Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Single-cell RNA sequencing reveals Immune Education promotes T cell survival in mice subjected to the cecal ligation and puncture sepsis model.

Background: Individual T cell responses vary significantly based on the microenvironment present at the time of immune response and on prior induced T cell memory. While the cecal ligation and puncture (CLP) model is the most commonly used murine sepsis model, the contribution of diverse T cell responses has not been explored. We defined T cell subset responses to CLP using single-cell RNA sequencing and examined the effects of prior induced T cell memory (Immune Education) on these responses. We hypothesized that Immune Education prior to CLP would alter T cell responses at the single cell level at a single, early post-CLP time point. Methods: Splenic T cells were isolated from C57BL/6 mice. Four cohorts were studied: Control, Immune-Educated, CLP, and Immune-Educated CLP. At age 8 weeks, Immune-Educated and Immune-Educated CLP mice received anti-CD3ϵ antibody; Control and CLP mice were administered an isotype control. CLP (two punctures with a 22-gauge needle) was performed at 12-13 weeks of life. Mice were sacrificed at baseline or 24-hours post-CLP. Unsupervised clustering of the transcriptome library identified six distinct T cell subsets: quiescent naïve CD4+, primed naïve CD4+, memory CD4+, naïve CD8+, activated CD8+, and CD8+ cytotoxic T cell subsets. T cell subset specific gene set enrichment analysis and Hurdle analysis for differentially expressed genes (DEGs) were performed. Results: T cell responses to CLP were not uniform - subsets of activated and suppressed T cells were identified. Immune Education augmented specific T cell subsets and led to genomic signatures favoring T cell survival in unoperated and CLP mice. Additionally, the combination of Immune Education and CLP effected the expression of genes related to T cell activity in ways that differed from CLP alone. Validating our finding that IL7R pathway markers were upregulated in Immune-Educated CLP mice, we found that Immune Education increased T cell surface IL7R expression in post-CLP mice. Conclusion: Immune Education enhanced the expression of genes associated with T cell survival in unoperated and CLP mice. Induction of memory T cell compartments via Immune Education combined with CLP may increase the model's concordance to human sepsis.

Polychlorinated dibenzodioxins/furans and dioxin-like polychlorinated biphenyls in fish and crustaceans of a recreationally fished estuary, following targeted remediation.

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) are a suite of harmful chemicals (hereafter collectively referred to as 'dioxins'), and their emission into aquatic habitats leads to persistent contamination of sediments, aquatic food-webs, and seafoods. Quantifying contaminant levels in seafood species is important for the ongoing management of exposure risk by fishers, particularly after any remediation actions. We present dioxin concentrations in four seafood species (Yellowfin Bream Acanthopagrus australis, Sea Mullet Mugil cephalus, Eastern School Prawn Metapenaeus macleayi, and Eastern King Prawn Penaeus plebejus) in a recreationally fished estuary, in relation to a contaminated site that has undergone a remediation process, partially removing contaminated sediments (Homebush Bay, Port Jackson, New South Wales, Australia). Dioxin concentrations in these species were measured before (2005/6) and after (2015/16) remediation at a range of locations in and around the remediated site. Dioxin concentrations and congener profiles differed substantially among taxa, and concentrations were frequently higher than Australian screening criteria. The two prawn species showed evidence of a decline in dioxin concentrations after remediation, but the fish species only showed a declining dioxin concentration with distance from the contaminated site (not between periods). There were some minor changes in the congener profile for some species following remediation. While there was evidence for greatly reduced dioxin concentrations in prawn species following remediation, the complex patterns for fish were likely affected by environmental changes, species-specific and temporal changes in lipid content, and animal movement patterns. Future monitoring may aid interpretation of the patterns and modelling of exposure risk associated with seafood consumption into the future.

M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture.

BACKGROUND: The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. METHODS: In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline. RESULTS: At 48 h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1ß, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα+ and ILß+ neutrophils and ILß+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1ß, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1ß+ neutrophils, IL-1ß+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline-treated and untreated post-CLP mice. CONCLUSION: Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.

Metal concentrations in the edible claw and body muscle of a popular recreational crab species (Scylla serrata).

