Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein-peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.

Whole-Body Disposition and Physiologically Based Pharmacokinetic Modeling of Adeno-Associated Viruses and the Transgene Product.

To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mAb) gene, whole-body disposition of both the vector and the transgene mAb was evaluated over 3 weeks. At steady-state, the following tissue-to-blood (T/B) concentration ratios were found for AAV8/9: ∼50 for liver; ∼10 for heart and muscle; ∼2 for brain, lung, kidney, adipose, and spleen; ≤1 for bone, skin, and pancreas. T/B values for mAb were compared with the antibody biodistribution coefficients, and five different clusters of organs were identified based on their transgene expression profile. All the biodistribution data were used to develop a novel AAV PBPK model that incorporates: (i) whole-body distribution of the vector; (ii) binding, internalization, and intracellular processing of the vector; (iii) transgene expression and secretion; and (iv) whole-body disposition of the secreted transgene product. The model was able to capture systemic and tissue PK of the vector and the transgene-produced mAb reasonably well. Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies.

Impacts of Skin Color and Hypoxemia on Noninvasive Assessment of Peripheral Blood Oxygen Saturation: A Scoping Review.

Standard pulse oximeters estimate arterial blood saturation (SaO2) non-invasively by emitting and detecting light of a specific wavelength through a cutaneous vascular bed, such as a digit or the ear lobe. The quantity measured at these peripheral sites is designated as oxygen saturation (SpO2). Most reliable pulse oximeters are calibrated from measurements of healthy volunteers using some form of oxygen desaturation method. As the degree of inducible hypoxemia is limited, the calibration below achievable desaturation levels is usually extrapolated, leading to potential measurement error at low SaO2 values, especially in highly pigmented skin. Such skin color-related errors (SCRE) are the topic of this scoping review. Specifically, this study aimed to identify the combined impact of skin color and reduced SaO2 on the non-invasive assessment of SpO2 and report the consequences of potential inaccuracies. Three databases were searched (Cumulated Index to Nursing and Allied Health Literature (CINAHL), PubMed, and Web of Science) for peer-reviewed prospective and retrospective studies published in English between 2000 and 2022 involving human patients with hypoxemia that included a measure of skin color (Fitzpatrick scale or race/ethnicity). Ten studies met the criteria and were included in the final review. Eight of these studies reported statistically significant higher pulse oximeter readings in darker-skinned patients with hypoxia compared to their arterial blood gas measurements. Occult hypoxia was more prevalent in Black and Hispanic patients than in White patients. Minority patients overall (Black, Asian, and American Indian) were more likely to have a SaO2 < 88% that was not detected by pulse oximetry (occult hypoxemia) during hospitalization. With greater levels of hypoxemia, the differences between SpO2 and SaO2 were greater. If SaO2 was < 90%, then SpO2 was overestimated in all ethnicities but worse in minorities. In conclusion, the bias found in pulse oximeter readings in the skin of color broadly impacts patients with hypoxemia. The failure of SpO2 measuring devices to detect occult hypoxemia can delay the delivery of life-saving treatment to critically ill patients requiring respiratory rehabilitation and supplemental oxygen therapy. This may lead to adverse health outcomes, increased in-hospital mortality, and complications such as organ dysfunction. An improvement in pulse oximeter detection mechanisms that would include all skin pigmentations is therefore much desired to optimize individual healthcare status and minimize disparities in treatment.

The curious cases of tetrahydrosalen-type ligands interacting with Ni(II): structures and ligand-based oxidation reactions.

This work centers around the nickel complexes derived from two tetrahydrosalen-type proligands: N,N'-bis(2-hydroxybenzyl)-o-phenylenediamine (H2salophan) and N,N'-bis(2-hydroxy-3-methylbenzyl)-o-phenylenediamine (H2salophan_Me). The reaction of H2salophan with Ni(OAc)2·4H2O generates a dinuclear complex Ni2(Hsalophan)2(OAc)2 or Na[Ni2(salophan)2(OAc)] when NaOH is added to assist ligand deprotonation. The reaction of H2salophan_Me with Ni(OAc)2·4H2O, however, yields a mononuclear complex Ni(Hsalophan_Me)2. Unlike the corresponding salen-type nickel complexes, these tetrahydrosalen-type complexes are paramagentic and air sensitive (in solution). Oxidation by O2 or peroxides results in dehydrogenation of the ligand backbone to form the salen-type complexes.

