Perioperative Methadone for Spine Surgery: A Scoping Review.

Complex spine surgery is associated with significant acute postoperative pain. Methadone possesses pharmacological properties that make it an attractive analgesic modality for major surgeries. This scoping review aimed to summarize the evidence for the perioperative use of methadone in adults undergoing complex spine surgery. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). A search was performed using MEDLINE, CINAHL, Cochrane Library, Scopus, Embase, and Joanna Briggs between January 1946 and April 2023. The initial search identified 317 citations, of which 12 met the criteria for inclusion in the review. There was significant heterogeneity in the doses, routes of administration, and timing of perioperative methadone administration in the included studies. On the basis of the available literature, methadone has been associated with reduced postoperative pain scores and reduced postoperative opioid consumption. Though safety concerns have been raised by observational studies, these have not been confirmed by prospective randomized studies. Further research is required to explore optimal methadone dosing regimens, the potential synergistic relationships between methadone and other pharmacological adjuncts, as well as the potential long-term antinociceptive benefits of perioperative methadone administration.

Mechanistic insight into biotransformation of novel triazine-based flame retardant 1,3,5-tris(2,3-dibromopropyl)-1,3,5-triazinane-2,4,6-trione by human cytochrome P450s.

The escalating focus on the environmental occurrence and toxicology of emerging pollutants underscores the imperative need for a profound exploration of their metabolic transformations mediated by human CYP450 enzymes. Such investigations have the potential to unravel the intricate metabolite profiles, substantially altering the toxicological outcomes. In this study, we integrated the computational simulations with in vitro metabolism experiments to investigate the metabolic activity and mechanism of an emerging pollutant, 1,3,5-tris(2,3-dibromopropyl)-1,3,5-triazinane-2,4,6-trione (TDBP-TAZTO), catalyzed by human CYP450s. The results highlight the important contributions of CYP2E1, 3A4 and 2C9 to the biotransformation of TDBP-TAZTO, leading to the identification of four distinct metabolites. The effective binding conformations governing biotransformation reactions of TDBP-TAZTO within active CYP450s are unveiled. Structural instability of primary hydroxyTDBP-TAZTO products suggests three potential outcomes: (1) generation of an alcohol metabolite through successive debromination and reduction reactions, (2) formation of a dihydroxylated metabolite through secondary hydroxylation by CYP450, and (3) production of an N-dealkylated metabolite via decomposition and isomerization reactions in the aqueous environment. The formation of a desaturated debrominated metabolite may arise from H-abstraction and barrier-free Br release during the primary oxidation, potentially competing with the generation of hydroxyTDBP-TAZTO. These findings provide detailed mechanistic insight into TDBP-TAZTO biotransformation by CYP450s, which can enrich our understanding of the metabolic fate and associated health risk of this chemical.

Regional Anesthesia Techniques in Modern Neuroanesthesia Practice: A Narrative Review of the Clinical Evidence.

Neurosurgical procedures are often associated with significant postoperative pain that is both underrecognized and undertreated. Given the potentially undesirable side effects associated with general anesthesia and with various pharmacological analgesic regimens, regional anesthetic techniques have gained in popularity as alternatives for providing both anesthesia and analgesia for the neurosurgical patient. The aim of this narrative review is to present an overview of the regional techniques that have been incorporated and continue to be incorporated into modern neuroanesthesia practice, presenting in a comprehensive way the evidence, where available, in support of such practice for the neurosurgical patient.

Anemia and Optimal Transfusion Thresholds in Brain-Injured Patients: A Narrative Review of the Literature.

Anemia is a highly prevalent condition that may compromise oxygen delivery to vital organs, especially among the critically ill. Although current evidence supports the adoption of a restrictive transfusion strategy and threshold among the nonbleeding critically ill patient, it remains unclear whether this practice should apply to the brain-injured patient, given the predisposition to cerebral ischemia in this patient population, in which even nonprofound anemia may exert a detrimental effect on clinical outcomes. The purpose of this review is to provide an overview of the pathophysiological changes related to impaired cerebral oxygenation in the brain-injured patient and to present the available evidence on the effect of anemia and varying transfusion thresholds on the clinical outcomes of patients with acute brain injury.

Accurate identification and measurement of the precipitate area by two-stage deep neural networks in novel chromium-based alloys.

