Alexander Ren

All Publications

• Safety, feasibility, and technique of stereo-electroencephalography in children younger than 3 years. Journal of neurosurgery. Pediatrics Uchitel, J., Fariyike, O. A., Rockwood, S. J., Steeman, S., Kim, L. H., Choi, J., Berg, A., Ren, A., Teeyagura, P., Grant, G., Buch, V., Mahaney, K. B., Prolo, L. M., Porter, B. E., Hyslop, A., Phillips, H. W. 2026: 1-10

  Abstract

  Stereo-electroencephalography (sEEG) is a minimally invasive technique for intracranial monitoring that was traditionally reserved for adults but is increasingly used in very young pediatric patients with drug-resistant epilepsy. The aim of this study was to evaluate its safety, feasibility, and technical considerations in pediatric patients younger than 3 years.The authors reviewed the records of 21 children younger than 3 years who underwent sEEG monitoring at Lucile Packard Children's Hospital between February 2013 and March 2025. Data were collected from patients' clinical records and operative reports. Skull thickness was measured at the thinnest point under electrodes. Primary outcome variables were 1) sEEG-related complications, and 2) electrode placement entry point error (EPE) and target point error (TPE).Twenty-one patients (67% male) had a mean ± SE age at seizure onset of 0.5 ± 0.5 years (range birth-1.6 years). Patients underwent 23 sEEG surgeries at a mean age of 2.2 ± 0.1 years (range 0.9-2.7 years). The Mayfield headframe with the Infinity Support System was used in 65% of cases. Overall, a mean of 19 ± 1 (range 9-27) depth electrodes were placed per patient. In total, 443 electrodes were placed, most often in the frontal (189 electrodes, 43%) and temporal (121 electrodes, 27%) regions. A total of 440 bolts were used, and the most common sizes were 20 mm (68%) and 13 mm (18%); 3 electrodes were placed without bolts. The mean skull thickness at the thinnest point of electrode placement was 2.0 ± 0.1 mm (range 1.5-3.2 mm). For 417 electrodes available for analysis, the mean EPE was 1.9 ± 0.1 mm, and the mean TPE was 2.8 ± 0.1 mm. Aside from a CSF leak from a bolt in 1 patient, there were no complications. The most common procedures included open resection (61% of sEEG cases) and laser ablation (30%). Procedures were performed at a mean of 43 ± 11 days (range 0-150 days) after sEEG removal, with a mean patient age of 2.3 ± 0.1 years (range 1.2-2.9 years).This study supports the safety and feasibility of sEEG in children younger than 3 years, even in those with a skull thickness < 2 mm. Moreover, the authors report the youngest patient in the literature to have undergone sEEG at 11 months, without complications. The minimum skull thickness in which an electrode was successfully secured with a bolt was 1.5 mm. With appropriate technical adaptations, sEEG can be accurately performed in children younger than 3 years.

  View details for DOI 10.3171/2025.9.PEDS25194

  View details for PubMedID 41650398

• Molecular and biophysical remodeling of the blood-brain barrier in glioblastoma: mechanistic drivers of tumor-neurovascular crosstalk FRONTIERS IN PHYSICS Abikenari, M., Sjoholm, M., Liu, J., Nageeb, G., Ha, J. H., Wu, J., Ren, A., Sayadi, J., Lim, J., Cho, K., Verma, R., Medikonda, R., Banu, M., Lim, M. 2025; 13

  View details for DOI 10.3389/fphy.2025.1723329

  View details for Web of Science ID 001651720600001

• Female department chairs and diversity among general surgery applicants and entering residents. Surgery open science Ren, A. L., Choi, J., Wren, S. M. 2025; 28: 101-103

