Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.

Retirement risk factors, exercise management and muscle mass in US senior horses.

BACKGROUND: Information on the management and health of US senior horses (≥15 years of age) is currently limited. OBJECTIVES: Provide information on (1) primary use of US senior horses, (2) reasons and risk factors for horse retirement, (3) exercise management, (4) prevalence of low muscle mass and (5) risk factors for, and owner-perceived consequences of, low muscle mass. STUDY DESIGN: Online survey. METHODS: Survey responses from 2717 owners of U.S.-resident senior horses (≥15 years of age) were analysed descriptively and inferentially, using ordered and binomial logistic regression, ANOVA and the Kruskal-Wallis test. RESULTS: The most frequently reported primary uses were pleasure riding/driving (38.5%) and full retirement (39.8%). Most horses (61.5%) were retired between 15 and 24 years of age, with health problems being the main reason. Age, female sex, Thoroughbred breed and various medical conditions were identified as risk factors for retirement. In working horses (i.e., those not retired or semi-retired), exercise intensity was negatively associated with age. The owner-reported prevalence of low muscle mass in all horses was 17.2% (95%CI = 15.7-18.7). In those affected by low muscle mass, the ability to work and welfare-related aspects were commonly perceived to be impaired. Increasing age, sex (gelding), pituitary pars intermedia dysfunction, osteoarthritis, laminitis and primary use (retired and semi-retired vs. use for competition) were identified as risk factors for owner-reported low muscle mass. MAIN LIMITATIONS: Potential response, recall and sampling bias. Causal relationships cannot be established. CONCLUSIONS: Although structured exercise into old age may provide health benefits (as seen in elderly people), a large proportion of horses were fully retired in the current study. Senior horses were mainly retired for health problems and characterising these problems may aid in extending their work/active life. Low muscle mass was perceived to affect horses' welfare and ability to work, and identification of prevention and treatment strategies is therefore warranted.

Weighted mean difference statistics for paired data in the presence of missing values.

Missing data is a common issue in many biomedical studies. Under a paired design, some subjects may have missing values in either one or both of the conditions due to loss of follow-up, insufficient biological samples, etc. Such partially paired data complicate statistical comparison of the distribution of the variable of interest between the two conditions. In this article, we propose a general class of test statistics based on the difference in weighted sample means without imposing any distributional or model assumption. An optimal weight is derived from this class of tests. Simulation studies show that our proposed test with the optimal weight performs well and outperforms existing methods in practical situations. Two cancer biomarker studies are provided for illustration.

Genomic screening methodology not requiring barcoding: Single nucleotide polymorphism-based, mixed-cell screening (SMICS).

Although high-throughput, cancer cell-line screening is a time-honored, important tool for anti-cancer drug development, this process involves the testing of each, individual drug in each, individual cell-line. Despite the availability of robotic liquid handling systems, this process remains a time-consuming and costly investment. The Broad Institute developed a new method called Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) to screen a mixture of barcoded, tumor cell-lines. Although this methodology significantly improved the efficiency of screening large numbers of cell-lines, the barcoding process itself was tedious that requires gene transfection and subsequent selection of stable cell-lines. In this study, we developed a new, genomic approach for screening multiple cancer cell-lines using endogenous "tags" that did not require prior barcoding: single nucleotide polymorphism-based, mixed-cell screening (SMICS). The code for SMICS is available at https://github.com/MarkeyBBSRF/SMICS.

Bayesian kinetic modeling for tracer-based metabolomic data.

