amygdala.” This negative valence network includes the three core structures of the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and the nucleus accumbens shell (NAc shell), in addition to major inputs from the basolateral amygdala (BLA). To better understand the major components of this system, we have reviewed their functions, inputs and outputs, along with the associated neural plasticity in animal models of opioid withdrawal. These models demonstrate the somatic, motivational, affective, and learning related models of opioid withdrawal and abstinence. Neuroadaptations in these stress and motivational systems are accompanied by negative affective and aversive experiences that commonly give rise to relapse. CeA neuroplasticity accounts for many of the aversive and fear-related effects of opioid withdrawal via glutamatergic plasticity and changes to corticotrophin-releasing factor (CRF)-containing neurons. Neuroadaptations in BNST pre-and post-synaptic GABA-containing neurons, as well as their noradrenergic modulation, may be responsible for a variety of aversive affective experiences and maladaptive behaviors. Opioid withdrawal yields a hypodopaminergic and amotivational state and results in neuroadaptive increases in excitability of the NAc shell, both of which are associated with increased vulnerability to relapse. Finally, BLA transmission to hippocampal and cortical regions impacts the perception of conditioned aversive effects of opioid withdrawal by higher executive systems. The prevention or reversal of these varied neuroadaptations in the extended amygdala during opioid withdrawal could lead to promising new interventions for this life-threatening condition.

Background:. Weekend presentation has been associated with adverse outcomes in emergent conditions, including stroke, myocardial infarction, and critical limb ischemia. We examine whether a weekend effect exists in the management of and outcomes after extremity degloving injuries. Methods:. The cohort included adults presenting with open extremity degloving injuries to a tertiary level one trauma center between June 2018 and May 2022. We collected demographics, comorbidities, injury information, interventions, and complications. Propensity score weighting was used to minimize confounding differences between those presenting on weekends (Sat–Sun) versus weekdays (Mon–Fri). Weighted regressions were used to examine differences in interventions by day of presentation. Multivariable weighted regressions accounting for differences in interventions received were used to examine whether weekend presentation was associated with amputation risk, complications, or functional deficits. Results:. Ninety-five patients with 100 open extremity degloving injuries were included. In total, 39% of injuries were weekend-presenting. There was a higher rate of noninsulin-dependent diabetes among patients presenting on weekends (P = 0.03). Weekend-presenting injuries had higher median Injury Severity Scores (P = 0.04). Propensity-weighted regression analysis revealed differences in interventions received on weekends, including lower rates of pedicled and free flaps and bone graft, and increased rates of negative-pressure wound therapy (P ≤ 0.02). Multivariable regression analysis revealed weekend presentation was a significant independent risk factor for amputation of the affected extremity [odds ratio 2.27, 95% CI (1.01–5.33), P = 0.05]. Conclusion:. Weekend presentation may impact interventions received and amputation risk in patients presenting with open extremity degloving injuries.

Increased availability of QL1/QL2 Lidar terrain data has resulted in large datasets, often including large quantities of redundant points. Because of these large memory requirements, practitioners often use decimation to reduce the number of points used to create models. This paper introduces a novel approach to improve decimation, thereby reducing the total count of ground points in a Lidar dataset while retaining more accuracy than Random Decimation. This reduction improves efficiency of downstream processes while maintaining output quality nearer to the undecimated dataset. Points are selected for retention based on their discrete curvature values computed from the mesh geometry of the TIN model of the points. Points with higher curvature values are preferred for retention in the resulting point cloud. We call this technique Curvature Weighted Decimation (CWD). We implement CWD in a new free, open-source software tool, CogoDN, which is also introduced in this paper. We evaluate the effectiveness of CWD against Random Decimation by comparing the resulting introduced error values for the two kinds of decimation over multiple decimation percentages, multiple statistical types, and multiple terrain types. The results show that CWD reduces introduced error values over Random Decimation when 15 to 50% of the points are retained.

