Anesthetic Considerations for Deep Brain Stimulation

Deep brain stimulation (DBS) was used to treat refractory Parkinson’s disease (PD) for the first time in 1987 by Professor Benabid’s group by placing stimulating electrodes into targeted brain structures. DBS is a widely accepted neurosurgical treatment for Parkinson’s disease (PD), benign tremor, dystonia, epilepsy, and other neuropsychiatric disorders with no significant changes in anatomical brain structures. Prior to the introduction of DBS, traditional treatment for PD involved surgical removal of parts of the brain known as thalamotomy, pallidotomy, and cingulotomy. Intraoperative identification of the affected areas of brain is possible through a couple of mechanisms involving electrical stimulation and monitoring of the brain function, known as “functional neurosurgery”. Implantation of electrodes in the targeted area and the insertion of a programmable pulse generator under the clavicle or in the abdomen are the main steps in DBS surgery. Anesthetic management for DBS remains controversial and might vary between institutions and physicians. Although no guidelines have been developed, there are some common anesthetic considerations for DBS surgery, including difficult airway management, facilitation of neuromonitoring, and anesthetic drugs interference with microelectrode recordings (MERs). Local anesthesia, general anesthesia, and monitored anesthesia care (MAC) have been used worldwide in patients undergoing DBS

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The µ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy.

Background:Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions. Methods:Adult patients with a score ≥4 on 11-point NRS for pain intensity received IV oliceridine either by bolus or PCA; multimodal analgesia was permitted. Safety was assessed using AE reports, study discontinuations, clinical laboratory and vital sign measures. Results:A total of 768 patients received oliceridine. The mean age (SD) was 54.1 (16.1) years, with 32% ≥65 years of age. Most patients were female (65%) and Caucasian (78%). Surgical patients comprised the majority of the study population (94%), most common being orthopedic (30%), colorectal (15%) or gynecologic (15%) procedures. Multimodal analgesia was administered to 84% of patients. Oliceridine provided a rapid reduction in NRS pain score by 2.2 ± 2.3 at 30 mins from a score of 6.3 ± 2.1 (at baseline) which was maintained to the end of treatment. No deaths or significant cardiorespiratory events were reported. The incidence of AEs leading to early discontinuation and serious AEs were 2% and 3%, respectively. Nausea (31%), constipation (11%), and vomiting (10%) were the most common AEs. AEs were mostly of mild (37%) or moderate (25%) severity and considered possibly or probably related to oliceridine in 33% of patients. Conclusion:Oliceridine IV for the management of moderate to severe acute pain was generally safe and well tolerated in the patients studied. ClinicalTrialsgov identifier:NCT02656875

Nanoliter contact angle probes tumor angiogenic ligand-receptor protein interactions

Any molecular recognition reaction supported by a solid-phase drives a specific change of the solid-solution interfacial tension. Sessile Contact Angle (CA) experiments can be readily used to track this thermodynamic parameter, prompting this well-known technique to be reinvented as an alternative, easy-access and label-free way to probe and study molecular recognition events. Here we deploy this technique, renamed for this application CONAMORE (CONtact Angle MOlecular REcognition), to study the interaction of the tumor-derived pro-angiogenic vascular endothelial growth factor-A (VEGF-A) with the extracellular domain of its receptor VEGFR2. We show that CONAMORE recognizes the high affinity binding of VEGF-A at nanomolar concentrations to surface-immobilized VEGFR2 regardless of the presence of a ten folds excess of a non specific interacting protein, and that it further proofs its specificity and reliability on competitive binding experiments involving neutralizing anti-VEGF-A antibodies. Finally, CONAMORE shows the outstanding capability to detect the specific interaction between VEGFR2 and low molecular weight ligands, such as Cyclo-VEGI, a VEGFR2 antagonist cyclo-peptide, that weights about 2 kDa

Primary Decompressive Craniectomy: Effects on Neurocritical Care Management, Long-Term Neurologic Status and Mortality

Objectives: Decompressive craniectomy (DC) is a surgical therapy used to treat patients foreseen to be at risk for high intracranial pressure (ICP). In this retrospective case control study, mortality, ICP values, neurocritical care (NCC) management necessity, and long-term neurologic status were examined in patients treated with DC and in a matched control group. Methods: The primary end-points were all-cause mortality and functional status of NCC patients both at discharge and at a 6 month follow-up. Secondary end-points were ICP values at established time points and the use of advanced NCC therapies. Patients who underwent primary DC were matched with individuals with similar demographic and pre-intervention ICP values who had been treated with standard NCC management alone. Results Neurologic status outcome at discharge and the 6 month follow-up was significantly better in patients treated with DC compared to those in the control group: Glasgow Outcome Scale (GOS) 4-5 in 15 versus 5 patients; p = 0.033, and 16 versus 6 patients, p = 0.033. Mortality at 6 months was similar in the study groups (10 versus 16 patients; p = 0.212). ICP values were similar at NCC admission but were better controlled 24 hours after DC than in the control group. Fewer patients treated with DC needed advanced NCC medical therapies. Conclusions: DC is an effective way to normalize ICP levels while reducing the need for aggressive medical therapies. Survival rate and neurological outcome in patients treated with DC were found to be better than in those receiving only medical treatment

Nanoanalytical analysis of bisphosphonate-driven alterations of microcalcifications using a 3D hydrogel system and in vivo mouse model

