Biochemical characterization of the Eya and PP2A-B55α interaction.

The eyes absent (Eya) proteins were first identified as co-activators of the six homeobox family of transcription factors and are critical in embryonic development. These proteins are also re-expressed in cancers after development is complete, where they drive tumor progression. We have previously shown that the Eya3 N-terminal domain (NTD) contains Ser/Thr phosphatase activity through an interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme and that this interaction increases the half-life of Myc through pT58 dephosphorylation. Here, we showed that Eya3 directly interacted with the NTD of Myc, recruiting PP2A-B55α to Myc. We also showed that Eya3 increased the Ser/Thr phosphatase activity of PP2A-B55α but not PP2A-B56α. Furthermore, we demonstrated that the NTD (∼250 amino acids) of Eya3 was completely disordered, and it used a 38-residue segment to interact with B55α. In addition, knockdown and phosphoproteomic analyses demonstrated that Eya3 and B55α affected highly similar phosphosite motifs with a preference for Ser/Thr followed by Pro, consistent with Eya3's apparent Ser/Thr phosphatase activity being mediated through its interaction with PP2A-B55α. Intriguingly, mutating this Pro to other amino acids in a Myc peptide dramatically increased dephosphorylation by PP2A. Not surprisingly, MycP59A, a naturally occurring mutation hotspot in several cancers, enhanced Eya3-PP2A-B55α-mediated dephosphorylation of pT58 on Myc, leading to increased Myc stability and cell proliferation, underscoring the critical role of this phosphosite in regulating Myc stability.

Leukotriene B4 receptor 2 governs macrophage migration during tissue inflammation.

Chronic inflammation is the underlying cause of many diseases, including type 1 diabetes, obesity, and non-alcoholic fatty liver disease. Macrophages are continuously recruited to tissues during chronic inflammation where they exacerbate or resolve the pro-inflammatory environment. Although leukotriene B4 receptor 2 (BLT2) has been characterized as a low affinity receptor to several key eicosanoids and chemoattractants, its precise roles in the setting of inflammation and macrophage function remain incompletely understood. Here we used zebrafish and mouse models to probe the role of BLT2 in macrophage function during inflammation. We detected BLT2 expression in bone marrow derived and peritoneal macrophages of mouse models. Transcriptomic analysis of Ltb4r2-/- and WT macrophages suggested a role for BLT2 in macrophage migration, and studies in vitro confirmed that whereas BLT2 does not mediate macrophage polarization, it is required for chemotactic function, possibly mediated by downstream genes Ccl5 and Lgals3. Using a zebrafish model of tailfin injury, we demonstrated that antisense morpholino-mediated knockdown of blt2a or chemical inhibition of BLT2 signaling impairs macrophage migration. We further replicated these findings in zebrafish models of islet injury and liver inflammation. Moreover, we established the applicability of our zebrafish findings to mammals by showing that macrophages of Ltb4r2-/- mice have defective migration during lipopolysaccharide stimulation in vivo. Collectively, our results demonstrate that BLT2 mediates macrophage migration during inflammation, which implicates it as a potential therapeutic target for inflammatory pathologies.

Non-Alcoholic Fatty Liver Disease: Translating Disease Mechanisms into Therapeutics Using Animal Models.

Nonalcoholic fatty liver disease (NAFLD) is a range of pathologies arising from fat accumulation in the liver in the absence of excess alcohol use or other causes of liver disease. Its complications include cirrhosis and liver failure, hepatocellular carcinoma, and eventual death. NAFLD is the most common cause of liver disease globally and is estimated to affect nearly one-third of individuals in the United States. Despite knowledge that the incidence and prevalence of NAFLD are increasing, the pathophysiology of the disease and its progression to cirrhosis remain insufficiently understood. The molecular pathogenesis of NAFLD involves insulin resistance, inflammation, oxidative stress, and endoplasmic reticulum stress. Better insight into these molecular pathways would allow for therapies that target specific stages of NAFLD. Preclinical animal models have aided in defining these mechanisms and have served as platforms for screening and testing of potential therapeutic approaches. In this review, we will discuss the cellular and molecular mechanisms thought to contribute to NAFLD, with a focus on the role of animal models in elucidating these mechanisms and in developing therapies.

The lifesaving effects of cardiac adhesions.

