Targeted Antioxidant Therapy Reduces Hyperglycemic Exacerbation of Myocardial Ischemia-Reperfusion.

INTRODUCTION: Acute hyperglycemia (HG) enhances inflammatory and oxidative stress and exacerbates myocardial infarct size during ischemia-reperfusion injury by activating splenic leukocytes. Formyl peptide receptor 1 (FPR1) on leukocytes is activated by and mediates myocardial ischemia-reperfusion injury. We hypothesize that selective FPR1 antagonist cinnamoyl-F-(D)L-F-(D)L-F (CF) or potent reducing agent tris (2-carboxyethyl) phosphine hydrochloride (TCEP) could abrogate hyperglycemic infarct exacerbation, both alone and synergistically via a novel CF-TCEP compound that would target leukocytes for antioxidative effect. METHODS: Acute HG was induced in wild type mice with an intraperitoneal dextrose injection followed by left coronary artery occlusion (30 min) and reperfusion (60 min). In treatment groups, CF (0.1 mg/kg or 1 mg/kg), TCEP (1 mg/kg or 20 mg/kg), or the CF-TCEP conjugate (0.1 mg/kg) was administered intravenously before reperfusion. The hearts were harvested to measure infarct size (IF). RESULTS: HG resulted in >50% increase in IF compared to euglycemic mice (52.1 ± 3.0 versus 34.0 ± 3.2%, P < 0.05). Neither CF nor TCEP independently exerted an infarct-sparing effect at lower doses (46.2 ± 2.1% or 50.9 ± 4.1%, P > 0.05 versus HG control) but at high doses, significantly attenuated IF exacerbation (23.2 ± 5.2% or 33.9 ± 3.6%, P < 0.05 versus HG control). However, the low-dose CF-TCEP conjugate significantly reduced IF (39.1 ± 1.7%, P < 0.05 versus HG control). IF was decreased to near euglycemic control levels (P > 0.05). CONCLUSIONS: The CF-TECP conjugate synergistically attenuated HG infarct exacerbation at significantly lower respective doses of CF and TCEP. In addition to the intrinsic anti-inflammatory effect of blocking FPR1, CF is also a feasible tool for leukocyte-targeted therapy to treat IRI.

Characterization of the robotic surgery experience in minimally invasive surgery fellowships from 2010 to 2021.

BACKGROUND: Robotic surgery has experienced exponential growth in the past decade. Few studies have evaluated the impact of robotics within minimally invasive surgery (MIS) fellowship training programs. The purpose of our study was to examine and characterize recent trends in robotic surgery within MIS fellowship training programs. METHODS: De-identified case log data from the Fellowship Council from 2010 to 2021 were evaluated. Percentage of operations performed with robot assistance over time was assessed and compared to the laparoscopic and open experience. Case logs were further stratified by operative category (e.g., bariatric, hernia, foregut), and robotic experience over time was evaluated for each category. Programs were stratified by percent robot use and the experience over time within each quartile was evaluated. RESULTS: MIS fellowship training programs with a robotic platform increased from 45.1% (51/113) to 90.4% (123/136) over the study period. The percentage of robotic cases increased from 2.0% (1127/56,033) to 23.2% (16,139/69,496) while laparoscopic cases decreased from 80.2% (44,954/56,033) to 65.3% (45,356/69,496). Hernia and colorectal case categories had the largest increase in robot usage [hernia: 0.7% (62/8614) to 38.4% (4661/12,135); colorectal 4.2% (116/2747) to 31.8% (666/2094)]. When stratified by percentage of robot utilization, current (2020-2021) programs in the > 95th percentile performed 21.8% (3523/16,139) of robotic operations and programs in the > 50th percentile performed 90.0% (14,533/16,139) of all robotic cases. The median number of robotic cases performed per MIS fellow significantly increased from 2010 to 2021 [0 (0-6) to 72.5 (17.8-171.5), p < 0.01]. CONCLUSIONS: Robotic use in MIS fellowship training programs has grown substantially in the past decade, but the laparoscopic and open experience remains robust. There remains an imbalance with the top 50% of busiest robotic programs performing over 90% of robot trainee cases. The experience in MIS programs varies widely and trainees should examine program case logs closely to confirm parallel interests.

