A global metagenomic map of urban microbiomes and antimicrobial resistance.

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

Tracking of marine predators to protect Southern Ocean ecosystems.

Southern Ocean ecosystems are under pressure from resource exploitation and climate change1,2. Mitigation requires the identification and protection of Areas of Ecological Significance (AESs), which have so far not been determined at the ocean-basin scale. Here, using assemblage-level tracking of marine predators, we identify AESs for this globally important region and assess current threats and protection levels. Integration of more than 4,000 tracks from 17 bird and mammal species reveals AESs around sub-Antarctic islands in the Atlantic and Indian Oceans and over the Antarctic continental shelf. Fishing pressure is disproportionately concentrated inside AESs, and climate change over the next century is predicted to impose pressure on these areas, particularly around the Antarctic continent. At present, 7.1% of the ocean south of 40°S is under formal protection, including 29% of the total AESs. The establishment and regular revision of networks of protection that encompass AESs are needed to provide long-term mitigation of growing pressures on Southern Ocean ecosystems.

Kismet/CHD7/CHD8 affects gut microbiota, mechanics, and the gut-brain axis in Drosophila melanogaster.

The gut microbiome affects brain and neuronal development and may contribute to the pathophysiology of neurodevelopmental disorders. However, it is unclear how risk genes associated with such disorders affect gut physiology in a manner that could impact microbial colonization and how the mechanical properties of the gut tissue might play a role in gut-brain bidirectional communication. To address this, we used Drosophila melanogaster with a null mutation in the gene kismet, an ortholog of chromodomain helicase DNA-binding protein (CHD) family members CHD7 and CHD8. In humans, these are risk genes for neurodevelopmental disorders with co-occurring gastrointestinal symptoms. We found that kismet mutant flies have a significant increase in gastrointestinal transit time, indicating the functional homology of kismet with CHD7/CHD8 in vertebrates. Rheological characterization of dissected gut tissue revealed significant changes in the mechanics of kismet mutant gut elasticity, strain stiffening behavior, and tensile strength. Using 16S rRNA metagenomic sequencing, we also found that kismet mutants have reduced diversity and abundance of gut microbiota at every taxonomic level. To investigate the connection between the gut microbiome and behavior, we depleted gut microbiota in kismet mutant and control flies and quantified the flies' courtship behavior. Depletion of gut microbiota rescued courtship defects of kismet mutant flies, indicating a connection between gut microbiota and behavior. In striking contrast, depletion of the gut microbiome in the control strain reduced courtship activity, demonstrating that antibiotic treatment can have differential impacts on behavior and may depend on the status of microbial dysbiosis in the gut prior to depletion. We propose that Kismet influences multiple gastrointestinal phenotypes that contribute to the gut-microbiome-brain axis to influence behavior. We also suggest that gut tissue mechanics should be considered as an element in the gut-brain communication loop, both influenced by and potentially influencing the gut microbiome and neurodevelopment.

Dose Range-Finding Toxicity Study in Rats With Recombinant Human Lactoferrin Produced in Komagataella phaffii.

The oral toxicity of recombinant human lactoferrin (rhLF, Helaina rhLF, Effera™) produced in Komagataella phaffii was investigated in adult Sprague Dawley rats by once daily oral gavage for 14 consecutive days. The study used groups of 3-6 rats/sex/dose. The vehicle control group received sodium citrate buffer, and the test groups received daily doses of 200, 1000, and 2000 mg of rhLF in sodium citrate buffer per kg body weight. Bovine LF at 2000 mg/kg body weight per day was used as a comparative control. Clinical observations, body weight, hematology, clinical chemistry, iron parameters, immunophenotyping, and gross examination at necropsy were used as criteria for detecting the effects of treatment in all groups and to help select dose levels for future toxicology studies. Quantitative LF levels were also analyzed as an indication of bioavailability. Overall, administration of Helaina rhLF by once daily oral gavage for 14 days was well tolerated in rats at levels up to 2000 mg/kg/day, or 57 × Helaina's intended commercial use in adults, and indicating that a high dose of 2000 mg/kg/day is appropriate for future definitive toxicology studies.

