Combining Intraoperative Electrocochleography with Robotics-Assisted Electrode Array Insertion.

OBJECTIVE: To describe the use of robotics-assisted electrode array (EA) insertion combined with intraoperative electrocochleography (ECochG) in hearing preservation cochlear implant surgery. STUDY DESIGN: Prospective, single-arm, open-label study. SETTING: All procedures and data collection were performed at a single tertiary referral center. PATIENTS: Twenty-one postlingually deaf adult subjects meeting Food and Drug Administration indication criteria for cochlear implantation with residual acoustic hearing defined as thresholds no worse than 65 dB at 125, 250, and 500 Hz. INTERVENTION: All patients underwent standard-of-care unilateral cochlear implant surgery using a single-use robotics-assisted EA insertion device and concurrent intraoperative ECochG. MAIN OUTCOME MEASURES: Postoperative pure-tone average over 125, 250, and 500 Hz measured at initial activation and subsequent intervals up to 1 year afterward. RESULTS: Twenty-two EAs were implanted with a single-use robotics-assisted insertion device and simultaneous intraoperative ECochG. Fine control over robotic insertion kinetics could be applied in response to changes in ECochG signal. Patients had stable pure-tone averages after activation with normal impedance and neural telemetry responses. CONCLUSIONS: Combining robotics-assisted EA insertion with intraoperative ECochG is a feasible technique when performing hearing preservation implant surgery. This combined approach may provide the surgeon a means to overcome the limitations of manual insertion and respond to cochlear feedback in real-time.

Quality Improvement of Pediatric Airway Emergency Carts: Standardization, Streamlining, and Simulation.

Objective Pediatric airway emergencies are amongst the most tenuous scenarios faced by on-call providers, requiring quick access to the appropriate equipment and a timely response. In the present study, we report on the testing and improvement of pediatric airway carts at our institution. The primary objective was to optimize our pediatric airway emergency carts to improve response times. Secondarily, we aimed to implement a training scenario to improve providers' familiarity and confidence in attaining and assembling equipment. Methods Surveys of airway cart configuration at our hospital and others were used to identify differences. Volunteer otolaryngology physicians were tasked with responding to a mock scenario using an existing cart or one modified based on the survey. Outcomes included (1) time to arrival of the provider with the appropriate equipment, (2) time from arrival to complete assembly of equipment, and (3) time for re-assembly of the equipment. Results The survey revealed differences in cart equipment and location. The inclusion of a flexible bronchoscope and a video tower, as well as the placement of the carts directly within the ICU, resulted in improved time to arrival by an average of 181 seconds, and improved equipment assembly time by an average of 85 seconds. Discussion Standardization of pediatric airway equipment on the cart and location near critically ill patients improved response efficiency. Simulation led to improved confidence and reduced reaction time among providers at all levels of experience. Conclusion The present study provides an example for the optimization of airway carts, which can be adapted by healthcare systems to their local milieu.

Endoscopic pituitary surgery: National database review.

BACKGROUND: Pituitary tumors surgery is increasingly performed via endoscopic transsphenoidal approach (TSP). This study describes outcomes of TSP surgery in the United States. METHODS: A retrospective cross-sectional analysis of adult patients with pituitary adenoma was performed using the Nationwide Readmissions Database, 2010-2015. RESULTS: A total of 5891 patients were identified. The average age was 51.29 ± 0.29 years. The risk of postoperative epistaxis, diabetes insipidus, cerebrospinal fluid (CSF) leak, and other general postoperative complications was 0.71%, 10.20%, 8.35%, and 2.37%, respectively. Independent risk factors of CSF leak included: age <65-year, male, body mass index ≥25, and multiple comorbidities (p < 0.001 each). The prevalence of CSF leak was not associated with hospital TSP volume and teaching status. CONCLUSION: This study provides a national epidemiological perspective on TSP in the United States. The risk of postoperative CSF leak appears to be associated with intrinsic patient factors rather than resource and expertise availability.

Zwitterionic Photografted Coatings of Cochlear Implant Biomaterials Reduce Friction and Insertion Forces.