  Abstract

  Academic surgical department chairs play a critical role in guiding the missions of their departments. One understudied aspect of chairs' influence is their effect on trainee recruitment and diversity. This study explores whether the appointment of female surgical chairs is associated with an increase in the proportion of female and underrepresented-in-medicine applicants and entrants to academic general surgery residency programs.Academic programs in which a female chair was appointed to replace a male chair were identified. Male-led programs were identified and matched 2:1 to each female-led program based on similar geographic location and time span. Data on applicant and entrant demographics for all included programs was obtained from the Association of American Medical Colleges. A difference-in-difference analysis of applicants and entrants was performed comparing female and underrepresented-in-medicine proportions between the pre-chair appointment and post-appointment years.No significant changes were found in the proportions of female or underrepresented-in-medicine applicants/entrants following the appointment of a female chair.Our study found that the appointment of new female chairs is not associated with the gender or racial/ethnic composition of residency applicants/entrants in the immediate post-appointment period. This indicates that increasing diversity among surgical trainees likely relies on the combined efforts of multiple department leaders and faculty members, as well as broader advocacy and outreach efforts in the surgical community.

  View details for DOI 10.1016/j.sopen.2025.10.008

  View details for PubMedID 41438000

  View details for PubMedCentralID PMC12721269

• The immunological landscape of traumatic brain injury: insights from pathophysiology to experimental models. Frontiers in neurology Abikenari, M., Ha, J. H., Liu, J., Ren, A., Cho, K. B., Lim, J., Kim, L. H., Medikonda, R., Choi, J., Lim, M. 2025; 16: 1668480

  Abstract

  Traumatic brain injury (TBI) is a complex, heterogeneous neuropathological disease that continues to be among the prominent causes of mortality and disability around the world. Translational success in TBI has been significant, yet therapies are limited as the intersection of the initial mechanical traumas and secondary neuroinflammatory cascades, which predispose to long-term neurological deficits, is poorly understood. The pathogenesis of TBI is not limited to the primary mechanical injury. The secondary damage, including ischemia, excitotoxicity, oxidative stress, and immune dysfunction, leads to neuronal apoptosis, the breakdown of the blood-brain barrier (BBB), and chronic neuroinflammation. The preclinical controlled cortical impact (CCI) and fluid percussion injury (FPI) TBI models have generated valuable biomechanical data related to TBI-induced immune responses, including microglial priming, astrocyte dysregulation, and peripheral leukocyte recruitment. However, experimental models today are unable to completely replicate the intricate immune cascades in human TBI, particularly delayed and context-specific innate and adaptive immune response activation. Cytokine signaling (IL-1β, TNF-α, and IL-6), neuroinflammatory amplification through the IL-23/IL-17 pathway, and autoantibody-mediated neurodegeneration are emerging as significant secondary injury mechanisms. Additionally, TBI-induced immunosuppression, which presents as generalized T lymphocyte depletion and aberrant macrophage polarization, enhances the risk of infection and delayed neurological recovery. Emerging immunotherapeutics such as cytokine blockade, complement blockade, and targeted modulation of T lymphocytes have the potential to optimize the post-TBI immune microenvironment for reducing secondary damage. Inclusion of next-generation experimental models combined with secondary injuries, such as hypoxia, polytrauma, and systemic inflammation, is needed to shift towards innovative, biomarker-driven, patient-stratified trials. Thus, integration of immunological phenotyping with translationally relevant models of TBI represents an important cornerstone in the development of targeted therapeutic treatments designed to improve neuroprotection, repair, and long-term functional outcome.

  View details for DOI 10.3389/fneur.2025.1668480

  View details for PubMedID 41050281

  View details for PubMedCentralID PMC12488441

• Correction of sodium channel mutations in sensory neurons reverses aberrant properties. Brain : a journal of neurology Shim, J., Tanaka, B., Taub, D. G., Mis, M. A., Schulman, B. R., Snavely, A., Cheng, Y. C., Laedermann, C., Buttermore, E. D., Ren, A., Hermawan, C., Dou, D., Kawaguchi, R., Geschwind, D. H., Dib-Hajj, S., Waxman, S. G., Woolf, C. J. 2025

