Citations

Background: Describe the incidence and associated outcomes of gastrointestinal (GI) manifestations of acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in hospitalized children (MIS-C). Methods: Retrospective review of the Viral Infection and Respiratory Illness Universal Study registry, a prospective observational, multicenter international cohort study of hospitalized children with acute COVID-19 or MIS-C from March 2020 to November 2020. The primary outcome measure was critical COVID-19 illness. Multivariable models were performed to assess for associations of GI involvement with the primary composite outcome in the entire cohort and a subpopulation of patients with MIS-C. Secondary outcomes included prolonged hospital length of stay defined as being >75th percentile and mortality. Results: Of the 789 patients, GI involvement was present in 500 (63.3%). Critical illness occurred in 392 (49.6%), and 18 (2.3%) died. Those with GI involvement were older (median age of 8 yr), and 18.2% had an underlying GI comorbidity. GI symptoms and liver derangements were more common among patients with MIS-C. In the adjusted multivariable models, acute COVID-19 was no associated with the primary or secondary outcomes. Similarly, despite the preponderance of GI involvement in patients with MIS-C, it was also not associated with the primary or secondary outcomes. Conclusions: GI involvement is common in hospitalized children with acute COVID-19 and MIS-C. GI involvement is not associated with critical illness, hospital length of stay or mortality in acute COVID-19 or MIS-C.

Tunneling nanotubes (TNTs) are thin, F-actin-based membranous protrusions that connect distant cells and can provide e a novel mechanism for intercellular communication. By establishing cytoplasmic continuity between interconnected cells, TNTs enable the bidirectional transfer of nuclear and cytoplasmic cargo, including organelles, nucleic acids, drugs, and pathogenic molecules. TNT-mediated nucleic acid transfer provides a unique opportunity for donor cells to directly alter the genome, transcriptome, and metabolome of recipient cells. TNTs have been reported to transport DNA, mitochondrial DNA, mRNA, viral RNA, and non-coding RNAs, such as miRNA and siRNA. This mechanism of transfer is observed in physiological as well as pathological conditions, and has been implicated in the progression of disease. Herein, we provide a concise overview of TNTs’ structure, mechanisms of biogenesis, and the functional effects of TNT-mediated intercellular transfer of nucleic acid cargo. Furthermore, we highlight the potential translational applications of TNT-mediated nucleic acid transfer in cancer, immunity, and neurological diseases.

Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)–modified T cells in the solid tumor microenvironment (TME). Here, using systemically delivered OVs and CAR T cells in immunocompetent mouse models, we have defined a mechanism by which OVs can potentiate CAR T cell efficacy against solid tumor models of melanoma and glioma. We show that stimulation of the native T cell receptor (TCR) with viral or virally encoded epitopes gives rise to enhanced proliferation, CAR-directed antitumor function, and distinct memory phenotypes. In vivo expansion of dual-specific (DS) CAR T cells was leveraged by in vitro preloading with oncolytic vesicular stomatitis virus (VSV) or reovirus, allowing for a further in vivo expansion and reactivation of T cells by homologous boosting. This treatment led to prolonged survival of mice with subcutaneous melanoma and intracranial glioma tumors. Human CD19 CAR T cells could also be expanded in vitro with TCR reactivity against viral or virally encoded antigens and was associated with greater CAR-directed cytokine production. Our data highlight the utility of combining OV and CAR T cell therapy and show that stimulation of the native TCR can be exploited to enhance CAR T cell activity and efficacy in mice.

The therapeutic activities elicited by mesenchymal stem cells (MSC) are in part mediated through paracrine action by the release of extracellular vesicles (EV) and secreted proteins. Collectively, these MSC-derived factors, referred to as the secretome product (SP), are intrinsically therapeutic and represent an attractive alternative to cell-based therapies. Herein, we developed a lyopreservation protocol to extend the shelf-life of the MSC-SP without compromising the structural or functional integrity of the vesicular components. The SP isolated from normoxia- and anoxia-exposed MSC elicited protective effects in an in vitro model of oxidative injury and the bioactivity was retained in the lyophilized samples. Three separate formulations of MSC-SP were isolated by tangential flow filtration using sucrose, trehalose, and mannitol as lyoprotectant agents. The MSC-SPs were lyophilized using a manifold protocol and the structural and functional integrity were assessed. The trehalose formulation of SP exhibited the highest EV and protein recovery after manifold-based lyophilization. To facilitate development as a therapeutic, a shelf lyophilization protocol was developed which markedly enhanced the recovery of EV and proteins. In conclusion, lyophilization represents an efficient method to preserve the structural and functional integrity of the MSC-SP and can be used to develop an off-the-shelf therapeutic.