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice.

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1ß), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

Volumetric Analysis of the Sinus and Orbit in Silent Sinus Syndrome After Endoscopic Sinus Surgery.

OBJECTIVE: The term "silent sinus syndrome" (SSS) describes spontaneous enophthalmos secondary to subclinical maxillary sinus atelectasis. Debate remains on whether treatment with endoscopic maxillary antrostomy alone is adequate in reversing atelectasis and globe displacement. This study aims to determine the degree of volume change of the diseased sinus and orbit as well as the change in orbital height in patients treated with endoscopic antrostomy without orbital floor augmentation. STUDY DESIGN: Retrospective review with image analysis. SETTING: Single tertiary care institution. METHODS: Three-dimensional (3D) analysis of computed tomographic imaging data was performed using 3D Slicer. 3D models of the maxillary sinus and orbit of the diseased and normal sides were created, and volume measurements were calculated using the segmentation program. RESULTS: Thirteen patients with SSS who underwent endoscopic sinus surgery (ESS) and had follow-up computed tomographic imaging were analyzed. After endoscopic antrostomy, the mean volume of the diseased maxillary sinus significantly increased by 9.82%, from 6.37 to 7.00 cm3 (p = .0302). There was no significant change in mean orbital volume; however, the mean orbital height decreased by 5.67%, from 38.09 to 35.93 mm from pretreatment to posttreatment samples (p = .0101). All patients had resolution of clinical or radiographic enophthalmos and orbital displacement with ESS alone. CONCLUSION: Endoscopic maxillary antrostomy alone in the treatment of SSS significantly increased maxillary sinus volume and decreased diseased orbital height. These changes were associated with clinical and radiographic improvement in globe displacement. These findings support performing ESS alone, reserving orbital augmentation for patients who do not exhibit adequate clinical improvement.

Analysis of cost and outcomes in bony versus soft tissue midface free flap reconstruction.

BACKGROUND: Outcomes and cost of soft tissue versus bony midface free flap reconstruction (MR) with and without virtual surgical planning (VSP) were evaluated. METHODS: Retrospective review of MR including ischemic time (IT), operative duration (OD), length of stay (LOS), and total cost (TC). Eighty-one soft tissue and 76 bony MR (VSP = 23) were reviewed. RESULTS: Bony MR was used for higher complexity defects (p = 0.003) and was associated with higher IT (p < 0.001), OD (p < 0.001), LOS (p = 0.032), and TC (p < 0.001). VSP was associated with a mean 111.2 ± 37.9 minute reduction in OD (p = 0.004) compared to non-VSP bony flaps. VSP was associated with higher itemized cost, but no increase in TC (p = 0.327). CONCLUSIONS: Bony MR was used for higher complexity MR and was associated with increased TC, LOS, OD, and IT. VSP shortened OD with no significant increase in TC.

Rate of Fat Graft Volume Loss After Parotidectomy.

BACKGROUND: Reconstruction after parotidectomy can include fat grafting, which allows for symmetry, but grafts have demonstrated volume loss over time. OBJECTIVES: To provide quantitative evidence for the rate of volume loss of fat grafts. METHODS: Patients who received parotidectomy with fat graft reconstruction at a single institution from August 2016 to October 2020 were identified. Relationships between clinical factors and the logarithmic rate of fat graft volume loss were analyzed. RESULTS: Twelve patients received parotidectomy, fat graft reconstruction, and underwent a postoperative magnetic resonance imaging (MRI) scan. Rate of fat graft volume loss was a mean of 1.8% per month (standard deviation [SD]: 2.1% per month). Total parotid fat graft volume loss was a mean of 57.4% (SD: 67.5%). The mean follow-up time was 35.5 months (range: 9-89.8 months). Correlations between body mass index (BMI), history of smoking, and history of alcohol consumption and logarithmic rates of fat graft volume loss were increased but not significantly. CONCLUSIONS: Fat grafts have the potential of 60% volume loss at approximately 1 year. If there is clinical suspicion that patients will require adjuvant radiation or have clinical factors such as a smoking or alcohol-use history, volume requirements may be even greater to maintain adequate parotid volume for aesthetic purposes.

