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Item type: Item , Access status: Open Access , Timely intervention in HMG-CoA Lyase deficiency: The role of newborn screening, metabolic management, and genomic sequencing(Molecular Genetics and Metabolism Reports, 2025-12-01) Menkovic, I; Makhijani, N; Francescatto, L; Pendyal, S; Stanley, C; Young, SP; Koeberl, DD; Niyazov, D; Stiles, AR3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is a rare autosomal recessive metabolic disease caused by variants in the HMGCL gene leading to an impairment in leucine catabolism and ketone synthesis. In the United States, HMG-CoA lyase deficiency is listed on the recommended uniform screening panel as a core condition for newborn screening. A positive newborn screen will typically show an elevation of C5-hydroxylated species on the acylcarnitine profile using a dried-blood spot collected between 24 and 48 h of life. Initial follow-up testing generally includes a plasma acylcarnitine profile and a urine organic acid profile. Clinically, this metabolic alteration can lead to severe metabolic decompensation, presenting as hypoketotic hypoglycemia and, when left untreated, potential long-term neurological impairments. This report highlights the case of a 38-day-old male with an initial abnormal newborn screen. Follow-up testing showed moderate elevations of C5-hydroxylated and C6-dicarboxylated species on the plasma acylcarnitine profile and marked elevations of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric and 3-hydroxyisovaleric acid detected by urine organic acid analysis. These findings were consistent with a biochemical diagnosis of HMG-CoA lyase deficiency. Confirmatory molecular testing included targeted HMGCL sequencing including deletion/duplication analysis; the results of which were negative. Genome sequencing was then requested which identified a deep intronic complex variant of unknown significance within intron 1 of HGMCL. RNA sequencing studies were sent as follow-up which revealed that the level of expression of the HMGCL gene was negligible in comparison with tissue-matched controls, thus confirming the biochemical diagnosis of HMG-CoA lyase deficiency.Item type: Item , Access status: Open Access , Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.(Nature communications, 2025-11) Küry, Sébastien; Stanton, Janelle E; van Woerden, Geeske M; Bosc-Rosati, Amélie; Hsieh, Tzung-Chien; Bray, Lise; Oloudé, Marielle; Rosenfelt, Cory; Scott-Boyer, Marie Pier; Most, Victoria; Wang, Tianyun; Papendorf, Jonas J; de Konink, Charlotte; Deb, Wallid; Vignard, Virginie; Studencka-Turski, Maja; Besnard, Thomas; Hajdukowicz, Anna M; Thiel, Franziska G; Wolfgramm, Sophie; Florenceau, Laëtitia; Cuinat, Silvestre; Marsac, Sylvain; Verrès, Yann; Dangoumau, Audrey; Poirier, Léa; Wentzensen, Ingrid M; Tuttle, Annabelle; Forster, Cara; Striesow, Johanna; Golnik, Richard; Ortiz, Damara; Jenkins, Laura; Rosenfeld, Jill A; Ziegler, Alban; Houdayer, Clara; Bonneau, Dominique; Torti, Erin; Begtrup, Amber; Monaghan, Kristin G; Mullegama, Sureni V; Volker-Touw, Catharina ML Nienke; van Gassen, Koen LI; Oegema, Renske; de Pagter, Mirjam S; Steindl, Katharina; Rauch, Anita; Ivanovski, Ivan; McDonald, Kimberly; Boothe, Emily; Dauber, Andrew; Baker, Janice; Fabie, Noelle Andrea V; Bernier, Raphael A; Turner, Tychele N; Srivastava, Siddharth; Dies, Kira A; Swanson, Lindsay C; Costin, Carrie; Abdulrazak, Alali; Jobling, Rebekah K; Pappas, John; Rabin, Rachel; Niyazov, Dmitriy; Chun-Hui Tsai, Anne; Kovak, Karen; Beck, David B; Malicdan, May Christine V; Adams, David R; Wolfe, Lynne; Ganetzky, Rebecca D; Muraresku, Colleen C; Babikyan, Davit; Sedláček, Zdeněk; Hančárová, Miroslava; Timberlake, Andrew T; Saif, Hind Al; Nestler, Berkley; King, Kayla; Hajianpour, MJ; Costain, Gregory; Prendergast, D'Arcy; Li, Chumei; Geneviève, David; Vitobello, Antonio; Sorlin, Arthur; Philippe, Christophe; Harel, Tamar; Toker, Ori; Sabir, Ataf; Lim, Derek; Hamilton, Mark J; Bryson, Lisa J; Cleary, Elaine; Weber, Sacha; Hoffman, Trevor L; Cueto-González, Anna M; Tizzano, Eduardo F; Gómez-Andrés, David; Codina-Solà, Marta; Ververi, Athina; Pavlidou, Efterpi; Lambropoulos, Alexandros; Garganis, Kyriakos; Rio, Marlène; Levy, Jonathan; Langas, Sarah J; McRae, Anne M; Lessard, Mathieu K; D'Agostino, Maria Daniela; De Bie, Isabelle; Wegler, Meret; Abou Jamra, Rami; Kamphausen, Susanne B; Bothe, Viktoria; Potocki, Lorraine; Olinger, Eric; Sznajer, Yves; Wiame, Elsa; Thompson, Michelle L; Schroeder, Molly C; Gooch, Catherine; Smith, Raphael A; Pandya, Arti; Busch, Larissa M; Völker, Uwe; Hammer, Elke; Wende, Kristian; Cogné, Benjamin; Isidor, Bertrand; Meiler, Jens; Ripoll, Clémentine; Bigou, Stéphanie; Laumonnier, Frédéric; Hildebrand, Peter W; Eichler, Evan E; McWalter, Kirsty; Krawitz, Peter M; Roux-Dalvai, Florence; Elgersma, Ype; Marcoux, Julien; Bousquet, Marie-Pierre; Droit, Arnaud; Poschmann, Jeremie; Grabrucker, Andreas M; Bolduc, Francois V; Bézieau, Stéphane; Ebstein, Frédéric; Krüger, ElkeNeurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.Item type: Item , Access status: Open Access , Normative values of ankle strength and its importance for rehabilitation and return to activity: A cross-sectional study.(World journal of orthopedics, 2025-10) da Fonseca, Lucas Furtado; Jeyaraman, Madhan; Jeyaraman, Naveen; Inojossa, Thiago Resende; Maciel, Eduardo Souza; de Cesar Netto, Cesar; Mansur, Nacime Salomão; Astur, Diego CostaBackground
