Linking Patterns of Intraoperative Neuromonitoring (IONM) Alerts to the Odds of a New Postoperative Neurological Deficit: Analysis of 27,808 Cervical Spine Procedures From a National Multi-institutional Database.

STUDY DESIGN/SETTING: Retrospective review of a national multi-institutional database of 27,808 extradural cervical spine procedures performed between January 2017 and May 2021. OBJECTIVE: Characterize intraoperative neuromonitoring alerts by the patterns of modalities and nerves/muscles involved and quantify risk of new-onset neurological deficit for patients with a primary diagnosis of myelopathy, stenosis, or radiculopathy. SUMMARY OF BACKGROUND DATA: Phenotyping alert patterns and linking those patterns with risk is needed to facilitate clinical decision-making. METHODS: Cases with alerts were categorized by patterns of modalities or nerves/muscles involved, and alert status at closure. Unadjusted odds ratios (ORs) for new-onset neurological deficit were calculated. A mixed-effects logistic regression model controlling for demographic and operative factors, with random intercepts to account for clustering in outcomes by surgeon and surgical neurophysiologist was also used to calculate ORs and probabilities of neurological deficit. RESULTS: There was significantly increased risk of a new neurological deficit for procedures involving posterior compared with anterior approaches (OR: 1.82, P=0.001) and procedures involving three levels compared with one (OR: 2.17, P=0.001). Odds of a deficit were lower for patients with radiculopathy compared with myelopathy (OR: 0.69, P=0.058). Compared with cases with no alerts, those with unresolved Spinal Cord alerts were associated with the greatest elevation in risk (OR: 289.05) followed by unresolved C5-6 Nerve Root (OR: 172.7), C5-T1 Nerve Root/Arm (OR: 162.89), C7 Nerve Root (OR:84.2), and C8-T1 Nerve Root alerts (OR:75.49, all P<0.001). Significant reductions in risk were seen for resolved Spinal Cord, C5-6 Nerve Root, and C8-T1 nerve alerts. Overall, unresolved motor evoked potential and somatosensory evoked potential alerts were associated with the greatest elevation in risk (OR:340.92) followed by unresolved motor evoked potential-only (OR:140.6) and unresolved somatosensory evoked potential-Only alerts (OR:78.3, all P<0.001). These relationships were similar across diagnostic cohorts. CONCLUSIONS: Risk elevation and risk mitigation after an intraoperative neuromonitoring alert during surgery is dependent on the type and pattern of alert.

Quantification of Degradation Products Formed during Heat Sterilization of Glucose Solutions by LC-MS/MS: Impact of Autoclaving Temperature and Duration on Degradation.

Heat sterilization of glucose solutions can lead to the formation of various glucose degradation products (GDPs) due to oxidation, hydrolysis, and dehydration. GDPs can have toxic effects after parenteral administration due to their high reactivity. In this study, the application of the F0 concept to modify specific time/temperature models during heat sterilization and their influence on the formation of GDPs in parenteral glucose solutions was investigated using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Glucose solutions (10%, w/v) were autoclaved at 111 °C, 116 °C, and 121 °C for different durations. The GDPs glyoxal, methylglyoxal, glucosone, 3-deoxyglucosone/3-deoxygalactosone, 3,4-dideoxyglucosone-3-ene, and 5-hydroxymethylfurfural were quantified after derivatization with o-phenylenediamine by an optimized LC-MS/MS method. For all GDPs, the limit of detection was <0.078 µg/mL, and the limit of quantification was <0.236 µg/mL. The autoclaving time of 121 °C and 15 min resulted in the lowest levels of 3-DG/3-DGal and 5-HMF, but in the highest levels of GO and 2-KDG. The proposed LC-MS/MS method is rapid and sensitive. So far, only 5-HMF concentrations are limited by the regulatory authorities. Our results suggest reconsidering the impurity limits of various GDPs, especially the more toxic ones such as GO and MGO, by the Pharmacopoeias.

Identification and quantification of glucose degradation products in heat-sterilized glucose solutions for parenteral use by thin-layer chromatography.