In crabs, metal concentrations differ among tissues, but may also differ in edible white meat (muscle) in different parts of the body. This case study compared metal contaminants in the claw and body muscle for a popular crab species (Giant Mud Crab, Scylla serrata). For lead and nickel, body muscle concentrations were generally lower than claw concentrations, while the converse was true for arsenic, cadmium and mercury. When body and appendage meat proportions were used to weight body and claw metal concentrations the estimated concentration in total edible muscle closely reflected the claw muscle for zinc, but remained elevated relative to claw muscle (to varying degrees) for arsenic, cadmium and mercury. Linear models for these relationships allowed the total edible muscle concentration to be estimated from measured claw muscle concentrations. The relationships reported are useful for modelling exposure risk, and in crab ecotoxicology more broadly.

Perfluoroalkyl acid depuration from the edible tissues of a migratory recreationally fished species.

Environmental emissions of perfluoroalkyl acids (PFAAs) impact estuarine species and the fisheries that rely on them. Migratory estuarine fishes may be captured for consumption in areas distant to known contaminant sources, but exposure risk depends on how quickly contaminants are depurated. This baseline presents the outcomes from a novel experiment simulating the migration of a popular recreational fish species (Dusky Flathead, Platycephalus fuscus) following environmental exposure to PFAAs, and assessing depuration from edible muscle tissues. Over the 33-day experiment, perfluorooctane sulfonate (PFOS) concentrations declined slowly, with modelling suggesting that concentrations fell below the relevant screening value (5.2 µg kg-1) within ∼558 h (285-1372 h; 90 % CI). Low concentrations (<1.2 µg kg-1) of perfluorohexane sulfonate also depurated rapidly. This study provides useful information for assessing potential exposure risk posed by recreationally targeted fish migrating away from contaminated areas. The experimental design employed has a real-world context that is relevant for future studies.

M1 Cholinergic Signaling Modulates Cytokine Levels and Splenocyte Sub-Phenotypes Following Cecal Ligation and Puncture.

Background: The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1/M4 muscarinic acetylcholine (ACh) receptor (M1/M4AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1/M4AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. Methods: Basal forebrain cholinergic activity (immunostaining), serum cytokine/chemokine levels (ELISA) and splenocyte subtypes (flow cytometry) were examined at baseline and following CLP in male C57BL/6 male mice. Rersults: At 48hrs. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1ß, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFa+ and ILb+ neutrophils and ILb+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline, a central-acting M1AChR agonist, activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1ß, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. The effects of CLP on percentages of IL-1ß+ neutrophils, IL-1ß+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline - treated and untreated post-CLP mice. Conclusion: Our findings indicate that M1/M4AChR-mediated responses modulate CLP-induced alterations in the distribution of some, but not all, leukocyte phenotypes and certain cytokines and chemokines.

Phosphorylation of insulin receptor substrates (IRS-1 and IRS-2) is attenuated following cecal ligation and puncture in mice.