The performance of advanced materials for extreme environments is underpinned by their microstructure, such as the size and distribution of nano- to micro-sized reinforcing phase(s). Chromium-based superalloys are a recently proposed alternative to conventional face-centred-cubic superalloys for high-temperature applications, e.g., Concentrated Solar Power. Their development requires the determination of precipitate volume fraction and size distribution using Electron Microscopy (EM), as these properties are crucial for the thermal stability and mechanical properties of chromium superalloys. Traditional approaches to EM image processing utilise filtering with a fixed contrast threshold, leads to weak robustness to background noise and poor generalisability to different materials. It also requires an enormous amount of time for manual object measurements on large datasets. Efficient and accurate object detection and segmentation are therefore highly desired to accelerate the development of novel materials like chromium-based superalloys. To address these bottlenecks, based on YOLOv5 and SegFormer structures, this study proposes an end-to-end, two-stage deep learning scheme, DT-SegNet, to perform object detection and segmentation for EM images. The proposed approach can thus benefit from the training efficiency of CNNs at the detection stage (i.e., a small number of training images required) and the accuracy of the ViT at the segmentation stage. Extensive numerical experiments demonstrate that the proposed DT-SegNet significantly outperforms the state-of-the-art segmentation tools offered by Weka and ilastik regarding a large number of metrics, including accuracy, precision, recall and F1-score. This model forms a useful tool to aid alloy development microstructure examinations, and offers significant advantages to address the large datasets associated with high-throughput alloy development approaches.

Enantioselective metabolism of novel chiral insecticide Paichongding by human cytochrome P450 3A4: A computational insight.

As a novel chiral neonicotinoid insecticide, Paichongding (IPP) has been widely applied in agriculture due to its excellent insecticidal activity. However, the enantioselective metabolism of IPP stereoisomers (5R7R-IPP, 5S7S-IPP, 5R7S-IPP, and 5S7R-IPP) mediated by enzymes in non-target organisms, especially the cytochrome P450s (CYPs), remains unknown. To address this knowledge gap, we developed an integrated computational framework to elucidate the binding interactions and enantioselective metabolism of IPP stereoisomers in human CYP3A4. The results reveal that 5R7R-IPP shows much stronger binding affinity to CYP3A4 than 5S7S-IPP, while enantiomers 5R7S-IPP and 5S7R-IPP have no essential difference in their binding potential, owing to their specific interactions with key CYP3A4 residues. Although enantiomers 5R7R-IPP and 5S7S-IPP feature distinct binding modes resulting from the chiral differences, their transformation activities are slightly different, with C5 and C13 being the primary metabolic sites, respectively. In contrast, CYP3A4 preferably metabolizes 5R7S-IPP over 5S7R-IPP. The metabolism of epimers 5R7R-IPP and 5R7S-IPP share C5-hydroxylation routes due to the conserved 5R-conformaitons, but differ with the transformation routes at C11/C13 and C3 sites. The 7R-chirality of 5S7R-IPP significantly reduces the metabolic potency compared to 5S7S-IPP. CYP3A4-catalyzed hydroxylation and desaturation of IPP stereoisomers generate various chiral metabolites, with C5- and C13-hydroxyIPPs further transforming into depropylated products. Furthermore, the toxicity assessment reveals that IPP, along with the majority of its hydroxylated, desaturated, and depropylated metabolites, can potentially induce adverse effects on human health, specifically hepatotoxicity, respiratory toxicity, and carcinogenicity. This study provides valuable insights into the enantioselective fate of chiral IPP metabolism by CYP3A4, and the identified metabolites can serve as potential biomarkers for monitoring IPP exposure and associated health risk in human body.

Compact A15 Frank-Kasper nano-phases at the origin of dislocation loops in face-centred cubic metals.

It is generally considered that the elementary building blocks of defects in face-centred cubic (fcc) metals, e.g., interstitial dumbbells, coalesce directly into ever larger 2D dislocation loops, implying a continuous coarsening process. Here, we reveal that, prior to the formation of dislocation loops, interstitial atoms in fcc metals cluster into compact 3D inclusions of A15 Frank-Kasper phase. After reaching the critical size, A15 nano-phase inclusions act as a source of prismatic or faulted dislocation loops, dependent on the energy landscape of the host material. Using cutting-edge atomistic simulations we demonstrate this scenario in Al, Cu, and Ni. Our results explain the enigmatic 3D cluster structures observed in experiments combining diffuse X-ray scattering and resistivity recovery. Formation of compact nano-phase inclusions in fcc structure, along with previous observations in bcc structure, suggests that the fundamental mechanisms of interstitial defect formation are more complex than historically assumed and require a general revision. Interstitial-mediated formation of compact 3D precipitates can be a generic phenomenon, which should be further explored in systems with different crystallographic lattices.

Multimodal Analgesia and Intraoperative Neuromonitoring.