Hydroxychloroquine Attenuates Myocardial Ischemic and Post-Ischemic Reperfusion Injury by Inhibiting the Toll-Like Receptor 9 - Type I Interferon Pathway.

Background: We hypothesized that hydroxychloroquine (HCQ) attenuates myocardial ischemia/reperfusion injury (IRI) via TLR9 - type I interferon (IFN-I) pathway inhibition. Methods: The left coronary artery of wild-type (WT) C57BL/6 and congenic TLR9-/- mice was occluded for 40 minutes, with or without 60 minutes of reperfusion (40'/0' or 40'/60'). Either ODN-2088 or HCQ (TLR9 inhibitors), or ODN-1826 (TLR9 agonist) was administered to determine effect on infarct size (IS). After 40'/0', cardiac perfusate (CP) was collected from harvested hearts and administered to either intact WT mice after 20 minutes of ischemia or isolated splenocytes. Type-I interferon (IFNα and IFNß) levels were measured in plasma and splenocyte culture supernatant, and levels of damage associated molecular patterns HMGB1 and cell-free DNA (cfDNA) were measured in CP. Results: After 40'/60', WT mice treated with HCQ or ODN-2088 had significantly reduced IS. TLR9-/- mice and HCQ-treated WT mice undergoing 40'/0' and 40'/60' similarly attenuated IS, with significantly lower IFN-Is in CP after 40'/0' and in plasma after 40'/60'. IS was significantly increased in 40'/0' CP-treated and ODN-1826-treated 20'/60' WT mice. CP-treated WT splenocytes produced significantly higher IFN-I in culture supernatant, which was significantly reduced with HCQ. Conclusions: The TLR9-IFN-I-mediated inflammatory response contributes significantly to both ischemic and post-ischemic myocardial ischemia-reperfusion injury. HMGB1 and cfDNA released from ischemic myocardium activated the intra-myocardial TLR9 - IFN-I inflammatory pathway during ischemia and the extra-myocardial TLR9 - IFN-I inflammatory pathway during reperfusion. Hydroxychloroquine reduces production of IFN-I and attenuates myocardial IRI, likely by inhibiting the TLR9-IFN-I pathway.

Topical Neck Cooling Without Systemic Hypothermia Attenuates Myocardial Ischemic Injury and Post-ischemic Reperfusion Injury.

Background: Following acute myocardial infarction (MI), irreversible damage to the myocardium can only be reduced by shortening the duration between symptom onset and revascularization. While systemic hypothermia has shown promising results in slowing pre-revascularization myocardial damage, it is resource intensive and not conducive to prehospital initiation. We hypothesized that topical neck cooling (NC), an easily implemented therapy for en route transfer to definitive therapy, could similarly attenuate myocardial ischemia-reperfusion injury (IRI). Methods: Using an in vivo mouse model of myocardial IRI, moderate systemic hypothermia or NC was applied following left coronary artery (LCA) occlusion and subsequent reperfusion, at early, late, and post-reperfusion intervals. Vagotomy was performed after late NC in an additional group. Hearts were harvested to measure infarct size. Results: Both hypothermia treatments equally attenuated myocardial infarct size by 60% compared to control. The infarct-sparing effect of NC was temperature-dependent and timing-dependent. Vagotomy at the gastroesophageal junction abolished the infarct-sparing effect of late NC. Cardiac perfusate isolated following ischemia had significantly reduced cardiac troponin T, HMGB1, cell-free DNA, and interferon α and ß levels after NC. Conclusions: Topical neck cooling attenuates myocardial IRI in a vagus nerve-dependent manner, with an effect comparable to that of systemic hypothermia. NC attenuated infarct size when applied during ischemia, with earlier initiation resulting in superior infarct sparing. This novel therapy exerts a cardioprotective effect without requiring significant change in core temperature and may be a promising practical strategy to attenuate myocardial damage while patients await definitive revascularization.