Ankle normative values are limited compared to isokinetic knee assessments. Chronic ankle instability correlates with agonist-antagonist imbalances, decreased evertor/invertor ratio, and plantar flexion deficits. Strengthening programs targeting evertor/invertor and dorsiflexor/plantar flexor balance help reduce injury recurrence. Bilateral neuromuscular deficits compromise the contralateral side, rendering healthy limbs unsuitable as recovery references. Defining normative healthy ankle parameters is crucial for establishing precise limits in non-surgical treatments and sports return criteria. While the limb symmetry index (LSI) is used for knees with a cutoff of > 90%, no such standardization exists for the ankle.Aim
To comprehensively evaluate isokinetic ankle strength profiles in non-athletic individuals.Methods
This is a cross-sectional study. Two hundred ankles were evaluated using the Biodex 3 System to assess eversion, inversion, dorsiflexion, and plantar flexion. Healthy individuals with an active lifestyle and no previous injuries were evaluated. The Maximum Torque, Agonist/Antagonist Ratio, LSI, and Muscular Deficiency Index (MDI) and the correlation with demographic variables were evaluated.Results
The mean age (mean ± SD) was 38.5 ± 13.5 years, and the body mass index (BMI) was 25.8 ± 4.2 in 69 men and 31 women. The mean maximum torque values by gender were (mean ± SD): 22.3 ± 6.6 female (F) and 33.4 ± 9.9 male (M) N/m for eversion; 30.10 ± 10.0 (F) and 37.0 ± 11.6 N/m (M) for inversion, 37.4 ± 10.0 (F) and 53.6 ± 13.0 N/m (M) for dorsiflexion, and 100.4 ± 37.2 (F) and 158.1 ± 33.4 (M) N/m for flexion. There was no correlation between age or BMI and maximum torque. The evertors/invertors ratio was 88.8%, and the dorsiflexors/plantar flexors ratio was 36.1%. The MDI and LSI were balanced between sides for every movement, having an average global difference of less than 10%.Conclusion
These findings provide gender-specific normative isokinetic values for the ankle in healthy, physically active adults. These reference parameters-especially LSI and MDI above 90%-can support clinical decision-making in rehabilitation planning and return-to-sport assessment, offering objective benchmarks for functional recovery.Item type: Item , Access status: Open Access , Discrete Superconvergence Analysis for Quantum Magnus Algorithms of Unbounded Hamiltonian SimulationFang, Di; Borns-Weil, Yonah; Zhang, JiaqiItem type: Item , Access status: Open Access , A molecular cell atlas of mouse lemur, an emerging model primate.(Nature, 2025-08) Tabula Microcebus Consortium; Ezran, Camille; Liu, Shixuan; Chang, Stephen; Ming, Jingsi; Botvinnik, Olga; Penland, Lolita; Tarashansky, Alexander; de Morree, Antoine; Travaglini, Kyle J; Zhao, Jia; Wang, Gefei; Hasegawa, Kazuteru; Sin, Hosu; Sit, Rene; Okamoto, Jennifer; Sinha, Rahul; Zhang, Yue; Karanewsky, Caitlin J; Pendleton, Jozeph L; Morri, Maurizio; Perret, Martine; Aujard, Fabienne; Stryer, Lubert; Artandi, Steven; Fuller, Margaret T; Weissman, Irving L; Rando, Thomas A; Ferrell, James E; Wang, Bo; De Vlaminck, Iwijn; Yang, Can; Casey, Kerriann M; Albertelli, Megan A; Pisco, Angela Oliveira; Karkanias, Jim; Neff, Norma; Wu, Angela Ruohao; Quake, Stephen R; Krasnow, Mark AMouse lemurs are the smallest and fastest reproducing primates, as well as one of the most abundant, and they are emerging as a model organism for primate biology, behaviour, health and conservation. Although much has been learnt about their ecology and phylogeny in Madagascar and their physiology, little is known about their cellular and molecular biology. Here we used droplet-based and plate-based single-cell RNA sequencing to create Tabula Microcebus, a transcriptomic atlas of 226,000 cells from 27 mouse lemur organs opportunistically obtained from four donors clinically and histologically characterized. Using computational cell clustering, integration and expert cell annotation, we define and biologically organize more than 750 lemur molecular cell types and their full gene expression profiles. This includes cognates of most classical human cell types, including stem and progenitor cells, and differentiating cells along the developmental trajectories of spermatogenesis, haematopoiesis and other adult tissues. We also describe dozens of previously unidentified or sparsely characterized cell types. We globally compare expression profiles to define the molecular relationships of cell types across the body, and explore primate cell and gene expression evolution by comparing lemur transcriptomes to those of human, mouse and macaque. This reveals cell-type-specific patterns of primate specialization and many cell types and genes for which the mouse lemur provides a better human model than mouse1. The atlas provides a cellular and molecular foundation for studying this model primate and establishes a general approach for characterizing other emerging model organisms.Item type: Item , Access status: Open Access , Mouse lemur cell atlas informs primate genes, physiology and disease.