On-Demand Thio-Succinimide Hydrolysis for the Assembly of Stable Protein-Protein Conjugates.

Chemical post-translational protein-protein conjugation is an important technique with growing applications in biotechnology and pharmaceutical research. Maleimides represent one of the most widely employed bioconjugation reagents. However, challenges associated with the instability of first- and second-generation maleimide technologies are yet to be fully addressed. We report the development of a novel class of maleimide reagents that can undergo on-demand ring-opening hydrolysis of the resulting thio-succinimide. This strategy enables rapid post-translational assembly of protein-protein conjugates. Thio-succinimide hydrolysis, triggered upon application of chemical, photochemical, or enzymatic stimuli, allowed homobifunctional bis-maleimide reagents to be applied in the production of stable protein-protein conjugates, with complete temporal control. Bivalent and bispecific protein-protein dimers constructed from small binders targeting antigens of oncological importance, PD-L1 and HER2, were generated with high purity, stability, and improved functionality compared to monomeric building blocks. The modularity of the approach was demonstrated through elaboration of the linker moiety through a bioorthogonal propargyl handle to produce protein-protein-fluorophore conjugates. Furthermore, extending the functionality of the homobifunctional reagents by temporarily masking reactive thiols included in the linker allowed the assembly of higher order trimeric and tetrameric single-domain antibody conjugates. The potential for the approach to be extended to proteins of greater biochemical complexity was demonstrated in the production of immunoglobulin single-domain antibody conjugates. On-demand control of thio-succinimide hydrolysis combined with the facile assembly of chemically defined homo- and heterodimers constitutes an important expansion of the chemical methods available for generating stable protein-protein conjugates.

Clinical outcomes in borderline and locally advanced pancreatic cancer with the addition of low-dose-rate brachytherapy to standard of care therapy.

PURPOSE: Surgical resection remains the only curative therapy for pancreatic cancer. Unfortunately, many patients have borderline or unresectable disease at diagnosis due to proximity of major abdominal vessels. Neoadjuvant chemotherapy and radiation are used to down-stage, however, there is a risk that there will be a positive/close surgical margin. The CivaSheet is a low-dose-rate (LDR) brachytherapy device placed at the time of surgery to target the area of highest risk of margin positivity. The purpose of this study is to assess the clinical value of brachytherapy in addition to standard-of-care therapy in pancreatic therapy. METHODS AND MATERIALS: Between 2017 and 2022 patients with borderline and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and radiation followed by surgical resection were included. There were 2 cohorts of patients: (1) Those who had the LDR brachytherapy device placed at the time of surgery and (2) those who did not. Sixteen of 19 (84%) patients who had brachytherapy were enrolled in a prospective clinical trial (NCT02843945). Patients were matched for comorbidities, cancer staging, and treatment details. The primary outcome was progression-free survival (PFS). RESULTS: Thirty-five patients were included in this analysis, 19 in the LDR brachytherapy group and 16 in the comparison cohort. The 2-year PFS was 21% vs. 0% (p = 0.11), 2-year OS was 26% vs. 13% (p = 0.43), and the pancreatic cancer cause-specific survival was 84% vs. 56% (p = 0.13) in favor of the brachytherapy patients. CONCLUSIONS: Use of LDR brachytherapy at the time of resection shows a trend towards improved progression free and overall survival for patients with borderline or locally advanced pancreatic cancer treated with neoadjuvant chemoradiation.

Shear wave elastography of the ulnar collateral ligament in division IA pitchers across a competitive collegiate season.