Two Hours of In Vivo Lung Perfusion Improves Lung Function in Sepsis-Induced Acute Respiratory Distress Syndrome.

Sepsis is the leading cause of acute respiratory distress syndrome (ARDS) in adults and carries a high mortality. Utilizing a previously validated porcine model of sepsis-induced ARDS, we sought to refine our novel therapeutic technique of in vivo lung perfusion (IVLP). We hypothesized that 2 hours of IVLP would provide non-inferior lung rehabilitation compared to 4 hours of treatment. Adult swine (n = 8) received lipopolysaccharide to develop ARDS and were placed on central venoarterial extracorporeal membrane oxygenation. Animals were randomized to 2 vs 4 hours of IVLP. The left pulmonary vessels were cannulated to IVLP using antegrade Steen solution. After IVLP treatment, the left lung was decannulated and reperfused for 4 hours. Total lung compliance and pulmonary venous gases from the right lung (control) and left lung (treatment) were sampled hourly. Biochemical analysis of tissue and bronchioalveolar lavage was performed along with tissue histologic assessment. Throughout IVLP and reperfusion, treated left lung PaO2/FiO2 ratio was significantly higher than the right lung control in the 2-hour group (332.2 ± 58.9 vs 264.4 ± 46.5, P = 0.01). In the 4-hour group, there was no difference between treatment and control lung PaO2/FiO2 ratio (258.5 ± 72.4 vs 253.2 ± 90.3, P = 0.58). Wet-to-dry weight ratios demonstrated reduced edema in the treated left lungs of the 2-hour group (6.23 ± 0.73 vs 7.28 ± 0.61, P = 0.03). Total lung compliance was also significantly improved in the 2-hour group. Two hours of IVLP demonstrated superior lung function in this preclinical model of sepsis-induced ARDS. Clinical translation of IVLP may shorten duration of mechanical support and improve outcomes.

Secondary Burn Progression Mitigated by an Adenosine 2A Receptor Agonist.

Current burn therapy is largely supportive with limited therapies to curb secondary burn progression. Adenosine 2A receptor (A2AR) agonists have anti-inflammatory effects with decreased inflammatory cell infiltrate and release of proinflammatory mediators. Using a porcine comb burn model, we examined whether A2AR agonists could mitigate burn progression. Eight full-thickness comb burns (four prongs with three spaces per comb) per pig were generated with the following specifications: temperature 115°C, 3-kg force, and 30-second application time. In a randomized fashion, animals (four per group) were then treated with A2AR agonist (ATL-1223, 3 ng/kg/min, intravenous infusion over 6 hours) or vehicle control. Necrotic interspace development was the primary outcome and additional histologic assessments were conducted. Analysis of unburned interspaces (72 per group) revealed that ATL-1223 treatment decreased the rate of necrotic interspace development over the first 4 days following injury (p < .05). Treatment significantly decreased dermal neutrophil infiltration at 48 hours following burn (14.63 ± 4.30 vs 29.71 ± 10.76 neutrophils/high-power field, p = .029). Additionally, ATL-1223 treatment was associated with fewer interspaces with evidence of microvascular thrombi through postburn day 4 (18.8% vs 56.3%, p = .002). Two weeks following insult, the depth of injury at distinct burn sites (adjacent to interspaces) was significantly reduced by ATL-1223 treatment (2.91 ± 0.47 vs 3.28 ± 0.58 mm, p = .038). This work demonstrates the ability of an A2AR agonist to mitigate burn progression through dampening local inflammatory processes. Extended dosing strategies may yield additional benefit and improve cosmetic outcome in those with severe injury.