Patients that incur myocardial disruption from penetrating cardiac injuries have an average 6%-10% expectancy rate of reaching the hospital alive. If prompt recognition on arrival is not immediate, the morbidity and mortality are significantly higher due to the secondary physiologic sequalae of either cardiogenic or hemorrhagic shock. Even after a triumphant arrival at a medical facility, out of that 6%-10%, half of those patients are not expected to survive. The unique significance of the presenting case breaks this tradition, expanding past the paradigms and issuing an exceptional understanding of the protective effects that cardiac surgery can futuristically cause through preformed adhesions. In our case, the cardiac adhesions achieved this by containing a penetrating cardiac injury that had caused complete ventricular disruption.

Real-World Adherence to Patient-Reported Outcome Monitoring as a Cancer Care Quality Metric.

PURPOSE: Routine collection of patient-reported outcomes (PROs) for patients with advanced solid malignancies is an evidence-based practice and critical component of high-quality cancer care, but real-world adherence is poorly characterized. We sought to describe real-world adherence to PRO monitoring and its potential predictors. METHODS: We conducted a retrospective cross-sectional study using deidentified electronic health record data from a National Cancer Institute Cancer Center, encompassing one academic and two community sites. Participants included individuals with lung cancer receiving systemic therapy from January 1 to December 31, 2019. The primary outcome was patient-level adherence, defined as the proportion of treatment visits during which a PRO questionnaire (spanning symptoms, functional status, and global quality-of-life domains) was completed within 30 days. Practice-level performance was calculated as unadjusted mean patient-level adherence. We modeled patient-level adherence using multivariable ordinary least squares regression and identified covariates associated with adherence using a significance threshold of P < .05. RESULTS: In 2019, there were 18,604 encounters for 1,105 patients with lung cancer (mean [standard deviation] age 65.8 [10.2] years; 621 [56.2%] female; 216 [19.6%] Black) receiving systemic therapy. The mean patient-level PRO adherence ranged from 27.2% to 70.0% across sites and was 49.4% overall. Advanced age (≥ 65 years) and Black or African American race were negatively associated with PRO adherence (P < .01). CONCLUSION: Across this real-world cohort of patients undergoing treatment for lung cancer, adherence to PRO monitoring lagged that achieved in seminal clinical trials, with potential age- and race-based disparities, demonstrating an implementation gap that could be addressed with standardized reporting of an adherence-based quality metric.

A zebrafish tailfin injury assay protocol for quantifying immune cell migration and infiltration.

Myeloid cells, such as macrophages, are critical components of the inflammatory response, in which infected, injured, or necrotic tissues are targeted for resolution. A key aspect of the inflammatory response is migration of myeloid cells to target tissues. Although studying immune cell migration in mammalian models in vivo is challenging, zebrafish are more tractable owing to their optical transparency and rapidity in generating transgenic lines. Here, we present a tailfin injury assay protocol for quantifying immune infiltration at injury sites. For complete details on the use and execution of this profile, please refer to Anderson-Baucum et al. (2021) and Kulkarni et al. (2021).

Targeting EYA2 tyrosine phosphatase activity in glioblastoma stem cells induces mitotic catastrophe.

Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.

Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype.

The metabolic inflammation (meta-inflammation) of obesity is characterized by proinflammatory macrophage infiltration into adipose tissue. Catalysis by deoxyhypusine synthase (DHPS) modifies the translation factor eIF5A to generate a hypusine (Hyp) residue. Hypusinated eIF5A (eIF5AHyp) controls the translation of mRNAs involved in inflammation, but its role in meta-inflammation has not been elucidated. Levels of eIF5AHyp were found to be increased in adipose tissue macrophages from obese mice and in murine macrophages activated to a proinflammatory M1-like state. Global proteomics and transcriptomics revealed that DHPS deficiency in macrophages altered the abundance of proteins involved in NF-κB signaling, likely through translational control of their respective mRNAs. DHPS deficiency in myeloid cells of obese mice suppressed M1 macrophage accumulation in adipose tissue and improved glucose tolerance. These findings indicate that DHPS promotes the post-transcriptional regulation of a subset of mRNAs governing inflammation and chemotaxis in macrophages and contributes to a proinflammatory M1-like phenotype.

ß-Cell pre-mir-21 induces dysfunction and loss of cellular identity by targeting transforming growth factor beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs.