Intraoperative neuromonitoring has been a valuable tool for ensuring the functional integrity of vital neural structures by providing real-time feedback to the operative team during procedures where neurological structures are at risk. Commonly used intravenous and inhaled anesthetic drugs are known to affect waveform parameters measured with various intraoperative neuromonitoring modalities. While the concept of opioid-sparing multimodal analgesia has gained popularity in recent years, the impact of such a strategy on intraoperative neuromonitoring remains poorly characterized, in contrast to the more well-established concepts and literature regarding the effects of other hypnotic agents on neuromonitoring quality. The purpose of this focused review is to provide an overview of the clinical evidence pertaining to the pharmacological interaction of certain multimodal analgesics with routine intraoperative neuromonitoring modalities.

Optimal Hemodynamic Parameters for Brain-injured Patients in the Clinical Setting: A Narrative Review of the Evidence.

Defining optimal hemodynamic targets for brain-injured patients is a challenging undertaking. The physiological interference observed in various intracranial pathologies can have varying effects on cerebral physiology at different time points. This narrative review provides an overview of cerebral autoregulatory physiology and common misconceptions, and examines the physiological considerations and clinical evidence for determining optimal hemodynamic parameters in acutely brain-injured patients with relevance to modern neuroanesthesia and neurocritical care practice.

Electroencephalographic Burst-Suppression, Perioperative Neuroprotection, Postoperative Cognitive Function, and Mortality: A Focused Narrative Review of the Literature.

Burst-suppression is an electroencephalographic pattern that results from a diverse array of pathophysiological causes and/or metabolic neuronal suppression secondary to the administration of anesthetic medications. The purpose of this review is to provide an overview of the physiological mechanisms that underlie the burst-suppression pattern and to present in a comprehensive way the available evidence both supporting and in opposition to the clinical use of this electroencephalographic pattern as a therapeutic measure in various perioperative settings.

Correlation Between Processed Electroencephalogram and Clinical Findings During Wake-Up Test in Prone Position for Scheduled Posterior Cervical Spine Surgery: A Case Report.

A 65-year-old man undergoing posterior cervical decompression and fusion demonstrated absent lower extremity evoked potential (EP) after prone positioning and before incision. Localized EP change pointed to either a technical or positional culprit. After excluding technical causes, we performed a wake-up test to rule out positioning as the culprit. During the test, we observed both symmetrical and asymmetrical hemispheric changes in density spectral array ß and γ bands that correlated with awakening, eye-opening, and extremity movements. By providing real-time information on brain state, processed electroencephalogram (EEG) can facilitate a safe wake-up test by showing high-power ß and γ activities that precede awakening.

Awake Craniotomy in a Patient With History of Post-Traumatic Stress Disorder-A Clinical Dilemma: A Case Report.

A 32-year-old man undergoing awake craniotomy for tumor resection was previously diagnosed with post-traumatic stress disorder (PTSD)-typically a relative contraindication for awake craniotomy. Preoperative neurocognitive assessment and counseling by a neuroanesthesiologist and neuropsychologist were undertaken to characterize his PTSD, identify triggers, and prepare him for the intraoperative events. Dexmedetomidine and remifentanil were used as intraoperative anxiolytics and analgesics. With an emphasis on open communication, the patient tolerated the awake craniotomy without complications. This case highlights the importance of multidisciplinary approach and meticulous perioperative preparation in successfully managing a patient who might otherwise be contraindicated for awake craniotomy.

Effect of bilateral scalp nerve blocks on postoperative pain and discharge times in patients undergoing supratentorial craniotomy and general anesthesia: a randomized-controlled trial.

PURPOSE: Post-craniotomy pain is a common clinical issue and its optimal management remains incompletely studied. Utilization of a regional scalp block has the potential advantage of reducing perioperative pain and opioid consumption, thereby facilitating optimal postoperative neurologic assessment. The purpose of this study was to assess the efficacy of regional scalp block on post-craniotomy pain and opioid consumption. METHODS: We performed a prospective randomized-controlled trial in adults scheduled to undergo elective supratentorial craniotomy under general anesthesia to assess the efficacy of postoperative bilateral scalp block with 0.5% bupivacaine with 1:200,000 epinephrine compared with placebo on postoperative pain and opioid consumption. The primary outcome was the visual analogue scale (VAS) for pain at 24 hr postoperatively. RESULTS: Eighty-nine patients were enrolled (n = 44 in block group; n = 45 in control group). There was no difference in the mean (standard deviation) VAS score at 24 hr postoperatively between the treatment group and the control group [31.2 (21.4) mm vs 23.0 (19.2) mm, respectively; mean difference, 6.6; 95% confidence interval, -2.3, 15.5; P = 0.15]. There was also no significant difference in postoperative opioid consumption. Distribution of individual VAS score and opioid consumption revealed that postoperative pain was highly variable following craniotomy. Time to hospital discharge was not different between treatment and placebo groups. No adverse events associated with scalp block were identified. CONCLUSION: These data show that bilateral scalp blocks using bupivacaine with epinephrine did not reduce mean postoperative VAS score or overall opioid consumption at 24 hr nor the time-to-discharge from the postanesthesia care unit or from hospital. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT00972790; registered 9 September, 2009.