Beta adrenergic receptor antagonist can modify Pseudomonas aeruginosa biofilm formation in vitro: Implications for chronic wounds.

Non-healing wounds are a major medical challenge, affecting over 6.5 million people in the US alone, with associated healthcare costs of about $16 billion annually. They can result in prolonged hospitalizations, work loss, disability, poor quality of life, and in diabetic patients with foot ulcers, amputation of the affected limb in 25% of patients. Though chronic ulcers may arise from different underlying diseases, the unifying feature is chronic infection, driving persistent inflammation that prolongs the healing process. One of the most frequently cultured or genetically identified pathogens in skin wounds is Pseudomonas aeruginosa. This species avidly forms biofilms in the wound that impede bacterial eradication by the host's immune mechanisms and limit efficacy of systemic antibiotics. Thus, non-antibiotic approaches to limit the growth and biofilm formation of this wound pathogen would be an advance in the treatment of chronic wounds. Prior work has demonstrated that the growth of other microbial species can be modulated by catecholamine agonists and antagonists of the adrenergic receptors (ARs). Here, we demonstrate that not only can the growth of this common wound pathogen be modulated by catecholamines, but also that the beta-AR antagonists can significantly decrease their growth, and importantly, limit their ability to form biofilms. These findings suggest that beta adrenergic antagonists may have a therapeutic role in the treatment of chronic skin wounds.

Influence of baseline kidney dysfunction on perioperative renal outcomes after endovascular aneurysm repair with suprarenal fixation.

BACKGROUND: Conflicting evidence exists regarding the comparative effects of endovascular aneurysm repair (EVAR) with and without suprarenal fixation. We compare outcomes in patients treated by EVAR with baseline normal kidney function and moderate and severe chronic kidney disease. METHODS: Patients with normal kidney function (glomerular filtration rate [GFR] ≥60 mL/min/1.73 m2) or moderate (GFR = 30-59 mL/min/1.73 m2) or severe (GFR <30 mL/min/1.73 m2) kidney disease who underwent EVAR (N = 5534) were identified from the American College of Surgeons National Surgical Quality Improvement Program targeted database (2011-2015). Groups were determined by the presence (Cook Zenith [Cook Medical, Bloomington, Ind] or Medtronic Endurant [Medtronic, Minneapolis, Minn]) or absence (Gore Excluder [W. L. Gore & Associates, Flagstaff, Ariz]) of a suprarenal fixation system. Postoperative renal complications, defined as rise in creatinine concentration of >2 mg/dL without dialysis or new dialysis requirements, were analyzed within the first 30 days with results stratified by degree of kidney disease. RESULTS: A total of 5534 patients underwent EVAR, with 3225 (58.3%) receiving a device using a suprarenal fixation system. Suprarenal fixation systems were less commonly used for symptomatic patients (11.0% vs 13.7%; P = .002) and patients with ruptured abdominal aortic aneurysm (4.5% vs 6.3%; P = .01). There was no difference in baseline kidney function between groups. EVAR with suprarenal fixation was associated with more renal complications (1.40% vs 0.65%; P = .008). In subgroup analysis, patients with moderate kidney dysfunction (n = 1780) had more renal complications (2.2% vs 0.8%; P = .02) with suprarenal fixation systems. No differences were seen in patients with normal kidney function (0.4% vs 0.2%; P = .32; n = 3597) or severe kidney dysfunction (14.3% vs 10.2%; P = .45; n = 157). This difference was driven mostly by postoperative elevation of creatinine concentration (0.6% vs 0.2%; P = .03) without requirements for new dialysis (0.8% vs 0.4%; P = .08). After adjustments with multivariate logistic regression models, EVAR with suprarenal fixation was associated with more renal complications (odds ratio, 2.65; 95% confidence interval, 1.32-5.34). CONCLUSIONS: In our study, EVAR with suprarenal fixation devices was associated with more perioperative renal complications in patients with moderate kidney dysfunction. Long-term evaluation of these patients undergoing EVAR should be considered.