  Abstract

  Inherited erythromelalgia, small fiber neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage gated sodium channel Nav1.7. How different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations remains unknown. Most of the work analysing the impact of these mutations on electrophysiological properties has utilized over-expression systems in cell lines and rodent sensory neurons, which may differ from the natural context. We have differentiated sensory neurons from iPSCs derived from patient samples that have the Nav1.7 A1632G mutation. This strategy reveals changes in electrophysiological properties not previously observed in cell lines, that may be important for disease presentation. Further, using CRISPR/Cas9, we corrected this mutation which reduced the underlying hyperexcitability, providing a path for personalized medicine to treat these disorders and introduced the mutation into control iPSCs which generated hyperexcitability providing causality. iPSC sensory neurons are a robust, scalable, and relevant model to study the effects of gain-of-function mutations in ion channels in pain-related disorders.

  View details for DOI 10.1093/brain/awaf155

  View details for PubMedID 40279376

• Nervus intermedius sectioning for the treatment of geniculate neuralgia. Journal of neurosurgery Ren, A. L., Ehsani, A., Park, D. J., Persad, A. R., Wu, J. Y., Hall, J. C., Zhang, M., Choi, J., Kim, L. H., Xu, R., Chang, S. D., Lim, M. 2025: 1-8

  Abstract

  Geniculate neuralgia (GN) is a rare facial pain syndrome characterized by severe stabbing pain in the ear canal. The exact cause of GN remains unclear; however, it is thought that the nervus intermedius (NI) is the primary implicated structure. When medical management fails, surgical interventions are offered to treat the pain. This study aimed to present a consecutive series of patients with GN who underwent craniotomy with NI sectioning, to offer insights into the safety and efficacy of the surgical approach.A retrospective review of consecutive institutional medical records from January 2000 to February 2024 identified patients diagnosed with GN who underwent surgical treatment. Patient records were manually reviewed for information regarding patient demographics, comorbidities, medication history, surgical techniques, and outcomes.The study included 47 NI sectioning procedures in 45 patients with GN (mean age 45.5 years). Most patients had concurrent trigeminal neuralgia (TN) and approximately one-third of patients had concurrent TN and glossopharyngeal neuralgia. Surgical procedures involved NI sectioning, often alongside microvascular decompression (MVD) for cranial nerves (CNs) V or IX/X/XI, with favorable early postoperative pain relief. Of 47 procedures, 38 (80.9%) improved pain (Barrow Neurological Institute [BNI] pain intensity score < IV) and 32 (68.1%) resolved pain (BNI score I) by the latest follow-up visit. There was a low incidence of complications, with 2 cases of unexpected hearing loss among all patients, no instances of permanent facial paralysis, and 1 case of permanent vestibular dysfunction. Additionally, 3 patients reported experiencing loss of taste following surgery.This case series suggests that NI sectioning is safe and likely efficacious in relieving the primary deep ear pain of GN, with a potential additive benefit when performed with MVD on CNs V or IX/X/XI, as needed. Further research is needed to refine treatment guidelines and clarify NI-specific otalgia given the overlapping innervation of the inner ear with other CNs.

  View details for DOI 10.3171/2024.11.JNS241141

  View details for PubMedID 40085931

• Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression. Cancer research Wu, C. Y., Chen, Y., Lin, Y. J., Wei, K. C., Chang, K. Y., Feng, L. Y., Chen, K. T., Li, G., Ren, A. L., Nitta, R. T., Wu, J. Y., Cho, K. B., Pant, A., Choi, J., Mackall, C. L., Kim, L. H., Wu, A. C., Chuang, J. Y., Huang, C. Y., Jackson, C. M., Chen, P. Y., Lim, M. 2024; 84 (23): 4017-4030

  Abstract

  Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

  View details for DOI 10.1158/0008-5472.CAN-24-0018

  View details for PubMedID 39618248

• Extraction of Unstructured Electronic Health Records to Evaluate Glioblastoma Treatment Patterns. JCO clinical cancer informatics Swaminathan, A., Ren, A. L., Wu, J. Y., Bhargava-Shah, A., Lopez, I., Srivastava, U., Alexopoulos, V., Pizzitola, R., Bui, B., Alkhani, L., Lee, S., Mohit, N., Seo, N., Macedo, N., Cheng, W., Wang, W., Tran, E., Thomas, R., Gevaert, O. 2024; 8: e2300091