BACKGROUND: Sepsis is characterized as an insulin resistant state. However, the effects of sepsis on insulin's signal transduction pathway are unknown. The molecular activity driving insulin signaling is controlled by tyrosine phosphorylation of the insulin receptor ß-subunit (IRß) and of insulin receptor substrate molecules (IRS) -1 and IRS-2. HYPOTHESIS: Cecal ligation and puncture (CLP) attenuates IRß, IRS-1 and IRS-2 phosphorylation. METHODS: IACUC-approved studies conformed to ARRIVE guidelines. CLP was performed on C57BL/6 mice; separate cohorts received intraperitoneal insulin at baseline (T0) or at 23 or 47 h. post-CLP, 1 h before mice were euthanized. We measured levels of (1) glucose and insulin in serum, (2) IRß, IRS-1 and IRS-2 in skeletal muscle and liver homogenate and (3) phospho-Irß (pIRß) in liver and skeletal muscle, phospho-IRS-1 (pIRS-1) in skeletal muscle and pIRS-2 in liver. Statistical significance was determined using ANOVA with Sidak's post-hoc correction. RESULTS: CLP did not affect the concentrations of IRß, IRS-1or IRS-2 in muscle or liver homogenate or of IRS-1 in liver. Muscle IRS-1 concentration at 48 h. post-CLP was higher than at T0. Post-CLP pIRS-1 levels in muscle and pIRß and pIRS-2 levels in liver were indistinguishable from T0 levels. At 48 h. post-CLP pIRß levels in muscle were higher than at T0. Following insulin administration, the relative abundance of pIRß in muscle and liver at T0 and at both post-CLP time points was significantly higher than abundance in untreated controls. In T0 controls, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was higher than in untreated mice. However, at both post-CLP time points, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was not distinguishable from the abundance in untreated mice at the same time point. Serum glucose concentration was significantly lower than T0 at 24 h., but not 48 h., post-CLP. Glucose concentration was lower following insulin administration to T0 mice but not in post-CLP animals. Serum insulin levels were significantly higher than baseline at both post-CLP time points. CONCLUSIONS: CLP impaired insulin-induced tyrosine phosphorylation of both IRS-1 in muscle and IRS-2 in liver. These findings suggest that the molecular mechanism underlying CLP-induced insulin resistance involves impaired IRS-1/IRS-2 phosphorylation.

Crabs ride the tide: incoming tides promote foraging of Giant Mud Crab (Scylla serrata).

BACKGROUND: Effective fisheries management of mobile species relies on robust knowledge of animal behaviour and habitat-use. Indices of behaviour can be useful for interpreting catch-per-unit-effort data which acts as a proxy for relative abundance. Information about habitat-use can inform stocking release strategies or the design of marine protected areas. The Giant Mud Crab (Scylla serrata; Family: Portunidae) is a swimming estuarine crab that supports significant fisheries harvest throughout the Indo-West Pacific, but little is known about the fine-scale movement and behaviour of this species. METHODS: We tagged 18 adult Giant Mud Crab with accelerometer-equipped acoustic tags to track their fine-scale movement using a hyperbolic positioning system, alongside high temporal resolution environmental data (e.g., water temperature), in a temperate south-east Australian estuary. A hidden Markov model was used to classify movement (i.e., step length, turning angle) and acceleration data into discrete behaviours, while also considering the possibility of individual variation in behavioural dynamics. We then investigated the influence of environmental covariates on these behaviours based on previously published observations. RESULTS: We fitted a model with two well-distinguished behavioural states describing periods of inactivity and foraging, and found no evidence of individual variation in behavioural dynamics. Inactive periods were most common (79% of time), and foraging was most likely during low, incoming tides; while inactivity was more likely as the high tide receded. Model selection removed time (hour) of day and water temperature (°C) as covariates, suggesting that they do not influence Giant Mud Crab behavioural dynamics at the temporal scale investigated. CONCLUSIONS: Our study is the first to quantitatively link fine-scale movement and behaviour of Giant Mud Crab to environmental variation. Our results suggest Giant Mud Crab are a predominantly sessile species, and support their status as an opportunistic scavenger. We demonstrate a relationship between the tidal cycle and foraging that is likely to minimize predation risk while maximizing energetic efficiency. These results may explain why tidal covariates influence catch rates in swimming crabs, and provide a foundation for standardisation and interpretation of catch-per-unit-effort data-a commonly used metric in fisheries science.

Co-Selection of Bacterial Metal and Antibiotic Resistance in Soil Laboratory Microcosms.

Accumulation of heavy metals (HMs) in agricultural soil following the application of superphosphate fertilisers seems to induce resistance of soil bacteria to HMs and appears to co-select for resistance to antibiotics (Ab). This study aimed to investigate the selection of co-resistance of soil bacteria to HMs and Ab in uncontaminated soil incubated for 6 weeks at 25 °C in laboratory microcosms spiked with ranges of concentrations of cadmium (Cd), zinc (Zn) and mercury (Hg). Co-selection of HM and Ab resistance was assessed using plate culture on media with a range of HM and Ab concentrations, and pollution-induced community tolerance (PICT) assays. Bacterial diversity was profiled via terminal restriction fragment length polymorphism (TRFLP) assay and 16S rDNA sequencing of genomic DNA isolated from selected microcosms. Based on sequence data, the microbial communities exposed to HMs were found to differ significantly compared to control microcosms with no added HM across a range of taxonomic levels.