[Para-Bombay phenotype caused by combined heterozygote of two bases deletion on fut1 alleles].

This study was purposed to investigate the molecular basis of a para-Bombay phenotype for screening and identification of rare blood group. ABO and H phenotypes of the proband were identified by serological techniques. The exon 6 to exon 7 of ABO gene and full coding region of α-1,2-fucosyltransferase (fut1) gene of the proband were analyzed by polymerase chain reaction and direct sequencing of the amplified fragments. The haplotype of compound heterozygote of fut1 was also identified by cloning sequencing. The results indicated that a rare para-Bombay phenotype was confirmed by serological techniques. Two deletion or insertion variant sites near nucleotide 547 and 880 were detected in fut1 gene. The results of cloning sequence showed that one haplotype of fut1 gene was two bases deletion at 547-552 (AGAGAG→AGAG), and another one was two bases deletion at position 880-882 (TTT→T). Both two variants caused a reading frame shift and a premature stop codon. It is concluded that a rare para-Bombay phenotype is found and confirmed in blood donor population. The molecular basis of this individual is compound heterozygote of two bases deletion on fut1 gene which weaken the activity of α-1, 2-fucosyltransferase.

Extensive and modular intrinsically disordered segments in C. elegans TTN-1 and implications in filament binding, elasticity and oblique striation.

TTN-1, a titin like protein in Caenorhabditis elegans, is encoded by a single gene and consists of multiple Ig and fibronectin 3 domains, a protein kinase domain and several regions containing tandem short repeat sequences. We have characterized TTN-1's sarcomere distribution, protein interaction with key myofibrillar proteins as well as the conformation malleability of representative motifs of five classes of short repeats. We report that two antibodies developed to portions of TTN-1 detect an approximately 2-MDa polypeptide on Western blots. In addition, by immunofluorescence staining, both of these antibodies localize to the I-band and may extend into the outer edge of the A-band in the obliquely striated muscle of the nematode. Six different 300-residue segments of TTN-1 were shown to variously interact with actin and/or myosin in vitro. Conformations of synthetic peptides of representative copies of each of the five classes of repeats--39-mer PEVT, 51-mer CEEEI, 42-mer AAPLE, 32-mer BLUE and 30-mer DispRep--were investigated by circular dichroism at different temperatures, ionic strengths and solvent polarities. The PEVT, CEEEI, DispRep and AAPLE peptides display a combination of a polyproline II helix and an unordered structure in aqueous solution and convert in trifluoroethanol to alpha-helix (PEVT, CEEEI, DispRep) and beta-turn (AAPLE) structures, respectively. The octads in BLUE motifs form unstable alpha-helix-like structures coils in aqueous solution and negligible heptad-based, alpha-helical coiled-coils. The alpha-helical structure, as modeled by threading and molecular dynamics simulations, tends to form helical bundles and crosses based on its 8-4-2-2 hydrophobic helical patterns and charge arrays on its surface. Our finding indicates that APPLE, PEVT, CEEEI and DispRep regions are all intrinsically disordered and highly reminiscent of the conformational malleability and elasticity of vertebrate titin PEVK segments. The proposed presence of long, modular and unstable alpha-helical oligomerization domains in the BLUE region of TTN-1 could bundle TTN-1 and stabilize oblique striation of the sarcomere.

Titin as a giant scaffold for integrating stress and Src homology domain 3-mediated signaling pathways: the clustering of novel overlap ligand motifs in the elastic PEVK segment.