Impact of great auricular nerve sacrifice on sensory disturbance after parotidectomy.

PURPOSE: To investigate the association between great auricular nerve (GAN) sacrifice during parotidectomy and postoperative sensory disturbance. MATERIALS AND METHODS: Patients who underwent parotidectomy between November 2016 and May 2020 at a single academic institution were included in this retrospective chart review. Operative notes were reviewed to determine incidence of GAN sacrifice. Prevalence of patient-reported sensory complaints in the GAN distribution and time to spontaneous resolution of symptoms were assessed. RESULTS: Of 305 parotidectomy patients, 111 (36.4%) endorsed complaints of postoperative sensory disturbances in the GAN distribution typically characterized by numbness or shooting pains. GAN sacrifice was present in 9 (8.1%) of 111 patients who experienced sensory disturbances compared to 9 (4.6%) who reported no sensory disturbances (p > 0.05). Twenty-five patients (32.5%) experienced spontaneous resolution of symptoms at their most recent follow-up at a mean of 6.2 months after onset of symptoms. Of those that experienced a sensory disturbance, GAN preservation was not significantly associated with likelihood of spontaneous recovery (p > 0.05). CONCLUSIONS: We report the largest series to date of post-operative sensory disturbance in parotidectomy patients as it relates to intraoperative GAN sacrifice. Although the relationship between GAN sacrifice and the incidence of postoperative sensory disturbance and its subsequent resolution were not significant, we continue to advocate for GAN preservation to reduce incidence of postoperative sensory disturbances.

First Bite Syndrome After Parotidectomy: A Case Series and Review of Literature.

INTRODUCTION: First bite syndrome (FBS) is a rare but potentially debilitating complication observed after surgery involving the upper cervical region. Patients classically complain of severe facial pain in the ipsilateral parotid region with the first few bites of a meal. OBJECTIVE: The aim of this study is to shed light on the incidence and potential risk factors of FBS, including a series of cases depicting FBS observed after parotidectomy. METHODS: Retrospective review of 419 patients who underwent parotidectomy at a single tertiary care facility between December 2016 and June 2020. RESULTS: With a mean follow-up time of 16.5 months, 8 (2%) patients were documented to have symptoms of FBS after parotid gland surgery. Six of these patients underwent partial parotidectomy by dissection of the deep lobe of the parotid (DLP). CONCLUSION: Patients undergoing dissection of the DLP are particularly at risk for the development of FBS. All patients should be appropriately counseled during informed consent discussions, especially in high-risk cases.

Outcomes in Head and Neck Free Flap Reconstruction Among Patients With a History of Venous Thromboembolism.

OBJECTIVE: To investigate if a history of venous thromboembolism (VTE) is a risk factor for complications in head and neck free flap surgery by assessing outcomes among patients with a history of deep vein thrombosis (DVT) and/or pulmonary embolism (PE). STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary care center. METHODS: All patients undergoing head and neck free flap reconstruction at our institution between September 1, 2006, and April 2, 2020, were assessed for inclusion. Patients with and without a history of DVT or PE preoperatively were identified and grouped for comparison. Groups were compared for demographics, comorbidities, and 30-day complications. Significance was assessed with chi-square and binary logistic regression analyses. RESULTS: Of the 1061 patients meeting inclusion criteria, 40 (3.8%) had a history of VTE. These patients were significantly older (mean [SD], years: 67.8 [11.7] vs 63.0 [14.1], P = .038) and significantly more likely to have history of chemotherapy (35.0% vs 18.7%, P = .010) and stroke (27.5% vs 4.5%, P < .001). After accounting for patient characteristics via binary logistic regression, VTE was independently associated with an increased risk for postoperative thrombosis of the free flap pedicle (odds ratio [95% CI] = 3.65 [1.12-11.90], P = .032) and reoperation (2.45 [1.25-4.80], P = .009). Patients with history of PE had a significantly increased risk for flap failure (7.70 [1.77-33.52], P = .007). Prior VTE was not independently associated with an increased risk for medical complications or readmission. CONCLUSION: Patients with a history of VTE may be at an increased risk for free flap compromise secondary to postoperative pedicle thrombosis. This risk should be considered in preoperative workup and postoperative monitoring.