  Abstract

  Data on lines of therapy (LOTs) for cancer treatment are important for clinical oncology research, but LOTs are not explicitly recorded in electronic health records (EHRs). We present an efficient approach for clinical data abstraction and a flexible algorithm to derive LOTs from EHR-based medication data on patients with glioblastoma multiforme (GBM).Nonclinicians were trained to abstract the diagnosis of GBM from EHRs, and their accuracy was compared with abstraction performed by clinicians. The resulting data were used to build a cohort of patients with confirmed GBM diagnosis. An algorithm was developed to derive LOTs using structured medication data, accounting for the addition and discontinuation of therapies and drug class. Descriptive statistics were calculated and time-to-next-treatment (TTNT) analysis was performed using the Kaplan-Meier method.Treating clinicians as the gold standard, nonclinicians abstracted GBM diagnosis with a sensitivity of 0.98, specificity 1.00, positive predictive value 1.00, and negative predictive value 0.90, suggesting that nonclinician abstraction of GBM diagnosis was comparable with clinician abstraction. Of 693 patients with a confirmed diagnosis of GBM, 246 patients contained structured information about the types of medications received. Of them, 165 (67.1%) received a first-line therapy (1L) of temozolomide, and the median TTNT from the start of 1L was 179 days.We described a workflow for extracting diagnosis of GBM and LOT from EHR data that combines nonclinician abstraction with algorithmic processing, demonstrating comparable accuracy with clinician abstraction and highlighting the potential for scalable and efficient EHR-based oncology research.

  View details for DOI 10.1200/CCI.23.00091

  View details for PubMedID 38857465

• Pediatric Trauma Center Access, Regional Injury Burden, and Socioeconomic Disadvantage. JAMA surgery Hur, D. G., Ren, A. L., Yue, T. M., Spain, D. A., Choi, J. 2024

  View details for DOI 10.1001/jamasurg.2024.0962

  View details for PubMedID 38748438

• Getting What You Pay For: Impact of Copayments on Physical Therapy and Opioid Initiation, Timing, and Continuation for Newly Diagnosed Low Back Pain. The spine journal : official journal of the North American Spine Society Jin, M. C., Jensen, M., Barros Guinle, M. I., Ren, A., Zhou, Z., Zygourakis, C. C., Desai, A. M., Veeravagu, A., Ratliff, J. K. 2024

  Abstract

  Physical therapy (PT) is an important component of low back pain (LBP) management. Despite established guidelines, heterogeneity in medical management remains common.We sought to understand how copayments impact timing and utilization of PT in newly diagnosed LBP.The IBM Watson Health MarketScan claims database was utilized in a longitudinal setting.Adult patients with LBP.The primary outcomes-of-interest were timing and overall utilization of PT services. Additional outcomes-of-interest included timing of opioid prescribing.Actual and inferred copayments based on non-PCP visit claims were used to evaluate the relationship between PT copayment and incidence of PT initiation. Multivariable regression models were used to evaluate factors influencing PT usage.Overall, 2,467,389 patients were included. PT initiation, among those with at ≥1 PT service during the year after LBP diagnosis (30.6%), occurred at a median of 8 days post-diagnosis (IQR 1-55). Among those with at least one PT encounter, incidence of subsequent PT visits was significantly lower for those with high initial PT copayments. High initial PT copayments, while inversely correlated with PT utilization, were directly correlated with subsequent opioid use (0.77 prescriptions/patient [$0 PT copayment] vs 1.07 prescriptions/patient [$50-74 PT copayment]; 1.15 prescriptions/patient [$75+ PT copayment]). Among patients with known opioid and PT copayments, higher PT copayments were correlated with faster opioid use while higher opioid copayments were correlated with faster PT use (Spearman p < 0.05). For multivariable whole-cohort analyses, incidence of PT initiation among patients with inferred copayments in the 50-75th and 75th-100th percentiles was significantly lower than those below the 50th percentile (HR=0.893 [95%CI 0.887-0.899] and HR=0.905 [95%CI 0.899-0.912], respectively).Higher PT copayments correlated with reduced PT utilization; higher PT copayments and lower opioid copayments were independent contributors to delayed PT initiation and higher opioid use. In patients covered by plans charging high PT copayments, opioid use was significantly higher. Co-pays may impact long-term adherence to PT.