The richness of proline sequences in titins qualifies these giant proteins as the largest source of intrinsically disordered structures in nature. An extensive search and analysis for Src homology domain 3 (SH3) ligand motifs revealed a myriad of broadly distributed SH3 ligand motifs, with the highest density in the PEVK segments of human titin. Besides the canonical class I and II motifs with opposite orientations, novel overlapping motifs consisting of one or more of each canonical motif are abundant. Experimentally, the binding affinity and critical residues of these putative titin-based SH3 ligands toward nebulin SH3 and other SH3-containing proteins in muscle and non-muscle cell extracts were validated with peptide array technology and by the sarcomere distribution of SH3-containing proteins. A 28-mer overlapping motif-containing PEVK module binds to nebulin SH3 in and around the canonical cleft, especially to the acidic residues in the loops, as revealed by NMR titration. Molecular dynamics and molecular docking studies indicated that the overlapping motif can bind in opposite orientations with comparable energy and contact areas and predicts correctly orientation-specific contacts in NMR data. We propose that the overlap ligand motifs are a new class of ligands with innate ability to dictate SH3 domain orientation and to facilitate the rate, strength, and stereospecificity of receptor interactions. Proline-rich sequences of titins are candidates as major hubs of SH3-dependent signaling pathways. The interplay of elasticity and dense clustering of mixed receptor orientations in titin PEVK segment have important implications for the mechanical sensing, force sensitivity, and inter-adapter interactions in signaling pathways.

Titin PEVK segment: charge-driven elasticity of the open and flexible polyampholyte.

The giant protein titin spans half of the sarcomere length and anchors the myosin thick filament to the Z-line of skeletal and cardiac muscles. The passive elasticity of muscle at a physiological range of stretch arises primarily from the extension of the PEVK segment, which is a polyampholyte with dense and alternating-charged clusters. Force spectroscopy studies of a 51 kDa fragment of the human fetal titin PEVK domain (TP1) revealed that when charge interactions were reduced by raising the ionic strength from 35 to 560 mM, its mean persistence length increased from 0.30 +/- 0.04 nm to 0.60 +/- 0.07 nm. In contrast, when the secondary structure of TP1 was altered drastically by the presence of 40 and 80% (v/v) of trifluoroethanol, its force-extension behavior showed no significant shift in the mean persistence length of approximately approximately 0.18 +/- 0.03 nm at the ionic strength of 15 mM. Additionally, the mean persistence length also increased from 0.29 to 0.41 nm with increasing calcium concentration from pCa 5-8 to pCa 3-4. We propose that PEVK is not a simple entropic spring as is commonly assumed, but a highly evolved, gel-like enthalpic spring with its elasticity dominated by the sequence-specific charge interactions. A single polyampholyte chain may be fine-tuned to generate a broad range of molecular elasticity by varying charge pairing schemes and chain configurations.

Binding of copper(II) ions to the polyproline II helices of PEVK modules of the giant elastic protein titin as revealed by ESI-MS, CD, and NMR.

Titin, a family of giant elastic proteins, constitutes an elastic sarcomere matrix in striated muscle. In the I-band region of the sarcomere, the titin PEVK segment acts as a molecular spring to generate elasticity as well as sites of adhesion with parallel thin filaments. Previously, we reported that PEVK consists of tandem repeats of 28 residue modules and that the "polyproline II-coil" motif is the fundamental conformational motif of the PEVK module. In order to characterize the factors that may affect and alter the PPII-coil conformational motifs, we have initiated a systematic study of the interaction with divalent cations (Cu2+, Ca2+, Zn2+, and Ni2+) and a conformational profile of PEVK peptides (a representative 28-mer peptide PR: PEPPKEVVPEKKAPVAPPKKPEVPPVKV and its subfragments PR1: kvPEPPKEVVPE, PR2: VPEKKAPVAPPK, PR3: KPEVPPVKV). UV-Vis absorption difference spectra and CD spectra showed that Cu2+ bound to PR1 with high affinity (20 microM), while its binding to PR2 and PR3 as well as the binding of other cations to all four peptides were of lower affinity (>100 microM). Conformational studies by CD revealed that Cu2+ binding to PR1 resulted in a polyproline II to turn transition up to a 1:2 PR1/Cu2+ ratio and a coil to turn transition at higher Cu2+ concentration. ESI-MS provided the stoichiometry of PEVK peptide-Cu2+ complexes at both low and high ion strength, confirming the specific high affinity binding of Cu2+ to PR1 and PR. Furthermore, NMR and ESI-MS/MS fragmentation analysis elucidated the binding sites of the PEVK peptide-Cu2+ complexes at (-2)KVPE2, 8VPE10, 13APV15, and 22EVP24. A potential application of Cu2+ binding in peptide sequencing by mass spectrometry was also revealed. We conclude that Cu2+ binds and bends PEVK peptides to a beta-turn-like structure at specific sites. The specific targeting of Cu2+ towards PPII is likely to be of significant value in elucidating the roles of PPII in titin elasticity as well as in interactions of proline-rich proteins.