(Nature, 2025-08) Ezran, Camille; Liu, Shixuan; Chang, Stephen; Ming, Jingsi; Guethlein, Lisbeth A; Wang, Michael FZ; Dehghannasiri, Roozbeh; Olivieri, Julia; Frank, Hannah K; Tarashansky, Alexander; Koh, Winston; Jing, Qiuyu; Botvinnik, Olga; Antony, Jane; Tabula Microcebus Consortium; Pisco, Angela Oliveira; Karkanias, Jim; Yang, Can; Ferrell, James E; Boyd, Scott D; Parham, Peter; Long, Jonathan Z; Wang, Bo; Salzman, Julia; De Vlaminck, Iwijn; Wu, Angela Ruohao; Quake, Stephen R; Krasnow, Mark AMouse lemurs (Microcebus spp.) are an emerging primate model organism, but their genetics, cellular and molecular biology remain largely unexplored. In an accompanying paper1, we performed large-scale single-cell RNA sequencing of 27 organs from mouse lemurs. We identified more than 750 molecular cell types, characterized their transcriptomic profiles and provided insight into primate evolution of cell types. Here we use the generated atlas to characterize mouse lemur genes, physiology, disease and mutations. We uncover thousands of previously unidentified lemur genes and hundreds of thousands of new splice junctions including over 85,000 primate splice junctions missing in mice. We systematically explore the lemur immune system by comparing global expression profiles of key immune genes in health and disease, and by mapping immune cell development, trafficking and activation. We characterize primate-specific and lemur-specific physiology and disease, including molecular features of the immune program, lemur adipocytes and metastatic endometrial cancer that resembles the human malignancy. We present expression patterns of more than 400 primate genes missing in mice, many with similar expression patterns to humans and some implicated in human disease. Finally, we provide an experimental framework for reverse genetic analysis by identifying naturally occurring nonsense mutations in three primate immune genes missing in mice and by analysing their transcriptional phenotypes. This work establishes a foundation for molecular and genetic analyses of mouse lemurs and prioritizes primate genes, isoforms, physiology and disease for future study.Item type: Item , Access status: Open Access , Model Uncertainty and Missing Data: An Objective Bayesian Perspective (with Discussion)(Bayesian Analysis, 2025-12-01) García-Donato, Gonzalo; Castellanos, María Eugenia; Cabras, Stefano; Quirós, Alicia; Forte, AnabelItem type: Item , Access status: Open Access , Generalized Beta Mixtures of Gaussians(Advances in Neural Information Processing Systems, 2011) Armagan, A; Dunson, DB; Clyde, MAIn recent years, a rich variety of shrinkage priors have been proposed that have great promise in addressing massive regression problems. In general, these new priors can be expressed as scale mixtures of normals, but have more complex forms and better properties than traditional Cauchy and double exponential priors. We first propose a new class of normal scale mixtures through a novel generalized beta distribution that encompasses many interesting priors as special cases. This encompassing framework should prove useful in comparing competing priors, considering properties and revealing close connections. We then develop a class of variational Bayes approximations through the new hierarchy presented that will scale more efficiently to the types of truly massive data sets that are now encountered routinely.Item type: Item , Access status: Open Access , Multimodality word-finding distinctions in cortical stimulation mapping.(Neurosurgery, 2013) Serafini, S; Clyde, MA; Tolson, M; Haglund, MMBACKGROUND: Cortical stimulation mapping (CSM) commonly uses visual naming to determine resection margins in the dominant hemisphere of patients with epilepsy. Visual naming alone may not identify all language sites in resection-prone areas, prompting additional tasks for comprehensive language mapping. OBJECTIVE: To demonstrate word-finding distinctions between visual, auditory, and reading modalities during CSM and the percentage of modality-specific language sites within dominant hemisphere subregions. METHODS: Twenty-eight patients with epilepsy underwent CSM by the use of visual, auditory, and sentence-completion tasks. Hierarchical logistic regression analyzed errors to identify language sites and provide modality-specific percentages within subregions. RESULTS: The percentage of sites classified as language sites based on auditory naming was twice as high in anterior temporal regions compared with visual naming, marginally higher in posterior temporal areas, and comparable in parietal regions. Sentence completion was comparable to visual and auditory naming in parietal regions and lower in most temporal areas. Of 470 sites