SLAMF7 Is a Critical Negative Regulator of IFN-α-Mediated CXCL10 Production in Chronic HIV Infection.

Current advances in combined antiretroviral therapy have rendered HIV infection a chronic, manageable disease; however, the problem of persistent immune activation still remains despite treatment. The immune cell receptor SLAMF7 has been shown to be upregulated in diseases characterized by chronic immune activation. In this study, we studied the function of the SLAMF7 receptor in immune cells of HIV patients and the impacts of SLAMF7 signaling on peripheral immune activation. We observed increased frequencies of SLAMF7+ PBMCs in HIV+ individuals in a clinical phenotype-dependent manner, with discordant and long-term nonprogressor patients showing elevated SLAMF7 levels, and elite controllers showing levels comparable to healthy controls. We also noted that SLAMF7 was sensitive to IFN-⍺ stimulation, a factor elevated during HIV infection. Further studies revealed SLAMF7 to be a potent inhibitor of the monocyte-derived proinflammatory chemokine CXCL10 (IP-10) and other CXCR3 ligands, except in a subset of HIV+ patients termed SLAMF7 silent (SF7S). Studies utilizing small molecule inhibitors revealed that the mechanism of CXCL10 inhibition is independent of known SLAMF7 binding partners. Furthermore, we determined that SLAMF7 activation on monocytes is able to decrease their susceptibility to HIV-1 infection in vitro via downregulation of CCR5 and upregulation of the CCL3L1 chemokine. Finally, we discovered that neutrophils do not express SLAMF7, are CXCL10+ at baseline, are able to secrete CXCL10 in response to IFN-⍺ and LPS, and are nonresponsive to SLAMF7 signaling. These findings implicate the SLAMF7 receptor as an important regulator of IFN-⍺-driven innate immune responses during HIV infection.

Economic burden and clinical impact of preoperative opioid dependence for patients undergoing lower extremity bypass surgery.

OBJECTIVE: Surgeons' prescription practices and the opioid epidemic have received significant attention in the media. Limited data exist, however, on the impact of prior or coexistent opioid use on vascular surgery outcomes. This study aimed to quantify the incidence, economic burden, and clinical impact of pre-existing opioid dependency in patients undergoing lower extremity bypass (LEB) surgery. METHODS: Data were collected from 1,132,645 weighted (230,858 unweighted) patient admissions for LEB in the National Inpatient Sample for the years 2002 to 2015. Patients with a concomitant diagnosis of opioid abuse or dependency were identified using International Classification of Diseases, Ninth Revision codes. Matched cohorts of patients with (n = 606 unweighted) and without (n = 32,343 unweighted) opioid dependence were created using coarsened exact matching to control for patient demographics. Linear regression was used to control for hospital-level factors and to identify differential outcomes for patients with opioid dependency. Our primary end points were hospital cost and length of stay. Our secondary end points were surgical complications and in-hospital mortality. RESULTS: There were 1,132,645 (230,858 unweighted) patient admissions for LEB in the National Inpatient Sample during 2002 to 2015. There were 3190 (0.3%) patients (643 unweighted) who had a diagnosis of pre-existing opioid dependency. The incidence of opioid dependency rose over time (2002, 0.13%; 2015, 0.63%; R2 = 0.90; P < .001). Before matching, opioid-dependent patients were younger (53.9 ± 12.3 years vs 66.7 ± 12.1 years; P < .001) and more likely to be male (65.2% vs 61.9%; P < .001), to be nonwhite (37.9% vs 24.1%; P < .001), to pay with Medicaid (29.6% vs 7.4%; P < .001), and to fall in the lowest income quartile based on ZIP code (39.6% vs 27.5%; P < .001). After matching, opioid-dependent patients (n = 606 unweighted vs n = 32,343 unweighted nonopioid-dependent patients) were at increased risk of surgical site infections (odds ratio [OR], 1.61; P = .006), major bleeding (OR, 1.56; P = .04), acute kidney injury (OR, 1.46; P = .02), and deep venous thrombosis (OR, 2.53; P = .005). Linear regression of matched cohorts revealed that opioid-dependent patients had an increased length of hospital stay (11.76 days vs 9.80 days; P < .001) and an increased mean inflation-adjusted in-hospital cost of U.S. $7032 ($37,522 vs $30,490; P < .001). CONCLUSIONS: The incidence of pre-existing opioid dependency in patients undergoing LEB continues to rise. Patients with opioid use disorder undergoing LEB surgery have substantial increases in length of hospital stay and costs. These findings highlight the importance of early preoperative recognition of this disorder in vascular surgery patients and open the opportunity for early intervention in that cohort.