Endothelial Transient Receptor Potential Vanilloid 4 Channels Mediate Lung Ischemia-Reperfusion Injury.

BACKGROUND: Lung ischemia-reperfusion injury (IRI), involving severe inflammation and edema, is a major cause of primary graft dysfunction after transplant. Activation of transient receptor potential vanilloid 4 (TRPV4) channels modulates vascular permeability. Thus, this study tests the hypothesis that endothelial TRPV4 channels mediate lung IRI. METHODS: A left lung hilar-ligation model was used to induce lung IR in C57BL/6 wild-type (WT), Trpv4-/-, tamoxifen-inducible endothelial Trpv4 knockout (Trpv4EC-/-), and tamoxifen-treated control (Trpv4fl/fl) (n ≥ 6 mice/group). WT mice were also treated with GSK2193874 (WT+GSK219), a TRPV4-specific inhibitor (1 mg/kg). Partial pressure of arterial oxygen, edema (wet-to-dry weight ratio), compliance, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid were assessed. Pulmonary microvascular endothelial cells were characterized in vitro after exposure to hypoxia-reoxygenation. RESULTS: Compared with WT, partial pressure of arterial oxygen after IR was significantly improved in Trpv4-/- mice (133.1 ± 43.9 vs 427.8 ± 83.1 mm Hg, P < .001) and WT+GSK219 mice (133.1 ± 43.9 vs 447.0 ± 67.6 mm Hg, P < .001). Pulmonary edema and neutrophil infiltration were also significantly reduced after IR in Trpv4-/- and WT+GSK219 mice vs WT. Trpv4EC-/- mice after IR demonstrated significantly improved oxygenation vs control (109.2 ± 21.6 vs 405.3 ± 41.4 mm Hg, P < .001) as well as significantly improved compliance and significantly less edema, neutrophil infiltration, and proinflammatory cytokine production (tumor necrosis factor-a, chemokine [C-X-C motif] ligand 1, interleukin 17, interferon-γ). Hypoxia-reoxygenation-induced permeability and chemokine (C-X-C motif) ligand 1 expression by pulmonary microvascular endothelial cells were significantly attenuated by TRPV4 inhibitors. CONCLUSIONS: Endothelial TRPV4 plays a key role in vascular permeability and lung inflammation after IR. TRPV4 channels may be a promising therapeutic target to mitigate lung IRI and decrease the incidence of primary graft dysfunction after transplant.

Topical Neck Cooling Prolongs Survival of Rats with Intra-Abdominal Feculent Sepsis by Activation of the Vagus Nerve.

Global hypothermia prolongs survival in rats with intraabdominal feculent sepsis by inhibiting inflammatory responses. We hypothesized that topical neck cooling (TNC) has similar benefits. Septic shock was induced by cecal ligation and incision (CLI) in Sprague Dawley rats. Rats were randomized to sham laparotomy, control with CLI, CLI with TNC, or vagotomy at the gastroesophageal junction before CLI and TNC. Two more groups underwent peritoneal washout with and without TNC two hours after CLI. TNC significantly lowered neck skin temperature (16.7 ± 1.4 vs. 30.5 ± 0.6 °C, p < 0.05) while maintaining core body normothermia. TNC rats recovered from anesthesia 70 min earlier than the control (p < 0.05). Three hours following CLI, the control and vagotomy with TNC groups had significantly more splenic contraction, fewer circulating leukocytes and higher plasma IL-1ß, IL-10 and TNF-α levels than TNC rats (p < 0.05). TNC prolonged survival duration after CLI by a median of four hours vs. control (p < 0.05), but no benefit was seen if vagotomy preceded TNC. Peritoneal washout alone increased survival by 3 h (9.2 (7.8-10.5) h). Survival duration increased dramatically with TNC preceding washout, to a 56% survival rate (>10 days). TNC significantly prolonged the survival of rats with severe intraabdominal sepsis by inhibiting systemic proinflammatory responses by activating vagal anti-inflammatory pathways.