HYPOTHESIS: Application of photografted zwitterionic coatings to cochlear implant (CI) biomaterials will reduce friction and insertion forces. BACKGROUND: Strategies to minimize intracochlear trauma during implantation of an electrode array are critical to optimize outcomes including preservation of residual hearing. To this end, advances in thin-film zwitterionic hydrogel coatings on relevant biomaterials may show promise, in addition to the potential of these materials for decreasing the intracochlear foreign body response. METHODS: Using a recently designed one-step process, thin-film coatings derived from zwitterionic sulfobetaine methacrylate (SBMA) were photopolymerized and photografted to the surface of polydimethylsiloxane (PDMS, silastic) samples and also to CI arrays from two manufacturers. Fluorescein staining and scanning electron microscopy with energy-dispersive X-ray spectroscopy verified and characterized the coatings. Tribometry was used to measure the coefficient of friction between uncoated and coated PDMS and synthetic and biological tissues. Force transducer measurements were obtained during insertion of uncoated (n = 9) and coated (n = 9) CI electrode arrays into human cadaveric cochleae. RESULTS: SBMA thin-film coating of PDMS resulted in >90% reduction in frictional coefficients with steel, ceramic, and dermal tissue from guinea pigs (p < 0.0001). We employed a novel method for applying covalently bonded, durable, and uniform coating in geographically selective areas at the electrode array portion of the implant. Image analysis confirmed uniform coating of PDMS systems and the CI electrode arrays with SBMA polymer films. During insertion of electrode arrays into human cadaveric cochleae, SBMA coatings reduced maximum force by ∼40% during insertion (p < 0.001), as well as decreasing force variability and the overall work of insertion. CONCLUSION: Thin-film SBMA photografted coatings on PDMS and electrode arrays significantly reduce frictional coefficients and insertional forces in cadaveric cochleae. These encouraging findings support that thin-film zwitterionic coating of CI electrode arrays may potentially reduce insertional trauma and thereby promote improved hearing and other long-term outcomes.

Vascular pedicled flaps for skull base defect reconstruction.

OBJECTIVE: Techniques for reconstruction of skull base defects have advanced greatly since the introduction of the vascular pedicled nasoseptal flap in 2006. The objective of this review is to assess the current state of the field by examining both intranasal and extranasal techniques of vascular pedicled skull base defect repair, their indications and success rates, and novel techniques that are currently under investigation. METHODS: A review of the literature describing the use of vascular pedicled flaps in skull base defect reconstruction was conducted using PubMed and Google Scholar. RESULTS: The nasoseptal flap remains the most widely used vascular pedicled flap for endoscopic repair of skull base defects. Its ease of harvest, wide arch of rotation, and high success rates make it a popular choice among surgeons. Several variations including a "rescue" nasopseptal flap have been developed. Other less commonly used pedicled intranasal flaps include the middle turbinate flap and the posterior pedicled inferior turbinate flap. Additionally, several novel vascular pedicled flaps have been developed and tested in small cohorts of patients. Extranasal flaps such as the pericranial flap and the temporoparietal fascia flap are used less frequently than intranasal flaps. However, they remain valuable options for reconstruction in certain situations. CONCLUSION: Advancements continue to be made in the field of skull base defect reconstruction using vascular pedicled flaps. Though the nasoseptal flap remains the most widely utilized option, additional intranasal techniques continue to be developed and tested to optimize surgical outcomes and patient care. LEVEL OF EVIDENCE: NA.

Fellowship training in microvascular surgery and post-fellowship practice patterns: a cross sectional survey of microvascular surgeons from facial plastic and reconstructive surgery programs.