Background: The ulnar collateral ligament (UCL) is a commonly injured elbow stabilizer during throwing. Shear wave elastography (SWE) is a technique that may reveal structural changes in the UCL that are indicative of ligament health and injury risk. The purpose of this study was to assess preseason and inseason shear wave velocity (SWV) in the UCL of collegiate pitchers and to asses repeatability of this measurement technique in healthy volunteers. Methods: Seventeen collegiate baseball pitchers and 11 sex-matched volunteers were recruited. Two-dimensional SWE of the UCL was performed by a single radiologist. In pitchers, SWV was measured at the proximal, midsubstance, and distal UCL for dominant and nondominant elbows preseason, midseason, and postseason, and Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow questionnaire scores were recorded. In volunteers, SWV was measured at UCL midsubstance in dominant elbows at 3 separate occasions over 1 week. An independent samples t-test was used to compare preseason midsubstance measures between pitchers and the healthy volunteers. A mixed-model analysis of covariance (covaried on preseason measures) was used to compare SWV measures at the preseason, midseason, and postseason time points. A similar generalized linear model for nonparametric data was used to compare KJOC scores. Type-I error was set at P < .05. Results: Mean preseason midsubstance dominant arm UCL SWV did not significantly differ between the pitchers (5.40 ± 1.65 m/s) compared to the healthy volunteers (4.35 ± 1.45 m/s). For inseason measures among the pitchers, a decrease in midsubstance (-1.17 ± 0.99 m/s, P = .021) and proximal (-1.55 ± 0.91 m/s, P = .001) SWV was observed at midseason compared to preseason. The proximal measure was also observed to be significantly lower than the nondominant arm (-1.97 ± 0.95 m/s, P < .001). Proximal SWV remained reduced relative to the preseason and the postseason mark (-1.13 ± 0.91 m/s, P = .015). KJOC scores decreased at midseason compared to preseason (P = .003) but then increased to a similar preseason value at the postseason measurement (preseason = 92 ± 3, midseason = 87 ± 3, postseason = 91 ± 3). The repeatability coefficient of SWE in the volunteer cohort was 1.98 m/s. Conclusion: Decreased SWV in the proximal and midsubstance of the dominant arm UCL at midseason suggests structural changes indicative of increasing laxity or 'softening' of the UCL. Associated decline in KJOC scores suggests that these changes are associated with functional decline. Future studies with more frequent sampling would be invaluable to further explore this observation and its significance for predicting and managing UCL injury risk.

The role of leukotriene inhibition using a 5-lipoxygenase (5-LO) inhibitor in a joint contracture model.

PURPOSE: Arthrofibrosis is a common inflammatory complication of joint trauma and surgery. 5lipoxygenase (5-LO) is a key enzyme involved in inflammation. Inhibition of 5-LO has been shown to reduce inflammation in heart and lung models but has not been examined in a joint contracture model. METHODS: Twenty-six rats underwent joint contracture. Six rats served as non-surgical controls. A 5-LO inhibitor, caffeic acid (CA), suspended in 10% ethanol was orally administered to 14 rats and ethanol without CA to the remaining 12 rats daily for 21 days. Leukotriene B4 (LTB4) levels were measured, both systemically and locally. 5-LO levels in the posterior capsule were quantified by measuring the ratio of the length of the posterior capsule demonstrating 5-LO immunostaining to the total length of the capsule. RESULTS: Joint contracture was successfully achieved in all rats who underwent manipulation. Levels of 5- LO measured in the posterior capsule were significantly increased in the animals who underwent surgery (56%/44-64) compared to the non-surgical control animals (7%/4-9). LTB4 levels were found to be significantly lower in the non-surgical control animals (107.79 ± 34.08 pg/ml) compared to all surgical animals (157.6 ± 55.3 pg/ml). CONCLUSION: Surgical intervention resulted in increased 5-LO activity of the synovial surface of the posterior capsule and increased LTB4 levels in the patellar tendon-fat pad. Oral administration of the 5LO inhibitor, CA, was ineffective at reducing systemic and local LTB4 levels and preventing knee joint contracture. Inhibiting 5-LO activity may still be effective in preventing arthrofibrosis and warrants further investigation.

Automated Lung Cancer Segmentation Using a PET and CT Dual-Modality Deep Learning Neural Network.

PURPOSE: To develop an automated lung tumor segmentation method for radiation therapy planning based on deep learning and dual-modality positron emission tomography (PET) and computed tomography (CT) images. METHODS AND MATERIALS: A 3-dimensional (3D) convolutional neural network using inputs from diagnostic PETs and simulation CTs was constructed with 2 parallel convolution paths for independent feature extraction at multiple resolution levels and a single deconvolution path. At each resolution level, the extracted features from the convolution arms were concatenated and fed through the skip connections into the deconvolution path that produced the tumor segmentation. Our network was trained/validated/tested by a 3:1:1 split on 290 pairs of PET and CT images from patients with lung cancer treated at our clinic, with manual physician contours as the ground truth. A stratified training strategy based on the magnitude of the gross tumor volume (GTV) was investigated to improve performance, especially for small tumors. Multiple radiation oncologists assessed the clinical acceptability of the network-produced segmentations. RESULTS: The mean Dice similarity coefficient, Hausdorff distance, and bidirectional local distance comparing manual versus automated contours were 0.79 ± 0.10, 5.8 ± 3.2 mm, and 2.8 ± 1.5 mm for the unstratified 3D dual-modality model. Stratification delivered the best results when the model for the large GTVs (>25 mL) was trained with all-size GTVs and the model for the small GTVs (<25 mL) was trained with small GTVs only. The best combined Dice similarity coefficient, Hausdorff distance, and bidirectional local distance from the 2 stratified models on their corresponding test data sets were 0.83 ± 0.07, 5.9 ± 2.5 mm, and 2.8 ± 1.4 mm, respectively. In the multiobserver review, 91.25% manual versus 88.75% automatic contours were accepted or accepted with modifications. CONCLUSIONS: By using an expansive clinical PET and CT image database and a dual-modality architecture, the proposed 3D network with a novel GTVbased stratification strategy generated clinically useful lung cancer contours that were highly acceptable on physician review.