Plasmacytoid Dendritic Cells Mediate Myocardial Ischemia/Reperfusion Injury by Secreting Type I Interferons.

Background We previously demonstrated that ischemically injured cardiomyocytes release cell-free DNA and HMGB1 (high mobility group box 1 protein) into circulation during reperfusion, activating proinflammatory responses and ultimately exacerbating reperfusion injury. We hypothesize that cell-free DNA and HMGB1 mediate myocardial ischemia-reperfusion injury by stimulating plasmacytoid dendritic cells (pDCs) to secrete type I interferon (IFN-I). Methods and Results C57BL/6 and interferon alpha receptor-1 knockout mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion (40'/60' IR) before infarct size was evaluated by 2,3,5-Triphenyltetrazolium chloride-Blue staining. Cardiac perfusate was acquired in ischemic hearts without reperfusion by antegrade perfusion of the isolated heart. Flow cytometry in pDC-depleted mice treated with multiple doses of plasmacytoid dendritic cell antigen-1 antibody via intraperitoneal injection demonstrated plasmacytoid dendritic cell antigen-1 antibody treatment had no effect on conventional splenic dendritic cells but significantly reduced splenic pDCs by 60%. pDC-depleted mice had significantly smaller infarct size and decreased plasma interferon-α and interferon-ß compared with control. Blockade of the type I interferon signaling pathway with cyclic GMP-AMP synthase inhibitor, stimulator of interferon genes antibody, or interferon regulatory factor 3 antibody upon reperfusion similarly significantly attenuated infarct size by 45%. Plasma levels of interferon-α and interferon-ß were significantly reduced in cyclic GMP-AMP synthase inhibitor-treated mice. Infarct size was significantly reduced by >30% in type I interferon receptor monoclonal antibody-treated mice and interferon alpha receptor-1 knockout mice. In splenocyte culture, 40'/0' cardiac perfusate treatment stimulated interferon-α and interferon-ß production; however, this effect disappeared in the presence of cyclic GMP-AMP synthase inhibitor. Conclusions Type I interferon production is stimulated following myocardial ischemia by cardiogenic cell-free DNA/HMGB1 in a pDC-dependent manner, and subsequently activates type I interferon receptors to exacerbate reperfusion injury. These results identify new potential therapeutic targets to attenuate myocardial ischemia-reperfusion injury.

Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.

Pulsed ultrasound attenuates the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury.

OBJECTIVE: Acute hyperglycemia during myocardial infarction worsens outcomes in part by inflammatory mechanisms. Pulsed ultrasound has anti-inflammatory potential in bone healing and neuromodulation. We hypothesized that pulsed ultrasound would attenuate the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury via the cholinergic anti-inflammatory pathway. METHODS: Acute hyperglycemia was induced in wild-type C57BL6 or acetylcholine-receptor knockout (α7nAChR-/-) mice by intraperitoneal injection of glucose. Pulsed ultrasound (frequency 7 MHz, bursting mechanical index 1.2, duration 1 second, repeated every 6 seconds for 2 minutes, 20-second total exposure) was performed at the spleen or neck after glucose injection. Separate mice underwent vagotomy before treatment. The left coronary artery was occluded for 20 minutes, followed by 60 minutes of reperfusion. The primary end point was infarct size in explanted hearts. RESULTS: Splenic pulsed ultrasound significantly decreased infarct size in wild-type C57BL6 mice exposed to acute hyperglycemia and myocardial ischemia-reperfusion injury (5.2% ± 4.4% vs 16.9% ± 12.5% of risk region, P = .013). Knockout of α7nAChR abrogated the beneficial effect of splenic pulsed ultrasound (22.2% ± 12.1%, P = .79 vs control). Neck pulsed ultrasound attenuated the hyperglycemic exacerbation of myocardial infarct size (3.5% ± 4.8%, P = .004 vs control); however, the cardioprotective effect disappeared in mice that underwent vagotomy. Plasma acetylcholine, ß2 adrenergic receptor, and phosphorylated Akt levels were increased after splenic pulsed ultrasound treatment. CONCLUSIONS: Pulsed ultrasound treatment of the spleen or neck attenuated the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury leading to a 3-fold decrease in infarct size. Pulsed ultrasound may provide cardioprotection via the cholinergic anti-inflammatory pathway and could be a promising new nonpharmacologic, noninvasive therapy to reduce infarct size during acute myocardial infarction and improve patient outcomes.