During heat sterilization of glucose solutions, a variety of glucose degradation products (GDPs) may be formed. GDPs can cause cytotoxic effects after parenteral administration of these solutions. The aim of the current study therefore was to develop a simple and quick high-performance thin-layer chromatography (HPTLC) method by which the major GDPs can be identified and (summarily) quantified in glucose solutions for parenteral administration. All GDPs were derivatized with o-phenylenediamine (OPD). The resulting GDP derivatives (quinoxalines) were applied to an HPTLC plate. After 20 minutes of chamber saturation with the solvent, the HPTLC plate was developed in a mixture of 1,4-dioxane-toluene-glacial acetic acid (49:49:2, v/v/v), treated with thymol-sulfuric acid spray reagent, and heated at 130°C for 10 minutes. Finally, the GDPs were quantified by using a TLC scanner. For validation, the identities of the quinoxaline derivatives were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Glyoxal (GO)/methylglyoxal (MGO) and 3-deoxyglucosone (3-DG)/3-deoxygalactosone (3-DGal) could be identified and quantified in pairs, glucosone (2-KDG), 5-hydroxymethylfurfural (5-HMF), and 3,4-dideoxyglucosone-3-ene (3,4-DGE) each individually. For 2-KDG, the linearity of the method was demonstrated in the range of 1-50 µg/mL, for 5-HMF and 3,4-DGE 1-75 µg/mL, for GO/MGO 2-150 µg/mL, and for 3-DG/3-DGal 10-150 µg/mL. All GDPs achieved a limit of detection (LOD) of 2 µg/mL or less and a limit of quantification (LOQ) of 10 µg/mL or less. R2 was 0.982 for 3.4-DGE, 0.997 for 5-HMF, and 0.999 for 2-KDG, 3-DG/3-DGal, and GO/MGO. The intraday precision was between 0.4 and 14.2% and the accuracy, reported as % recovery, between 86.4 and 112.7%. The proposed HPTLC method appears to be an inexpensive, fast, and sufficiently sensitive approach for routine quantitative analysis of GDPs in heat-sterilized glucose solutions.

Therapeutic Impact of Traction Release After C5 Nerve Root Motor Evoked Potential (MEP) Alerts in Cervical Spine Surgery.

STUDY DESIGN: A retrospective review of 40,919 cervical spine surgeries monitored with motor evoked potentials (MEPs) from a multi-institutional intraoperative neuromonitoring database. OBJECTIVE: The objective of this study was to determine the clinical impact of interventions prompted by C5 spinal nerve root MEP alerts. SUMMARY OF BACKGROUND DATA: MEPs have been shown to diagnose acute C5 palsies, but additional data are needed regarding the clinical impact of interventions in response to C5 MEP alerts. MATERIALS AND METHODS: Procedures with isolated C5 MEP alerts were categorized as fully resolved, partially resolved, or unresolved based on the status of signals at closure. Clinical outcomes were based on neurological assessment in the immediate postoperative period. The sensitivity, specificity, likelihood ratios, and odds ratios (ORs) of C5 MEP alerts for acute C5 palsies were calculated. RESULTS: The odds of an acute C5 palsy greatly increased if there was a C5 MEP alert [OR=340.9; 95% confidence (CI): 173.0, 671.6; P<0.0001], and increased further if the alert persisted through closure (OR=820.8; 95% CI: 398.1, 1692.0; P<0.0001). Relative to procedures with unresolved C5 MEP alerts, the risk of an acute C5 palsy significantly decreased if a C5 MEP alert was fully resolved by closure (OR=0.07; 95% CI: 0.02, 0.25; P<0.0001). For alerts resolved during positioning or exposure, 90.9% were resolved with the release of positional traction, and for resolved alerts that occurred after exposure, 36.3% involved just traction release, 14.1% involved both traction release and surgical action, and 30.3% involved just surgical action. The sensitivity of C5 MEP alerts for acute C5 palsies was anesthetic dependent: 89.7% (26/29) in the total intravenous regimen cohort but just 50.0% (10/20) in the inhalational anesthesia cohort. CONCLUSIONS: The timely release of positional traction is an effective intervention for resolving C5 MEP alerts and reducing the odds of an acute postoperative C5 palsy. Surgical maneuvers, such as the release of distraction or graft adjustment, should be attempted in conjunction with traction release depending on the surgical context of the alert. LEVEL OF EVIDENCE: Level IV.

Utility of motor evoked potentials to diagnose and reduce lower extremity motor nerve root injuries during 4,386 extradural posterior lumbosacral spine procedures.