Δ9-Tetrahydrocannabinol Suppresses Monocyte-Mediated Astrocyte Production of Monocyte Chemoattractant Protein 1 and Interleukin-6 in a Toll-Like Receptor 7-Stimulated Human Coculture.

Cannabis is widely used in the United States, with an estimated prevalence of 9.5%. Certain cannabinoids in Cannabis sativa, Δ9-tetrahydrocannabinol (THC) in particular, possess immune-modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial (e.g., in treating inflammatory diseases) or detrimental to normal immune defense against pathogens. The potential beneficial effect of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., human immunodeficiency virus-associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human coculture system, monocyte-derived interleukin (IL)-1ß due to Toll-like receptor 7 (TLR7) activation has been identified to promote astrocyte production of monocyte chemoattractant protein (MCP)-1 and IL-6. THC treatment of the TLR7-stimulated coculture suppressed monocyte secretion of IL-1ß, resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1ß production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1ß production similar to that of THC, suggesting that THC acts, in part, through CB2. THC also suppressed key elements of the IL-1ß production pathway, including IL1B mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1ß through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6. SIGNIFICANCE STATEMENT: Because cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human coculture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ9-tetrahydrocannabinol, and a cannabinoid receptor-2 selective agonist suppress specific monocyte-mediated astrocyte inflammatory responses.

Translational regulation in response to stress in Saccharomyces cerevisiae.

The budding yeast Saccharomyces cerevisiae must dynamically alter the composition of its proteome in order to respond to diverse stresses. The reprogramming of gene expression during stress typically involves initial global repression of protein synthesis, accompanied by the activation of stress-responsive mRNAs through both translational and transcriptional responses. The ability of specific mRNAs to counter the global translational repression is therefore crucial to the overall response to stress. Here we summarize the major repressive mechanisms and discuss mechanisms of translational activation in response to different stresses in S. cerevisiae. Taken together, a wide range of studies indicate that multiple elements act in concert to bring about appropriate translational responses. These include regulatory elements within mRNAs, altered mRNA interactions with RNA-binding proteins and the specialization of ribosomes that each contribute towards regulating protein expression to suit the changing environmental conditions.

Suppression of CpG-ODN-mediated IFNα and TNFα response in human plasmacytoid dendritic cells (pDC) by cannabinoid receptor 2 (CB2)-specific agonists.

Plasmacytoid dendritic cells (pDC) compose 0.2-0.5% of circulating leukocytes but play a significant role in mounting host immune responses. Elevated and chronic activation of pDC are implicated in autoimmune disease like systemic lupus erythematosus and rheumatoid arthritis. Δ9-tetrahydrocannabinol (THC) is a well characterized cannabinoid with potent anti-inflammatory activity, but acceptance of THC as a treatment for autoimmune disorders has been hindered due to psychotropic activity. The psychotropic effects of THC are mediated through cannabinoid receptor 1 (CB1) expressed in the central nervous system while the immunomodulatory effects of THC result from THC binding to CB1 and CB2 on immune cells. Synthetic CB2-selective agonists have been developed to explore immune modulation by cannabinoids in the absence of psychotropic effects. The goal of these studies was to determine if the CB2-selective agonists, JWH-015 and JWH-133, have comparable efficacy to THC in modulating IFNα and TNFα responses by primary human pDC. Treatment with JWH-133 and JWH-015 inhibited CpG-induced IFNα and TNFα responses by pDC. Further, the phosphorylation of IRF7, TBK1, NFκB, and IKKγ, key events in pDC activation, were suppressed by THC, JWH-133, and JWH-015. Likewise, the phosphorylation of AKT at the S473 and T308 residues were differentially modulated by treatment with THC and both JWH compounds. Collectively, these results demonstrate the potential for CB2 targeted therapeutics for treatment of inflammatory conditions involving aberrant pDC activity.

Unenhanced Velocity-Selective MR Angiography (VS-MRA): Initial Clinical Evaluation in Patients With Peripheral Artery Disease.

BACKGROUND: Safe and accurate imaging of the peripheral arterial system is important for diagnosis and treatment planning of patients with peripheral artery disease (PAD). PURPOSE: To evaluate image quality and diagnostic performance of unenhanced magnetic resonance angiography (MRA) based on velocity-selective (VS) magnetization preparation (termed VS-MRA). STUDY TYPE: Prospective. POPULATION: Thirty-one symptomatic PAD patients underwent VS-MRA. Twenty-four of them underwent clinical digital subtraction angiography (DSA) examination, 18.8 ± 5.2 days after the MR scans. FIELD STRENGTH/SEQUENCE: 1.5T MRI that included VS-MRA (homemade research sequence) and phase-contrast flow imaging (clinical sequence). ASSESSMENT: Image quality (0: nondiagnostic, 3: excellent) and stenosis severity (0: normal, 3: occlusion) of VS-MRA images were assessed independently by three reviewers. Arterial signal-to-noise-ratio (SNR) and artery-to-muscle contrast-to-noise ratio (CNR) were calculated. STATISTICAL TESTS: The sensitivity and specificity of VS-MRA were calculated for the detection of significant stenosis (>50%) with DSA as the reference standard. Interobserver agreement among the three reviewers was evaluated by using Cohen κ-statistics. RESULTS: The image quality score of VS-MRA was 2.7 ± 0.5 for Reader 1, 2.8 ± 0.5 for Reader 2, and 2.8 ± 0.4 for Reader 3; SNR and CNR were 37.8 ± 12.5 and 30.5 ± 11.8, respectively. Segment-based analysis revealed that VS-MRA had sensitivities of 85.3%, 74.5%, and 78.4%, respectively, for the three reviewers, and specificities of 93.5%, 96.8%, and 95.2%. The interobserver agreement for the stenosis grading was good, as demonstrated by Cohen κ values of 0.76 (Reader 1 vs. Reader 2), 0.82 (Reader 1 vs. Reader 3), and 0.79 (Reader 2 vs. Reader 3). DATA CONCLUSION: Unenhanced VS-MRA allows clear depiction of the peripheral arteries and accurate stenosis grading, as evidenced by high image quality scores and strong agreement with DSA. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:744-751.

A tractable, simplified ex vivo human skin model of wound infection.

The prevalence of infection in chronic wounds is well documented in the literature but not optimally studied due to the drawbacks of current methodologies. Here, we describe a tractable and simplified ex vivo human skin model of infection that addresses the critical drawbacks of high costs and limited translatability. Wounds were generated from excised abdominal skin from cosmetic procedures and cultured, inoculated with Staphylococcus aureus strain UAMS-1, or under aseptic conditions. After three days, the infected wounds exhibited biofilm formation and significantly impaired reepithelialization compared to the control. Additionally, promigratory and proreparative genes were significantly downregulated, while proinflammatory genes were significantly upregulated, demonstrating molecular characterizations of impaired healing as in chronic wounds. This model allows for a simplified and versatile tool for the study of wound infection and subsequent development of novel therapies.

Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34+ hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed 2,3,7,8-tetrachlorodibenzo-p-dioxin-elicited suppression of early B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism.

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Not Yet Applicable for Widespread Out-of-Hospital Use: A Case of Nonsurvivable Complication from Prolonged REBOA Inflation.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is being considered for temporizing catastrophic hemorrhage before arriving at a specialty center for definitive surgical management. CASE: We describe the clinical case of a 72-year-old male with a ruptured infrarenal aortic abdominal aneurysm initially stabilized with REBOA at an outside facility and transferred to our care. Transport time was >100 minutes. Despite successful surgical repair of the ruptured aneurysm, the patient expired from multiple-organ failure likely related to ischemia-reperfusion injuries from prolonged balloon occlusion of the aorta. CONCLUSIONS: Ischemia-mitigating techniques and therapies need to improve drastically before the clinical application of REBOA can be effectively extended to outside the vicinity of specialty centers.

Motorized scooter injuries in the era of scooter-shares: A review of the national electronic surveillance system.

INTRODUCTION: There has been a spike in recent news regarding motorized scooter injuries due to the expansion of scooter sharing companies. Given the paucity of literature on this topic, the purpose of our study was to describe and quantify emergency department encounters associated with motorized scooter related injuries. METHODS: The National Electronic Injury Surveillance System (NEISS) was queried for motorized scooter related injuries from 2013 to 2017. Patient demographics, diagnosis, injury location, narrative description of incident, and disposition data were collected from emergency department encounters. RESULTS: There were an estimated 32,400 motorized scooter injuries from 2013 to 2017. The estimated incidence did not change significantly over time with 1.9 cases per 100,000 in 2013 and 2.6 cases per 100,000 in 2017. A 77.0% increase in scooter injuries was noted for millennials from 2016 to 2017. Head injuries were the most common body area injured (27.6%). Fractures or dislocations (25.9%) were the most common diagnosis. The most common site of fracture was the wrist and lower arm (35.4%). There were no deaths. Major orthopaedic injury and concussion were the strongest independent predictors of hospital admission. CONCLUSIONS: Head injuries were the most commonly injured body part, while fractures or dislocations were the most common diagnosis. These results highlight the importance of using protective equipment while riding motorized scooters, and lay a foundation for future policies requiring helmet use.

Interferon-α-Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by Δ9-Tetrahydrocannabinol.

Patients with HIV routinely use medicinal cannabinoids to treat neuropathic pain, anxiety, and human immunodeficiency virus (HIV)-associated wasting. However, Δ9-tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in cannabis, suppresses T-cell function and secretion of interferons, both critically important in the antiviral immune response. Interferon-α (IFNα), a key cytokine in T-cell activation and peripheral control of HIV infection, can potentiate responsiveness to interleukin-7 (IL-7), a crucial homeostatic cytokine for peripheral T-cell maintenance. The objective of this investigation was to compare the response of T cells to stimulation by IFNα and IL-7 in T cells from healthy and HIV+ donors in the absence and presence of THC. To compare T-cell responses between healthy and HIV+ donors signaling through IFNα receptor, IFNα-induced expression of IL-7α receptor (IL-7Rα), cognate signaling through IL-7R, and on IL-7-mediated T-cell proliferation were measured by flow cytometry and real-time quantitative polymerase chain reaction. CD8+ T cells from HIV+ donors showed a diminished response to IFNα-induced phosphorylated signal transducer and activator of transcription-1 activation compared with CD8+ T cells from healthy donors, whereas CD4+ T cells from HIV+ donors and healthy donors were comparable. Treatment with IFNα promoted IL-7R expression and potentiated IL-7-induced STAT5 phosphorylation to augment IL-7-mediated proliferation by T cells from healthy and HIV+ donors. Finally, HIV+ donors exhibited reduced sensitivity to THC-mediated suppression by IFNα- and IL-7-mediated stimulation compared with healthy donors. These results further support THC as being immune suppressive while identifying putatively beneficial aspects of cannabinoid-based therapies in HIV+ patients.

Bayesian inference reveals positive but subtle effects of experimental fishery closures on marine predator demographics.