Abstract Background Although endovascular recanalization therapy demonstrates robust clinical efficacy in acute ischemic stroke (AIS), not all victims of these cerebrovascular accidents can benefit from it and achieve a favorable prognosis after successful reperfusion. Therefore, alternative neuroprotective strategies are urgently needed for AIS patients after vessel recanalization. Nitric oxide (NO) levels are low after AIS and NO donor drugs may be neuroprotective against cerebral ischemia–reperfusion injury. Glyceryl trinitrate (GTN), often used in the clinic as a NO donor, may provide a novel neuroprotective strategy. This rationale, design, and protocol for a prospective pilot study plans to explore the preliminary safety, feasibility, and neuroprotective benefits of Arterial Glyceryl Trinitrate in Acute Ischemic Stroke after Thrombectomy for Neuroprotection (AGAIN). Methods AGAIN, a prospective RCT, is proposed for AIS patients after mechanical thrombectomy. Subjects will be randomly assigned in a 1:1 fashion (n = 40) to either the control group or the intervention group. Participants assigned to the intervention group will be administered 800 μg GTN in the catheter immediately after recanalization, whereas those in the control group will be administered the same volume of normal saline. All participants from either group will be given concurrent treatment with standard of care therapies in accordance with the current guidelines for stroke management. The primary outcome is safety [symptomatic intracranial hemorrhage (ICH), hypotension, neurological deterioration, ICH, fatal ICH, as well as headache, tachycardia, emesis, and seizures], whereas secondary outcomes included changes in poststroke functional outcomes, infarction volumes, and blood nitrate index detection. Discussions This study is a prospective randomized controlled trial to test the safety and efficacy of intra-arterial GTN in AIS patients after endovascular therapy. The results from this study will give insight for future GTN studies and new neuroprotective strategies for future AIS treatment strategies. Trial registration number ChiCTR2100045254. Registered on March 21, 2021.

Abstract The pathogenesis of asthma has been partially linked to lung and gut microbiome. We utilized a steroid‐resistant chronic model of cockroach antigen‐induced (CRA) asthma with corticosteroid (fluticasone) treatment to examine lung and gut microbiome during disease. The pathophysiology assessment demonstrated that mucus and airway hyperresponsiveness were increased in the chronic CRA with no alteration in the fluticasone (Flut)‐treated group, demonstrating steroid resistance. Analysis of mRNA from lungs showed no decrease of MUC5AC or Gob5 in the Flut‐treated group. Furthermore, flow‐cytometry in lung tissue showed eosinophils and neutrophils were not significantly reduced in the Flut‐treated group compared to the chronic CRA group. When the microbiome profiles were assessed, data showed that only the Flut‐treated animals were significantly different in the gut microbiome. Finally, a functional analysis of cecal microbiome metabolites using PiCRUSt showed several biosynthetic pathways were significantly enriched in the Flut‐treated group, with tryptophan pathway verified by ELISA with increased kynurenine in homogenized cecum samples. While the implications of these data are unclear, they may suggest a significant impact of steroid treatment on future disease pathogenesis through microbiome and associated metabolite pathway changes.

California and most other coastlines around the world are being impacted by both long-term sea-level rise and short-term extreme events. Due to California’s long and intensively developed coastline, it is an important area for evaluating responses to these challenges. The predominant historic approach to coastal erosion in California and globally has been the construction of hard coastal armoring such as seawalls and rock revetments. The concept of living shorelines—defined as using natural elements like plants, sand, or rocks to stabilize the coastline—has been widely proposed as a soft or green response to coastal erosion and flooding. However, these approaches have very limited application in high-energy environments such as California’s 1100-mile-long outer coast and are not realistic solutions for protection from wave attack at high tides or long-term sea-level rise. Each of the state’s coastal communities need to identify their most vulnerable areas, develop adaptation plans, and plan eventual relocation strategies in response to an accelerating sea-level rise.