The Use of Alternative Routes for the Delivery of Intra-Arterial Chemotherapy for Retinoblastoma.

BACKGROUND: The introduction of intra-arterial chemotherapy (IAC) for treatment of retinoblastoma considerably changed the paradigm by which this disease is managed, with event-free survival rates being above 70%. OBJECTIVE: To analyze efficacy of IAC treatment using alternative approaches to ophthalmic artery catheterization (OAC), such as external carotid artery approach or balloon-assisted drug delivery. METHODS: This is a retrospective chart review for subjects receiving IAC for retinoblastoma. The primary approach was OAC. In cases in which selective OAC was not feasible, alternative routes including catheterization of the external carotid artery or use of a balloon-assisted drug infusion were used. RESULTS: This study included 197 consecutive patients with 207 retinoblastomas who underwent 658 IAC procedures overall. The mean age at diagnosis was 24 mo, and 54.5% of the study population was male. Success rate with IAC was 97% (639). Alternative approaches to OAC were, in total, 42 cases (6.4%)-external carotid artery catheterization and use of ICA balloon were performed in 22 (3.3%) and 20 (3%) cases, respectively. A mean of 3.1 IAC cycles were performed for each patient. In total, there were 23 technical failures of the primary OAC technique (3.4%). Periprocedural adverse events occurred in 4 procedures (0.6%). Use of an alternative technique for chemotherapy delivery other than selective OAC in at least one IAC cycle was not a predictor of enucleation. CONCLUSION: IAC is a safe and effective treatment option for retinoblastoma. Chemotherapy delivery using alternative techniques is as effective as selective OAC.

Ophthalmic artery catheterization for retinoblastoma treatment: does reflux affect tumor response?

BACKGROUND: Intra-arterial chemotherapy (IAC) for retinoblastoma (Rb) has been established as a primary treatment for the disease. To determine whether the presence of reflux into the ICA is associated with tumor response or with any other adverse events in pediatric retinoblastoma patients. METHODS: A retrospective chart review was performed for patients diagnosed with Rb and managed with ophthalmic artery catheterization (OAC). RESULTS: The total study cohort included 205 Rb tumors of 205 eyes in 194 consecutive patients who underwent 624 successful intra-arterial chemotherapy infusions using OAC. Of the 205 eyes, 65 eyes (32.7%) underwent 157 OAC procedures constituted group A (no reflux), 64 eyes (31.2%) underwent 236 OAC procedures constituted group B (variable pattern), and 74 eyes (36.1%) underwent 231 OAC procedures constituted group C (reflux). There was no significant difference in baseline characteristics between the three cohorts. Also, there was no significant difference in tumor characteristics between the three groups, except for genetic status. There was no significant difference between the three groups in terms of tumor response at completion of the treatment regimen. Complete tumor response was achieved at 70.2% in Group A, at 83.3% in Group B, and at 78.5% in group C (P=0.39). Similarly, eye enucleation occurred at 38.5% in group A, 31.8% in group B, and 31.5% in group C. None of the patients in both groups had any neurological adverse events or new onset of seizures. CONCLUSIONS: The presence of reflux, which may complicate the procedure and prolong it, was not associated with poor outcomes in our analysis.

Mechanical Thrombectomy in Acute Ischemic Stroke Patients Greater than 90 Years of Age: Experience in 26 Patients in a Large Tertiary Care Center and Outcome Comparison with Younger Patients.