BACKGROUND: Stable Isotope Resolved Metabolomics (SIRM) is a new biological approach that uses stable isotope tracers such as uniformly [Formula: see text]-enriched glucose ([Formula: see text]-Glc) to trace metabolic pathways or networks at the atomic level in complex biological systems. Non-steady-state kinetic modeling based on SIRM data uses sets of simultaneous ordinary differential equations (ODEs) to quantitatively characterize the dynamic behavior of metabolic networks. It has been increasingly used to understand the regulation of normal metabolism and dysregulation in the development of diseases. However, fitting a kinetic model is challenging because there are usually multiple sets of parameter values that fit the data equally well, especially for large-scale kinetic models. In addition, there is a lack of statistically rigorous methods to compare kinetic model parameters between different experimental groups. RESULTS: We propose a new Bayesian statistical framework to enhance parameter estimation and hypothesis testing for non-steady-state kinetic modeling of SIRM data. For estimating kinetic model parameters, we leverage the prior distribution not only to allow incorporation of experts' knowledge but also to provide robust parameter estimation. We also introduce a shrinkage approach for borrowing information across the ensemble of metabolites to stably estimate the variance of an individual isotopomer. In addition, we use a component-wise adaptive Metropolis algorithm with delayed rejection to perform efficient Monte Carlo sampling of the posterior distribution over high-dimensional parameter space. For comparing kinetic model parameters between experimental groups, we propose a new reparameterization method that converts the complex hypothesis testing problem into a more tractable parameter estimation problem. We also propose an inference procedure based on credible interval and credible value. Our method is freely available for academic use at https://github.com/xuzhang0131/MCMCFlux . CONCLUSIONS: Our new Bayesian framework provides robust estimation of kinetic model parameters and enables rigorous comparison of model parameters between experimental groups. Simulation studies and application to a lung cancer study demonstrate that our framework performs well for non-steady-state kinetic modeling of SIRM data.

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.

Balancing after randomization in orthopedic trials: Are we even or even paying attention?

A cornerstone of evidence-based medicine is the randomized controlled trial (RCT). While randomization seeks to balance study groups on potential confounders, this is not always achieved. Especially in orthopedic research where RCTs are often of modest size, imbalances can exist and may be a significant issue. We sought to describe whether orthopedic RCTs assess balancing between study groups, use statistical hypothesis testing to compare baseline characteristics between groups, and have balanced baseline characteristics between groups. All RCTs from four leading orthopedic journals published between July 2019 and June 2020 were identified and those reporting original trial results reviewed for discussion of balancing, use of statistical significance testing to compare baseline characteristics, and patient reported outcome measures (PROMs) at baseline. Standardized mean differences of baseline PROMs were calculated to assess balancing. Of 86 orthopedic RCTs reviewed, 59 (69%) assessed balancing and 50 (58%) used statistical significance testing to compare baseline characteristics. Of 74 articles specifying a primary outcome, 33 (45%) used a PROM with 23 (70%) reporting baseline PROM values. Of these articles, 17 (74%) had a difference of less than 0.25 standard deviations (SDs) between groups, 4 (17%) had a difference of between 0.25 and 0.50 SDs, and 3 (13%) had a difference greater than 0.5 SDs. Orthopedic RCTs usually assess balancing after randomization though there is room for improvement with over half of articles using hypothesis testing to assess baseline differences as opposed to a measure of the magnitude of the difference.

Mechanisms of γδ T cell accumulation in visceral adipose tissue with aging.