tested with both visual and auditory naming, 95 sites were distinctly auditory, whereas 48 sites were distinctly visual. The remaining sites overlapped. CONCLUSION: Distinct cortical areas were found for distinct input modalities, with language sites in anterior tip regions found most often by using auditory naming. The vulnerability of anterior temporal tip regions to resection in this population and distinct sites for each modality suggest that a multimodality approach may be needed to spare crucial language sites, if sparing those sites can be shown to significantly reduce the rate of postoperative language deficits without sacrificing seizure control.Item type: Item , Access status: Open Access , Combined use of an electrostatic precipitator and a high-efficiency particulate air filter in building ventilation systems: Effects on cardiorespiratory health indicators in healthy adults.(Indoor air, 2018-05) Day, DB; Xiang, J; Mo, J; Clyde, MA; Weschler, CJ; Li, F; Gong, J; Gong, J; Chung, M; Zhang, Y; Zhang, JHigh-efficiency particulate air (HEPA) filtration in combination with an electrostatic precipitator (ESP) can be a cost-effective approach to reducing indoor particulate exposure, but ESPs produce ozone. The health effect of combined ESP-HEPA filtration has not been examined. We conducted an intervention study in 89 volunteers. At baseline, the air-handling units of offices and residences for all subjects were comprised of coarse, ESP, and HEPA filtration. During the 5-week long intervention, the subjects were split into 2 groups, 1 with just the ESP removed and the other with both the ESP and HEPA removed. Each subject was measured for cardiopulmonary risk indicators once at baseline, twice during the intervention, and once 2 weeks after baseline conditions were restored. Measured indoor and outdoor PM2.5 and ozone concentrations, coupled with time-activity data, were used to calculate exposures. Removal of HEPA filters increased 24-hour mean PM2.5 exposure by 38 (95% CI: 31, 45) μg/m3 . Removal of ESPs decreased 24-hour mean ozone exposure by 2.2 (2.0, 2.5) ppb. No biomarkers were significantly associated with HEPA filter removal. In contrast, ESP removal was associated with a -16.1% (-21.5%, -10.4%) change in plasma-soluble P-selectin and a -3.0% (-5.1%, -0.8%) change in systolic blood pressure, suggesting reduced cardiovascular risks.Item type: Item , Access status: Open Access , Age modification of ozone associations with cardiovascular disease risk in adults: a potential role for soluble P-selectin and blood pressure.(Journal of thoracic disease, 2018-07) Day, Drew B; Clyde, Merlise A; Xiang, Jianbang; Li, Feng; Cui, Xiaoxing; Mo, Jinhan; Gong, Jicheng; Weschler, Charles J; Zhang, Yinping; Zhang, Junfeng JimBackground
Studies have suggested that age increases susceptibility to ozone-associated mortality, but the underlying mechanisms are unclear. In a previous study, personal exposure to ozone was significantly associated with a platelet activation biomarker, plasma soluble P-selectin (sCD62P), and blood pressure in 89 healthy adults, aged 22-52 years. The present study examines whether age modifies these associations in the same adults and in additional adults.Methods
Interaction terms of age and exposure were analyzed using hierarchical Bayesian mixed effects ridge regressions. Data from a similar additional study involving 71 healthy participants, aged 19-26 years, were pooled with the data from the first study to evaluate age effect modification when more young adults were added to the analysis.Results
In the 89 adults, significant age interactions were observed for past 24-hour and 2-week ozone exposures and sCD62P. Based on the pooled data (89 plus 71 adults), a 10 ppb increase in 24-hour ozone exposure was associated with increases in sCD62P and systolic blood pressure (SBP) by 22.3% (95% CI: 14.3%, 31.2%) and 1.35 (-0.18, 2.84) mmHg, respectively, at age 25; these values increased to 48.6% (32.7%, 65.1%) and 4.98 (2.56, 7.35) mmHg, respectively, at age 40.Conclusions
These results mechanistically suggest that increasing age enhances cardiovascular effects of ozone.Item type: Item , Access status: Open Access , AAPM Truth-based CT (TrueCT) reconstruction grand challenge.(Medical physics, 2025-04) Abadi, Ehsan; Segars, W Paul; Felice, Nicholas; Sotoudeh-Paima, Saman; Hoffman, Eric A; Wang, Xiao; Wang, Wei; Clark, Darin; Ye, Siqi; Jadick, Giavanna; Fryling, Milo; Frush, Donald P; Samei, EhsanBackground
This Special Report summarizes the 2022, AAPM grand challenge on Truth-based CT image reconstruction.Purpose
To provide an objective framework for evaluating CT reconstruction methods using virtual imaging resources consisting of a library of simulated CT projection images of a population of human models with various diseases.Methods
Two hundred unique anthropomorphic, computational models were created with varied diseases consisting of 67 emphysema, 67 lung lesions, and 66 liver lesions. The organs were modeled based on clinical CT images of real patients. The emphysematous regions were modeled using segmentations from patient CT cases in the COPDGene Phase I dataset. For the lung and liver lesion cases, 1-6 malignant lesions were created and inserted into the human models, with lesion diameters ranging from 5.6 to 21.9 mm for lung lesions and 3.9 to 14.9 mm for liver lesions. The contrast defined between the liver lesions and liver parenchyma was 82 ± 12 HU, ranging from 50 to 110 HU. Similarly, the contrast between the lung lesions and the lung parenchyma was defined as 781 ± 11 HU, ranging from 725 to 805 HU. For the emphysematous regions, the defined HU values were -950 ± 17 HU ranging from -918 to -979 HU. The developed human models were imaged with a validated CT simulator. The resulting CT sinograms were shared with the participants. The participants reconstructed CT images from the sinograms and sent back their reconstructed images. The reconstructed images were then scored by comparing the results against the corresponding ground truth values. The scores included both task-generic (root mean square error [RMSE] and structural similarity matrix [SSIM]), and task-specific (detectability index [d'] and lesion volume accuracy) metrics. For the cases with multiple lesions, the measured metric was averaged across all the lesions. To combine the metrics with each other, each metric was normalized to a range of 0 to 1 per disease type, with "0" and "1" being the worst and best measured values across all cases of the disease type for all received reconstructions.Results
The True-CT challenge attracted 52 participants, out of which 5 successfully completed the challenge and submitted the requested 200 reconstructions. Across all participants and disease types, SSIM absolute values ranged from 0.22 to 0.90, RMSE from 77.6 to 490.5 HU, d' from 0.1 to 64.6, and volume accuracy ranged from 1.2 to 753.1 mm3. The overall scores demonstrated that participant "A" had the best performance in all categories, except for the metrics of d' for lung lesions and RMSE for liver lesions. Participant "A" had an average normalized score of 0.41 ± 0.22, 0.48 ± 0.32, and 0.42 ± 0.33 for the emphysema, lung lesion, and liver lesion cases, respectively.Conclusions
The True-CT challenge successfully enabled objective assessment of CT reconstructions with the unique advantage of access to a diverse population of diseased human models with known ground truth. This study highlights the significant potential of virtual imaging trials in objective assessment of medical imaging technologies.Item type: Item , Access status: Open Access , Association of Vasopressor Choice with Clinical and Functional Outcomes Following Moderate to Severe Traumatic Brain Injury: A TRACK-TBI Study.(Neurocritical care, 2022-02) Toro, Camilo; Temkin, Nancy; Barber, Jason; Manley, Geoffrey; Jain, Sonia; Ohnuma, Tetsu; Komisarow, Jordan; Foreman, Brandon; Korley, Frederick K; Vavilala, Monica S; Laskowitz, Daniel T; Mathew, Joseph P; Hernandez, Adrian; Sampson, John; James, Michael L; Goldstein, Benjamin A; Markowitz, Amy J; Krishnamoorthy, Vijay; TRACK-TBI InvestigatorsBackground
Early hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury.Methods
We conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score < 13) who were admitted to the intensive care unit and received an intravenous vasopressor within 48 h of admission. The primary exposure was initial vasopressor choice (phenylephrine versus norepinephrine), and the primary outcome was 6-month Glasgow Outcomes Scale Extended (GOSE), with the following secondary outcomes: length of hospital stay, length of intensive care unit stay, in-hospital mortality, new requirement for dialysis, and 6-month Disability Rating Scale. Regression analysis was used to assess differences in outcomes between patients exposed to norepinephrine versus phenylephrine, with propensity weighting to address selection bias due to the nonrandom allocation of the treatment groups and patient dropout.Results
The final study sample included 156 patients, of whom 79 (51%) received norepinephrine, 69 (44%) received phenylephrine, and 8 (5%) received an alternate drug as their initial vasopressor. 121 (77%) of patients were men, with a mean age of 43.1 years. Of patients receiving norepinephrine as their initial vasopressor, 32% had a favorable outcome (GOSE 5-8), whereas 40% of patients receiving phenylephrine as their initial vasopressor had a favorable outcome. Compared with phenylephrine, exposure to norepinephrine was not significantly associated with improved 6-month GOSE (weighted odds ratio 1.40, 95% confidence interval 0.66-2.96, p = 0.37) or any secondary outcome.Conclusions
The majority of patients with moderate to severe TBI received either phenylephrine or norepinephrine as first-line agents for blood pressure support following brain injury. Initial choice of norepinephrine, compared with phenylephrine, was not associated with improved clinical or functional outcomes.Item type: Item , Access status: Open Access , Current Concepts in Cranial Reconstruction: Review of Alloplastic Materials.(Plastic and reconstructive surgery. Global open, 2022-08) Johnston, Darin T; Lohmeier, Steven J; Langdell, Hannah C; Pyfer, Bryan J; Komisarow, Jordan; Powers, David B; Erdmann, DetlevCranioplasty for acquired cranial defects can be complex and challenging. Benefits include improved cosmesis, protection of intracranial structures, and restoration of neurocognitive function. These defects can be reconstructed with preserved craniectomy bone flaps, split autografts, or alloplastic materials. When alloplastic cranioplasty is planned, the material should be carefully selected. There is confusion on which material should be used in certain scenarios, particularly in composite defects.Methods
The PubMed database was used to conduct a nonsystematic review of literature related to these materials and the following factors: time required in preoperative planning and fabrication, intraoperative time, feasibility of intraoperative modification, fixation method (direct or indirect), implant cost, overall complication rate, and surgical revision rates.Results
Surgical revision rates for alloplastic materials range from 10% to 23%. Retention of titanium mesh at 4 years is 85% in composite reconstruction with free fasciocutaneous and free myocutaneous flaps. In composite reconstruction with locoregional and free muscle flaps, the retention of titanium mesh at 4 years is 47%. The retention of nontitanium and nonpreserved autogenous reconstruction is 72% and 82%, respectively.Conclusions
Alloplastic materials should be considered for reconstruction of large (>100 cm2) cranial defects, especially for adult patients younger than 30 years, and all patients with bone flaps that are fragmented or have been cryopreserved for an extended period. Preformed titanium mesh provides a favorable primary reconstructive option when a staged reconstruction is not possible or indicated but should be avoided in composite defects reconstructed with locoregional scalp and free muscle flaps.Item type: Item , Access status: Open Access , Incidence and Clinical Impact of Myocardial Injury Following Traumatic Brain Injury: A Pilot TRACK-TBI Study.(Journal of neurosurgical anesthesiology, 2022-04) Krishnamoorthy, Vijay; Manley, Geoffrey T; Jain, Sonia; Sun, Shelly; Foreman, Brandon; Komisarow, Jordan; Laskowitz, Daniel T; Mathew, Joseph P; Hernandez, Adrian; James, Michael L; Vavilala, Monica S; Markowitz, Amy J; Korley, Frederick K; TRACK-TBI InvestigatorsBackground
Traumatic brain injury (TBI) is a major global health problem. Little research has addressed extracranial organ dysfunction following TBI, particularly myocardial injury. Using a sensitive marker of myocardial injury-high sensitivity troponin (hsTn)-we examined the incidence of early myocardial injury following TBI and explored its association with neurological outcomes following moderate-severe TBI.Methods
We conducted a pilot cohort study of 133 adult (age above 17 y) subjects enrolled in the TRACK-TBI 18-center prospective cohort study. Descriptive statistics were used to examine the incidence of myocardial injury (defined as hsTn >99th percentile for a standardized reference population) across TBI severities, and to explore the association of myocardial injury with a 6-month extended Glasgow Outcome Score among patients with moderate-severe TBI.Results
The mean (SD) age of the participants was 44 (17) years, and 87 (65%) were male. Twenty-six patients (20%) developed myocardial injury following TBI; myocardial injury was present in 15% of mild TBI patients and 29% of moderate-severe TBI patients (P=0.13). Median (interquartile range) hsTn values were 3.8 ng/L (2.1, 9.0), 5.8 ng/L (4.5, 34.6), and 10.2 ng/L (3.0, 34.0) in mild, moderate, and severe TBI participants, respectively (P=0.04). Overall, 11% of participants with moderate-severe TBI and myocardial injury experienced a good outcome (6-mo extended Glasgow Outcome Score≥5) at 6 months, compared with 65% in the group that did not experience myocardial injury (P=0.01).Conclusions
Myocardial injury is common following TBI, with a likely dose-response relationship with TBI severity. Early myocardial injury was associated with poor 6-month clinical outcomes following moderate-severe TBI.Item type: Item , Access status: Open Access , Risk Factors and Neurological Outcomes Associated With Circulatory Shock After Moderate-Severe Traumatic Brain Injury: A TRACK-TBI Study.(Neurosurgery, 2022-09) Toro, Camilo; Hatfield, Jordan; Temkin, Nancy; Barber, Jason; Manley, Geoffrey; Ohnuma, Tetsu; Komisarow, Jordan; Foreman, Brandon; Korley, Frederick K; Vavilala, Monica S; Laskowitz, Daniel T; Mathew, Joseph P; Hernandez, Adrian; Sampson, John; James, Michael L; Raghunathan, Karthik; Goldstein, Benjamin A; Markowitz, Amy J; Krishnamoorthy, Vijay; TRACK-TBI InvestigatorsBackground
Extracranial multisystem organ failure is a common sequela of severe traumatic brain injury (TBI). Risk factors for developing circulatory shock and long-term functional outcomes of this patient subset are poorly understood.Objective
To identify emergency department predictors of circulatory shock after moderate-severe TBI and examine long-term functional outcomes in patients with moderate-severe TBI who developed circulatory shock.Methods
We conducted a retrospective cohort study using the Transforming Clinical Research and Knowledge in TBI database for adult patients with moderate-severe TBI, defined as a Glasgow Coma Scale (GCS) score of <13 and stratified by the development of circulatory shock within 72 hours of hospital admission (Sequential Organ Failure Assessment score ≥2). Demographic and clinical data were assessed with descriptive statistics. A forward selection regression model examined risk factors for the development of circulatory shock. Functional outcomes were examined using multivariable regression models.Results
Of our moderate-severe TBI population (n = 407), 168 (41.2%) developed circulatory shock. Our predictive model suggested that race, computed tomography Rotterdam scores <3, GCS in the emergency department, and development of hypotension in the emergency department were associated with developing circulatory shock. Those who developed shock had less favorable 6-month functional outcomes measured by the 6-month GCS-Extended (odds ratio 0.36, P = .002) and 6-month Disability Rating Scale score (Diff. in means 3.86, P = .002) and a longer length of hospital stay (Diff. in means 11.0 days, P < .001).Conclusion
We report potential risk factors for circulatory shock after moderate-severe TBI. Our study suggests that developing circulatory shock after moderate-severe TBI is associated with poor long-term functional outcomes.Item type: Item , Access status: Open Access , The joint impacts of sex and race/ethnicity on incidence of grade 1 versus grades 2-3 meningioma across the lifespan.(Neuro-oncology advances, 2023-05) Walsh, Kyle M; Price, Mackenzie; Neff, Corey; Komisarow, Jordan M; Wimberly, Courtney E; Kruchko, Carol; Barnholtz-Sloan, Jill S; Ostrom, Quinn TBackground
Previous research has identified older age, African-American race, and female sex as meningioma risk factors, but there is limited information on their joint effects, or on how these demographic factors vary across strata of tumor grade.Methods
The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC's National Program of Cancer Registries and NCI's Surveillance, Epidemiology and End Results Program which covers ~100% of the U.S. population and aggregates incidence data on all primary malignant and nonmalignant brain tumors. These data were used to explore the joint impacts of sex and race/ethnicity on average annual age-adjusted incidence rates of meningioma. We calculated meningioma incidence rate ratios (IRRs) by sex and race/ethnicity, across strata of age and tumor grade.Results
Compared to individuals who are non-Hispanic White, individuals who are non-Hispanic Black had significantly higher risk of grade 1 (IRR = 1.23; 95% CI: 1.21-1.24) and grade 2-3 meningioma (IRR = 1.42; 95% CI: 1.37-1.47). The female-to-male IRR peaked in the fifth decade of life across all racial/ethnic groups and tumor grades, but was 3.59 (95% CI: 3.51-3.67) for WHO grade 1 meningioma and 1.74 (95% CI: 1.63-1.87) for WHO grade 2-3 meningioma.Conclusions
This study reveals the joint effects of sex and race/ethnicity on meningioma incidence throughout the lifespan and across strata of tumor grade, highlighting incidence disparities among females and African-Americans that may inform future strategies for tumor interception.Item type: Item , Access status: Open Access , Safety, Efficacy, and Clinical Outcomes of Dexmedetomidine for Sedation in Traumatic Brain Injury: A Scoping Review.(Journal of neurosurgical anesthesiology, 2024-04) Hatfield, Jordan; Soto, Alexandria L; Kelly-Hedrick, Margot; Kaplan, Samantha; Komisarow, Jordan M; Ohnuma, Tetsu; Krishnamoorthy, VijayDexmedetomidine is a promising alternative sedative agent for moderate-severe Traumatic brain injury (TBI) patients. Although the data are limited, the posited benefits of dexmedetomidine in this population are a reduction in secondary brain injury compared with current standard sedative regimens. In this scoping review, we critically appraised the literature to examine the effects of dexmedetomidine in patients with moderate-severe TBI to examine the safety, efficacy, and cerebral and systemic physiological outcomes within this population. We sought to identify gaps in the literature and generate directions for future research. Two researchers and a librarian queried PubMed, Embase, Scopus, and APA PsycINFO databases. Of 920 studies imported for screening, 11 were identified for inclusion in the review. The primary outcomes in the included studied were cerebral physiology, systemic hemodynamics, sedation levels and delirium, and the presence of paroxysmal sympathetic hyperactivity. Dexmedetomidine dosing ranged from 0.2 to 1 ug/kg/h, with 3 studies using initial boluses of 0.8 to 1.0 ug/kg over 10 minutes. Dexmedetomidine used independently or as an adjunct seems to exhibit a similar hemodynamic safety profile compared with standard sedation regimens, albeit with transient episodes of bradycardia and hypotension, decrease episodes of agitation and may serve to alleviate symptoms of sympathetic hyperactivity. This scoping review suggests that dexmedetomidine is a safe and efficacious sedation strategy in patients with TBI. Given its rapid onset of action and anxiolytic properties, dexmedetomidine may serve as a feasible sedative for TBI patients.Item type: Item , Access status: Open Access , Incidence of Myocardial Injury and Cardiac Dysfunction After Adult Traumatic Brain Injury: A Systematic Review and Meta-analysis.