Background: Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory tract infection, especially in infants, and increases the risk of recurrent wheezing and asthma. Recently, researchers have proposed a possible association between respiratory diseases and microbiome alterations. However, this connection has not been fully established. Herein, we conducted a systematic literature review to evaluate the reported evidence of microbiome alterations in patients with RSV infection. Methods: The systematic literature review on the association between RSV and microbiome in humans was conducted by searching PubMed, EMBASE, Scopus, and CINAHL from 2012 until February 2022. The results were analyzed qualitatively, focusing on the relationship between microbiome and RSV infection with available key microbiome-related parameters. Results: In the 405 articles identified by searching databases, 12 (Respiratory tract: 9, Gut: 2, Both: 1) articles in line with the research aims were eligible for this qualitative review. The types of samples for the respiratory tract microbiome and the sequencing methods utilized varied from study to study. This review revealed that the overall microbial composition in both the respiratory tract and gut in RSV-infected patients was different from that in healthy controls. Our generated results demonstrated an increase in the abundance of Haemophilus and Streptococcus, which could contribute to the distinctive separation based on the beta diversity in the respiratory tract. Conclusions: The respiratory tract and gut microbiome changed in patients with RSV infection. Further research with a well-organized longitudinal design is warranted to clarify the impact of microbiome alterations on disease pathogenesis.

Concussion may affect sport performance capabilities related to the visual perception of environmental events, rapid decision-making, and the generation of effective movement responses. Immersive virtual reality (VR) offers a means to quantify, and potentially enhance, the speed, accuracy, and consistency of responses generated by integrated neural processes. A cohort of 24 NCAA Division I male wrestlers completed VR assessments before and after a 3-week VR training program designed to improve their perceptual-motor performance. Prior to training, the intra-individual variability (IIV) among 40 successive task trials for perceptual latency (i.e., time elapsed between visual stimulus presentation and the initiation of movement response) demonstrated strong discrimination between 10 wrestlers who self-reported a history of concussion from 14 wrestlers who denied ever having sustained a concussion (Area Under Curve ≥ 0.750 for neck, arm, and step movements). Natural log transformation improved the distribution normality of the IIV values for both perceptual latency and response time (i.e., time elapsed between visual stimulus presentation and the completion of movement response). The repeated measures ANOVA results demonstrated statistically significant (p < 0.05) pre- and post-training differences between groups for the IIV in perceptual latency and the IIV in response time for neck, arm, and step movements. Five of the six IIV metrics demonstrated a statistically significant magnitude of change for both groups, with large effect sizes. We conclude that a VR assessment can detect impairments in perceptual-motor performance among college wrestlers with a history of concussion. Although significant post-training group differences were evident, VR training can yield significant performance improvements in both groups.

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness.

BackgroundAlthough endovascular mechanical thrombectomy demonstrates clinical efficacy in posterior circulation acute ischemic stroke (AIS), only one third of these patients attain functional independence with a third of patients’ expiring despite vascular recanalization. Neuroprotection strategies, such as therapeutic hypothermia (TH) have been considered a promising adjunctive treatment in AIS. We propose the following rationale, design and protocol for a prospective randomized controlled trial (RCT) aimed to determine whether Vertebrobasilar Artery Cooling Infusion (VACI) improves functional outcomes in posterior circulation AIS patients post mechanical thrombectomy.MethodsSubjects in the study will be assigned randomly to either the cooling infusion or the control group in a 1:1 ratio (n = 40). Patients allocated to the cooling infusion group will receive 300 ml cool saline at 4C through the catheter (30 ml/min) into vertebral artery after thrombectomy. The control group will receive the same volume of 37C saline. All patients enrolled will receive standard care according to current guidelines for stroke management. The primary outcome is symptomatic intracranial hemorrhage (ICH), whereas the secondary outcomes include functional outcome score, infarction volume, mortality, ICH, fatal ICH, cerebral vasospasm, coagulation abnormality, pneumonia and urinary infection.DiscussionsThis study will determine the preliminary safety, feasibility, and neuroprotective benefits of VACI in posterior circulation AIS patients with reperfusion therapy. The results of this study may provide evidence for VACI as a new therapy in posterior circulation AIS.Clinical Trial Registration:www.chictr.org.cn, ChiCTR2200065806, registered on November 15, 2022.