Pulsed Ultrasound of the Spleen Prolongs Survival of Rats With Severe Intra-abdominal Sepsis.

BACKGROUND: The spleen is an important contributor to the uncontrolled, excessive release of proinflammatory signals during sepsis that leads to the development of tissue injury and diffuse end-organ dysfunction. Therapeutic pulsed ultrasound (pUS) has been shown to inhibit splenic leukocyte release and reduce cytokine production in other inflammatory disease processes. We hypothesized that pUS treatment inhibits spleen-derived inflammatory responses and increases survival duration in rats with severe intra-abdominal sepsis leading to septic shock. MATERIALS AND METHODS: Rats with intra-abdominal sepsis, induced by cecal ligation and incision, underwent abdominal washout, intra-peritoneal administration of cefazolin, and then either no further treatment (control), splenectomy, or pUS of the spleen. Animals were observed for the primary endpoint of survival duration. RESULTS: Survival curves were significantly different for all groups (P < 0.01). Median survival increased from 9.5 h in control rats to 19.8 h in pUS rats and 35.0 h in splenectomy rats (P < 0.01). At 4 h after cecal ligation and incision, the pUS group had decreased splenic contraction and leukocyte count (P = 0.03) compared with control, indicating reduced exodus of splenic leukocytes. In addition, elevation in plasma TNF-α and MCP-1 was significantly attenuated in the pUS group (P < 0.05 versus control). Splenic ß2 adrenergic receptor levels and phosphorylated Akt were significantly more elevated in the pUS group (P < 0.01 versus control). CONCLUSIONS: pUS significantly prolonged the survival duration of rats with severe intra-abdominal sepsis. This treatment may be an effective, noninvasive therapy that dampens detrimental immune responses during septic shock by activating ß2 adrenergic receptor-Akt phosphorylation in the cholinergic anti-inflammatory pathway.

Isolated Lung Perfusion in the Management of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. While our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. There is a dramatic need for the development and breakthrough of new methods for the treatment of ARDS. Isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. Initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ARDS. This review presents current tenants of ARDS management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (EVLP) has paved the way for current investigations utilizing in vivo lung perfusion (IVLP) in the treatment of severe ARDS.

Gastrointestinal Complications After Cardiac Surgery: Highly Morbid but Improving Over Time.

BACKGROUND: Gastrointestinal complications after cardiac surgery are associated with high morbidity and mortality. We sought to determine the granular impact of individual gastrointestinal complications after cardiac surgery and assess contemporary outcomes. MATERIALS AND METHODS: Patients undergoing cardiac surgery from 2010 to 2017 (6070 patients) were identified from an institutional Society of Thoracic Surgeons database. Records were paired with institutional data assessing gastrointestinal complications and cost. Patients were stratified by early (2010-2013) and current (2014-2017) eras. RESULTS: A total of 280 (4.6%) patients experienced gastrointestinal complications including Clostridiumdifficile infection (94, 33.6%), gastrointestinal bleed (86, 30.7%), hepatic failure (66, 23.6%), prolonged ileus (59, 21.1%), mesenteric ischemia (47, 16.8%), acute cholecystitis (17, 6.0%), and pancreatitis (14, 5.0%). Gastrointestinal complications were associated with higher rates of early postoperative major morbidity [206 (73.6%) versus 773 (13.4%), P < 0.0001], mortality [78 (27.9%) versus 161 (2.8%), P < 0.0001], length of stay (23 versus 6 d, P < 0.0001), and discharge to a facility [115 (41.1%) versus 1395 (24.1%), P < 0.0001]. Patients suffering gastrointestinal complications had worse risk-adjusted long-term survival (hazard ratio: 3.0, P < 0.0001) and higher adjusted cost ($9,173, P = 0.05). Between eras, there was no difference in incidence of gastrointestinal complications [139 (4.4%) versus 141 (4.8%), P = 0.51] or rate of specific complications (all P > 0.05). However, long-term survival increased in modern era (P < 0.0001). CONCLUSIONS: Although incidence of gastrointestinal complications after cardiac surgery has not changed over time, long-term survival has improved. Gastrointestinal complications remain associated with high resource utilization and major morbidity, but patients are now more likely to recover, highlighting the benefit of quality improvement efforts.