  View details for DOI 10.1016/j.spinee.2024.01.008

  View details for PubMedID 38262499

• Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. Nature communications Michael, B. D., Dunai, C., Needham, E. J., Tharmaratnam, K., Williams, R., Huang, Y., Boardman, S. A., Clark, J. J., Sharma, P., Subramaniam, K., Wood, G. K., Collie, C., Digby, R., Ren, A., Norton, E., Leibowitz, M., Ebrahimi, S., Fower, A., Fox, H., Tato, E., Ellul, M. A., Sunderland, G., Held, M., Hetherington, C., Egbe, F. N., Palmos, A., Stirrups, K., Grundmann, A., Chiollaz, A. C., Sanchez, J. C., Stewart, J. P., Griffiths, M., Solomon, T., Breen, G., Coles, A. J., Kingston, N., Bradley, J. R., Chinnery, P. F., Cavanagh, J., Irani, S. R., Vincent, A., Baillie, J. K., Openshaw, P. J., Semple, M. G., Taams, L. S., Menon, D. K. 2023; 14 (1): 8487

  Abstract

  To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

  View details for DOI 10.1038/s41467-023-42320-4

  View details for PubMedID 38135686

  View details for PubMedCentralID 8285118

• Selective prediction for extracting unstructured clinical data. Journal of the American Medical Informatics Association : JAMIA Swaminathan, A., Lopez, I., Wang, W., Srivastava, U., Tran, E., Bhargava-Shah, A., Wu, J. Y., Ren, A. L., Caoili, K., Bui, B., Alkhani, L., Lee, S., Mohit, N., Seo, N., Macedo, N., Cheng, W., Liu, C., Thomas, R., Chen, J. H., Gevaert, O. 2023

  Abstract

  While there are currently approaches to handle unstructured clinical data, such as manual abstraction and structured proxy variables, these methods may be time-consuming, not scalable, and imprecise. This article aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction.We trained selective classifiers (logistic regression, random forest, support vector machine) to extract 5 variables from clinical notes: depression (n = 1563), glioblastoma (GBM, n = 659), rectal adenocarcinoma (DRA, n = 601), and abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601) of adenocarcinoma. We varied the cost of false positives (FP), false negatives (FN), and abstained notes and measured total misclassification cost.The depression selective classifiers abstained on anywhere from 0% to 97% of notes, and the change in total misclassification cost ranged from -58% to 9%. Selective classifiers abstained on 5%-43% of notes across the GBM and colorectal cancer models. The GBM selective classifier abstained on 43% of notes, which led to improvements in sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier and when compared to structured proxy variables.We showed that selective classifiers outperformed both non-selective classifiers and structured proxy variables for extracting data from unstructured clinical notes.Selective prediction should be considered when abstaining is preferable to making an incorrect prediction.

  View details for DOI 10.1093/jamia/ocad182

  View details for PubMedID 37769323

• Translational Models in Glioma Immunotherapy Research. Current oncology (Toronto, Ont.) Ren, A. L., Wu, J. Y., Lee, S. Y., Lim, M. 2023; 30 (6): 5704-5718

  Abstract

  Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research.