Scaling of Activity Space in Marine Organisms across Latitudinal Gradients.

AbstractUnifying models have shown that the amount of space used by animals (e.g., activity space, home range) scales allometrically with body mass for terrestrial taxa; however, such relationships are far less clear for marine species. We compiled movement data from 1,596 individuals across 79 taxa collected using a continental passive acoustic telemetry network of acoustic receivers to assess allometric scaling of activity space. We found that ectothermic marine taxa do exhibit allometric scaling for activity space, with an overall scaling exponent of 0.64. However, body mass alone explained only 35% of the variation, with the remaining variation best explained by trophic position for teleosts and latitude for sharks, rays, and marine reptiles. Taxon-specific allometric relationships highlighted weaker scaling exponents among teleost fish species (0.07) than sharks (0.96), rays (0.55), and marine reptiles (0.57). The allometric scaling relationship and scaling exponents for the marine taxonomic groups examined were lower than those reported from studies that had collated both marine and terrestrial species data derived using various tracking methods. We propose that these disparities arise because previous work integrated summarized data across many studies that used differing methods for collecting and quantifying activity space, introducing considerable uncertainty into slope estimates. Our findings highlight the benefit of using large-scale, coordinated animal biotelemetry networks to address cross-taxa evolutionary and ecological questions.

Outcomes after sublobar resection versus lobectomy in non-small cell carcinoma in situ.

OBJECTIVE: Guidelines for treatment of non-small cell lung cancer identify patients with tumors ≤2 cm and pure carcinoma in situ histology as candidates for sublobar resection. Although the merits of lobectomy, sublobar resection, and lymphoid (LN) sampling, have been investigated in early-stage non-small cell lung cancer, evaluation of these modalities in patients with IS disease can provide meaningful clinical information. This study aims to compare these operations and their relationship with regional LN sampling in this population. METHODS: The National Cancer Database was used to identify patients diagnosed with non-small cell lung cancer clinical Tis N0 M0 with a tumor size ≤2 cm from 2004 to 2017. The χ2 tests were used to examine subgroup differences by type of surgery. Kaplan-Meier method and Cox proportional hazard model were used to compare overall survival. RESULTS: Of 707 patients, 56.7% (401 out of 707) underwent sublobar resection and 43.3% (306 out of 707) underwent lobectomy. There was no difference in 5-year overall survival in the sublobar resection group (85.1%) compared with the lobectomy group (88.9%; P = .341). Multivariable survival analyses showed no difference in overall survival (hazard ratio, 1.044; P = .885) in the treatment groups. LN sampling was performed in 50.9% of patients treated with sublobar resection. In this group, LN sampling was not associated with improved survival (84.9% vs 85.0%; P = .741). CONCLUSIONS: We observed no difference in overall survival between sublobar resection and lobectomy in patients with cTis N0 M0 non-small cell lung cancer with tumors ≤2 cm. Sublobar resection may be an appropriate surgical option for this population. LN sampling was not associated with improved survival in patients treated with sublobar resection.

Esophagectomy vs Gastrectomy for Early Stage Adenocarcinoma of the Gastroesophageal Junction: What is the Optimal Oncologic Surgical Treatment?