Fragment-based computational design of antibodies targeting structured epitopes.

De novo design methods hold the promise of reducing the time and cost of antibody discovery while enabling the facile and precise targeting of predetermined epitopes. Here, we describe a fragment-based method for the combinatorial design of antibody binding loops and their grafting onto antibody scaffolds. We designed and tested six single-domain antibodies targeting different epitopes on three antigens, including the receptor-binding domain of the SARS-CoV-2 spike protein. Biophysical characterization showed that all designs are stable and bind their intended targets with affinities in the nanomolar range without in vitro affinity maturation. We further discuss how a high-resolution input antigen structure is not required, as similar predictions are obtained when the input is a crystal structure or a computer-generated model. This computational procedure, which readily runs on a laptop, provides a starting point for the rapid generation of lead antibodies binding to preselected epitopes.

Chemical and Enzymatic Methods for Post-Translational Protein-Protein Conjugation.

Fusion proteins play an essential role in the biosciences but suffer from several key limitations, including the requirement for N-to-C terminal ligation, incompatibility of constituent domains, incorrect folding, and loss of biological activity. This perspective focuses on chemical and enzymatic approaches for the post-translational generation of well-defined protein-protein conjugates, which overcome some of the limitations faced by traditional fusion techniques. Methods discussed range from chemical modification of nucleophilic canonical amino acid residues to incorporation of unnatural amino acid residues and a range of enzymatic methods, including sortase-mediated ligation. Through summarizing the progress in this rapidly growing field, the key successes and challenges associated with using chemical and enzymatic approaches are highlighted and areas requiring further development are discussed.

π-Clamp-Mediated Homo- and Heterodimerization of Single-Domain Antibodies via Site-Specific Homobifunctional Conjugation.

Post-translational protein-protein conjugation produces bioconjugates that are unavailable via genetic fusion approaches. A method for preparing protein-protein conjugates using π-clamp-mediated cysteine arylation with pentafluorophenyl sulfonamide functional groups is described. Two computationally designed antibodies targeting the SARS-CoV-2 receptor binding domain were produced (KD = 146, 581 nM) with a π-clamp sequence near the C-terminus and dimerized using this method to provide a 10-60-fold increase in binding (KD = 8-15 nM). When two solvent-exposed cysteine residues were present on the second protein domain, the π-clamp cysteine residue was selectively modified over an Asp-Cys-Glu cysteine residue, allowing for subsequent small-molecule conjugation. With this strategy, we build molecule-protein-protein conjugates with complete chemical control over the sites of modification.

Platform for Orthogonal N-Cysteine-Specific Protein Modification Enabled by Cyclopropenone Reagents.

Protein conjugates are valuable tools for studying biological processes or producing therapeutics, such as antibody-drug conjugates. Despite the development of several protein conjugation strategies in recent years, the ability to modify one specific amino acid residue on a protein in the presence of other reactive side chains remains a challenge. We show that monosubstituted cyclopropenone (CPO) reagents react selectively with the 1,2-aminothiol groups of N-terminal cysteine residues to give a stable 1,4-thiazepan-5-one linkage under mild, biocompatible conditions. The CPO-based reagents, all accessible from a common activated ester CPO-pentafluorophenol (CPO-PFP), allow selective modification of N-terminal cysteine-containing peptides and proteins even in the presence of internal, solvent-exposed cysteine residues. This approach enabled the preparation of a dual protein conjugate of 2×cys-GFP, containing both internal and N-terminal cysteine residues, by first modifying the N-terminal residue with a CPO-based reagent followed by modification of the internal cysteine with a traditional cysteine-modifying reagent. CPO-based reagents enabled a copper-free click reaction between two proteins, producing a dimer of a de novo protein mimic of IL2 that binds to the ß-IL2 receptor with low nanomolar affinity. Importantly, the reagents are compatible with the common reducing agent dithiothreitol (DTT), a useful property for working with proteins prone to dimerization. Finally, quantum mechanical calculations uncover the origin of selectivity for CPO-based reagents for N-terminal cysteine residues. The ability to distinguish and specifically target N-terminal cysteine residues on proteins facilitates the construction of elaborate multilabeled bioconjugates with minimal protein engineering.