BACKGROUND: There is a lack of published literature on the training in microvascular reconstructive techniques in facial plastic and reconstructive surgery (FPRS) fellowships or of the extent these techniques are continued in practice. This cross-sectional web-based survey study was conducted to describe the volume, variety, and intended extent of practice of free tissue transfers during fellowship and the post-fellowship pattern of microsurgical practice among FPRS surgeons in various private and academic practice settings across the United States. METHODS: This survey was sent to recent graduates (n = 94) of a subset of U.S. Facial Plastic and Reconstructive Surgery fellowship programs that provide significant training in microvascular surgery. RESULTS: Among survey respondents (n = 21, 22% response rate), two-thirds completed 20-100 microvascular cases during fellowship using mainly radial forearm, fibula, anterior lateral thigh, latissimus and rectus free tissue transfers. In post-fellowship practice, those who continue practicing microvascular reconstruction (86%) complete an average of 33 cases annually. The choice of donor tissues for reconstruction mirrored their training. They are assisted primarily by residents (73%) and/or fellows (43%), while some worked with a micro-trained partner, surgical assistant, or performed solo procedures. Interestingly, among those who began in private practice (29%), only half remained with that practice, while those who joined academic practices (71%) largely remained at their initial post-fellowship location (87%). CONCLUSIONS: These results provide the first formal description of the training and practice patterns of FPRS-trained microvascular surgeons. They describe a diverse fellowship training experience that often results in robust microvascular practice. The maintenance of substantial microsurgical caseloads after fellowship runs counter to the perception of high levels of burnout from free tissue transfers among microvascular surgeons. TRIAL REGISTRATION: This study was approved as exempt by the University of Florida Institutional Review Board (#201601526).

Neuroprotection via AT2 receptor agonists in ischemic stroke.

Stroke is a devastating disease that afflicts millions of people each year worldwide. Ischemic stroke, which accounts for ~88% of cases, occurs when blood supply to the brain is decreased, often because of thromboembolism or atherosclerotic occlusion. This deprives the brain of oxygen and nutrients, causing immediate, irreversible necrosis within the core of the ischemic area, but more delayed and potentially reversible neuronal damage in the surrounding brain tissue, the penumbra. The only currently approved therapies for ischemic stroke, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) and the endovascular clot retrieval/destruction processes, are aimed at restoring blood flow to the infarcted area, but are only available for a minority of patients and are not able in most cases to completely restore neurological deficits. Consequently, there remains a need for agents that will protect neurones against death following ischemic stroke. Here, we evaluate angiotensin II (Ang II) type 2 (AT2) receptor agonists as a possible therapeutic target for this disease. We first provide an overview of stroke epidemiology, pathophysiology, and currently approved therapies. We next review the large amount of preclinical evidence, accumulated over the past decade and a half, which indicates that AT2 receptor agonists exert significant neuroprotective effects in various animal models, and discuss the potential mechanisms involved. Finally, after discussing the challenges of delivering blood-brain barrier (BBB) impermeable AT2 receptor agonists to the infarcted areas of the brain, we summarize the evidence for and against the development of these agents as a promising therapeutic strategy for ischemic stroke.

Neuroprotection by post-stroke administration of an oral formulation of angiotensin-(1-7) in ischaemic stroke.

NEW FINDINGS: What is the central question of this study? Angiotensin-(1-7) decreases cerebral infarct volume and improves neurological function when delivered centrally before and during ischaemic stroke. Here, we assessed the neuroprotective effects of angiotensin-(1-7) when delivered orally post-stroke. What is the main finding and its importance? We show that oral delivery of angiotensin-(1-7) attenuates cerebral damage induced by middle cerebral artery occlusion in rats, without affecting blood pressure or cerebral blood flow. Importantly, these treatments begin post-stroke at times coincident with the treatment window for tissue plasminogen activator, providing supporting evidence for clinical translation of this new therapeutic strategy. ABSTRACT: As a target for stroke therapies, the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas [ACE2/Ang-(1-7)/Mas] axis of the renin-angiotensin system can be activated chronically to induce neuroprotective effects, in opposition to the deleterious effects of angiotensin II via its type 1 receptor. However, more clinically relevant treatment protocols with Ang-(1-7) that involve its systemic administration beginning after the onset of ischaemia have not been tested. In this study, we tested systemic post-stroke treatments using a molecule where Ang-(1-7) is included within hydroxypropyl-ß-cyclodextrin [HPßCD-Ang-(1-7)] as an orally bioavailable treatment. In three separate protocols, HPßCD-Ang-(1-7) was administered orally to Sprague-Dawley rats after induction of ischaemic stroke by endothelin-1-induced middle cerebral artery occlusion: (i) to assess its effects on cerebral damage and behavioural deficits; (ii) to determine its effects on cardiovascular parameters; and (iii) to determine whether it altered cerebral blood flow. The results indicate that post-stroke oral administration of HPßCD-Ang-(1-7) resulted in 25% reductions in cerebral infarct volumes and improvement in neurological functions (P < 0.05), without inducing any alterations in blood pressure, heart rate or cerebral blood flow. In conclusion, Ang-(1-7) treatment using an oral formulation after the onset of ischaemia induces significant neuroprotection in stroke and might represent a viable approach for taking advantage of the protective ACE2/Ang-(1-7)/Mas axis in this disease.

Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach.

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4-9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

Post-stroke angiotensin II type 2 receptor activation provides long-term neuroprotection in aged rats.

Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.

Serum activity of angiotensin converting enzyme 2 is decreased in patients with acute ischemic stroke.

Levels of angiotensin converting enzyme 2 (ACE2), a cardio and neuro-protective carboxypeptidase, are dynamically altered after stroke in preclinical models. We sought to characterize the previously unexplored changes in serum ACE2 activity of stroke patients and the mechanism of these changes. Serum samples were obtained from patients during acute ischemic stroke (n=39), conditions mimicking stroke (stroke-alert, n=23), or from control participants (n=20). Enzyme activity levels were analyzed by fluorometric assay and correlated with clinical variables by regression analyses. Serum ACE2 activity was significantly lower in acute ischemic stroke as compared to both control and stroke-alert patients, followed by an increase to control levels at three days. Serum ACE2 activity significantly correlated with the presence of ischemic stroke after controlling for other factors (P=0.01). Additional associations with ACE2 activity included a positive correlation with systolic blood pressure at presentation in stroke-alert (R(2)=0.24, P=0.03), while stroke levels showed no correlation (R(2)=0.01, P=0.50). ACE2 sheddase activity was unchanged between groups. These dynamic changes in serum ACE2 activity in stroke, which concur with preclinical studies, are not likely to be driven primarily by acute changes in blood pressure or sheddase activity. These findings provide new insight for developing therapies targeting this protective system in ischemic stroke.

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke.

The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis represents a promising target for inducing stroke neuroprotection. Here, we explored stroke-induced changes in expression and activity of endogenous angiotensin-converting enzyme 2 and other system components in Sprague-Dawley rats. To evaluate the clinical feasibility of treatments that target this axis and that may act in synergy with stroke-induced changes, we also tested the neuroprotective effects of diminazene aceturate, an angiotensin-converting enzyme 2 activator, administered systemically post stroke. Among rats that underwent experimental endothelin-1-induced ischemic stroke, angiotensin-converting enzyme 2 activity in the cerebral cortex and striatum increased in the 24 hours after stroke. Serum angiotensin-converting enzyme 2 activity was decreased within 4 hours post stroke, but rebounded to reach higher than baseline levels 3 days post stroke. Treatment after stroke with systemically applied diminazene resulted in decreased infarct volume and improved neurological function without apparent increases in cerebral blood flow. Central infusion of A-779, a Mas receptor antagonist, resulted in larger infarct volumes in diminazene-treated rats, and central infusion of the angiotensin-converting enzyme 2 inhibitor MLN-4760 alone worsened neurological function. The dynamic alterations of the protective angiotensin-converting enzyme 2 pathway after stroke suggest that it may be a favorable therapeutic target. Indeed, significant neuroprotection resulted from poststroke angiotensin-converting enzyme 2 activation, likely via Mas signaling in a blood flow-independent manner. Our findings suggest that stroke therapeutics that target the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis may interact cooperatively with endogenous stroke-induced changes, lending promise to their further study as neuroprotective agents.

Neuroprotective mechanisms of the ACE2-angiotensin-(1-7)-Mas axis in stroke.