BACKGROUND: Several independent randomized controlled trials have shown superior efficacy of mechanical thrombectomy (MT) for management of acute ischemic stroke (AIS). However, elderly patients have been underrepresented or excluded in these trials. The aim of this study was to investigate the feasibility and safety of MT in patients with AIS ≥90 years old. METHODS: A retrospective review was performed of patients ≥90 years old presenting with AIS who underwent MT between 2010 and 2018. RESULTS: Of 453 patients with AIS, 5.74% (n = 26) were ≥90 years old, and 69.32% (n = 314) were 60-89 years old. Of baseline characteristics between both groups, there was a significant difference in age, sex, body mass index, smoking, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Mean National Institutes of Health Stroke Scale score on admission was higher in the nonagenarians (17 vs. 15). Similar proportions of both groups received tissue plasminogen activator, 57.69% (n = 15) versus 42.68% (n = 134), P = 0.14). There was no difference in periprocedural and postprocedural complications, good Thrombolysis In Cerebral Infarction scores (88.46% [n = 23] vs. 87.58% [n = 275], P = 1.00), good modified Rankin Scale scores (34.62% [n = 4] vs. 49.36% [n = 155], P = 0.40), or mortality (11.54% [n = 3] vs. 13.06% [n = 41], P = 0.82). CONCLUSIONS: Age is a factor that affects functional outcome following MT. Advancements in catheter techniques, technical experience, and great outcomes with MT allow for pushing the boundaries to consider age as one factor, rather than an exclusion criterion. Our results show that MT is safe and feasible in nonagenarians.

Mechanical Thrombectomy in Distal Vessels: Revascularization Rates, Complications, and Functional Outcome.

INTRODUCTION: Pivotal trials have shown the tremendous efficacy of mechanical thrombectomy in proximal occlusions. However distal occlusions involving second-order branches of the middle cerebral artery and beyond, anterior cerebral and posterior cerebral arteries were not represented. In this study, we investigated the feasibility and safety of distal circulation mechanical thrombectomy. METHODS: A retrospective review of patients presenting with distal circulation acute ischemic stroke who underwent mechanical thrombectomy 2010 and 2018. RESULTS: Of 453 patients who underwent mechanical thrombectomy for acute ischemic stroke, 76 had a distal occlusion. The mean National Institute Health Stroke Scale on admission was 12. Vessels involved included second-order branches of the middle cerebral artery (89%), third- and fourth-order branches of the middle cerebral artery (5%), second-order branch of the anterior cerebral artery (3%), and posterior cerebral artery (3%). Most procedures required 1 pass to recanalize the vessel (55%, n = 42). Thrombolysis in Cerebral Infarction score ≥IIb was achieved in 89% of subjects. Mortality rate was 8% and independent functional outcome of m Rankin score ≤2 at 3 months was seen in 64.7% with clinical follow-up. On multivariate analysis, distal circulation had a significantly shorter length of stay by about 2 days, compared with proximal circulation. Subjects with proximal occlusion were more than 5 times more likely to have a good Thrombolysis in Cerebral Infarction score compared with the distal group. There was no significant difference in periprocedural and postprocedural complications, good functional outcome at 3 months, and mortality between both groups. CONCLUSIONS: Mechanical thrombectomy procedure for distal circulation strokes is as effective and safe as a proximal group. Though distal vessels supply smaller brain area; however, when symptoms are pronounced, the benefit of the procedure outweighs the risks.

Transradial approach for the treatment of brain aneurysms using flow diversion: feasibility, safety, and outcomes.

BACKGROUND: The aim of this paper is to describe our experience with the transradial approach (TRA) for intracranial aneurysms treatment using the Pipeline Embolization device (PED). We also performed a logistic regression comparing outcomes between TR and transfemoral approach (TFA). METHODS: The clinical and imaging characteristics as well as periprocedural outcomes of patients treated for aneurysms using a TRA with PED were analyzed retrospectively. RESULTS: A total of 598 aneurysms were treated with pipeline during a period extending from 2010-2019 (N.=580 [97%] using TFA vs. N.=18 [3%] using TRA). About 84.28% (N.=504) were females, and the average age was 55.5 years. There was no significant difference between both approaches in procedural duration, complication rate, morbidity, and aneurysms obliteration. We did not encounter any access site complication in the TR group compared to 2% in the TF; however, this did not reach statistical significance. One case was converted to TFA due to the need for more support. Multivariate analysis did not show that the access site was an independent predictor of the complications, morbidity, and aneurysms obliteration. CONCLUSIONS: The results of this study illustrate that the transradial approach is a safe and effective means of treating intracranial aneurysms with PED. The TRA in selected patients offers better safety with high rates of procedural success.