OBJECTIVE: ß-cell microRNA-21 (miR-21) is increased by islet inflammatory stress but it decreases glucose-stimulated insulin secretion (GSIS). Thus, we sought to define the effects of miR-21 on ß-cell function using in vitro and in vivo systems. METHODS: We developed a tetracycline-on system of pre-miR-21 induction in clonal ß-cells and human islets, along with transgenic zebrafish and mouse models of ß-cell-specific pre-miR-21 overexpression. RESULTS: ß-cell miR-21 induction markedly reduced GSIS and led to reductions in transcription factors associated with ß-cell identity and increased markers of dedifferentiation, which led us to hypothesize that miR-21 induces ß-cell dysfunction by loss of cell identity. In silico analysis identified transforming growth factor-beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs as predicted miR-21 targets associated with the maintenance of ß-cell identity. Tgfb2 and Smad2 were confirmed as direct miR-21 targets through RT-PCR, immunoblot, pulldown, and luciferase assays. In vivo zebrafish and mouse models exhibited glucose intolerance, decreased peak GSIS, decreased expression of ß-cell identity markers, increased insulin and glucagon co-staining cells, and reduced Tgfb2 and Smad2 expression. CONCLUSIONS: These findings implicate miR-21-mediated reduction of mRNAs specifying ß-cell identity as a contributor to ß-cell dysfunction by the loss of cellular differentiation.

Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes. METHODS: We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point. RESULTS: We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics. CONCLUSIONS: In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection.

Clinical and Radiographic Comparison Between Open Versus Minimally Invasive Transforaminal Lumbar Interbody Fusion With Bilateral Facetectomies.

STUDY DESIGN: Age- and sex-matched cohort study. OBJECTIVES: To compare outcomes after open versus minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) with bilateral facetectomies. METHODS: We retrospectively compared patients who underwent single- or 2-level MIS-TLIF with an age- and sex-matched open-TLIF cohort. Surgical data was collected for operative time, estimated blood loss (EBL), and drain use. Clinical outcomes included the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), length of stay (LOS), complications, and reoperations. Lumbar radiographs were measured for changes in global lumbar lordosis (LL) and segmental lordosis (SL). RESULTS: Between 2016 and 2020, 38 MIS-TLIF patients were compared with 38 open-TLIF patients. No subfascial drain was used in the MIS-TLIF group (P < .001). The MIS-TLIF group had longer operative time (310.8 vs 276.5 minutes; P = .046) but less EBL (282.4 vs 420.8 mL; P = .007). LOS (P = .15), complication rates (P = .50), and revision rates (P = .17) were equivalent. VAS and ODI improved but did not differ between groups. In the open-TLIF group, LL and SL were restored or improved in 81.6% and 86.9% of cases, respectively. In the MIS-TLIF group, LL and SL were restored or improved in 86.8% and 97.4% of cases, respectively. There were no differences in changes in LL and SL between groups. CONCLUSIONS: Compared with the age- and sex-matched open-TLIF cohort, patients undergoing MIS-TLIF had reduced EBL and subfascial drain use but increased operative time. There were no differences in complications, reoperations, or LOS. Both groups demonstrated improvement in VAS and ODI. MIS-TLIF with bilateral facetectomies provided equivalent improvements in global and segmental LL.

A novel Cre-enabled tetracycline-inducible transgenic system for tissue-specific cytokine expression in the zebrafish: CETI-PIC3.

Maladaptive signaling by pro-inflammatory cytokines (PICs), such as TNFα, IL1ß and IFNÉ£, can activate downstream signaling cascades that are implicated in the development and progression of multiple inflammatory diseases. Despite playing critical roles in pathogenesis, the availability of in vivo models in which to model tissue-specific induction of PICs is limited. To bridge this gap, we have developed a novel multi-gene expression system dubbed Cre-enabled and tetracycline-inducible transgenic system for conditional, tissue-specific expression of pro-inflammatory cytokines (CETI-PIC3). This binary transgenic system permits the stoichiometric co-expression of proteins Tumor necrosis factor a (Tnfa), Interleukin-1 beta (Il1b) and Interferon gamma (Ifng1), and H2B-GFP fluorescent reporter in a dose-dependent manner. Furthermore, cytokine misexpression is enabled only in tissue domains that can be defined by Cre recombinase expression. We have validated this system in zebrafish using an insulin:cre line. In doubly transgenic fish, quantitative real-time polymerase chain reaction demonstrated increased expression levels of tnfa, il1b and ifng1 mRNA. Moreover, specific expression in pancreatic ß cells was demonstrated by both Tnfa immunofluorescence and GFP fluorescence. Cytokine-overexpressing islets elicited specific responses: ß cells exhibited increased expression of genes associated with reactive oxidative species-mediated stress and endoplasmic reticulum stress, surveilling and infiltrating macrophages were increased, and ß cell death was promoted. This powerful and versatile model system can be used for modeling, analysis and therapy development of diseases with an underlying inflammatory etiology.This article has an associated First Person interview with the first author of the paper.