CivaSheet intraoperative radiation therapy for pancreatic cancer.

The treatment of borderline resectable (BR) pancreatic cancer is challenging and requires a multidisciplinary approach with chemotherapy, radiation and surgical resection. Despite using chemotherapy and radiotherapy in the neoadjuvant setting, achievement of negative surgical margins remains technically challenging. Positive margins are associated with increased local recurrences and worse overall survival and there are no standard options for treatment. The CivaSheet is an FDA-cleared implantable sheet with a matrix of unidirectional planar low-dose-rate (LDR) Palladium-103 (Pd-103) sources. The sources are shielded on one side with gold to spare radio-sensitive structures such as the bowel. The sheet can easily be customized and implanted at the time of surgery when there is concern for close or positive margins. The CivaSheet provides an interesting solution to target the region of close/positive margins after pancreatectomy. Here we discuss the physical properties, the dosimetry, clinical workflow and early patient outcomes with the CivaSheet in pancreatic cancer.

A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms.

Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.

Facile Installation of Post-translational Modifications on the Tau Protein via Chemical Mutagenesis.

Post-translational modifications of proteins are ubiquitous in living organisms, as they enable an accurate control of the interactions of these macromolecules. For mechanistic studies, it would be highly advantageous to be able to produce in vitro post-translationally modified proteins with site-specificity. Here, we demonstrate one facile way to achieve this goal through the use of post-translational chemical mutagenesis. We illustrate this approach by performing site-specific phosphorylation and methylation of tau, a protein that stabilizes microtubules and whose aggregation is closely linked with Alzheimer's disease. We then verify the effects of the post-translational modifications on the ability of tau to control microtubule polymerization, revealing in particular an unexpected role for phosphorylation at S199, which is outside the microtubule-binding region of tau. These results show how the chemical mutagenesis approach that we present enables the systematic analysis of site-specific post-translational modifications of a key protein involved in the pathogenesis of Alzheimer's disease.

The use of the reds noninvasive lung fluid monitoring system to assess readiness for discharge in patients hospitalized with acute heart failure: A pilot study.

BACKGROUND: Inadequate decongestion is common in hospitalized heart failure (HF) patients and may contribute to readmissions. Our purpose was to use remote dielectric sensing (ReDS) technology to measure lung congestion at discharge in patients admitted with acute HF and to see if a device-targeted intervention could reduce HF readmission rates. METHODS: We conducted a prospective pilot study of patients admitted with acute decompensated HF randomized to receive standard therapy or ReDS-guided therapy to determine the timing of hospital discharge based on the amount of lung congestion present after diuresis. ReDS measurement was performed for all patients once they were deemed ready for discharge. Patients in the treatment arm with residual lung congestion defined by ReDS ≥39% had HF consultation and further diuresis. RESULTS: Of 108 HF patients (50% male, age 73.6 ±â€¯12.6 years, BMI 29.3 ±â€¯4.3 kg/m2, EF 38.5 ±â€¯15.1%, BNP 1138 ±â€¯987 pg/mL), 32% demonstrated residual lung congestion at the time of proposed hospital discharge. ReDS guided therapy triggered additional diuresis in 30% (18/60) of the patients in the treatment arm (average weight loss 5.6 pounds, p = 0.02). 30-day HF readmission rates were similar in the treatment and the control arms (1.7% vs 4.2%; p = 0.44). Patients discharged as planned with residual lung congestion with ReDS ≥39% had higher 30-day readmission rate compared to patients who were adequately decongested at discharge with ReDS <39% (11.8% vs. 1.4%, p = 0.03). CONCLUSION: In our single-center cohort, ReDS testing demonstrated that 32% of HF patients deemed ready for discharge have clinically significant residual lung congestion which was associated with a higher risk of readmission. ReDS-guided management was associated with significant decongestion but not a reduction in HF readmissions in this sample.

A Biomechanical Comparison of Modified Radioscapholunate Fusion Constructs for Radiocarpal Arthritis.

PURPOSE: This biomechanical study compared fixation constructs used in radioscapholunate (RSL) arthrodesis. We hypothesized that plates and screws, pin plate, and headless screws would all provide similarly stable fixation constructs. METHODS: We chose 27 fresh-frozen cadaveric extremities, 14 of which were matched pairs and randomized them into 3 groups to match age, body mass index, and sex. An RSL arthrodesis was simulated with plates and screws, pin plates, or headless compression screws via a standard dorsal approach to the wrist. Specimens were mounted into a custom jig and cycled through an arc of 120° for 5,000 cycles to simulate 6 weeks range of motion (ROM). A 9-mm stroke differential variable reluctance transducer recorded continuous displacement, and gross hardware failure in the form of screw or pin cutout was investigated after the simulation. RESULTS: Greater distraction across the RSL articulation was observed in the headless screws compared with the plate-and-screws and pin-plate constructs, with no difference between the plates and screws and pin plates. Greater average displacement was observed in the headless screws compared with the plate-and-screws and pin-plate constructs, with no difference between the pin plates and plates and screws. Gross hardware failure was observed least in plates and screws followed by pin plates. CONCLUSIONS: Plate-and-screw and pin-plate constructs are biomechanically superior in resisting RSL distraction compared with headless compression screws for RSL arthrodesis over 6 weeks of simulated ROM in the absence of healing. CLINICAL RELEVANCE: The results of this study demonstrated negligible arthrodesis site distraction in the plate-and-screws and pin-plate constructs when 6 weeks of ROM was simulated. When translated to a clinical scenario, these findings may allow earlier discontinuation of external immobilization after surgery.

Iodine quantification and detectability thresholds among major dual-energy CT platforms.

OBJECTIVES: To estimate the minimum detectable iodine concentration on multiple dual-energy CT (DECT) platforms. METHODS AND MATERIALS: A phantom containing iodine concentrations ranging from 0 to 10 mg ml-1 was scanned with five dual-energy platforms (two rapid kilo volt switching (r-kVs), one dual source (DS), one sequential acquisition and one split-filter). Serial dilutions of 300 mg ml-1 iodinated contrast material were used to generate concentrations below 2 mg ml-1. Iodine density and virtual monoenergetic images were reviewed by three radiologists to determine the minimum visually detectable iodine concentration. Contrast-to-noise ratios (CNRs) were calculated. RESULTS: 1 mg mL-1 (~0.8 mg mL-1 corrected) was the minimum visually detectable concentration among the platforms and could be seen by all readers on the third-generation r-kVs and DS platforms. CONCLUSIONS: At low concentrations, CNR for monoenergetic images was highest on the DS platform and lowest in the sequential acquisition and split-filter platforms. ADVANCES IN KNOWLEDGE: The results of this study corroborate previous in vivo estimates of iodine detection limits at DECT and provide a comparison for the performance of different DECT platforms at low iodine concentrations in vitro.

Enhanced Immunoaffinity Purification of Human Neutrophil Flavocytochrome B for Structure Determination by Electron Microscopy.

Determination of the structure of human neutrophil (PMN) flavocytochrome b (Cytb) is a necessary step for the understanding of the structure-function essentials of NADPH oxidase activity. This understanding is crucial for structure-driven therapeutic approaches addressing control of inflammation and infection. Our work on purification and sample preparation of Cytb has facilitated progress toward the goal of structure determination. Here we describe exploiting immunoaffinity purification of Cytb for initial examination of its size and shape by a combination of classical and cryoelectron microscopic (EM) methods. For these evaluations, we used conventional negative-stain transmission electron microscopy (TEM) to examine both detergent-solubilized Cytb as single particles and Cytb in phosphatidylcholine reconstituted membrane vesicles as densely packed random, partially ordered, and subcrystalline arrays. In preliminary trials, we also examined single particles by cryoelectron microscopy (cryoEM) methods. We conclude that Cytb in detergent and reconstituted in membrane is a relatively compact, symmetrical protein of about 100 Å in maximum dimension. The negative stain, preliminary cryoEM, and crude molecular models suggest that the protein is probably a heterotetramer of two p22phox and gp91phox subunits in both detergent micelles and membrane vesicles. This exploratory study also suggests that high-resolution 2D electron microscopic approaches may be accessible to human material collected from single donors.