BACKGROUND CONTEXT: Motor evoked potentials (MEPs) have excellent sensitivity for monitoring the functional integrity of the lateral corticospinal tract of the spinal cord. The sensitivity for nerve root function, however, is not as well established; consequently, MEPs are often not utilized for posterior extradural spine procedures distal to the conus. Spontaneous electromyography (sEMG) and somatosensory evoked potentials (SSEPs) are often included for these procedures, but their limited sensitivity has been well documented. Given the risk of motor nerve root injuries during spine procedures, and specifically increased vulnerability of the L4 and L5 nerves, the sensitivity of MEPs was evaluated for diagnostic accuracy and therapeutic impact. PURPOSE: To determine the diagnostic sensitivity of MEPs during lumbosacral spine procedures and the potential therapeutic impact of the resolution of MEP alerts. STUDY DESIGN: A total of 4,386 posterior extradural lumbosacral spine procedures utilizing multimodality intraoperative neuromonitoring (IONM) with sEMG, SSEPs, and MEPs were abstracted from a multi-institutional database. All cases took place between October 2015 and October 2017. No external funding was provided. OUTCOME MEASURES: Sensitivity and specificity, as well as positive and negative likelihood ratios for new postoperative neurologic deficits were calculated for each modality individually as well as when combined (multimodality). PATIENT SAMPLE: Age 18 and older METHODS: Data entered in the electronic medical record were analyzed. Alerts to sEMG activity, decreases in SSEP amplitude, or decreases in MEP amplitude were documented as well as the status of the alerts at closure: resolved or unresolved. The presence of an sEMG alert or an unresolved MEP or SSEP alert at closure was considered a positive diagnostic result, and these results were assessed relative to presence of new immediate onset neurologic deficits as documented in the electronic record. RESULTS: The sensitivity and specificity of multimodality IONM for new immediate-onset lower extremity motor deficits were 100.0% (95% confidence interval: [64.6, 100.0]) and 92.2% (91.1, 93.1), respectively. Looking at the modalities in isolation, the sensitivity of MEPs was considerably better than either lower extremity sEMG or posterior tibial nerve SSEPs: 100.0% (78.5, 100.0) versus just 14.3% (4.0, 39.9) and 28.6% (8.2, 64.1), respectively. Surprisingly, the specificity of lower extremity MEPs was better than sEMG, 97.9% (97.5, 98.3) versus 95.4% (94.7, 96.0) (χ2=43.0, p<.001). The specificity of lower extremity SSEPs was 99.0% (98.5, 99.3). Only 4.4% of all procedures had a lower extremity MEP alert. There were 14 significant new nerve root injuries and all 14 had unresolved MEPs at closure. Total 85.7% of those nerve root injuries were dorsiflexion foot drop injuries and all had unresolved tibialis anterior MEP alerts. Although the overall rate of nerve root injuries was 0.32% (14/4,386), the rate for procedures with unresolved isolated tibialis anterior MEP alerts was 44.4% (12/27). The therapeutic impact is evident in the 2.0% of cases (87/4,386) with lower extremity MEP alerts that were able to be fully resolved by closure and for which the rate of injury was zero. CONCLUSIONS: The diagnostic accuracy of MEPs for anterior tibialis-related nerve root dysfunction supports the inclusion of this modality during routine posterior extradural lumbosacral procedures, especially when the L4 or L5 nerve roots are at risk. Moreover, therapeutic interventions that lead to the resolution of MEP alerts avert postoperative neurologic injuries.

Matrix effect on leaching of Bisphenol A diglycidyl ether (BADGE) from epoxy resin based inner lacquer of aluminium tubes into semi-solid dosage forms.

To study the impact of different semi-solid dosage form components on the leaching of Bisphenol A (BPA) and Bisphenol A diglycidyl ether (BADGE) from the epoxy resin-based inner lacquer of aluminium tubes, the tubes were filled with different matrix preparations and stored at an elevated temperature. Despite compliance with the European Standards EN 15348 and EN 15766 on porosity and polymerisation of internal coatings of aluminium tubes, the commercially available tubes used in the study contained an increased amount of polymerisation residues, such as unbound BPA, BADGE and BADGE derivatives in the lacquer, as determined by acetonitrile extraction. Storage of Macrogol ointments in these tubes resulted in an almost quantitative migration of the unbound polymerisation residues from the coating into the ointment. In addition, due to alterations observed in the RP-HPLC chromatograms of the matrix spiked with BADGE and BADGE derivatives it is supposed that the leachates can react with formulation components. The contamination of the medicinal product by BPA, BADGE and BADGE derivatives can be precluded by using aluminium tubes with an internal lacquer with a low degree of unbound polymerisation residues.