Characterization of Arylalkylamine N-Acyltransferase from Tribolium castaneum: An Investigation into a Potential Next-Generation Insecticide Target.

The growing issue of insecticide resistance has meant the identification of novel insecticide targets has never been more important. Arylalkylamine N-acyltransferases (AANATs) have been suggested as a potential new target. These promiscuous enzymes are involved in the N-acylation of biogenic amines to form N-acylamides. In insects, this process is a key step in melanism, hardening of the cuticle, removal of biogenic amines, and in the biosynthesis of fatty acid amides. The unique nature of each AANAT isoform characterized indicates each organism accommodates an assembly of discrete AANATs relatively exclusive to that organism. This implies a high potential for selectivity in insecticide design, while also maintaining polypharmacology. Presented here is a thorough kinetic and structural analysis of AANAT found in one of the most common secondary pests of all plant commodities in the world, Tribolium castaneum. The enzyme, named TcAANAT0, catalyzes the formation of short-chain N-acylarylalkylamines, with short-chain acyl-CoAs (C2-C10), benzoyl-CoA, and succinyl-CoA functioning in the role of acyl donor. Recombinant TcAANAT0 was expressed and purified from E. coli and was used to investigate the kinetic and chemical mechanism of catalysis. The kinetic mechanism is an ordered sequential mechanism with the acyl-CoA binding first. pH-rate profiles and site-directed mutagenesis studies identified amino acids critical to catalysis, providing insights about the chemical mechanism of TcAANAT0. A crystal structure was obtained for TcAANAT0 bound to acetyl-CoA, revealing valuable information about its active site. This combination of kinetic analysis and crystallography alongside mutagenesis and sequence analysis shines light on some approaches possible for targeting TcAANAT0 and other AANATs for novel insecticide design.

TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death.

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors activate cell death and confer disease resistance by unknown mechanisms. We demonstrate that plant Toll/interleukin-1 receptor (TIR) domains of NLRs are enzymes capable of degrading nicotinamide adenine dinucleotide in its oxidized form (NAD+). Both cell death induction and NAD+ cleavage activity of plant TIR domains require known self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD+-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase. We identify a variant of cyclic adenosine diphosphate ribose as a biomarker of TIR enzymatic activity. TIR enzymatic activity is induced by pathogen recognition and functions upstream of the genes enhanced disease susceptibility 1 (EDS1) and N requirement gene 1 (NRG1), which encode regulators required for TIR immune function. Thus, plant TIR-NLR receptors require NADase function to transduce recognition of pathogens into a cell death response.

A content analysis of HPV vaccine online continuing medical education purpose statements and learning objectives.

Numerous online HPV vaccine education interventions for clinicians have been created to improve HPV vaccinations rates. The aims for this study were to (1) assess the content of the purpose statements and learning objectives of online HPV vaccine continuing medical education (CME) activities developed for clinicians and (2) identify themes and gaps in the purpose statements and learning objectives. A content analysis was conducted of the purpose statements and learning objectives for each HPV vaccine online CME activity. Open coding identified the following purpose statements topics: 1) delivering recommendations, 2) HPV epidemiology, 3) HPV vaccine, 4) guidelines, and 5) medical news. The following topics for learning objectives were identified: 1) delivering recommendations, 2) strategies, 3) HPV epidemiology, 4) HPV vaccine, 5) guidelines, 6) prevention services, 7) HPV vaccination advocacy, and 8) disparities. Phrases about guidelines for vaccine administration and vaccine recommendation guidelines were the most common for purpose statements and learning objectives, respectively. One learning objective focused on behavior/skill change, which is concerning considering clinicians do not feel well prepared to provide strong vaccine recommendations. Clear and intentional purpose statements and learning objectives must be used to guide the development of effective CME activities.

Lung injury from inhaling butane hash oil mimics pneumonia.