γδ T cells are resident in visceral adipose tissue (VAT) where they show an age-associated increase in numbers and contribute to local and systemic chronic inflammation. However, regulation of this population and mechanisms for the age-dependent accumulation are not known. In this study, we identified a progressive trend of γδ T cell accumulation in VAT over the lifespan in mice and explored physiological mechanisms contributing to accumulation. Using isochronic parabiotic pairs of wild-type (WT) and T cell receptor delta knockout (TCRδ KO) mice at young and old age, we confirmed that VAT γδ T cells are predominately a tissue-resident population which is sustained in aging. Migration of peripheral γδ T cells into VAT was observed at less than 10%, with a decreasing trend by aging, suggesting a minor contribution of recruitment to γδ T cell accumulation with aging. Since tissue-resident T cell numbers are tightly regulated by a balance between proliferation and programmed cell death, we further explored these processes. Using in vivo EdU incorporation and the proliferation marker Ki67, we found that the absolute number of proliferating γδ T cells in VAT is significantly higher in the aged compared to young and middle-aged mice, despite a decline in the proportion of proliferating to non-proliferating cells by age. Analysis of apoptosis via caspase 3/7 activation revealed that VAT γδ T cells show reduced apoptosis starting at middle age and continuing into old age. Further, induction of apoptosis using pharmacological inhibitors of Bcl2 family proteins revealed that VAT γδ T cells at middle age are uniquely protected from apoptosis via a mechanism independent of traditional anti-apoptotic Bcl2-family proteins. Collectively, these data indicate that protection from apoptosis at middle age increases survival of tissue-resident γδ T cells resulting in an increased number of proliferative cells from middle age onward, and leading to the age-associated accumulation of γδ T cells in VAT. These findings are important to better understand how adipose tissue dysfunction and related changes in the immune profile contribute to inflammaging among the elderly.

Does prophylactic local tobramycin injection lower open fracture infection rates?

Objective: To determine whether local aqueous tobramycin injection in combination with systemic perioperative IV antibiotic prophylaxis will reduce the rate of fracture-related infection (FRI) after open fracture fixation. Other Outcomes of Interest: (1) To compare fracture nonunion rates and report differences between treatment and control groups and (2) compare bacterial speciation and antibiotic sensitivity among groups that develop FRI. Design: Phase 3 prospective, randomized clinical trial. Setting: Two level 1 trauma centers. Participants: Six hundred subjects (300 in study/tobramycin group and 300 in control/standard practice group) will be enrolled and assigned to the study group or control group using a randomization table. Patients with open extremity fractures that receive definitive internal surgical fixation will be considered. Intervention: Aqueous local tobramycin will be injected into the wound cavity (down to bone) after debridement, irrigation, and fixation, following closure. Main Outcome Measurements: Outcomes will look at the presence or absence of FRI, the rate of fracture nonunion, and determine speciation of gram-negative and Staph bacteria in each group with a FRI. Results: Not applicable. Conclusion: The proposed work will determine whether local tobramycin delivery plus perioperative standard antibiotic synergism will minimize the occurrence of open extremity FRI. Level of Evidence: Level 1.

Validated Preclinical Mouse Model for Therapeutic Testing against Multidrug-Resistant Pseudomonas aeruginosa Strains.

The rise in infections caused by antibiotic-resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that, without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and death. Therefore, there is an ever-growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing mouse model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, by both 50% lethal dose (LD50) analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used as comparators during the future evaluation of novel antimicrobials, and we confirmed that the model can effectively differentiate between successful and unsuccessful treatments, as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa strains, with the ability to provide rapid preclinical evaluation of novel antimicrobials and support data from clinical studies during the investigational drug development process. IMPORTANCE The prevalence of antibiotic resistance among bacterial pathogens is a growing problem that necessitates the development of new antibiotics. Preclinical animal models are important tools to facilitate and speed the development of novel antimicrobials. Successful outcomes in animal models not only justify progression of new drugs into human clinical trials but also can support FDA decisions if clinical trial sizes are small due to a small population of infections with specific drug-resistant strains. However, in both cases the preclinical animal model needs to be well characterized and provide robust and reproducible data. Toward this goal, we have refined an existing mouse model to better predict the efficacy of novel antibiotics. This improved model provides an important tool to better predict the clinical success of new antibiotics.

Association of Phosphate-Containing versus Phosphate-Free Solutions on Ventilator Days in Patients Requiring Continuous Kidney Replacement Therapy.