Petroclival meningiomas, which arise from the upper two-thirds of the clivus and are medial to the trigeminal nerve, carry significant surgical risk. Patients whose operations are tailored to maximize tumor resection while minimizing neurological morbidity have favorable outcomes. Subtotally resected tumors can be subsequently considered for radiosurgery in an attempt to limit recurrence. Here the authors report the case of a 40-year-old woman with postpartum trigeminal neuropathy secondary to a petroclival meningioma. The patient underwent an aggressive subtotal resection via a posterior petrosal approach with preservation of neurological function followed by adjuvant radiosurgery. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21227

SummaryBackground and aimsExtra‐intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited.MethodsAs a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty‐four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds.ResultsFor use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence.ConclusionsConsensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician‐reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.

Background: Continuous passive motion (CPM) has been used for decades, but we are not aware of any randomized controlled trials (RCTs) in which CPM has been compared with physical therapy (PT) for rehabilitation following release of elbow contracture. Methods: In this single-blinded, single-center RCT, we randomly assigned patients undergoing arthroscopic release of elbow contracture to a rehabilitation protocol involving either CPM or PT. The primary outcomes were the rate of recovery and the arc of elbow motion (range of motion) at 1 year. The rate of recovery was evaluated by measuring range of motion at 6 weeks and 3 months. The secondary outcomes included other range-of-motion-related outcomes, patient-reported outcome measures (PROMs), flexion strength and endurance, grip strength, and forearm circumference at multiple time points. Results: A total of 24 patients were assigned to receive CPM, and 27 were assigned to receive PT. At 1 year, CPM was superior to PT with regard to the range of motion, with an estimated treatment difference of 9° (95% confidence interval [CI], 3° to 16°; p = 0.007). Similarly, the use of CPM led to a greater range of motion at 6 weeks and 3 months than PT. The percentage of lost motion recovered at 1 year was higher in the CPM group (51%) than in the PT group (36%) (p = 0.01). The probability of restoring a functional range of motion at 1 year was 62% higher in the CPM group than in the PT group (risk ratio for functional range of motion, 1.62; 95% CI, 1.01 to 2.61; p = 0.04). PROM scores were similar in the 2 groups at all time points, except for a difference in the American Shoulder and Elbow Surgeons (ASES) elbow function subscale, in favor of CPM, at 6 weeks. The use of CPM decreased swelling and reduced the loss of flexion strength, flexion endurance, and grip strength on day 3, with no between-group differences thereafter. Conclusions: Among patients undergoing arthroscopic release of elbow contracture, those who received CPM obtained a faster recovery and a greater range of motion at 1 year, with a higher chance of restoration of functional elbow motion than those who underwent routine PT. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract Introduction Skull base neuroanatomy is classically taught using surgical atlases. Although these texts are critical and rich resources for learning three-dimensional (3D) relationships between key structures, we believe they could be optimized and complemented with step-by-step anatomical dissections to fully meet the learning needs of trainees. Methods Six sides of three formalin-fixed latex-injected specimens were dissected under microscopic magnification. A far lateral craniotomy was performed by each of three neurosurgery resident/fellow at varying stages of training. The study objective was the completion and photodocumentation of the craniotomy to accompany a stepwise description of the exposure to provide a comprehensive, intelligible, and anatomically oriented resource for trainees at any level. Illustrative case examples were prepared to supplement approach dissections. Results The far lateral approach provides a wide and versatile corridor for posterior fossa operation, with access spanning the entire cerebellopontine angle (CPA), foramen magnum, and upper cervical region. Key Steps Include The study includes the following steps: positioning and skin incision, myocutaneous flap, placement of burr holes and sigmoid trough, fashioning of the craniotomy bone flap, bilateral C1 laminectomy, occipital condyle/jugular tubercle drilling, and dural opening. Conclusion Although more cumbersome than the retrosigmoid approach, a far lateral craniotomy offers unparalleled access to lesions centered lower or more medially in the CPA, as well as those with significant extension into the clival or foramen magnum regions. Dissection-based neuroanatomic guides to operative approaches provide a unique and rich resource for trainees to comprehend, prepare for, practice, and perform complex cranial operations, such as the far lateral craniotomy.