Vascular calcification predicts atherosclerotic plaque rupture and cardiovascular events. Retrospective studies of women taking bisphosphonates (BiPs), a proposed therapy for vascular calcification, showed that BiPs paradoxically increased morbidity in patients with prior acute cardiovascular events but decreased mortality in event-free patients. Calcifying extracellular vesicles (EVs), released by cells within atherosclerotic plaques, aggregate and nucleate calcification. We hypothesized that BiPs block EV aggregation and modify existing mineral growth, potentially altering microcalcification morphology and the risk of plaque rupture. Three-dimensional (3D) collagen hydrogels incubated with calcifying EVs were used to mimic fibrous cap calcification in vitro, while an ApoE-/- mouse was used as a model of atherosclerosis in vivo. EV aggregation and formation of stress-inducing microcalcifications was imaged via scanning electron microscopy (SEM) and atomic force microscopy (AFM). In both models, BiP (ibandronate) treatment resulted in time-dependent changes in microcalcification size and mineral morphology, dependent on whether BiP treatment was initiated before or after the expected onset of microcalcification formation. Following BiP treatment at any time, microcalcifications formed in vitro were predicted to have an associated threefold decrease in fibrous cap tensile stress compared to untreated controls, estimated using finite element analysis (FEA). These findings support our hypothesis that BiPs alter EV-driven calcification. The study also confirmed that our 3D hydrogel is a viable platform to study EV-mediated mineral nucleation and evaluate potential therapies for cardiovascular calcification

Analysis of a nanoparticle‑enriched fraction of plasma reveals miRNA candidates for down syndrome pathogenesis

Down syndrome (DS) is caused by the presence of part or all of a third copy of chromosome 21. DS is associated with several phenotypes, including intellectual disability, congenital heart disease, childhood leukemia and immune defects. Specific microRNAs (miRNAs/miR) have been described to be associated with DS, although none of them so far have been unequivocally linked to the pathology. The present study focuses to the best of our knowledge for the first time on the miRNAs contained in nanosized RNA carriers circulating in the blood. Fractions enriched in nanosized RNA-carriers were separated from the plasma of young participants with DS and their non-trisomic siblings and miRNAs were extracted. A microarray-based analysis on a small cohort of samples led to the identification of the three most abundant miRNAs, namely miR-16-5p, miR-99b-5p and miR-144-3p. These miRNAs were then profiled for 15 pairs of DS and non‑trisomic sibling couples by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results identified a clear differential expression trend of these miRNAs in DS with respect to their non-trisomic siblings and gene ontology analysis pointed to their potential role in a number of typical DS features, including ‘nervous system development’, ‘neuronal cell body’ and certain forms of ‘leukemia’. Finally, these expression levels were associated with certain typical quantitative and qualitative clinical features of DS. These results contribute to the efforts in defining the DS‑associated pathogenic mechanisms and emphasize the importance of properly stratifying the miRNA fluid vehicles in order to probe biomolecules that are otherwise hidden and/or not accessible to (standard) analysis

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): study protocol for a patient-blinded, randomised controlled superiority trial of liposomal bupivacaine

Background: Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine. Methods: SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0–10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned. Discussion: The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely. Trial registration: ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017

Subcutaneous dissociative conscious sedation (sDCS) an alternative method for airway regional blocks: a new approach

<p>Abstract</p> <p>Background</p> <p>Predicted difficult airway is a definite indication for awake intubation and spontaneous ventilation. Airway regional blocks which are commonly used to facilitate awake intubation are sometimes impossible or forbidden. On the other hand deep sedation could be life threatening in the case of compromised airway.</p> <p>The aim of this study is evaluating "Subcutaneous Dissociative Conscious Sedation" (sDCS) as an alternative method to airway regional blocks for awake intubation.</p> <p>Methods</p> <p>In this prospective, non-randomized study, 30 patients with predicted difficult airway (laryngeal tumors), who were scheduled for direct laryngoscopic biopsy (DLB), underwent "Subcutaneous Dissociative Conscious Sedation" (sDCS) exerted by intravenous fentanyl 3-4ug/kg and subcutaneous ketamine 0.6-0.7 mg/kg. The tongue and pharynx were anesthetized with lidocaine spray (4%<b>)</b>. 10 minutes after a subcutaneous injection of ketamine direct laryngoscopy was performed. Extra doses of fentanyl 50-100 ug were administered if the patient wasn't cooperative enough for laryngoscopy.</p> <p>Patients were evaluated for hemodynamic stability (heart rate and blood pressure), oxygen saturation (Spo₂), patient cooperation (obedient to open the mouth for laryngoscopy and the number of tries for laryngoscopy), patient comfort (remaining moveless), hallucination, nystagmus and salivation (need for aspiration before laryngoscopy).</p> <p>Results</p> <p>Direct laryngoscopy was performed successfully in all patients. One patient needed extra fentanyl and then laryngoscopy was performed successfully on the second try. All patients were cooperative enough during laryngoscopy. Hemodynamic changes more than 20% occurred in just one patient. Oxygen desaturation (spo₂< 90%) didn't occur in any patient.</p> <p>Conclusions</p> <p>Subcutaneous Dissociative Conscious Sedation (sDCS) as a new approach to airway is an acceptable and safe method for awake intubation and it can be suggested as a noninvasive substitute of low complication rate for regional airway blocks.</p> <p>Registration ID in IRCT</p> <p>IRCT201012075333N1</p

Highlights of the São Paulo ISEV workshop on extracellular vesicles in cross-kingdom communication

In the past years, extracellular vesicles (EVs) have become an important field of research since EVs have been found to play a central role in biological processes. In pathogens, EVs are involved in several events during the host–pathogen interaction, including invasion, immunomodulation, and pathology as well as parasite–parasite communication. In this report, we summarised the role of EVs in infections caused by viruses, bacteria, fungi, protozoa, and helminths based on the talks and discussions carried out during the International Society for Extracellular Vesicles (ISEV) workshop held in São Paulo (November, 2016), Brazil, entitled Cross-organism Communication by Extracellular Vesicles: Hosts, Microbes and Parasites. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.11Ysciescopu

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches.

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly