Extracranial Complications in Monitored and Nonmonitored Patients with Traumatic Brain Injury in the BEST TRIP Trial and a Companion Observational Cohort.

INTRODUCTION: Extracranial complications occur commonly in patients with traumatic brain injury (TBI) and can have implications for patient outcome. Patient-specific risk factors for developing these complications are not well studied, particularly in low and middle-income countries (LMIC). The study objective was to determine patient-specific risk factors for development of extracranial complications in TBI. METHODS: We assessed the relationship between patient demographic and injury factors and incidence of extracranial complications using data collected September 2008-October 2011 from the BEST TRIP trial, a randomized controlled trial assessing TBI management protocolized on intracranial pressure (ICP) monitoring versus imaging and clinical exam, and a companion observational patient cohort. RESULTS: Extracranial infections (55%), respiratory complications (19%), hyponatremia (27%), hypernatremia (27%), hospital acquired pressure ulcers (6%), coagulopathy (9%), cardiac arrest (10%), and shock (5%) occurred at a rate of ≥5% in our study population; overall combined rate of these complications was 82.3%. Tracheostomy in the intensive care unit (P < 0.001), tracheostomy timing (P = 0.025), mannitol and hypertonic saline doses (P < 0.001), brain-specific therapy days and brain-specific therapy intensity (P < 0.001), extracranial surgery (P < 0.001), and neuroworsening with pupil asymmetry (P = 0.038) were all significantly related to the development of one of these complications by univariable analysis. Multivariable analysis revealed ICP monitor use and brain-specific therapy intensity to be the most common factors associated with individual complications. CONCLUSIONS: Extracranial complications are common following TBI. ICP monitoring and treatment are related to extra-cranial complications. This supports the need for reassessing the risk-benefit balance of our current management approaches in the interest of improving outcome.

Incidence and Risk Model of Post-Traumatic Hydrocephalus in Patients with Traumatic Brain Injury.

OBJECTIVE: Post-traumatic hydrocephalus (PTH) is a complication following traumatic brain injury (TBI). Early diagnosis and treatment are essential to improving outcomes. We report the incidence and risk factors of PTH in a large TBI population while considering death as a competing risk. METHODS: We conducted a retrospective cohort study on consecutive TBI patients with radiographic intracranial abnormalities admitted to our academic medical center from 2009 to 2015. We assessed patient demographics, perioperative data, and in-hospital data as risk factors for PTH using survival analysis with death as a competing risk. RESULTS: Among 7,473 patients, the overall incidence of PTH requiring shunt surgery was 0.94%. The adjusted cumulative incidence was 0.99%. The all-cause cumulative hazard for death was 32.6%, which was considered a competing risk during analysis. Craniectomy (HR 11.53, P < 0.001, 95% CI 5.57-223.85), venous sinus injury (HR 4.13, P = 0.01, 95% CI 1.53-11.16), and age ≤5 (P < 0.001) were significant risk factors for PTH. Glasgow Coma Score (GCS) > 13 was protective against shunt placement (HR 0.50, P = 0.04, 95% CI 0.26-0.97). Shunt surgery occurred after hospital discharge in 60% of patients. CONCLUSIONS: We describe the incidence and risk factors for PTH in a large traumatic brain injury (TBI) population. Most cases of PTH were diagnosed after hospital discharge, suggesting that close follow-up and multidisciplinary diagnostic vigilance for PTH are needed to prevent morbidity and disability.

Perioperative complications and secondary retethering after pediatric tethered cord release surgery.

OBJECTIVE: Tethered cord syndrome refers to a constellation of symptoms characterized by neurological, musculoskeletal, and urinary symptoms, caused by traction on the spinal cord, which can be secondary to various etiologies. Surgical management of simple tethered cord etiologies (e.g., fatty filum) typically consists of a single-level lumbar laminectomy, intradural exploration, and coagulation and sectioning of the filum. More complex etiologies such as lipomyelomeningoceles or scar formation after myelomeningocele repair involve complex dissection and dural reconstruction. The purpose of this study was to evaluate operative complications and long-term outcomes of secondary retethering related to pediatric tethered cord release (TCR) at a tertiary children's hospital. METHODS: Medical records of children who underwent surgery for TCR from July 2014 to March 2023 were retrospectively reviewed. Data collected included demographics, perioperative characteristics, surgical technique, and follow-up duration. Primary outcomes were 60-day postoperative complications and secondary retethering requiring repeat TCR surgery. Univariate and multivariate analyses were performed to identify risk factors associated with complications and secondary retethering. RESULTS: A total of 363 TCR surgeries (146 simple, 217 complex) in 340 patients were identified. The mean follow-up was 442.8 ± 662.2 days for simple TCRs and 733.9 ± 750.3 days for complex TCRs. The adjusted 60-day complication-free survival rate was 96.3% (95% CI 91.3%-98.4%) for simple TCRs and 88.7% (95% CI 82.3%-91.4%) for complex TCRs. Lower weight, shorter surgical times, and intensive care unit admission were associated with complications for simple TCRs. Soft-tissue drains increased complications for complex TCRs. The secondary retethering rates were 1.4% for simple TCRs and 11.9% for complex TCRs. The 1-, 3-, and 5-year progression-free survival rates in complex cases were 94.7% (95% CI 89.1%-97.4%), 77.7% (95% CI 67.3%-85.3%), and 62.6% (95% CI 46.5%-75.1%), respectively. Multivariate analysis revealed that prior detethering (OR 8.15, 95% CI 2.33-28.50; p = 0.001) and use of the operative laser (OR 10.43, 95% CI 1.36-80.26; p = 0.024) were independently associated with secondary retethering in complex cases. CONCLUSIONS: This is the largest series to date examining postoperative complications and long-term secondary retethering in TCR surgery. Simple TCR surgeries demonstrated safety, rare complications, and low secondary retethering rates. Complex TCR surgeries presented higher risks of complications and secondary retethering. Modifiable risk factors such as operative laser use influenced secondary retethering in complex cases.

Validation of smartphone app-based digital patient reported outcomes in full-endoscopic spine surgery.

PURPOSE: Patient reported outcome measures (PROMs) are important tools to assess patient function, pain, disability, and quality of life. We aim to study the efficiency and validity of digital PROMs collection using a smartphone app compared to traditional paper PROMs. METHODS: Patients undergoing evaluation for full-endoscopic spine surgery were recruited from the outpatient clinic at Harborview Medical Center. Visual analogue scale (VAS), Oswestry disability index (ODI), and EQ5-5D PROMs were administered on paper and through a smartphone app called SpineHealthie. Compliance rates were collected, and PROM results were assessed for correlation between paper and digital methods. RESULTS: 123 patients were enrolled. 57.7% of patients completed paper PROMs, 82.9% completed digital PROMs, and 48.8% completed both. Of the patients that completed both, Spearman's correlation was greatest for VAS leg, ODI, and EQ5 index scores. Correlation was weaker for VAS back pain, neck pain, and upper extremity pain. Patients tended to report lower disability and higher quality of life on the digital PROM compared to the paper PROM. CONCLUSION: The SpineHealthie app effectively and accurately collects PROMs digitally, showing strong concordance with traditional paper PROMs. We conclude that digital PROMs constitute a promising strategy for monitoring patients after spine surgery over time.

Remote patient monitoring following full endoscopic spine surgery: feasibility and patient satisfaction.

OBJECTIVE: The utilization of telemedicine in healthcare has increased dramatically during the recent COVID-19 pandemic. This study aimed to investigate the feasibility to perform remote patient monitoring after full endoscopic spine surgery via a smartphone application that also allows communication with patients. METHODS: A smartphone application (SPINEhealthie) was designed at the University of Washington and used to collect patient-reported outcome measures (PROMs) and to provide chat communication between patients and their care team. A total of 71 patients were included in the study and prospectively followed for 3 months postoperatively. Patient demographic characteristics, compliance with surveys, and frequency of chat utilization were recorded. The ease of use, the participants' experiences with the app interface design, and the usefulness of the app were assessed by using the mHealth App Usability Questionnaire (MAUQ). RESULTS: Of all eligible patients, 71/78 (91.0%) agreed to participate. Of these, 60 (85%) patients provided at least 1 postoperative PROM. There was good coverage of the immediate postoperative period with 45 (63.4%) patients providing ≥ 5 PROMs within the 1st week after surgery. The authors observed a 33.2% increase in patient compliance in postoperative PROMs and a 45.7% increase in chat function utilization between the first and last of the three enrollment periods of the study, during which continuous updates were made to improve the app's functionality. Sixty-two (87.3%) patients responded to the user satisfaction survey after using the app for at least 40 days. The MAUQ results revealed excellent rates of satisfaction for ease of use (78.6% of the maximum score), app interface design (71.4%), and usefulness (71.4%), resulting in a total mean MAUQ score of 110 (74.8%). Communication with the doctor (38 votes) was found to be the top feature of the app. Additionally, physical therapy instructions (33 votes) and imaging review (29 votes) were the top two features that patients would like to see in future app versions. Lastly, the authors have presented a case example of a 68-year-old man who used the app for postoperative monitoring and communication after undergoing a two-level lumbar endoscopic unilateral laminotomy for bilateral decompression. CONCLUSIONS: Postoperative remote patient monitoring and communication after full endoscopic surgery is feasible using the SPINEhealthie app. Importantly, patients were willing to share their medical information using a mobile device, and they were eager to use it postoperatively as a supplementary tool.

Incidence and Risk Model of Venous Thromboembolism in Patients with Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Venous thromboembolism (VTE) is a significant source of morbidity and mortality in hospitalized patients. We describe our experience with VTE prophylaxis and treatment in patients with aneurysmal subarachnoid hemorrhage (aSAH), risk factors for VTE, and a hazard model describing the daily risk of VTE. METHODS: A retrospective cohort study was performed on patients with aSAH admitted from 2014 to 2018. Patients were screened for VTE based on clinical suspicion. Demographics, perioperative data, and in-hospital data were assessed as risk factors for VTE using survival analysis with death as a competing risk. RESULTS: Among 485 patients, the overall incidence of VTE, deep vein thrombosis, and pulmonary embolism were 5.6%, 4.3%, and 2.3%, respectively. Increasing length of stay in the intensive care unit (hazard ratio [HR], 1.79; P < 0.0001; 95% confidence interval [CI], 1.49-2.16) and ventilation immediately after aneurysm treatment was associated with VTE (HR, 8.87; P < 0.01; 95% CI, 1.86-42.38). Hunt and Hess grade was negatively associated with VTE (HR, 0.61; P = 0.045; 95% CI, 0.37-1.00) due to its increased association with the competing risk of death (HR, 2.57; P < 0.0001; 95% CI, 1.89-3.49). The adjusted 4-year cumulative incidence for VTE is 11.1% and at mean day of hospital discharge is 5.4%. Treatment of VTEs with anticoagulation and/or inferior vena cava filter placement was not associated with immediate complications. CONCLUSIONS: We describe the largest single-institution cohort of VTEs in aSAH patients. Our hazard model quantifies the cumulative incidence of VTEs during the course of hospitalization. We suggest a standardized protocol for screening, prophylaxis, and treatment of VTEs in this patient population.

Tiger Nut (Cyperus esculentus) as a Functional Ingredient in Gluten-Free Extruded Snacks.

Tiger nut (TN) is a nutritious source of gluten-free flour, used generally in healthy beverages, but its incorporation in gluten-free extruded snacks has not been explored. TN flour was blended at different concentrations (up to 70%) with rice flour and soluble fiber, for the development of gluten-free snacks on a twin-screw extruder. The effect of TN inclusion in the formulations was evaluated on relevant physiochemical characteristics of the snacks. Viscoamylograph of the raw formulations showed that TN addition increased (p < 0.01) onset temperature and delayed peak viscosity. In the extruded flours, TN contributed to limit the starch degradation during extrusion. Diameter, expansion ratio, true density, and total pore volume of the extrudates were reduced (pf < 0.01) by the increased TN content in the formulations, while bulk density rose. The surfaces of the extruded snacks were modified by the increasing inclusion of TN in substitution of rice in the formulations. Extrudates containing 10% TN showed the best overall texture profile. Moreover, TN addition enhanced the ash and protein content of the snacks and increased their total antioxidant activity. This study demonstrated that incorporation of 10% TN flour into rice-based formulation was suitable for making gluten-free snacks with acceptable physical properties.

Economic Impact of COVID-19 on a High-Volume Academic Neurosurgical Practice.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is a novel disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that rapidly spread around the globe. The dramatic increase in the number of cases and deaths have placed tremendous strain on health care systems worldwide. As health care workers and society adjust to focus treatment and prevention of COVID-19, other facets of the health care enterprise are affected, particularly surgical volume and revenue. The purpose of this study was to describe the financial impact of COVID-19 on an academic neurosurgery department. METHODS: A retrospective review of weekly average daily work relative value units (wRVUs) were compared before and after COVID-19 in the fiscal year 2020. A comparative time period of the same months in the year prior was also included for review. We also review strategies for triaging neurosurgical disease as needing emergent, urgent, or routine operative treatment. RESULTS: Daily average wRVU after COVID-19 dropped significantly with losses in all weeks examined. Of the 7 weeks in the current post-COVID period, the weekly daily average wRVU was 173 (range, 128-363). The mean decline was 51.4% compared with the pre-COVID era. Both inpatient and outpatient revenue was affected. CONCLUSIONS: COVID-19 had a profound detrimental effect on surgical productivity and revenue generation.

Pseudoaneurysm of the Superficial Temporal Artery After Intracranial Pressure Monitoring Device Placement: Case Report of a Rare Complication.

BACKGROUND AND IMPORTANCE: Pseudoaneurysms involving the superficial temporal artery (STA), either iatrogenic or caused by direct trauma, are rare. The STA is prone to injury due to its long course throughout the scalp. Injuries can cause cosmetic defects and/or skin breakdown leading to further complications. CLINICAL PRESENTATION: We report a case of delayed iatrogenic pseudoaneurysm of the STA after placement of an intracranial pressure monitor in the setting of acute traumatic brain injury. The patient had a delayed development of a pulsatile mass over his right frontal region, with computed tomography angiography concerning for a pseudoaneurysm of the STA. This was managed with surgical resection with complete resolution of symptoms at follow-up. CONCLUSION: We review the literature regarding the etiology, pathogenesis, and management of these lesions. While iatrogenic injuries to the STA have been previously reported, this is a curious case related to placement of an intracranial pressure monitor. We recommend direct surgical resection of the pseudoaneurysm for cosmetic effect and prevention of further wound breakdown.

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma.

CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-IgG), a dual-antigen T cell engager (DATE), and a CD133-specific chimeric antigen receptor T cell (CAR-T): CART133. All three showed activity against patient-derived CD133+ GBM cells, and CART133 cells demonstrated superior efficacy in patient-derived GBM xenograft models without causing adverse effects on normal CD133+ hematopoietic stem cells in humanized CD34+ mice. Thus, CART133 cells may be a therapeutically tractable strategy to target CD133+ CSCs in human GBM or other treatment-resistant primary cancers.

A Synthetic Human Antibody Antagonizes IL-18Rß Signaling Through an Allosteric Mechanism.

