STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy.

In idiopathic Parkinson's disease (PD), pathologic αSyn aggregates drive oxidative and nitrative stress that may cause genomic and mitochondrial DNA damage. These events are associated with activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) immune pathway, but it is not known whether STING is activated in or contributes to α-synucleinopathies. Herein, we used primary cell cultures and the intrastriatal αSyn preformed fibril (αSyn-PFF) mouse model of PD to demonstrate that αSyn pathology causes STING-dependent neuroinflammation and dopaminergic neurodegeneration. In microglia-astrocyte cultures, αSyn-PFFs induced DNA double-strand break (DSB) damage response signaling (γH2A.X), as well as TBK1 activation that was blocked by STING inhibition. In the αSyn-PFF mouse model, we similarly observed TBK1 activation and increased γH2A.X within striatal microglia prior to the onset of dopaminergic neurodegeneration. Using STING-deficient (Stinggt) mice, we demonstrated that striatal interferon activation in the α-Syn PFF model is STING-dependent. Furthermore, Stinggt mice were protected from α-Syn PFF-induced motor deficits, pathologic αSyn accumulation, and dopaminergic neuron loss. We also observed upregulation of STING protein in the substantia nigra pars compacta (SNpc) of human PD patients that correlated significantly with pathologic αSyn accumulation. STING was similarly upregulated in microglia cultures treated with αSyn-PFFs, which primed the pathway to mount stronger interferon responses when exposed to a STING agonist. Our results suggest that microglial STING activation contributes to both the neuroinflammation and neurodegeneration arising from α-synucleinopathies, including PD.

ppBAM: ProteinPaint BAM track for read alignment visualization and variant genotyping.

SUMMARY: ProteinPaint BAM track (ppBAM) is designed to assist variant review for cancer research and clinical genomics. With performant server-side computing and rendering, ppBAM supports on-the-fly variant genotyping of thousands of reads using Smith-Waterman alignment. To better visualize support for complex variants, reads are realigned against the mutated reference sequence using ClustalO. ppBAM also supports the BAM slicing API of the NCI Genomic Data Commons (GDC) portal, letting researchers conveniently examine genomic details of vast amounts of cancer sequencing data and reinterpret variant calls. AVAILABILITY AND IMPLEMENTATION: BAM track examples, tutorial, and GDC file access links are available at https://proteinpaint.stjude.org/bam/. Source code is available at https://github.com/stjude/proteinpaint.

Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease Inhibition.

Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society.

Cardiovascular Subphenotypes in Acute Respiratory Distress Syndrome.

OBJECTIVES: To use clustering methods on transthoracic echocardiography (TTE) findings and hemodynamic parameters to characterize circulatory failure subphenotypes and potentially elucidate underlying mechanisms in patients with acute respiratory distress syndrome (ARDS) and to describe their association with mortality compared with current definitions of right ventricular dysfunction (RVD). DESIGN: Retrospective, single-center cohort study. SETTING: University Hospital ICU, Birmingham, United Kingdom. PATIENTS: ICU patients that received TTE within 7 days of ARDS onset between April 2016 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Latent class analysis (LCA) of TTE/hemodynamic parameters was performed in 801 patients, 62 years old (interquartile range, 50-72 yr old), 63% male, and 40% 90-day mortality rate. Four cardiovascular subphenotypes were identified: class 1 (43%; mostly normal left and right ventricular [LV/RV] function), class 2 (24%; mostly dilated RV with preserved systolic function), class 3 (13%, mostly dilated RV with impaired systolic function), and class 4 (21%; mostly high cardiac output, with hyperdynamic LV function). The four subphenotypes differed in their characteristics and outcomes, with 90-day mortality rates of 19%, 40%, 78%, and 59% in classes 1-4, respectively ( p < 0.0001). Following multivariable logistic regression analysis, class 3 had the highest odds ratio (OR) for mortality (OR, 6.9; 95% CI, 4.0-11.8) compared with other RVD definitions. Different three-variable models had high diagnostic accuracy in identifying each of these latent subphenotypes. CONCLUSIONS: LCA of TTE parameters identified four cardiovascular subphenotypes in ARDS that more closely aligned with circulatory failure mechanisms and mortality than current RVD definitions.

The function of BK channels extracted and purified within SMALPs.

Human BK channels are large voltage and Ca2+-activated K+ channels, involved in several important functions within the body. The core channel is a tetramer of α subunits, and its function is modulated by the presence of ß and γ accessory subunits. BK channels composed of α subunits, as well as BK channels composed of α and ß1 subunits, were successfully solubilised from HEK cells with styrene maleic acid (SMA) polymer and purified by nickel affinity chromatography. Native SMA-PAGE analysis of the purified proteins showed the α subunits were extracted as a tetramer. In the presence of ß1 subunits, they were co-extracted with the α subunits as a heteromeric complex. Purified SMA lipid particles (SMALPs) containing BK channel could be inserted into planar lipid bilayers (PLB) and single channel currents recorded, showing a high conductance (≈260 pS), as expected. The open probability was increased in the presence of co-purified ß1 subunits. However, voltage-dependent gating of the channel was restricted. In conclusion, we have demonstrated that SMA can be used to effectively extract and purify large, complex, human ion channels, from low expressing sources. That these large channels can be incorporated into PLB from SMALPs and display voltage-dependent channel activity. However, the SMA appears to reduce the voltage dependent gating of the channels.

Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma.

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.

Hyperdynamic Left Ventricular Ejection Fraction in ICU Patients With Sepsis.

OBJECTIVES: To evaluate the cause and prognosis of hyperdynamic left ventricular ejection fraction in critically ill patients with sepsis. DESIGN: Retrospective, single-center cohort study. SETTING: University Hospital ICU, Birmingham, United Kingdom. PATIENTS: ICU patients who received a transthoracic echocardiogram within 7 days of sepsis between April 2016 and December 2019. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The 90-day mortality rates of normal (55-70%), depressed (< 55%), and hyperdynamic left ventricular ejection fraction (> 70%) were compared. Multivariate logistic regression analysis was performed to determine the association of left ventricular ejection fraction phenotypes with mortality and the association of clinical variables with left ventricular ejection fraction phenotypes. One thousand fourteen patients met inclusion criteria and were 62 years old (interquartile range, 47-72), with mostly respiratory infections (n = 557; 54.9%). Ninety-day mortality was 32.1% (n = 325). Patients with hyperdynamic left ventricular ejection fraction had a higher mortality than depressed and normal left ventricular ejection fraction cohorts (58.9% [n = 103] vs 34.0% [n = 55] vs 24.7% [n = 167]; p < 0.0001, respectively). After multivariate logistic regression, hyperdynamic left ventricular ejection fraction was independently associated with mortality (odds ratio, 3.90 [2.09-7.40]), whereas depressed left ventricular ejection fraction did not (odds ratio, 0.62 [0.28-1.37]). Systemic vascular resistance was inversely associated with hyperdynamic left ventricular ejection fraction (odds ratio, 0.79 [0.58-0.95]), and age, frailty, and ischemic heart disease were associated with depressed left ventricular ejection fraction. CONCLUSIONS: Hyperdynamic left ventricular ejection fraction was associated with mortality in septic ICU patients and may reflect unmitigated vasoplegia from sepsis. Depressed left ventricular ejection fraction was not associated with mortality but was associated with cardiovascular disease.

Predictors of survival and time to progression following operative management of intramedullary spinal cord astrocytomas.

PURPOSE: Surgical resection is considered standard of care for primary intramedullary astrocytomas, but the infiltrative nature of these lesions often precludes complete resection without causing new post-operative neurologic deficits. Radiotherapy and chemotherapy serve as potential adjuvants, but high-quality data evaluating their efficacy are limited. Here we analyze the experience at a single comprehensive cancer center to identify independent predictors of postoperative overall and progression-free survival. METHODS: Data was collected on patient demographics, tumor characteristics, pre-operative presentation, resection extent, long-term survival, and tumor progression/recurrence. Kaplan-Meier curves modeled overall and progression-free survival. Univariable and multivariable accelerated failure time regressions were used to compute time ratios (TR) to determine predictors of survival. RESULTS: 94 patients were included, of which 58 (62%) were alive at last follow-up. On multivariable analysis, older age (TR = 0.98; p = 0.03), higher tumor grade (TR = 0.12; p < 0.01), preoperative back pain (TR = 0.45; p < 0.01), biopsy [vs GTR] (TR = 0.18; p = 0.02), and chemotherapy (TR = 0.34; p = 0.02) were significantly associated with poorer survival. Higher tumor grade (TR = 0.34; p = 0.02) and preoperative bowel dysfunction (TR = 0.31; p = 0.02) were significant predictors of shorter time to detection of tumor growth. CONCLUSION: Tumor grade and chemotherapy were associated with poorer survival and progression-free survival. Chemotherapy regimens were highly heterogeneous, and randomized trials are needed to determine if any optimal regimens exist. Additionally, GTR was associated with improved survival, and patients should be counseled about the benefits and risks of resection extent.

Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial.

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration: isrctn.org Identifier: ISRCTN16912075.

Right Ventricular Dysfunction and Its Association With Mortality in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

OBJECTIVES: To assess whether right ventricular dilation or systolic impairment is associated with mortality and/or disease severity in invasively ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. DESIGN: Retrospective cohort study. SETTING: Single-center U.K. ICU. PATIENTS: Patients with coronavirus disease 2019 acute respiratory distress syndrome undergoing invasive mechanical ventilation that received a transthoracic echocardiogram between March and December 2020. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Right ventricular dilation was defined as right ventricular:left ventricular end-diastolic area greater than 0.6, right ventricular systolic impairment as fractional area change less than 35%, or tricuspid annular plane systolic excursion less than 17 mm. One hundred seventy-two patients were included, 59 years old (interquartile range, 49-67), with mostly moderate acute respiratory distress syndrome (n = 101; 59%). Ninety-day mortality was 41% (n = 70): 49% in patients with right ventricular dilation, 53% in right ventricular systolic impairment, and 72% in right ventricular dilation with systolic impairment. The right ventricular dilation with systolic impairment phenotype was independently associated with mortality (odds ratio, 3.11 [95% CI, 1.15-7.60]), but either disease state alone was not. Right ventricular fractional area change correlated with Pao2:Fio2 ratio, Paco2, chest radiograph opacification, and dynamic compliance, whereas right ventricular:left ventricle end-diastolic area correlated negatively with urine output. CONCLUSIONS: Right ventricular systolic impairment correlated with pulmonary pathophysiology, whereas right ventricular dilation correlated with renal dysfunction. Right ventricular dilation with systolic impairment was the only right ventricular phenotype that was independently associated with mortality.

Incidence and risk factors of acute kidney injury in COVID-19 patients with and without acute respiratory distress syndrome (ARDS) during the first wave of COVID-19: a systematic review and Meta-Analysis.

BACKGROUND: Acute kidney injury (AKI) is common among patients with COVID-19. However, AKI incidence may increase when COVID-19 patients develop acute respiratory distress syndrome (ARDS). Thus, this systematic review and meta-analysis aimed to assess the incidence and risk factors of AKI, need for kidney replacement therapy (KRT), and mortality rate among COVID-19 patients with and without ARDS from the first wave of COVID-19. METHODS: The databases MEDLINE and EMBASE were searched using relevant keywords. Only articles available in English published between December 1, 2019, and November 1, 2020, were included. Studies that included AKI in COVID-19 patients with or without ARDS were included. Meta-analyses were conducted using random-effects models. RESULTS: Out of 618 studies identified and screened, 31 studies met the inclusion criteria. A total of 27,500 patients with confirmed COVID-19 were included. The overall incidence of AKI in patients with COVID-19 was 26% (95% CI 19% to 33%). The incidence of AKI was significantly higher among COVID-19 patients with ARDS than COVID-19 patients without ARDS (59% vs. 6%, p < 0.001). Comparing ARDS with non-ARDS COVID-19 cohorts, the need for KRT was also higher in ARDS cohorts (20% vs. 1%). The mortality among COVID-19 patients with AKI was significantly higher (Risk ratio = 4.46; 95% CI 3.31-6; p < 0.00001) than patients without AKI. CONCLUSION: This study shows that ARDS development in COVID-19-patients leads to a higher incidence of AKI and increased mortality rate. Therefore, healthcare providers should be aware of kidney dysfunction, especially among elderly patients with multiple comorbidities. Early kidney function assessment and treatments are vital in COVID-19 patients with ARDS.