Enhanced Recovery After Thoracic Surgery.

Enhanced recovery pathways (ERPs), used across multiple surgical subspecialties, is a multidisciplinary delivery of perioperative care designed to lessen the psychological stress of patients undergoing surgery. Thoracic ERP has been implemented but is not widespread, and variations exist between programs. Evidence of the benefit of thoracic ERP is emerging. This article presents common components of a thoracic surgery ERP and reviews contemporary outcomes.

Emergent life events in the delivery of a caregiver-mediated evidence-based intervention for children with autism spectrum disorder in publicly funded mental health services.

LAY ABSTRACT: Mental health clinicians often report significant challenges when delivering evidence-based interventions (EBI) in community settings, particularly when unexpected client stressors (or emergent life events; ELEs) interfere with the therapy process. The current study sought to extend the study of ELEs to children with Autism Spectrum Disorder (ASD) by examining the occurrence and impact of ELEs in the context of a collaborative, caregiver-mediated intervention for reducing challenging behaviors in children with ASD. This intervention was An Individualized Mental Health Intervention for children with ASD (referred to as AIM HI). Participants included 38 clinicians and child clients who were enrolled in a community effectiveness trial of AIM HI. Video recordings of 100 therapy sessions were coded for caregiver-reported ELEs and also how well clinicians adhered to the AIM HI protocol. Results indicated that mild to severe ELEs were reported in 36% of therapy sessions, and were reported for 58% of children at some point during the intervention. Children who had a greater number of diagnoses (in addition to the autism diagnosis) tended to have more ELEs. In addition, clinicians with less years of experience tended to have sessions with more ELEs. There was no significant link between ELEs and how well clinicians adhered to the AIM HI protocol. Findings offer implications for the implementation of EBI, particularly the importance of incorporating clinician training in addressing complex presentations and crises in the context of EBIs.

Preoperative bleeding requiring transfusion: An under-reported indication for hemorrhoidectomy.

BACKGROUND: Though hemorrhoids commonly cause minor gastrointestinal bleeding, major hemorrhage requiring blood transfusion is believed to be rare. We sought to identify the prevalence and risk factors for preoperative transfusion in surgical hemorrhoidectomy patients. METHODS: Patients undergoing surgical hemorrhoidectomy at a single institution (2012-2017) were evaluated for preoperative bleeding requiring transfusion. Bivariate analysis compared patients requiring transfusion to those who did not, and multivariable analysis evaluated for independent risk factors for transfusion. RESULTS: Out of 520 patients, 7.3% experienced hemorrhoidal bleeding requiring transfusion, and 80.6% reported bleeding. On multivariable analysis, the use of either an anticoagulant or non-aspirin antiplatelet agent was associated with transfusion (OR 3.08, p = 0.03). Patients requiring transfusion had extensive preoperative workups, including colonoscopy (94.7%), flexible sigmoidoscopy (7.89%), upper endoscopy (50%) and capsule endoscopy (26.3%). CONCLUSIONS: Bleeding requiring transfusion is an under-reported complication of hemorrhoids. Increased recognition could lead to expeditious surgical treatment and less costly diagnostic workup.

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death.

BACKGROUND: Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs. METHODS: A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion. RESULTS: After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm H2O vs. 10.2 ± 3.5 ml/cm H2O, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1ß expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group. CONCLUSIONS: EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.

In-Session Caregiver Behaviors during Evidence-Based Intervention Delivery for Children with ASD in Community Mental Health Services.

An Individualized Mental Health Intervention for ASD, ("AIM HI"), is a collaborative, caregiver-mediated and child-directed intervention for reducing challenging behaviors in children with autism spectrum disorder developed for delivery in community mental health programs. Using observational data from AIM HI sessions, the present study characterized the occurrence of two types of in-session caregiver behaviors: expressed concerns (i.e., expressing concerns about treatment strategies; expressing difficulty using skills; expressing difficulty completing homework) and participation engagement (i.e., asking questions; participating in session activities; showing commitment to therapy). Further analyses examined cultural differences in caregiver behaviors and associations between caregiver behaviors and clinician adherence. Participants included 39 caregiver-clinician dyads enrolled in a community effectiveness trial of AIM HI. Video recordings from 107 sessions during the first two months of treatment were coded for in-session caregiver behaviors and clinician adherence. Results indicated that expressed concerns were observed in 47% of sessions. When controlling for household income, Latinx caregivers were rated lower for expressing concerns about treatment strategies and demonstrated lower participation engagement behaviors in session compared with non-Latinx White caregivers, suggesting that cultural factors may impact verbal engagement in sessions. Finally, expressing concerns about treatment strategies, expressing difficulty using skills, and participation engagement were positively associated with clinician adherence. Findings suggest that some expressed concerns and participation engagement behaviors may be indicators of positive caregiver engagement in the context of a collaborative intervention, and lower levels of such caregiver engagement may actually impede clinicians' delivery of intensive evidence-based intervention in routine care.

High-Resolution Mapping of Homologous Recombination Events in rad3 Hyper-Recombination Mutants in Yeast.

The Saccharomyces cerevisae RAD3 gene is the homolog of human XPD, an essential gene encoding a DNA helicase of the TFIIH complex involved in both nucleotide excision repair (NER) and transcription. Some mutant alleles of RAD3 (rad3-101 and rad3-102) have partial defects in DNA repair and a strong hyper-recombination (hyper-Rec) phenotype. Previous studies showed that the hyper-Rec phenotype associated with rad3-101 and rad3-102 can be explained as a consequence of persistent single-stranded DNA gaps that are converted to recombinogenic double-strand breaks (DSBs) by replication. The systems previously used to characterize the hyper-Rec phenotype of rad3 strains do not detect the reciprocal products of mitotic recombination. We have further characterized these events using a system in which the reciprocal products of mitotic recombination are recovered. Both rad3-101 and rad3-102 elevate the frequency of reciprocal crossovers about 100-fold. Mapping of these events shows that three-quarters of these crossovers reflect DSBs formed at the same positions in both sister chromatids (double sister-chromatid breaks, DSCBs). The remainder reflects DSBs formed in single chromatids (single chromatid breaks, SCBs). The ratio of DSCBs to SCBs is similar to that observed for spontaneous recombination events in wild-type cells. We mapped 216 unselected genomic alterations throughout the genome including crossovers, gene conversions, deletions, and duplications. We found a significant association between the location of these recombination events and regions with elevated gamma-H2AX. In addition, there was a hotspot for deletions and duplications at the IMA2 and HXT11 genes near the left end of chromosome XV. A comparison of these data with our previous analysis of spontaneous mitotic recombination events suggests that a sub-set of spontaneous events in wild-type cells may be initiated by incomplete NER reactions, and that DSCBs, which cannot be repaired by sister-chromatid recombination, are a major source of mitotic recombination between homologous chromosomes.