Most contemporary theories for the chemical origins of life include the prebiotic synthesis of informational polymers, including strong interpretations of the RNA World hypothesis. Existing challenges to the prebiotic emergence of RNA have encouraged exploration of the possibility that RNA was preceded by an ancestral informational polymer, or proto-RNA, that formed more easily on the early Earth. We have proposed that the proto-nucleobases of proto-RNA would have readily formed glycosides with ribose and that these proto-nucleosides would have formed base pairs as monomers in aqueous solution, two properties not exhibited by the extant nucleosides or nucleotides. Here we demonstrate that putative proto-nucleotides of the model proto-nucleobases barbituric acid and melamine can be formed in the same one-pot reaction with ribose-5-phosphate. Additionally, the proto-nucleotides formed in these reactions spontaneously form assemblies that are consistent with the presence of Watson–Crick-like base pairs. Together, these results provide further support for the possibility that heterocycles closely related to the extant bases of RNA facilitated the prebiotic emergence of RNA-like molecules, which were eventually replaced by RNA over the course of chemical and biological evolution.

Objective Addressing gaps in COVID-19 vaccine-hesitancy research, the current study aimed to add depth and nuance to the exploratory research examining vaccine-hesitant groups. Using a larger, but more focused conversation occurring on social media, the results can be used by health communicators to frame emotionally resonant messaging to improve COVID-19 vaccine advocacy while also mitigating negative concerns for vaccine-hesitant individuals. Methods Social media mentions were collected using a social media listening software, Brandwatch, to examine topics and sentiments in COVID-19 hesitancy discourse during a period of September 1, 2020, through December 31, 2020. The results from this query included publicly available mentions on two popular social media sites, Twitter and Reddit. The dataset of 14,901 global, English language messages were analyzed using a computer-assisted process in SAS text-mining and Brandwatch software. The data revealed eight unique topics before being analyzed by sentiment. Results Among the COVID-19 hesitancy data, trust-related topics emerged that included declining vaccine acceptance, a parallel pandemic of distrust, and a call for politicians to let the scientific process work, among others. Positive sentiment revealed interest in the sources which included healthcare professionals, doctors, and government organizations. Pfizer was found to elicit both positive and negative emotions in the vaccine-hesitancy data. The negative sentiment tended to dominate the hesitancy conversation, accelerating once vaccines hit the market. Conclusions Relevant topics were identified to help support targeted communication, strategically accelerate vaccine acceptance, and mitigate COVID-19 vaccine hesitancy among the public. Strategic methods of online and offline messaging tactics are suggested to reach diverse, malleable populations of interest. Topics of personal anecdotes of safety, effectiveness, and recommendations among families are identified as persuasive communication opportunities.

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal, stress responses, insomnia and other symptoms. This review of rodent models of PTSD examines trauma effects on fear-related learning, cognition, and avoidance, emotional and arousal behaviors and on mitochondrial dysfunction in relevant neural pathways. The review focuses on research that includes four elements: consensus PTSD rodent models, behavioral phenotyping, mitochondrial dysfunction within key neural regions. This approach allows for the integration of behavioral, neural and cellular findings in PTSD models. The PTSD models reviewed include fear conditioning, predator/social stress, chronic restraint stress, single prolonged stress, social isolation, chronic unpredictable stress and early life stress. These models produce a variety of PTSD-related behaviors that include associative and non-associative fear- and stress-related responses, hyperarousal, avoidance behaviors, cognitive disturbances, social withdrawal, compulsive behaviors, anhedonia-, anxiety- and depression-related behaviors. Neural regions included fear- and stress-related regions of the prefrontal cortex, hippocampal, amygdala, nucleus accumbens and hypothalamus. PTSD models produced mitochondrial dysfunction that includes dysregulation of oxidative phosphorylation and other metabolic pathways including β-oxidation of fatty acids and the tricarboxylic acid pathway. These models generated neural reactive oxygen species that damage DNA, proteins, and lipids. Trauma models further altered mitochondrial structure and replication and affected neuroinflammatory responses, signal transduction and apoptosis. Antidepressant medications used for the treatment of PTSD reversed stress-induced changes in some PTSD-like behaviors and many elements of brain mitochondrial dysfunction. Future studies can develop PTSD models which are ecologically valid and result in a broader manifestation of PTSD-related behaviors as it is clinically defined. This review highlights mitochondrial mechanisms associated with PTSD-like behaviors that have been produced in an array of consensus PTSD models and identifies putative circuit-based targets for more effective treatment for this debilitating disorder.