  View details for DOI 10.3390/curroncol30060428

  View details for PubMedID 37366911

• Opioid usage in lumbar disc herniation patients with nonsurgical, early, and late surgical treatments. World neurosurgery Zhou, Z., Jin, M. C., Jensen, M. R., Barros Guinle, M. I., Ren, A., Agarwal, A. A., Leaston, J., Ratliff, J. K. 2023

  Abstract

  Assess opioid usage in surgical and non-surgical patients with lumbar disc herniation receiving different treatment approaches and timing.Individuals with newly diagnosed lumbar intervertebral disc without myelopathy were queried from Optum Clinformatics DataMart. Patients were categorized into 3 cohorts: nonsurgical, early surgery, and late surgery. Early surgery cohort patients had surgery within 30-days post-diagnosis; late surgery cohort patients had surgery after 30 days but before 1-year post-diagnosis. The index date was defined as the diagnosis date for nonsurgical patients, and the initial surgery date for surgical patients. The primary outcome was the average daily opioid morphine milligram equivalent (MME) prescribed. Additional outcomes included the percentage of opioid-using patients and cumulative opioid burden.A total of 573,082 patients met inclusion criteria: 533,226 patients received nonsurgical treatments, 22,312 patients received early surgery, and 17,544 patients received late surgery. Both surgical cohorts experienced a "post-surgical hump" of opioid usage, which then sharply declined and gradually plateaued, with daily opioid MME consistently lower in the early as opposed to late surgery cohort. The early surgery cohort also consistently had a lower prevalence of opioid-using patients than the late surgery cohort. Patients receiving nonsurgical demonstrated the highest one-year post-index cumulative opioid burden, and the early surgery cohort consistently had lower cumulative opioid MME than the late surgery cohort.Early surgery in lumbar disc herniation patients is associated with lower long-term average daily MME, incidence of opioid use, and one-year cumulative MME burden compared to nonsurgical and late surgery treatment approaches.

  View details for DOI 10.1016/j.wneu.2023.02.029

  View details for PubMedID 36775237

• Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses. Brain : a journal of neurology Needham, E. J., Ren, A. L., Digby, R. J., Norton, E. J., Ebrahimi, S., Outtrim, J. G., Chatfield, D. A., Manktelow, A. E., Leibowitz, M. M., Newcombe, V. F., Doffinger, R., Barcenas-Morales, G., Fonseca, C., Taussig, M. J., Burnstein, R. M., Samanta, R. J., Dunai, C., Sithole, N., Ashton, N. J., Zetterberg, H., Gisslén, M., Edén, A., Marklund, E., Openshaw, P. J., Dunning, J., Griffiths, M. J., Cavanagh, J., Breen, G., Irani, S. R., Elmer, A., Kingston, N., Summers, C., Bradley, J. R., Taams, L. S., Michael, B. D., Bullmore, E. T., Smith, K. G., Lyons, P. A., Coles, A. J., Menon, D. K. 2022

  Abstract

  COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], glial fibrillary acidic protein [GFAP] and total tau) and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalisation, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterised by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

  View details for DOI 10.1093/brain/awac321

  View details for PubMedID 36065116

• Immunometabolism, a new therapeutic development for immunotherapies of high-grade gliomas: a narrative review. Chinese clinical oncology Wu, J. Y., Ren, A. L., Lim, M. 2022; 11 (4): 26

  Abstract

  Immunotherapy has yielded significant improvements in survival for many cancer types, but its impact on glioblastoma (GBM) has been relatively muted. There is a growing interest in understanding the role of cancer metabolism and its role in tumor growth and therapeutic response. Thus, it is equally important to consider the clinical implications of immune cell metabolism on cancer progression and implications for therapeutic development. Our objective is to present new developments in immunometabolic research that are relevant to immunotherapy development for high-grade gliomas.A literature search and review was conducted, regarding original research articles studying metabolic pathways of immune cells in high-grade gliomas. Searches were conducted in PubMed and Embase databases on May 15 and June 13, 2022. English-language original research articles were selected and prioritized based on their inclusion of findings related to metabolic changes in myeloid and lymphoid cells in the glioma tumor microenvironment.There are many metabolic mechanisms by which immune cells in high-grade gliomas, like GBM, contribute to tumor growth and persistence via immunosuppression and high therapeutic resistance. There are also several ways that metabolic optimization has already been shown to improve immunotherapies already in clinical trials or in use, including dendritic cell vaccines and chimeric antigen receptor T cells.The implications of immunometabolic research presented here should be taken into consideration in future research and immunotherapy development of high-grade gliomas for our best chances at improving patient survival.