BACKGROUND AND OBJECTIVES: Hypophosphatemia is commonly observed in patients receiving continuous KRT. Patients who develop hypophosphatemia may be at risk of respiratory and neuromuscular dysfunction and therefore subject to prolongation of ventilator support. We evaluated the association of phosphate-containing versus phosphate-free continuous KRT solutions with ventilator dependence in critically ill patients receiving continuous KRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a single-center, retrospective, pre-post cohort study of adult patients receiving continuous KRT and mechanical ventilation during their intensive care unit stay. Zero-inflated negative binomial regression with and without propensity score matching was used to model our primary outcome: ventilator-free days at 28 days. Intensive care unit and hospital lengths of stay as well as hospital mortality were analyzed with a t test or a chi-squared test, as appropriate. RESULTS: We identified 992 eligible patients, of whom 649 (65%) received phosphate-containing solutions and 343 (35%) received phosphate-free solutions. In multivariable models, patients receiving phosphate-containing continuous KRT solutions had 12% (95% confidence interval, 0.17 to 0.47) more ventilator-free days at 28 days. Patients exposed to phosphate-containing versus phosphate-free solutions had 17% (95% confidence interval, -0.08 to -0.30) fewer days in the intensive care unit and 20% (95% confidence interval, - 0.12 to -0.32) fewer days in the hospital. Concordant results were observed for ventilator-free days at 28 days in the propensity score matched analysis. There was no difference in hospital mortality between the groups. CONCLUSIONS: The use of phosphate-containing versus phosphate-free continuous KRT solutions was independently associated with fewer ventilator days and shorter stay in the intensive care unit.

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation.

Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

Use of Wearable Sensors to Assess the Effects of Performing a Cognitive Task on Sensory Integration of Balance in Healthy Individuals.

This study investigated the effects of performing a cognitive task on the sensory integration of balance in healthy individuals. Ten subjects (five F/five M; 21.5 ± 2.17 years; 69.9 ± 3.4 inches; 155.6 ± 26.1 lbs; Caucasian), without known balance issues, performed the modified Clinical Test of Sensory Interaction of Balance (mCTSIB) with and without a cognitive task. The cognitive task involved counting down in threes from a randomly assigned number between 95 and 100. Postural sway area and postural sway jerk were assessed through the use of inertial sensors placed around the subjects' lower lumbar region. Each subject performed four trials for the four conditions of the mCTSIB: eyes open firm (EOFirm), eyes closed firm (ECFirm), eyes open foam (EOFoam), and eyes closed foam (ECFoam). We tested the effect of performing a cognitive task on the sensory integration of balance. We hypothesized that sensory cognitive interaction would be more apparent for more complex conditions and would be better assessed with postural sway jerk compared to postural sway area measure. With the addition of a cognitive task for the mCTSIB: (1) postural sway area increased in the baseline condition, i.e., EOFirm (p < 0.05), but did not increase in the most difficult condition, i.e., ECFoam; (2) postural sway jerk increased in all conditions of the mCTSIB (p < 0.05); (3) cognitive performance did not deteriorate across conditions of the mCTSIB. Postural sway jerk was shown to be a more sensitive measure in detecting the effect of a cognitive task on sensory integration for postural control. Overall, inertial sensors can be used to reliably assess postural sway differences related to sensory−cognitive integration.

Visceral fat-specific regulation of plasminogen activator inhibitor-1 in aged septic mice.

Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI-1, especially in the aged (murine endotoxemia), that circulating PAI-1 protein levels match the trajectory of PAI-1 transcript levels in VAT (clinical sepsis), and that PAI-1 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI-1 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI-1 induction in VAT, were identified. In aged mice with sepsis, PAI-1 gene expression was significantly higher in VAT than in other major organs. VAT PAI-1 gene expression correlated with PAI-1 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI-1 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI-1 is secreted robustly in response to recombinant transforming growth factor ß (TGFß) and tumor necrosis factor α (TNFα) treatment; however, neutralization was effective only for TNFα indicating that TGFß is not an endogenous modulator of PAI-1. Within VAT, TNFα was localized to neutrophils and macrophages. PAI-1 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI-1 in a similar fashion. PAI-1 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI-1 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI-1 contributes to AKI in sepsis, understanding PAI-1 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI-1 overproduction.

Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice.

ABSTRACT: Despite the known deleterious effects of obesity, clinical data indicate that overweight or obese patients experience higher rates of sepsis survival compared to normal and underweight patients; a phenomenon called the obesity paradox. Results from preclinical sepsis studies have not been able to replicate these findings. The objective of this study was to test the existence of the obesity paradox in a murine model of cecal slurry (CS)-induced sepsis with insulin-resistant diet-induced obese mice. Male C57BL/6 mice were provided high-fat (HFD) or low-fat (LFD) diets for 20 weeks. HFD-fed mice experienced higher rates of survival compared to LFD-fed mice after septic challenge induced by CS injection (66% vs. 25%, P = 0.01, survival assessed for 14 days). Despite the survival advantage, HFD-fed mice had higher rates of positive bacterial cultures and increased markers of kidney injury. Circulating levels of IL-6, IL-1ß, TNFα, and IL-23 were equivalent 24 h after CS-injection; however, IL-17A was uniquely increased in HFD-fed mice. While LFD-fed mice maintained euglycemia, HFD-fed mice were hyperglycemic 6 and 12 h after CS-injection. Stable isotope resolved metabolomics analysis of liver tissue showed diverging pathways of glucose utilization during sepsis, with LFD-fed mice significantly upregulating glycolytic activity and HFD-fed mice decreasing glucose entry into the TCA cycle. This murine study corroborates clinical data that obesity confers a survival benefit in sepsis, albeit at the expense of more significant organ injury. The mechanisms promoting survival in the obese remain unknown; however, this model appears to be well-poised to begin answering this question. Differences in glucose utilization are a novel target to investigate this paradox.

Very-Low Energy Monopolar Reduces Post-Tonsillectomy Hemorrhage Versus Standard Energy Techniques.

OBJECTIVES/HYPOTHESIS: To compare rates of post-tonsillectomy hemorrhage (PTH) between a very-low energy transfer monopolar technique (VLET) and standard energy techniques. STUDY DESIGN: Retrospective controlled cohort study. METHODS: All tonsillectomies performed by practice physicians during the period January 1, 2010 to August 31, 2019 were identified. Three groups were created based on surgeon technique utilization: the study group (VLET) and two control groups (exclusive standard energy monopolar [Standard]; exclusive "hot" technique without exclusive monopolar use [Mixed "Hot"]). Each group's PTH occurrences requiring surgical intervention (PTHRSI) were identified and rates compared. RESULTS: During the study period 11,348 tonsillectomies were performed (4,427 Standard, 1,374 VLET, 5,547 Mixed "Hot"), and 167 (1.47%) PTHRSI events identified (14 primary (<24 hours), 153 secondary (>24 hours), 12 repeat (>1PTHRSI/patient). Compared to the Standard group secondary and total PTHRSI rates (1.47%, 1.60%), the Mixed "Hot" group experienced similar rates (1.57%, P = .54; 1.68%, P = .64), but the VLET group experienced significantly lower rates (0.15%, P = .0026, adjusted odds ratio [OR] 0.114 [0.028-0.469]; 0.22%, P = .0016, adjusted OR 0.155 [0.048-0.494]). Age was a significant risk factor for both secondary and total PTHRSI (P = .0025, P = .0024, adjusted OR 1.02/year [1.01-1.03]). No significant difference in rate of primary PTHRSI was seen collectively or in any age group. The <12VLET Group experienced 0 episodes of secondary PTHRSI and a total PTHRSI rate of 0.09% in 1060 tonsillectomies. CONCLUSIONS: Standard energy techniques had an adjusted odds ratio over 8-fold higher for secondary PTHRSI and over 6-fold higher for total PTHRSI compared to the minimized energy transfer VLET technique. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2505-2511, 2021.

Adipose-Derived Inflammatory and Coagulant Mediators in Patients With Sepsis.