DNA damage and mitochondria in cancer and aging.

Age and DNA repair deficiencies are strong risk factors for developing cancer. This is reflected in the comorbidity of cancer with premature aging diseases associated with DNA damage repair deficiencies. Recent research has suggested that DNA damage accumulation, telomere dysfunction and the accompanying mitochondrial dysfunction exacerbate the aging process and may increase the risk of cancer development. Thus, an area of interest in both cancer and aging research is the elucidation of the dynamic crosstalk between the nucleus and the mitochondria. In this review, we discuss current research on aging and cancer with specific focus on the role of mitochondrial dysfunction in cancer and aging as well as how nuclear to mitochondrial DNA damage signaling may be a driving factor in the increased cancer incidence with aging. We suggest that therapeutic interventions aimed at the induction of autophagy and mediation of nuclear to mitochondrial signaling may provide a mechanism for healthier aging and reduced tumorigenesis.

Expression and purification of recombinant G protein-coupled receptors: A review.

Given their extensive role in cell signalling, GPCRs are significant drug targets; despite this, many of these receptors have limited or no available prophylaxis. Novel drug design and discovery significantly rely on structure determination, of which GPCRs are typically elusive. Progress has been made thus far to produce sufficient quantity and quality of protein for downstream analysis. As such, this review highlights the systems available for recombinant GPCR expression, with consideration of their advantages and disadvantages, as well as examples of receptors successfully expressed in these systems. Additionally, an overview is given on the use of detergents and the styrene maleic acid (SMA) co-polymer for membrane solubilisation, as well as purification techniques.

Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia. A Pilot Randomized Controlled Clinical Trial.

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses.Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care.Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation.Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics.Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.Clinical trial registered with EudraCT (2012-00343-29).

A Snapshot of Compliance with the Sepsis Six Care Bundle in Two Acute Hospitals in the West Midlands, UK.

BACKGROUND: The sepsis six care bundle has been adopted by hospitals in England and Wales for the management of patients with sepsis, with the aim of increasing survival when all elements of the bundle are achieved. AIM: To assess compliance with the Sepsis Six Care Bundle in two acute NHS hospitals in the West Midlands. MATERIALS AND METHODS: Adults admitted to hospital over a 24-hour period were screened for sepsis. Sepsis was identified using the Systemic Inflammatory Response (SIRS) criteria and the quick sequential organ failure assessment (qSOFA) score. Adherence to the Sepsis Six Care Bundle was assessed. RESULTS: 249 patients were screened and 24 patients were identified as having sepsis (9.6%). One patient received all six elements of the bundle. Compliance was highest for giving intravenous fluids (58.3%) and antibiotics (58.3%), and lowest for measuring urine output (16.7%). CONCLUSIONS: Further research is needed to establish the reasons for low compliance. HOW TO CITE THIS ARTICLE: Frankling C, Patel J, Sharif B, Melody T, Yeung J, Gao F, et al. A Snapshot of Compliance with the Sepsis Six Care Bundle in Two Acute Hospitals in the West Midlands, UK. Indian J Crit Care Med 2019;23(7):310-315.

Structure and function of membrane proteins encapsulated in a polymer-bound lipid bilayer.

New technologies for the purification of stable membrane proteins have emerged in recent years, in particular methods that allow the preparation of membrane proteins with their native lipid environment. Here, we look at the progress achieved with the use of styrene-maleic acid copolymers (SMA) which are able to insert into biological membranes forming nanoparticles containing membrane proteins and lipids. This technology can be applied to membrane proteins from any host source, and, uniquely, allows purification without the protein ever being removed from a lipid bilayer. Not only do these SMA lipid particles (SMALPs) stabilise membrane proteins, allowing structural and functional studies, but they also offer opportunities to understand the local lipid environment of the host membrane. With any new or different method, questions inevitably arise about the integrity of the protein purified: does it retain its activity; its native structure; and ability to perform its function? How do membrane proteins within SMALPS perform in existing assays and lend themselves to analysis by established methods? We outline here recent work on the structure and function of membrane proteins that have been encapsulated like this in a polymer-bound lipid bilayer, and the potential for the future with this approach. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain.