Guidelines for the management of gastroesophageal junction (GEJ) adenocarcinoma recommend esophagectomy as the preferred surgical treatment. Gastrectomy has been proposed as an equivalent procedure. This study aims to compare the oncologic outcomes of these operations. The National Cancer Database was queried for patients with clinical T1N0M0 (all sizes) and T2N0M0 (≤2cm) GEJ adenocarcinoma from 2004-2017. Patients treated with surgery-only were included and were stratified by surgical treatment. Propensity-score matching (PSM) was used to create a balanced cohort. Multivariable logistic regression was performed to evaluate for factors predictive of treatment. Kaplan-Meier (KM) and Cox proportional hazards models were used to compare overall survival (OS). 2,446 patients were identified. 75.1% received esophagectomy, while 24.9% were treated with gastrectomy. Patients at high volume facilities were more likely to undergo esophagectomy (OR 1.750, P < 0.001). Factors associated with lower likelihood of undergoing esophagectomy included age ≥75 years (OR 0.588, P = 0.001), female sex (OR 0.706, P = 0.003), and non-White race (OR 0.430, P < 0.001), compared to age ≤50 years, male, and White race, respectively. In the unmatched cohort, gastrectomy was associated with a higher rate of positive margins (4.1% vs 2.3%, P = 0.022). PSM yielded 591 pairs. In the matched cohort, patients treated with esophagectomy had improved 5-year OS compared to gastrectomy (70.6% vs 66.5%, P = 0.030). Multivariable analysis showed improved OS in patients treated with esophagectomy compared to gastrectomy (HR 0.767, P = 0.010). Esophagectomy is associatedwith improved survival and a lower incidence of positive margins in patients with early-stage GEJ adenocarcinoma when compared to gastrectomy.

Procalcitonin Levels in Identifying Bacterial Infections in Children with and without COVID-19.

Objective: Elevated procalcitonin levels have been associated with bacterial infection in children. Observational studies reported high procalcitonin values in COVID-19. Data on bacterial coinfections in pediatric COVID-19 is sparse; small studies suggest a low coinfection rate. In this study, we aimed to quantify the positive predictive value (PPV) of procalcitonin in identifying bacterial infection in children with and without COVID-19. Materials and Methods: A retrospective chart review was performed for 215 children <21 years admitted to our tertiary children's hospital between February 1, 2013, and July 15, 2020, who had procalcitonin levels measured within 48 hours of admission. Confirmed bacterial infection was defined as positive blood, urine, or cerebrospinal fluid (CSF) culture, positive endotracheal culture with evidence of leukocytosis on Gram stain, or pneumonia by chest radiograph. Suspected bacterial infection was defined as confirmed bacterial infection or administration of antibiotics for >48 hours. Results: Of the 215 patients, 73 were admitted for COVID-19 (66% multisystem inflammatory syndrome in children [MIS-C], 34% acute COVID-19). The PPV of an elevated procalcitonin level >1.0 ng/mL in identifying suspected bacterial infections for those with MIS-C was 6.3% (95% CI=0-15), in acute COVID-19 was 29% (95% CI=0-62%), and in the non-COVID-19 cohort was 75% (95% CI=62-88%). For identification of confirmed bacterial infection, PPV of an elevated procalcitonin level was 0% in MIS-C, 14% (95% CI=0-40%) in acute COVID-19, and 55% (95% CI=40-69%) in the non-COVID-19 cohort. Conclusion: We found a low PPV of elevated procalcitonin level above 1 ng/mL in identifying either culture-confirmed or presumed bacterial infection in children hospitalized with COVID-19-related illness.

Esophagogastric Junction Outflow Obstruction and Hiatal Hernia: Is Hernia Repair Alone Sufficient?

Introduction: Esophagogastric junction outflow obstruction (EGJOO) is attributed to primary/idiopathic causes or secondary/mechanical causes, including hiatal hernias (HH). While patients with HH and EGJOO (HH+EGJOO) may undergo HH repair without myotomy, it is unclear if an underlying motility disorder is missed by therapy which addresses only the secondary EGJOO cause. The goal of this study was to determine if HH repair alone is sufficient management for HH+EGJOO patients. Methods: A retrospective review of patients who underwent HH repair between January 1, 2016 and January 31, 2020 was performed. Patients who underwent high-resolution esophageal manometry(HREM) within one year before HH repair were included. Patients with and without EGJOO on pre-operative HREM were compared. Results: Sixty-three patients were identified. Pre-operative HREM findings included: 43 (68.3%) normal, 13 (20.6%) EGJOO, 4 (6.3%) minor disorder or peristalsis, 2 (3.2%) achalasia, and 1 (1.6%) major disorder of peristalsis. No differences between patients with EGJOO or normal findings on pre-operative manometry were found in pre-operative demographics/risk factors, pre-operative symptoms, and pre-operative HREM, except higher integrated relaxation pressure in EGJOO patients. No differences were noted in length of stay, 30-day complications, long-term persistent symptoms, or recurrence with mean follow-up of 26-months. Of the 3 (23.1%) EGJOO patients with persistent symptoms, 2 underwent HREM demonstrating persistent EGJOO and none required endoscopic/surgical myotomy. Conclusion: Most HH+EGJOO patients experienced symptom resolution following HH repair alone and none required additional intervention to address a missed primary motility disorder. Further study is required to determine optimal management of patients with persistent EGJOO following HH repair.