The interleukin-18 subfamily belongs to the interleukin-1 family and plays an important role in modulating innate and adaptive immune responses. Dysregulation of IL-18 has been implicated in or correlated with numerous diseases, including inflammatory diseases, autoimmune disorders, and cancer. Thus, blockade of IL-18 signaling may offer therapeutic benefits in many pathological settings. Here, we report the development of synthetic human antibodies that target human IL-18Rß and block IL-18-mediated IFN-γ secretion by inhibiting NF-κB and MAPK dependent pathways. The crystal structure of a potent antagonist antibody in complex with IL-18Rß revealed inhibition through an unexpected allosteric mechanism. Our findings offer a novel means for therapeutic intervention in the IL-18 pathway and may provide a new strategy for targeting cytokine receptors.

Novel gluten-free formulations from lentil flours and nutritional yeast: Evaluation of extrusion effect on phytochemicals and non-nutritional factors.

The food industry is increasingly innovating and applying new processing technologies and ingredients to develop novel food products that meet the consumers' demand. In this study, the effect of extrusion (at 140 °C and 160 °C) was evaluated in different lentil flours formulations enriched with nutritional yeast, in terms of α-galactosides (raffinose, stachyose, verbascose), inositol phosphates (IPs), trypsin inhibitors and lectins content. The content of α-galactosides and IPs was determined by high performance liquid chromatography. Trypsin inhibitor activity (TIA) was evaluated using a small-scale quantitative assay. The lectin content was analyzed using a haemagglutination assay and a Competitive Indirect Enzyme-linked immunosorbent assay. Extrusion promoted a significant increase, up to 85% in total α-galactosides content. After extrusion, IPs content was significantly decreased and TIA as well as lectins content had a reduction higher than 90%. Extrusion demonstrated to have a beneficial effect by increasing desirable prebiotic compounds and decreasing non-nutritional factors.

Brain abscess caused by Trueperella bernardiae in a child.

BACKGROUND: Recurrent intracranial abscesses secondary to refractory otitis media present a challenge which demands multidisciplinary collaboration. CASE DESCRIPTION: We present the first known case of pediatric brain abscess caused by a polymicrobial infection of Trueperella bernardiae, Actinomyces europaeus, and mixed anaerobic species resulting from acute-on-chronic suppurative left otitis media. This patient required two separate stereotactic abscess drainages and a complex course of antibiotics for successful management. CONCLUSION: Surgery is essential in the management of cerebral abscess both in agent identification and therapeutic drainage. Management of abscesses secondary to unusual and polymicrobial organisms often requires consultation from other medical and surgical specialties.

Endovascular Treatment of Concomitant Carotid Fibromuscular Dysplasia and Atherosclerotic Disease After Failed Open Surgical Treatment.

We describe a case of concomitant fibromuscular dysplasia (FMD) and atherosclerotic internal carotid artery (ICA) disease in a symptomatic patient. Sixty-eight-year-old female presented for evaluation of a transient ischemic attack. Imaging revealed severe proximal >80% ICA stenosis with severe FMD to mid and distal ICA. Planned hybrid approach with left carotid endarterectomy (CEA) and balloon angioplasty was aborted intraoperatively due to lack of back bleeding. Open gradual rigid dilation was then performed with resumption of back bleeding. Completion angiogram revealed widely patent flow through CEA patch with no residual defects. Patient awoke from operation neurologically intact. At 6-month follow-up, carotid duplex revealed severe recurrent ICA stenosis. Endovascular intervention was performed with balloon dilation to the proximal and mid-ICA with stenting of a moderate 60% ostial common carotid stenosis. She recovered well from procedure with 3-month carotid duplex showing widely patent common carotid stent and ICA with no areas of stenosis. Informed consent has been obtained from the patient for publication of the case report and accompanying images.