Patient-reported barriers are associated with lower hepatocellular carcinoma surveillance rates in patients with cirrhosis.

Over 20% of patients with cirrhosis are nonadherent with hepatocellular carcinoma (HCC) surveillance recommendations; however, few studies have evaluated the impact of patient-level factors on surveillance receipt. We characterized the association between HCC surveillance receipt and patient knowledge, attitudes, and perceived barriers in a racially diverse and socioeconomically disadvantaged cohort of patients with cirrhosis. Patients with cirrhosis followed at a large urban hospital were invited to complete a survey about HCC surveillance between August 2014 and December 2015. Multivariable logistic regression was performed to identify factors associated with HCC surveillance receipt during the 12-month period preceding and 6-month period after survey administration. We achieved a response rate of 71.8% (n = 541 of 753). Patients demonstrated high levels of HCC-related knowledge (summary score, 77.7%); however, 48.6% believed that eating a healthy diet precluded the need for HCC surveillance, and 34.0% believed that HCC surveillance was not necessary if they had a normal physical exam and/or lacked clinical symptoms. Patients expressed worry about developing and dying from HCC, but nearly half (49.9%) of patients reported barriers to receiving HCC surveillance, including difficulty with the scheduling process (30.5%), costs of surveillance testing (25.3%), and transportation difficulties (17.3%). HCC surveillance receipt was significantly higher in patients who knew cirrhosis is a risk factor for developing HCC (odds ratio [OR], 3.09; 95% confidence interval [CI], 1.25-7.62) and significantly lower in those reporting barriers to surveillance (OR, 0.42; 95% CI, 0.25-0.70). CONCLUSION: Patients with cirrhosis are knowledgeable and interested in HCC surveillance; however, patient-reported barriers are associated with lower surveillance rates in clinical practice and represent potential intervention targets to improve HCC surveillance effectiveness. (Hepatology 2017;65:875-884).

Comparison of Ultrasound-Guided Thrombin Injection of Iatrogenic Pseudoaneurysms Based on Neck Dimension.

BACKGROUND: Ultrasound-guided thrombin injection (UGTI) of femoral artery pseudoaneurysms after endovascular procedures is an effective therapy. There is controversy in the literature regarding injecting pseudoaneurysms with short and/or wide necks. This article reports our experience in UGTI of pseudoaneurysms in 1 hospital regarding the efficacy of this treatment in all pseudoaneurysms regardless of the size of the necks. METHODS: A retrospective review of 46 patients diagnosed between 2011 and 2016 with groin pseudoaneurysms using established duplex ultrasound criteria. Mean age was 68 years (range 27-87). Ten pseudoaneurysms thrombosed spontaneously, 5 were thrombosed by ultrasound-guided compression, and 2 were treated surgically due to disqualifying criteria. In this retrospective review, we analyzed the remaining 29 pseudoaneurysms regarding the dimensions of their neck lengths and outcomes after attempting thrombin injection. RESULTS: The mean aneurysm neck length and width were 1.03 ± 0.9 cm and 0.30 ± 0.1 cm, respectively. All 29 patients were evaluated with respect to pseudoaneurysm size, neck length, neck width, and complexity. Successful treatment of 29 pseudoaneurysms (2 external iliac, 20 common femoral, 2 deep femoral, and 5 superficial femoral) with UGTI was achieved without complications in 100% of the cases, regardless of pseudoaneurysm size, neck dimensions, or complexity. Anticoagulation status did not affect the efficacy of the procedure. Nine of the 29 pseudoaneurysms (31.0%) had neck length less than 0.5 cm. CONCLUSIONS: This study demonstrates the safety and efficacy of UGTI in treating iatrogenic pseudoaneurysm in 29 of 29 patients, even in patients with pseudoaneurysm with short neck lengths. Our experiences support injecting all pseudoaneurysms irrespective of dimension.

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin.

RATIONALE: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. OBJECTIVES: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses. METHODS: The migratory accuracy of blood neutrophils from young (aged <35 yr) and old (aged >60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. MEASUREMENTS AND MAIN RESULTS: In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly. CONCLUSIONS: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).