IntroductionA lack of obvious long-term effects of concussion on standard clinical measures of behavioral performance capabilities does not preclude the existence of subtle neural processing impairments that appear to be linked to elevated risk for subsequent concussion occurrence, and which may be associated with greater susceptibility to progressive neurodegenerative processes. The purpose of this observational cohort study was to assess virtual reality motor response variability and survey responses as possible indicators of suboptimal brain function among military cadets and college athletes with self-reported history of concussion (HxC).MethodsThe cohort comprised 75 college students (20.7 ± 2.1 years): 39 Reserve Officer Training Corp (ROTC) military cadets (10 female), 16 football players, and 20 wrestlers; HxC self-reported by 20 (29.2 ± 27.1 months prior, range: 3–96). A virtual reality (VR) test involving 40 lunging/reaching responses to horizontally moving dots (filled/congruent: same direction; open/incongruent: opposite direction) was administered, along with the Sport Fitness and Wellness Index (SFWI) survey. VR Dispersion (standard deviation of 12 T-scores for neck, upper extremity, and lower extremity responses to congruent vs. incongruent stimuli originating from central vs. peripheral locations) and SFWI response patterns were the primary outcomes of interest.ResultsLogistic regression modeling of VR Dispersion (range: 1.5–21.8), SFWI (range: 44–100), and an interaction between them provided 81% HxC classification accuracy (Model χ2[2] = 26.03, p

BackgroundIntegrated movement and cognitive load paradigms are used to expose impairments associated with concussion and musculoskeletal injury. There is currently little information on the discriminatory nature of dual-task complexity and the relative influence of physical exertion on cognitive outcomes.PurposeAssess cognitive performance while under motor conditions of increasing complexity before and after a standardized exercise protocol.Methods34 participants were recruited (17 male and 17 female; 24 ± 1.4 yrs). A modified Eriksen flanker test was used to assess cognitive performance under four conditions (seated, single-leg stance, walking, and lateral stepping) before and after a 20-min moderate-to vigorous intensity treadmill protocol. The flanker test consisted of 20 sets of 5-arrow configurations, appearing in random order. To complete the response to cognitive stimulus, participants held a smartphone horizontally and were instructed to respond as quickly and as accurately as possible by tilting the device in the direction corresponding to the orientation of the middle arrow. The metrics used for analysis included average reaction time (ms), inverse efficiency index (average reaction time penalized for incorrect responses), and conflict effect (the average time cost of responding to an incongruent repetition vs. a congruent repetition). Mixed effects (condition by time) RMANOVAs were conducted to examine the effects of motor task complexity and physical exertion on cognitive performance.ResultsThere was a condition by time interaction for inverse efficiency index (p < 0.001), in which participants displayed higher cognitive efficiency for the pre-activity lateral stepping condition compared to the other three conditions (Cohen's d = 1.3–1.6). For reaction time and conflict effect, there were main effects for condition (p = 0.004 and 0.006, respectively), in which performance during lateral stepping was improved in relation to the seated condition (reaction time Cohen's d = 0.68; conflict effect Cohen's d = 0.64).ConclusionParticipants tended to display better dual-task cognitive performance under more stimulating or complex motor tasks before physical exertion, likely associated with the inverted-U arousal-performance relationship. When using dual-task assessments, clinicians should be mindful of the accompanying motor task and baseline exertion levels and their potential to disrupt or optimize cognitive performance.