Innate Control of Tissue-Reparative Human Regulatory T Cells.

Regulatory T cell (Treg) therapy is a potential curative approach for a variety of immune-mediated conditions, including autoimmunity and transplantation, in which there is pathological tissue damage. In mice, IL-33R (ST2)-expressing Tregs mediate tissue repair by producing the growth factor amphiregulin, but whether similar tissue-reparative Tregs exist in humans remains unclear. We show that human Tregs in blood and multiple tissue types produced amphiregulin, but this was neither a unique feature of Tregs nor selectively upregulated in tissues. Human Tregs in blood, tonsil, synovial fluid, colon, and lung tissues did not express ST2, so ST2+ Tregs were engineered via lentiviral-mediated overexpression, and their therapeutic potential for cell therapy was examined. Engineered ST2+ Tregs exhibited TCR-independent, IL-33-stimulated amphiregulin expression and a heightened ability to induce M2-like macrophages. The finding that amphiregulin-producing Tregs have a noneffector phenotype and are progressively lost upon TCR-induced proliferation and differentiation suggests that the tissue repair capacity of human Tregs may be an innate function that operates independently from their classical suppressive function.

A rapid in vitro methodology for simultaneous target discovery and antibody generation against functional cell subpopulations.

Cell surface antigen discovery is of great interest for biomedical research both for isolation of rare cell populations and therapeutic targeting. We developed a rapid, cost-effective, fully in vitro technology which facilities the simultaneous target discovery and human antibody generation on the surface of virtually any cell population of interest. We apply our technique to human colorectal cancer-initiating cells (CICs) and identify hundreds of unique human antibodies. We characterized the top three antibody candidates targeting these CICs and identify their protein targets as integrin α7 (ITGA7), HLA-A1 and integrin ß6 (ITGB6). We demonstrate that these antibodies can be used to isolate self-renewing colorectal CICs, and that the integrin α7 antibody can prospectively identify glioblastoma brain tumor initiating cells as well as human muscle stem cells. We also demonstrate that genetic ablation of integrin ß6 impedes colorectal CIC function. The methodology can be readily applied to other cell populations including stem cells, cancer, or immune cells to facilitate the rapid identification of novel targets and simultaneous generation of potent and specific antibodies with therapeutic potential.

Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response.

Dysregulation of the ErbB family of receptor tyrosine kinases is involved in the progression of many cancers. Antibodies targeting the dimerization domains of family members EGFR and HER2 are approved cancer therapeutics, but efficacy is restricted to a subset of tumors and resistance often develops in response to treatment. A third family member, HER3, heterodimerizes with both EGFR and HER2 and has also been implicated in cancer. Consequently, there is strong interest in developing antibodies that target HER3, but to date, no therapeutics have been approved. To aid the development of anti-HER3 antibodies as cancer therapeutics, we combined antibody engineering and functional genomics screens to identify putative mechanisms of resistance or synthetic lethality with antibody-mediated anti-proliferative effects. We developed a synthetic antibody called IgG 95, which binds to HER3 and promotes ubiquitination, internalization, and receptor down-regulation. Using an shRNA library targeting enzymes in the ubiquitin proteasome system, we screened for genes that effect response to IgG 95 and uncovered the E3 ubiquitin ligase RNF41 as a driver of IgG 95 anti-proliferative activity. RNF41 has been shown previously to regulate HER3 levels under normal conditions and we now show that it is also responsible for down-regulation of HER3 upon treatment with IgG 95. Moreover, our findings suggest that down-regulation of RNF41 itself may be a mechanism for acquired resistance to treatment with IgG 95 and perhaps other anti-HER3 antibodies. Our work deepens our understanding of HER3 signaling by uncovering the mechanistic basis for the anti-proliferative effects of potential anti-HER3 antibody therapeutics.

Protocadherin-1 is essential for cell entry by New World hantaviruses.

The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1-a member of the cadherin superfamily7,8-to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.