(Journal of neurosurgical anesthesiology, 2024-10) Chaikittisilpa, Nophanan; Kiatchai, Taniga; Liu, Sunny Yang; Kelly-Hedrick, Margot; Vavilala, Monica S; Lele, Abhijit V; Komisarow, Jordan; Ohnuma, Tetsu; Colton, Katharine; Krishnamoorthy, VijayMyocardial injury and cardiac dysfunction after traumatic brain injury (TBI) have been reported in observational studies, but there is no robust estimate of their incidences. We conducted a systematic review and meta-analysis to estimate the pooled incidence of myocardial injury and cardiac dysfunction among adult patients with TBI. A literature search was conducted using MEDLINE and EMBASE databases from inception to November 2022. Observational studies were included if they reported at least one abnormal electrocardiographic finding, elevated cardiac troponin level, or echocardiographic evaluation of systolic function or left ventricular wall motion in adult patients with TBI. Myocardial injury was defined as elevated cardiac troponin level according to the original studies and cardiac dysfunction was defined as the presence of left ventricular ejection fraction <50% or regional wall motion abnormalities assessed by echocardiography. The meta-analysis of the pooled incidence of myocardial injury and cardiac dysfunction was performed using random-effect models. The pooled estimated incidence of myocardial injury after TBI (17 studies, 3,773 participants) was 33% (95% CI: 27%-39%, I2 :s 93%), and the pooled estimated incidence of cardiac dysfunction after TBI (9 studies, 557 participants) was 16.% (95% CI: 9%-25.%, I2 : 84%). Although there was significant heterogeneity between studies and potential overestimation of the incidence of myocardial injury and cardiac dysfunction, our findings suggest that myocardial injury occurs in approximately one-third of adults after TBI, and cardiac dysfunction occurs in approximately one-sixth of patients with TBI.Item type: Item , Access status: Open Access , Intraoperative brain tumor classification via laser-induced fluorescence spectroscopy and machine learning.(Journal of neurosurgery, 2025-08) Zachem, Tanner J; Sperber, Jacob E; Chen, Sully F; Adil, Syed M; Wissel, Benjamin D; Chamberlin, Gregory; Owolo, Edwin; Nguyen, Annee; Crowell, Kerri-Anne; Herndon, James E; Abi Hachem, Ralph; Jang, David W; Cummings, Thomas J; Johnson, Margaret O; Eward, William; Patel, Anoop P; Komisarow, Jordan M; Cook, Steven H; Southwell, Derek; Fecci, Peter E; Friedman, Allan H; Goodwin, C Rory; Codd, Patrick JObjective
To optimize neurosurgical tumor resection, tissue types and borders must be appropriately identified. Authors of this study established the use of a nondestructive laser-based endogenous fluorescence spectroscopy device, "TumorID," to almost immediately classify a specimen as glioma, meningioma, pituitary adenoma, or nonneoplastic tissue in the operating room, utilizing a machine learning algorithm.Methods
TumorID requires only 0.5 seconds to collect data, without the need for any dyes or tissue manipulation, and utilizes a 100-mW, 405-nm laser that does not damage the tissue. The system was used in the operating room to scan ex vivo specimens from 46 patients (mean age 52 years) with glioma (8 patients), meningioma (10 patients), pituitary adenoma (23 patients), and nonneoplastic tissue resected during an epilepsy operation (5 patients). A support vector machine algorithm was trained to distinguish between these lesions and classify them in near real time. Statistical significance was determined through a generalized estimating equation on the area under the known fluorophore emission regions for free reduced nicotinamide adenine dinucleotide (NADH), bound NADH, flavin adenine dinucleotide, and neutral porphyrins.Results
Ultimately, the machine learning model showed a high degree of classification power with a multiclass area under the receiver operating characteristic curve of 0.809 ± 0.002. The areas under the curve for neutral porphyrins were found to be statistically significant (p < 0.001) and to have the largest impact on model output.Conclusions
This initial ex vivo clinical study demonstrated the ability of TumorID to rapidly differentiate and classify various pathologies and surrounding brain in a configuration that can be easily translated to scan in vivo. This classification power could allow TumorID to augment surgical decision-making by enabling rapid intraoperative tissue diagnostics and border delineation, potentially improving patient outcomes by allowing for a more informed and complete resection.