Purpose: We compared work outcomes in patients with oropharyngeal cancer (OPC), randomized to intensity-modulated proton (IMPT) versus intensity-modulated photon therapy (IMRT) for chemoradiation therapy (CRT). Patients and Methods: In 147 patients with stage II-IVB squamous cell OPC participating in patient-reported outcomes assessments, a prespecified secondary aim of a randomized phase II/III trial of IMPT (n = 69) versus IMRT (n = 78), we compared absenteeism, presenteeism (i.e., the extent to which an employee is not fully functional at work), and work productivity losses. We used the work productivity and activity impairment questionnaire at baseline (pre-CRT), at the end of CRT, and at 6 months, 1 year, and 2 years. A one-sided Cochran-Armitage test was used to analyze within-arm temporal trends, and a χ2 test was used to compare between-arm differences. Among working patients, at each follow-up point, a 1-sided Wilcoxon rank-sum test was used to compare work-productivity scores. Results: Patient characteristics in IMPT versus IMRT arms were similar. In the IMPT arm, within-arm analysis demonstrated that an increasing proportion of patients resumed working after IMPT, from 60% (40 of 67) pre-CRT and 71% (30 of 42) at 1 year to 78% (18 of 23) at 2 years (P = 0.025). In the IMRT arm, the proportion remained stable, with 57% (43 of 76) pre-CRT, 54% (21 of 39) at 1 year, and 52% (13 of 25) working at 2 years (P = 0.47). By 2 years after CRT, the between-arm difference between patients who had IMPT and those who had IMRT trended toward significance (P = 0.06). Regardless of treatment arm, among working patients, the most severe work impairments occurred from treatment initiation to the end of CRT, with significant recovery from absenteeism, presenteeism, and productivity impairments by the 2-year follow-up (P < 0.001 for all). Higher magnitudes of recovery from absenteeism (at 1 year, P = 0.05; and at 2 years, P = 0.04) and composite work impairment scores (at 1 year, P = 0.04; and at 2 years, P = 0.04) were seen in patients treated with IMPT versus those treated with IMRT. Conclusion: In patients with OPC receiving curative CRT, patients randomized to IMPT demonstrated increasing work and productivity recovery trends. Studies are needed to identify mechanisms underlying head and neck CRT treatment causing work disability and impairment.

Abstract Background Low-biomass microbiome studies (such as those of the lungs, placenta, and skin) are vulnerable to contamination and sequencing stochasticity, which obscure legitimate microbial signal. While human lung microbiome studies have rigorously identified sampling strategies that reliably capture microbial signal from these low-biomass microbial communities, the optimal sampling strategy for characterizing murine lung microbiota has not been empirically determined. Performing accurate, reliable characterization of murine lung microbiota and distinguishing true microbial signal from noise in these samples will be critical for further mechanistic microbiome studies in mice. Results Using an analytic approach grounded in microbial ecology, we compared bacterial DNA from the lungs of healthy adult mice collected via two common sampling approaches: homogenized whole lung tissue and bronchoalveolar lavage (BAL) fluid. We quantified bacterial DNA using droplet digital PCR, characterized bacterial communities using 16S rRNA gene sequencing, and systematically assessed the quantity and identity of bacterial DNA in both specimen types. We compared bacteria detected in lung specimens to each other and to potential source communities: negative (background) control specimens and paired oral samples. By all measures, whole lung tissue in mice contained greater bacterial signal and less evidence of contamination than did BAL fluid. Relative to BAL fluid, whole lung tissue exhibited a greater quantity of bacterial DNA, distinct community composition, decreased sample-to-sample variation, and greater biological plausibility when compared to potential source communities. In contrast, bacteria detected in BAL fluid were minimally different from those of procedural, reagent, and sequencing controls. Conclusions An ecology-based analytical approach discriminates signal from noise in this low-biomass microbiome study and identifies whole lung tissue as the preferred specimen type for murine lung microbiome studies. Sequencing, analysis, and reporting of potential source communities, including negative control specimens and contiguous biological sites, are crucial for biological interpretation of low-biomass microbiome studies, independent of specimen type. Video abstract