Synthesis and Functional Reconstitution of Light-Harvesting Complex II into Polymeric Membrane Architectures.

One of most important processes in nature is the harvesting and dissipation of solar energy with the help of light-harvesting complex II (LHCII). This protein, along with its associated pigments, is the main solar-energy collector in higher plants. We aimed to generate stable, highly controllable, and sustainable polymer-based membrane systems containing LHCII-pigment complexes ready for light harvesting. LHCII was produced by cell-free protein synthesis based on wheat-germ extract, and the successful integration of LHCII and its pigments into different membrane architectures was monitored. The unidirectionality of LHCII insertion was investigated by protease digestion assays. Fluorescence measurements indicated chlorophyll integration in the presence of LHCII in spherical as well as planar bilayer architectures. Surface plasmon enhanced fluorescence spectroscopy (SPFS) was used to reveal energy transfer from chlorophyll b to chlorophyll a, which indicates native folding of the LHCII proteins.

Nanoscopic leg irons: harvesting of polymer-stabilized membrane proteins with antibody-functionalized silica nanoparticles.

Silica-based nanoparticles (SiNPs) are presented to harvest complex membrane proteins, which have been embedded into unilammelar polymersomes via in vitro membrane assisted protein synthesis (iMAP). Size-optimized SiNPs have been surface-modified with polymer-targeting antibodies, which are employed to harvest the protein-containing polymersomes. The polymersomes mimic the cellular membrane. They are chemically defined and preserve their structural-functional integrity as virtually any membrane protein species can be synthesized into such architecture via the ribosomal context of a cellular lysate. The SiNPs resemble 'heavy leg irons' catching the polymersomes in order to enable gravity-based generic purification and concentration of such proteopolymersomes from the crude mixture of cellular lysates.

Automated software analysis of corneal micrographs for peripheral neuropathy.

PURPOSE: A relationship has been reported between the presence of peripheral neuropathy and the density and shape of corneal nerve fibers. Peripheral neuropathy is a debilitating condition that arises from many common health problems, and its presence is often confirmed with an invasive clinical test called intramuscular electromyography (EMG). In this study, the possibility of developing an alternative or adjunct test to EMG based on the appearance of nerve fibers in corneal micrographs was explored. Since corneal imaging is virtually noninvasive compared with EMG, such a test may be administered more liberally and frequently, before neuropathy symptoms occur. METHODS: A software program that automatically traces nerve fibers in corneal micrographs and generates measures based on these traces was implemented. This software was applied to a database of images collected by confocal laser scanning corneal microscopy from diabetic subjects whose levels of neuropathy were measured with EMG and from healthy subjects. RESULTS: Trends in the nerve fiber density and various measures of shape were calculated and observed, to explore the possibility of using these measures as a clinical tool for corroborating symptoms, confirming an evaluation, or evaluating risk factors for developing neuropathy. CONCLUSIONS: Preliminary statistical trends show a potential for measuring and observing neuropathy severity or for providing an objective risk measure for a patient's ensuing condition. More work is needed in the development of the measures and in their testing to prove that the measures can be made repeatable in a clinical environment.

Contamination of semi-solid dosage forms by leachables from aluminium tubes.

The objective of this study was to determine to what extent bisphenol A (BPA), bisphenol A diglycidyl ether (BADGE) and its derivatives are extractable from epoxy-based coatings of aluminium tubes for pharmaceutical use and to monitor their leaching into different kinds of semi-solid dosage forms. Migration increasing factors should be evaluated. Extraction tests using acetonitrile for 10 days at 40 degrees C turned out to be suitable to estimate the maximum amount of extractables. A plain variability in the nature and amount of extractables among tubes of different vendors (n=7) could be demonstrated. Leaching of the remnants into various semi-solid drug products (ointment, cream, gel) during storage (30 degrees C/40 degrees C) was verifiable. Leachable profiles were, apart from storage time and temperature, decisively influenced by the matrix. In particular, matrix polarity seemed to play a crucial role. Thus, the highest amount of leachables was found in isopropanol-based carbomer gel. Furthermore, in-use conditions (mechanical stress) enhanced migration significantly. In order to ensure quality and safety of semi-solid formulae, interactions between the coating material and the drug product should be thoroughly evaluated.