The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis [ACE2-Ang-(1-7)-Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that describe the protective role of the ACE2-Ang-(1-7)-Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II (AngII) via its type 1 receptor, including anti-inflammatory, anti-oxidant, vasodilatory, and angiogenic effects, and the role of altered kinase-phosphatase signaling. Interactions of Mas with other receptors, including bradykinin receptors and AngII type 2 receptors are also considered. A more complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting.

Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism.

Caloric restriction has consistently been shown to extend life span and ameliorate aging-related diseases. These effects may be due to diet-induced reactive oxygen species acting to up-regulate sirtuins and related protective pathways, which research suggests may be partially inhibited by dietary anti-oxidant supplementation. Because caloric restriction is not sustainable long term for most humans, we investigated an alternative dietary approach, intermittent fasting (IF), which is proposed to act on similar biological pathways. We hypothesized that a modified IF diet, where participants maintain overall energy balance by alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal), would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by anti-oxidant supplementation. To assess the tolerability of the diet and to explore effects on biological mechanisms related to aging and metabolism, we recruited a cohort of 24 healthy individuals in a double-crossover, double-blinded, randomized clinical trial. Study participants underwent two 3-week treatment periods-IF and IF with anti-oxidant (vitamins C and E) supplementation. We found strict adherence to study-provided diets and that participants found the diet tolerable, with no adverse clinical findings or weight change. We detected a marginal increase (2.7%) in SIRT3 expression due to the IF diet, but no change in expression of other genes or oxidative stress markers analyzed. We also found that IF decreased plasma insulin levels (1.01 µU/mL). Although our study suggests that the IF dieting paradigm is acceptable in healthy individuals, additional research is needed to further assess the potential benefits and risks.

The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke.

Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke. We determined the effects of central and peripheral administration of C21 on the cerebral damage and neurological deficits in rats elicited by endothelin-1 induced middle cerebral artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained in rats injected systemically (intraperitoneal) with C21 either before or after endothelin-1 induced MCAO. The protective effects of C21 were reversed by central administration of an AT2R inhibitor, PD123319. While C21 did not alter cerebral blood flow at the doses used here, peripheral post-stroke administration of this agent significantly attenuated the MCAO-induced increases in inducible nitric oxide synthase, chemokine (C-C) motif ligand 2 and C-C chemokine receptor type 2 mRNAs in the cerebral cortex, indicating that the cerebroprotective action is associated with an anti-inflammatory effect. These results strengthen the view that AT2R agonists may have potential therapeutic value in ischemic stroke, and provide the first evidence of cerebroprotection induced by systemic post stroke administration of a selective AT2R agonist.

Cerebroprotective action of angiotensin peptides in stroke.

The goal of the present review is to examine the evidence for beneficial actions of manipulation of the RAS (renin-angiotensin system) in stroke, with particular focus on Ang-(1-7) [angiotensin-(1-7)] and its receptor Mas. The RAS appears to be highly involved in the multifactorial pathophysiology of stroke. Blocking the effects of AngII (angiotensin II) at AT1R (AngII type 1 receptor), through the use of commonly prescribed ACE (angiotensin-converting enzyme) inhibitors or AT1R blockers, has been shown to have therapeutic effects in both ischaemic and haemorrhagic stroke. In contrast with the deleterious actions of over activation of AT1R by AngII, stimulation of AT2Rs (AngII type 2 receptors) in the brain has been demonstrated to elicit beneficial effects in stroke. Likewise, the ACE2/Ang-(1-7)/Mas axis of the RAS has been shown to have therapeutic effects in stroke when activated, countering the effects of the ACE/AngII/AT1R axis. Studies have demonstrated that activating this axis in the brain elicits beneficial cerebral effects in rat models of ischaemic stroke, and we have also demonstrated the cerebroprotective potential of this axis in haemorrhagic stroke using stroke-prone spontaneously hypertensive rats and collagenase-induced striatal haemorrhage. The mechanism of cerebroprotection elicited by ACE2/Ang-(1-7)/Mas activation includes anti-inflammatory effects within the brain parenchyma. The major hurdle to overcome in translating these results to humans is devising strategies to activate the ACE2/Ang-(1-7)/Mas cerebroprotective axis using post-stroke treatments that can be administered non-invasively.