hnRNPs Interacting with mRNA Localization Motifs Define Axonal RNA Regulons.

mRNA translation in axons enables neurons to introduce new proteins at sites distant from their cell body. mRNA-protein interactions drive this post-transcriptional regulation, yet knowledge of RNA binding proteins (RBP) in axons is limited. Here we used proteomics to identify RBPs interacting with the axonal localizing motifs of Nrn1, Hmgb1, Actb, and Gap43 mRNAs, revealing many novel RBPs in axons. Interestingly, no RBP is shared between all four RNA motifs, suggesting graded and overlapping specificities of RBP-mRNA pairings. A systematic assessment of axonal mRNAs interacting with hnRNP H1, hnRNP F, and hnRNP K, proteins that bound with high specificity to Nrn1 and Hmgb1, revealed that axonal mRNAs segregate into axon growth-associated RNA regulons based on hnRNP interactions. Axotomy increases axonal transport of hnRNPs H1, F, and K, depletion of these hnRNPs decreases axon growth and reduces axonal mRNA levels and axonal protein synthesis. Thus, subcellular hnRNP-interacting RNA regulons support neuronal growth and regeneration.

Axonal localization of neuritin/CPG15 mRNA is limited by competition for HuD binding.

HuD protein (also known as ELAVL4) has been shown to stabilize mRNAs with AU-rich elements (ARE) in their 3' untranslated regions (UTRs), including Gap43, which has been linked to axon growth. HuD also binds to neuritin (Nrn1) mRNA, whose 3'UTR contains ARE sequences. Although the Nrn1 3'UTR has been shown to mediate its axonal localization in embryonic hippocampal neurons, it is not active in adult dorsal root ganglion (DRG) neurons. Here, we asked why the 3'UTR is not sufficient to mediate the axonal localization of Nrn1 mRNA in DRG neurons. HuD overexpression increases the ability of the Nrn1 3'UTR to mediate axonal localizing in DRG neurons. HuD binds directly to the Nrn1 ARE with about a two-fold higher affinity than to the Gap43 ARE. Although the Nrn1 ARE can displace the Gap43 ARE from HuD binding, HuD binds to the full 3'UTR of Gap43 with higher affinity, such that higher levels of Nrn1 are needed to displace the Gap43 3'UTR. The Nrn1 3'UTR can mediate a higher level of axonal localization when endogenous Gap43 is depleted from DRG neurons. Taken together, our data indicate that endogenous Nrn1 and Gap43 mRNAs compete for binding to HuD for their axonal localization and activity of the Nrn1 3'UTR.

The Development and Psychometric Evaluation of a Supplementary Index Score of the Neuropsychological Assessment Battery Screening Module that is Sensitive to Traumatic Brain Injury.

OBJECTIVE: This study examines the validity of the NAB Screening Module (screening module of the neuropsychological assessment battery, S-NAB) in an acute traumatic brain injury (TBI) inpatient population and provides psychometric evaluation of an original index sensitive to TBI impairment. METHOD: The utility of the S-NAB as a TBI screen was examined using a between groups design. One-hundred and four patients with mild complicated to severe TBI were recruited from a consecutive cohort of patients admitted as inpatients to a UK Major Trauma Centre. Ninety-eight control participants were selected from the S-NAB normative sample. All TBI patients completed the S-NAB during their inpatient stay. RESULTS: Control participants scored significantly higher than TBI participants on the Total Screening index (t = 3.626, p < 0.01), The Attention index (t = 7.882, p < 0.01), and the Executive index (t = 5.577, p < 0.01). A briefer TBI Impairment index of six subtests was constructed which accurately discriminated TBI patients from normative controls (t = 9.9, p < 0.01; Cohen's d = 1.54). The TBI index had excellent classification accuracy (AUC = 0.83), superior to that of the standard S-NAB indices. The TBI Index, Attention Index, and Total Screening Index demonstrated increasing impairment with increased severity of injury. CONCLUSIONS: The S-NAB TBI index is a robust, reliable screening index for use with acute TBI patients, which is sensitive to the effects of acute TBI. It affords a briefer cognitive screen than the S-NAB and demonstrates a dose response relationship to TBI severity.