INTRODUCTION: "Dabbing", a relatively new form of THC use which utilizes Butane Hash Oil (BHO), an extraction of dried cannabis containing high levels of butane and terpene byproducts. The extraction process yields a waxy substance that is heated, vaporized and inhaled. We describe a lung injury as a result of BHO use. CASE: A previously healthy 18-year-old female presented to the ED with shortness of breath for 3-4 days. Initial oxygen saturation was 79% on room air. She was refractory to bronchodilators, steroids and supplemental O2. She has a 1-pack year smoking history and daily BHO abuse. Chest x-ray was positive for bilateral patchy infiltrates with mild hyperinflation. CT was negative for Pulmonary Embolus or other acute pathologic process. Sputum gram stain and blood cultures were negative. Arterial blood gases confirmed a pO2 of 73 mmHg. On physical exam she was tachycardic and tachypneic. Respiratory auscultation showed decreased air entry bilaterally with diffuse expiratory wheezing, bilateral rhonchi and a prolonged expiratory phase. We concluded her severe pneumonitis was secondary to daily BHO inhalation. DISCUSSION: Heating BHO to high temperatures, releases up to 75% of THC, compared to 5-20% THC in traditional smoked cannabis. At 978°F terpenes degrade into methacrolein and benzene. Methacrolein is structurally similar to acrolein, a pulmonary irritant, which causes acute lung injury and pulmonary edema in laboratory animals. We hypothesize a mechanism of lung injury and acute respiratory failure secondary to inhalation of high levels of methacrolein and benzene related to relatively novel phenomena of BHO use.

Electromagnetic Interference with Protocolized Electrosurgery Dispersive Electrode Positioning in Patients with Implantable Cardioverter Defibrillators.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Electromagnetic interference from monopolar electrosurgery may disrupt implantable cardioverter defibrillators.Current management recommendations by the American Society of Anesthesiologists and Heart Rhythm Society are based on expert clinical opinion since there is a paucity of data regarding the risk of electromagnetic interference to implantable cardioverter defibrillators during surgery. WHAT THIS ARTICLE TELLS US THAT IS NEW: With protocolized electrosurgery dispersive electrode positioning in patients with implantable cardioverter defibrillators, the risk of clinically meaningful electromagnetic interference was 7% in above-the-umbilicus noncardiac surgery and 0% in below-the-umbilicus surgery. In cardiac surgery, clinically meaningful electromagnetic interference with use of an underbody dispersive electrode was 29%.Despite protocolized dispersive electrode positioning, the risk of electromagnetic interference in above-the-umbilicus surgery is high, supporting recommendations to suspend antitachycardia therapy when monopolar electrosurgery is used above the umbilicus.With protocolized dispersive electrode positioning, the risk of electromagnetic interference in below-the-umbilicus surgery is negligible, implying that suspending antitachycardia therapy might be unnecessary in these cases.With an underbody dispersive electrode, the risk of electromagnetic interference in cardiac surgery is high. BACKGROUND: The goal of this study was to determine the occurrence of intraoperative electromagnetic interference from monopolar electrosurgery in patients with an implantable cardioverter defibrillator undergoing surgery. A protocolized approach was used to position the dispersive electrode. METHODS: This was a prospective cohort study including 144 patients with implantable cardioverter defibrillators undergoing surgery between May 2012 and September 2016 at an academic medical center. The primary objectives were to determine the occurrences of electromagnetic interference and clinically meaningful electromagnetic interference (interference that would have resulted in delivery of inappropriate antitachycardia therapy had the antitachycardia therapy not been programmed off) in noncardiac surgeries above the umbilicus, noncardiac surgeries at or below the umbilicus, and cardiac surgeries with the use of an underbody dispersive electrode. RESULTS: The risks of electromagnetic interference and clinically meaningful electromagnetic interference were 14 of 70 (20%) and 5 of 70 (7%) in above-the-umbilicus surgery, 1 of 40 (2.5%) and 0 of 40 (0%) in below-the-umbilicus surgery, and 23 of 34 (68%) and 10 of 34 (29%) in cardiac surgery. Had conservative programming strategies intended to reduce the risk of inappropriate antitachycardia therapy been employed, the occurrence of clinically meaningful electromagnetic interference would have been 2 of 70 (2.9%) in above-the-umbilicus surgery and 3 of 34 (8.8%) in cardiac surgery. CONCLUSIONS: Despite protocolized dispersive electrode positioning, the risks of electromagnetic interference and clinically meaningful electromagnetic interference with surgery above the umbilicus were high, supporting published recommendations to suspend antitachycardia therapy whenever monopolar electrosurgery is used above the umbilicus. For surgery below the umbilicus, these risks were negligible, implying that suspending antitachycardia therapy is likely unnecessary in these patients. For cardiac surgery, the risks of electromagnetic interference and clinically meaningful electromagnetic interference with an underbody dispersive electrode were high. Conservative programming strategies would not have eliminated the risk of clinically meaningful electromagnetic interference in either noncardiac surgery above the umbilicus or cardiac surgery.