Global forage-fish landings are increasing, with potentially grave consequences for marine ecosystems. Predators of forage fish may be influenced by this harvest, but the nature of these effects is contentious. Experimental fishery manipulations offer the best solution to quantify population-level impacts, but are rare. We used Bayesian inference to examine changes in chick survival, body condition and population growth rate of endangered African penguins Spheniscus demersus in response to 8 years of alternating time-area closures around two pairs of colonies. Our results demonstrate that fishing closures improved chick survival and condition, after controlling for changing prey availability. However, this effect was inconsistent across sites and years, highlighting the difficultly of assessing management interventions in marine ecosystems. Nevertheless, modelled increases in population growth rates exceeded 1% at one colony; i.e. the threshold considered biologically meaningful by fisheries management in South Africa. Fishing closures evidently can improve the population trend of a forage-fish-dependent predator-we therefore recommend they continue in South Africa and support their application elsewhere. However, detecting demographic gains for mobile marine predators from small no-take zones requires experimental time frames and scales that will often exceed those desired by decision makers.

Characterizing Serpinb2 as a Modulator of TCDD-Induced Suppression of the B Cell.

2,3,7,8-Tetrachlordibenzo- p-dioxin (TCDD) is an environmental pollutant that can cause various toxic effects, including chloracne, metabolic syndrome, and immune suppression. Most of the toxicity associated with TCDD is mediated through activation of the aryl hydrocarbon receptor (AHR). Recent research has suggested the presence of a wide-range of interindividual variability in TCDD-mediated suppression of the Immunoglobulin-M (IgM) response across the human population. In an attempt to identify putative modifiers of AHR-mediated immunosuppression beyond the AHR, B cells were isolated from a panel of genetically diverse mouse strain to scan for modulators that drive interstrain differences in TCDD-mediated suppression of the IgM response. Results implicated a region of mouse Chromosome 1 near a gene encoding serine peptidase inhibitor, clade B, member 2 ( Serpinb2) whose human ortholog is plasminogen activator inhibitor 2 (PAI2). Further downstream analyses indicated that Serpinb2 is dysregulated by TCDD and, furthermore, that B cells from Serpinb2 -/- mice are significantly more sensitive to TCDD-mediated suppression as compared to littermate controls. This study suggests a protective role of Serpinb2 within TCDD-mediated immunosuppression and, furthermore, a novel function of Serpinb2-related activity in the IgM response.

Continuous Flow Perfused Cadaver Model for Endovascular Training, Research, and Development.

BACKGROUND: Endovascular simulation employing computer, animal, and static models are common and useful adjuncts for teaching endovascular procedures and developing novel, complex endovascular techniques. Unfortunately, these models lack realistic haptic feedback and thus do not faithfully replicate many of the technical challenges associated with clinical endovascular procedures (e.g., arterial calcification, rigidity, and stenosis). We sought to develop a realistic and reproducible perfused cadaver model for endovascular training, device development, and research. METHODS: Fresh frozen, elderly (age 50-80 years) male cadavers were thawed and prepared for open dissection. The entire arterial tree (ascending aorta to femoral arteries) was dissected free and major branch vessels exposed. Sheaths were placed to allow outflow from selected vessels. A Dacron conduit was sewn to the ascending aorta to generate arterial inflow, which was provided by a centrifugal pump. Aortic aneurysms were created in the descending thoracic and abdominal aorta. Digital subtraction arteriography and various endovascular interventions were performed, including stent grafts and EndoAnchors deployment. RESULTS: Continuous antegrade flow was achieved in the thoracic, abdominal, iliac, and femoral segments. Open and percutaneous access at the femoral region was obtained with realistic back-bleeding and tactile feedback. Adequate, fluoroscopically documented flow was observed in both cannulated major and noncannulated smaller branches. We performed angiography with standard techniques via a pigtail catheter and contrast injector throughout the arterial system. Abdominal and thoracic endografts were deployed with appropriate angiographic guidance and realistic haptic feedback for both guidewire and stent grafts. Additional applications, including selective cannulation, aorto-iliac occlusive disease interventions, and anchor placement, were also successfully simulated. Finally, the model was used as a platform to test investigational devices. CONCLUSIONS: Our pressurized cadaver flow model successfully replicated multiple aspects of advanced endovascular procedures with haptic feedback. This novel human cadaver model allows for training and device development under clinically realistic conditions.