Abstract Database queries are one of the most important functions of a relational database. Users are interested in viewing a variety of data representations, and this may vary based on database purpose and the nature of the stored data. The Air Force Institute of Technology has approximately 100 data logs which will be converted to the standardized Scorpion Data Model format. A relational database is designed to house this data and its associated sensor and non-sensor metadata. Deterministic polynomial-time queries were used to test the performance of this schema against two other schemas, with databases of 100 and 1000 logs of repeated data and randomized metadata. Of these approaches, the one that had the best performance was chosen as AFIT’s database solution, and now more complex and useful queries need to be developed to enable filter research. To this end, consider the combined Multi-Objective Knapsack/Set Covering Database Query. Algorithms which address The Set Covering Problem or Knapsack Problem could be used individually to achieve useful results, but together they could offer additional power to a potential user. This paper explores the NP-Hard problem domain of the Multi-Objective KP/SCP, proposes Genetic and Hill Climber algorithms, implements these algorithms using Java, populates their data structures using SQL queries from two test databases, and finally compares how these algorithms perform.

The iRGD tumor-penetrating peptide can achieve tumor specific drug delivery but whether and how it can penetrate into desmoplastic tumors is unknown. Here, the authors show that β5 integrin expression on tumor cells, mediated by CAFs-derived TGF-β, is required for iRGD penetration into the desmoplastic PDAC microenvironment and that iRGD-based combination therapy is effective in PDAC mouse models.

Abstract Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25–75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

In many scenarios where robots or autonomous systems may be deployed, the capacity to infer and reason about the intentions of other agents can improve the performance or utility of the system. For example, a smart home or assisted living facility is better able to select assistive services to deploy if it understands the goals of the occupants in advance. In this article, we present a framework for reasoning about intentions using probabilistic logic programming. We employ ProbLog, a probabilistic extension to Prolog, to infer the most probable intention given observations of the actions of the agent and sensor readings of important aspects of the environment. We evaluated our model on a domain modeling a smart home. The model achieved 0.75 accuracy at full observability. The model was robust to reduced observability.

Objective The telemedicine industry has rapidly grown during the COVID-19 pandemic, and telemedicine has become a common form of care. The present study looks at the online conversation regarding telemedicine at the beginning of the pandemic and one year later. The Technology Acceptance Model is utilized to explain the findings. Methods Brandwatch and NUVI software captured social mentions on Twitter regarding telemedicine during the beginning of the pandemic (March 15, 2020–April 20, 2020) and one year later (March 12, 2021–April 19, 2021). SAS text-mining software analyzed the social mentions and organized them into ten unique topics for each time period. The research team analyzed the topics and organized them into themes. A network analysis was also performed to examine structure and influence within the network. Results In March–April 2020, the themes focused on the use of telehealth in general, telehealth for mental health applications, and Medicare covering telehealth services. In March–April 2021, the themes focused on news events regarding telehealth and the rise in prominence of telehealth services. The network analysis shows a shift in the distribution of telehealth information among influential accounts and reveals that the network became more connected, with a change in the control of information spread. Conclusions Technology Acceptance Model explains the social acceptance and spread of telemedicine. The transition in the conversation about telemedicine suggests a pattern of greater system use consistent with the Technology Acceptance Model. Telemedicine may have greatly increased in use because of the pandemic, but data suggests that its use may persist after the pandemic subsides.

Several environmental factors can influence the development and establishment of the early-life microbiota. For example, exposure to different environmental factors from birth to childhood will shape the lung and gut microbiota and the development of the immune system, which will impact respiratory tract infection and widespread disease occurrence during infancy and later in life. Respiratory syncytial virus (RSV) infects most infants by the age of two and is the primary cause of bronchiolitis in children worldwide. Approximately a third of infants hospitalized with bronchiolitis develop asthma later in life. However, it is unclear what factors increase susceptibility to severe RSV-bronchiolitis and the subsequent asthma development. In recent years, the role of the gut and lung microbiota in airway diseases has received increased interest, and more studies have focused on this field. Different epidemiological studies and experimental animal models have associated early-life gut microbiota dysbiosis with an increased risk of lung disease later in life. This work will review published evidence that correlated environmental factors that affect the early-life microbiota composition and their role in developing severe RSV infection.