Cognitive behavioral treatments for insomnia and pain in adults with comorbid chronic insomnia and fibromyalgia: clinical outcomes from the SPIN randomized controlled trial.

STUDY OBJECTIVES: To examine the effects of cognitive behavioral treatments for insomnia (CBT-I) and pain (CBT-P) in patients with comorbid fibromyalgia and insomnia. METHODS: One hundred thirteen patients (Mage = 53, SD = 10.9) were randomized to eight sessions of CBT-I (n = 39), CBT-P (n = 37), or a waitlist control (WLC, n = 37). Primary (self-reported sleep onset latency [SOL], wake after sleep onset [WASO], sleep efficiency [SE], sleep quality [SQ], and pain ratings) and secondary outcomes (dysfunctional beliefs and attitudes about sleep [DBAS]; actigraphy and polysomnography SOL, WASO, and SE; McGill Pain Questionnaire; Pain Disability Index; depression; and anxiety) were examined at posttreatment and 6 months. RESULTS: Mixed effects analyses revealed that both treatments improved self-reported WASO, SE, and SQ relative to control at posttreatment and follow-up, with generally larger effect sizes for CBT-I. DBAS improved in CBT-I only. Pain and mood improvements did not differ by group. Clinical significance analyses revealed the proportion of participants no longer reporting difficulties initiating and maintaining sleep was higher for CBT-I posttreatment and for both treatments at 6 months relative to control. Few participants achieved >50% pain reductions. Proportion achieving pain reductions of >30% (~1/3) was higher for both treatments posttreatment and for CBT-I at 6 months relative to control. CONCLUSIONS: CBT-I and CBT-P improved self-reported insomnia symptoms. CBT-I prompted improvements of larger magnitude that were maintained. Neither treatment improved pain or mood. However, both prompted clinically meaningful, immediate pain reductions in one third of patients. Improvements persisted for CBT-I, suggesting that CBT-I may provide better long-term pain reduction than CBT-P. Research identifying which patients benefit and mechanisms driving intervention effects is needed. CLINICAL TRIAL: Sleep and Pain Interventions in Fibromyalgia (SPIN), clinicaltrials.gov, NCT02001077.

A prospective study of the pathophysiology of carcinoid crisis.

BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed.

Shock subtypes by left ventricular ejection fraction following out-of-hospital cardiac arrest.

BACKGROUND: Post-resuscitation hemodynamic instability following out-of-hospital cardiac arrest (OHCA) may occur from myocardial dysfunction underlying cardiogenic shock and/or inflammation-mediated distributive shock. Distinguishing the predominant shock subtype with widely available clinical metrics may have prognostic and therapeutic value. METHODS: A two-hospital cohort was assembled of patients in shock following OHCA. Left ventricular ejection fraction (LVEF) was assessed via echocardiography or cardiac ventriculography within 1 day post arrest and used to delineate shock physiology. The study evaluated whether higher LVEF, indicating distributive-predominant shock physiology, was associated with neurocognitive outcome (primary endpoint), survival, and duration of multiple organ failures. The study also investigated whether volume resuscitation exhibited a subtype-specific association with outcome. RESULTS: Of 162 patients with post-resuscitation shock, 48% had normal LVEF (> 40%), consistent with distributive shock physiology. Higher LVEF was associated with less favorable neurocognitive outcome (OR 0.74, 95% CI 0.58-0.94 per 10% increase in LVEF; p = 0.01). Higher LVEF also was associated with worse survival (OR 0.81, 95% CI 0.67-0.97; p = 0.02) and fewer organ failure-free days (ß = - 0.67, 95% CI - 1.28 to - 0.06; p = 0.03). Only 51% of patients received a volume challenge of at least 30 ml/kg body weight in the first 6 h post arrest, and the volume received did not differ by LVEF. Greater volume resuscitation in the first 6 h post arrest was associated with favorable neurocognitive outcome (OR 1.59, 95% CI 0.99-2.55 per liter; p = 0.03) and survival (OR 1.44, 95% CI 1.02-2.04; p = 0.02) among patients with normal LVEF but not low LVEF. CONCLUSIONS: In post-resuscitation shock, higher LVEF-indicating distributive shock physiology-was associated with less favorable neurocognitive outcome, fewer days without organ failure, and higher mortality. Greater early volume resuscitation was associated with more favorable neurocognitive outcome and survival in patients with this shock subtype. Additional studies with repeated measures of complementary hemodynamic parameters are warranted to validate the clinical utility for subtyping post-resuscitation shock.