ABSTRACT: Results from preclinical sepsis studies using rodents are often criticized as not being reproducible in humans. Using a murine model, we previously reported that visceral adipose tissues (VAT) are highly active during the acute inflammatory response, serving as a major source of inflammatory and coagulant mediators. The purpose of this study was to determine whether these findings are recapitulated in patients with sepsis and to evaluate their clinical significance. VAT and plasma were obtained from patients undergoing intra-abdominal operations with noninflammatory conditions (control), local inflammation, or sepsis. In mesenteric and epiploic VAT, gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1ß) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators was increased in sepsis compared with control and local inflammation groups. In the omentum, increased expression was limited to IL-1ß, PAI-1, and PAI-2, showing a depot-specific regulation. Histological analyses showed little correlation between cellular infiltration and gene expression, indicating a resident source of these mediators. Notably, a strong correlation between PAI-1 expression in VAT and circulating protein levels was observed, both being positively associated with markers of acute kidney injury (AKI). In another cohort of septic patients stratified by incidence of AKI, circulating PAI-1 levels were higher in those with versus without AKI, thus extending these findings beyond intra-abdominal cases. This study is the first to translate upregulation of VAT mediators in sepsis from mouse to human. Collectively, the data suggest that development of AKI in septic patients is associated with high plasma levels of PAI-1, likely derived from resident cells within VAT.

Feasibility as a mechanism for model identification and validation.

As new technologies permit the generation of hitherto unprecedented volumes of data (e.g. genome-wide association study data), researchers struggle to keep up with the added complexity and time commitment required for its analysis. For this reason, model selection commonly relies on machine learning and data-reduction techniques, which tend to afford models with obscure interpretations. Even in cases with straightforward explanatory variables, the so-called 'best' model produced by a given model-selection technique may fail to capture information of vital importance to the domain-specific questions at hand. Herein we propose a new concept for model selection, feasibility, for use in identifying multiple models that are in some sense optimal and may unite to provide a wider range of information relevant to the topic of interest, including (but not limited to) interaction terms. We further provide an R package and associated Shiny Applications for use in identifying or validating feasible models, the performance of which we demonstrate on both simulated and real-life data.

National Database Outcomes of Esophageal Dilations.

OBJECTIVES/HYPOTHESIS: To better assess rates of postoperative complications and mortality following esophageal dilation, and to identify factors associated with adverse outcomes. STUDY DESIGN: Observational, retrospective cohort study. METHODS: We queried a national database of insurance claims for Current Procedural Terminology (CPT) codes representing esophageal dilation performed between 2011 and 2017. Patients aged 18 to 100 who were continuously enrolled with their insurance provider were included. Demographic information, additional CPT codes, concomitant diagnoses, and anticoagulant medication data were collected for all patients included. Postoperative mortality was assessed and International Classification of Diseases (ICD)9/10 codes for complications, including esophageal perforation, hemorrhage, mediastinitis, and sepsis were flagged. RESULTS: We identified 202,965 encounters for esophageal dilation. Of these procedures, 193 were performed on a patient who underwent percutaneous endoscopic gastrostomy (PEG) during the study period and was analyzed separately. Another 244 dilations were excluded due to repeat entries. Of the remaining 202,528 procedures remaining, 42,310 were repeat dilations in the same patient. Data analysis was confined to each patient's initial dilation. 160,218 initial dilations remained. Of these, 62,107 were performed on male patients and 98,111 were performed on female patients. The average age was 57.7 years. There were 12 mortalities within 30 days postoperatively, representing 0.0075% of all dilations. Esophageal perforation and esophageal hemorrhage were the most common reported complications, with 139 and 110 occurrences, respectively. The overall per-dilation complication rate was 0.215%. CONCLUSIONS: Evidence from a national insurance claim database suggests that esophageal dilation is a safe procedure with a low rate of serious complications and a 30-day all-cause mortality rate of less than 1 per 10,000 dilations. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2436-2440, 2021.