  View details for DOI 10.21037/cco-22-58

  View details for PubMedID 36098097

• Health Care Resource Utilization in Management of Opioid-Naive Patients With Newly Diagnosed Neck Pain. JAMA network open Jin, M. C., Jensen, M., Zhou, Z., Rodrigues, A., Ren, A., Barros Guinle, M. I., Veeravagu, A., Zygourakis, C. C., Desai, A. M., Ratliff, J. K. 2022; 5 (7): e2222062

  Abstract

  Importance: Research has uncovered heterogeneity and inefficiencies in the management of idiopathic low back pain, but few studies have examined longitudinal care patterns following newly diagnosed neck pain.Objective: To understand health care utilization in patients with new-onset idiopathic neck pain.Design, Setting, and Participants: This cross-sectional study used nationally sourced longitudinal data from the IBM Watson Health MarketScan claims database (2007-2016). Participants included adult patients with newly diagnosed neck pain, no recent opioid use, and at least 1 year of continuous postdiagnosis follow-up. Exclusion criteria included prior or concomitant diagnosis of traumatic cervical disc dislocation, vertebral fractures, myelopathy, and/or cancer. Only patients with at least 1 year of prediagnosis lookback were included. Data analysis was performed from January 2021 to January 2022.Main Outcomes and Measures: The primary outcome of interest was 1-year postdiagnosis health care expenditures, including costs, opioid use, and health care service utilization. Early services were those received within 30 days of diagnosis. Multivariable regression models and regression-adjusted statistics were used.Results: In total, 679 030 patients (310 665 men [45.6%]) met the inclusion criteria, of whom 7858 (1.2%) underwent surgery within 1 year of diagnosis. The mean (SD) age was 44.62 (14.87) years among nonsurgical patients and 49.69 (9.53) years among surgical patients. Adjusting for demographics and comorbidities, 1-year regression-adjusted health care costs were $24 267.55 per surgical patient and $515.69 per nonsurgical patient. Across all health care services, $95 379 949 was accounted for by nonsurgical patients undergoing early imaging who did not receive any additional conservative therapy or epidural steroid injections, for a mean (SD) of $477.53 ($1375.60) per patient and median (IQR) of $120.60 ($20.70-$452.37) per patient. On average, patients not undergoing surgery, physical therapy, chiropractic manipulative therapy, or epidural steroid injection, who underwent either early advanced imaging (magnetic resonance imaging or computed tomography) or both early advanced and radiographic imaging, accumulated significantly elevated health care costs ($850.69 and $1181.67, respectively). Early conservative therapy was independently associated with 24.8% (95% CI, 23.5%-26.2%) lower health care costs.Conclusions and Relevance: In this cross-sectional study, early imaging without subsequent intervention was associated with significantly increased health care spending among patients with newly diagnosed idiopathic neck pain. Early conservative therapy was associated with lower costs, even with increased frequency of therapeutic services, and may have reduced long-term care inefficiency.

  View details for DOI 10.1001/jamanetworkopen.2022.22062

  View details for PubMedID 35816312

• Neurological update: COVID-19. Journal of neurology Ren, A. L., Digby, R. J., Needham, E. J. 2021; 268 (11): 4379-4387

  Abstract

  Coronavirus Disease 2019 is predominantly a disorder of the respiratory system, but neurological complications have been recognised since early in the pandemic. The major pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, immunologically mediated neurological disorders and the detrimental effects of critical illness on the nervous system. It is still unclear whether direct invasion of the nervous system by the Severe Acute Respiratory Syndrome Coronavirus 2 occurs; given the vast numbers of people infected at this point, this uncertainty suggests that nervous system infection is unlikely to represent a significant issue if it occurs at all. In this review, we explore what has been learnt about the neurological complications of COVID-19 over the course of the pandemic, and by which mechanisms these complications most commonly occur.

  View details for DOI 10.1007/s00415-021-10581-y

  View details for PubMedID 33929617

  View details for PubMedCentralID PMC8085652