Eastern king prawn Penaeus plebejus stock enhancement-Genetic evidence that hatchery bred prawns have survived in the wild after release.

Eastern king prawn (Penaeus plebejus) is endemic to eastern Australia and is of high commercial and recreational value. As part of a recreational fisheries enhancement initiative, hatchery reared juveniles from Queensland were released into two, more Southern New South Wales (NSW) estuaries between 2014 and 2015. Responsible stock enhancement programs rely on knowledge of the population structure of the released species. Previously, in consideration of fisheries data, it was assumed the king prawn populations in Australia are one single breeding stock. In the present study, our first aim was to test this posit of no genetic differentiation using mtDNA control region (mtCR) sequences from the wild samples collected from four estuaries ranging from Queensland/NSW border (source of the stocked animals) to Southern NSW. The second objective was to test for signals of hatchery-released animals in the two stocked estuaries. All four surveyed populations had an extremely high level of haplotype diversity (average h = 99.8%) and low level of haplotype sharing between populations. Estimates of PhiPT values were <0.01 or close to zero and AMOVA test did not indicate any significant differences among populations. Further, phylogenetic analysis and principal coordinate analysis did not support division of samples by population. Collectively these results suggest that eastern king prawn populations along the NSW coast can be considered as a single stock and stocking from the Queensland samples will not necessarily impact the genetic composition of the overall stock. After stocking of two estuaries, sharing of haplotypes was moderate to very high in the stocked sites (>80% in some collections) but negligible in the two unstocked estuaries (≤2%, which is assumed to be background coancestry unrelated to the hatchery). Moreover, some haplotypes present in the hatchery broodstock were detected in stocked sites, but not in unstocked sites. The highest stocking signal was detected in the estuary which becomes isolated from the sea by sand barrier suggesting such "lakes" maybe more favourable for stocking than estuaries directly open to the sea. Findings in the current study should assist in designing and implementation of future prawn stocking programs.

Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model.

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR-/- (Myeloid-AT1a-) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a+). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a+ mice but not in Myeloid-AT1a- mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.

The cost of treatments for retained traumatic hemothorax: A decision analysis.

INTRODUCTION: Early video-assisted thorascopic surgery (VATS) is the recommended intervention for retained hemothorax in trauma patients. Alternative options, such as lytic therapy, to avoid surgery remain controversial. The purpose of this decision analysis was to assess expected costs associated with treatment strategies. METHODS: A decision tree analysis estimated the expected costs of three initial treatment strategies: 1) VATS, 2) intrapleural tissue plasminogen activator (TPA) lytic therapy, and 3) intrapleural non-TPA lytic therapy. Probability parameters were estimated from published literature. Costs were based on National Inpatient Sample data and published estimates. Our model compared overall expected costs of admission for each strategy. Sensitivity analyses were conducted to explore the impact of parameter uncertainty on the optimal strategy. RESULTS: In the base case analysis, using TPA as the initial approach had the lowest total cost (U.S. $37,007) compared to VATS ($38,588). TPA remained the optimal initial approach regardless of the probability of complications after VATS. TPA was an optimal initial approach if TPA success rate was >83% regardless of the failure rate with VATS. VATS was the optimal initial strategy if its total cost of admission was <$33,900. CONCLUSION: Lower treatment costs with lytic therapy does not imply significantly lower total cost of trauma admission. However, an initial approach with TPA lytic therapy may be preferred for retained traumatic hemothorax to lower the total cost of admission given its high probability of avoiding the operating room with its resultant increased costs. Future studies should identify differences in quality of life after recovery from competing interventions.