Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy.

Regulating the activity of discrete neuronal populations in living mammals after delivery of modified ion channels can be used to map functional circuits and potentially treat neurological diseases. Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity in motor circuits when exposed to magnetic fields. AAV-mediated delivery of a cre-dependent nanobody-TRPV1 calcium channel into the striatum of adenosine 2a (A2a) receptor-cre driver mice led to restricted expression within D2 neurons, resulting in motor freezing when placed in a 3T MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed focal activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus (STN) projection neurons in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and a corresponding improvement in motor rotational behavior during magnetic field exposure. These data demonstrate that AAV delivery of magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in vivo using clinically available devices for both preclinical analysis of circuit effects on behavior and potential human clinical translation.

Management of refractory bacterial meningitis-associated cerebral vasospasm: illustrative case.

BACKGROUND: Cerebral vasospasm is an alarming complication of acute bacterial meningitis with potentially devastating consequences. It is essential for providers to recognize and treat it appropriately. Unfortunately, there is no well-established approach to the management of postinfectious vasospasm, which makes it especially challenging to treat these patients. More research is needed to address this gap in care. OBSERVATIONS: Here, the authors describe a patient with postmeningitis vasospasm that was refractory to induced hypertension, steroids, and verapamil. He eventually responded to a combination of intravenous (IV) and intra-arterial (IA) milrinone followed by angioplasty. LESSONS: To our knowledge, this is the first report of successfully using milrinone as vasodilator therapy in a patient with postbacterial meningitis-associated vasospasm. This case supports the use of this intervention. In future cases of vasospasm after bacterial meningitis, IV and IA milrinone should be trialed earlier with consideration of angioplasty.

Foundations of the Diagnosis and Management of Low-Grade Gliomas.

In the past, low-grade gliomas-World Health Organization (WHO) grade I and II tumors-were generally expected to have a much better prognosis than higher-grade (WHO grade III and IV) gliomas. However, diffuse gliomas (WHO grade II), unlike WHO grade I gliomas, are by definition infiltrative, limiting resection and potentially contributing to poor outcomes like those seen with malignant gliomas. Rapid progress in the understanding of the pathogenesis of these tumors indicates that specific molecular factors, especially isocitrate dehydrogenase mutation status and the presence or absence of the 1p/19q codeletion (deletion of the short arm of chromosome 1 and long arm of chromosome 19), are much more important than grade in determining prognosis and response to treatment. These molecular characteristics outweigh the histologic distinctions and have been quickly incorporated into the WHO classification of gliomas. Management of these tumors with surgery, radiation, and chemotherapy has similarly been transformed by these developments, highlighting the need for a customized approach for patients with low-grade gliomas.

Myofascial Flap Closure Decreases Complications in Complex Surgery of the Craniocervical Junction in Ehlers-Danlos Patients.

INTRODUCTION: Patients with Ehlers-Danlos syndrome (EDS) are at elevated risk for soft tissue complications when undergoing decompression with or without fusion of the craniocervical junction. We have previously shown that muscle flap closure can decrease reoperative rates. This study investigated whether myofascial flap closure improved clinical outcomes after simple or complex surgery of the craniocervical junction in EDS patients specifically. METHODS: We performed a retrospective chart review of EDS patients who had undergone surgery for Chiari malformation at the Weill Cornell Medical Center between 2013 and 2020. Postoperative complications were recorded, including infection, wound dehiscence, seroma, hematoma, hardware removal, cerebrospinal fluid (CSF) leak, reoperation, and pseudomeningocele. Patients were stratified by type of closure and type of surgery. Fisher exact test was used for statistical comparison. RESULTS: Between 2013 and 2020, 62 EDS patients who had surgery of the cervicocranial junction were reviewed. Of these, 31 patients had complex surgery with myofascial flap closure and 22 had simple surgery with traditional closure. The mean age at the time of surgery was 21.3 years. There were no significant differences in wound complications or reoperation rates between the simple surgery and complex surgery groups. In addition, there were no significant differences in complications between complex surgery with flap closure and simple surgery with traditional closure. Our CSF cutaneous fistula rate was 0%, considerably lower than rates reported in the literature, and, in one case, a patient developed a postoperative pseudomeningocele secondary to a dural leak, but the myofascial flap closure prevented its progression. CONCLUSIONS: Patients with EDS undergoing surgery of the cervicocranial junction may benefit from myofascial flap closure. Flap closure reduced complications after complex surgery of the craniocervical junction to the level of simple surgery. Our CSF leak rate was exceptionally low and only one patient experienced pseudomeningocele. Myofascial flaps are safe to perform in the EDS cohort and prevented CSF cutaneous fistula formation.

A Comparison Between Immediate and Babysitter Deep Inferior Epigastric Perforator Flap Breast Reconstruction in Postoperative Outcomes.

BACKGROUND: Delayed-immediate, or "babysitter," deep inferior epigastric perforator (DIEP) flap reconstruction, defined as immediate tissue expander or implant placement at the time of mastectomy followed by eventual exchange for DIEP flap, is becoming increasingly popular in breast cancer patients anticipated to receive adjuvant radiotherapy. In this study, we aim to compare delayed-immediate to immediate DIEP flap patients in postoperative outcomes including major complications and surgical site morbidity. METHODS: A retrospective cohort study between immediate and delayed-immediate DIEP flap patients was performed. Patient demographics, comorbidities, and preoperative cancer treatment were compared between the 2 cohorts. Clinical outcomes of interest included dehiscence, necrosis, and infection of the breast, abdomen, and umbilicus in the 90-day postoperative period as well as breast hematoma, anastomotic failure, flap loss, and venous thromboembolism. RESULTS: Of the 248 patients (443 breasts) included in this study, 193 women (344 breasts) and 55 women (99 breasts) were in the immediate and delayed-immediate cohorts, respectively. The 2 cohorts were comparable in age, body mass index, and comorbidities (P > 0.05). Despite significantly higher rates of preoperative cancer treatment (P < 0.05), delayed-immediate patients were not at an elevated risk for major complications. The 2 cohorts were also comparable in surgical site outcomes, with the exception of breast skin necrosis, which was significantly higher in incidence in the immediate cohort (16.0% vs 2.0%, P < 0.001). CONCLUSIONS: This study is the first to directly compare delayed-immediate to immediate DIEP flap reconstruction in postoperative outcomes. Our findings show that babysitter DIEP flaps are a safe option for patients, even in those expected to undergo breast irradiation preoperatively.

Interns Without Subinternships.

Surgical interns who have completed medical school in the era of Covid-19 will not have the same experience gained through the traditional multi-month fourth-year surgical subinternships. During subinternships, medical students learn relevant anatomic and radiographic features of surgical pathologies, hone technical skills, and gain exposure to surgical consults and procedures. This lack of intensive exposure will have this cohort starting at a lower comfort and knowledge level compared to years prior. Residency programs, especially subspeciality programs, should review and utilize national resources to facilitate the transition to intern year, such as the American College of Surgeons Entering Resident Readiness Assessment and American College of Surgeons/ Association of Program Directors in Surgery/Association for Surgical Education Resident Prep Curriculum. We recommend the use of a specialty-tailored intern boot-camp and longitudinal curriculum that focuses on learning procedural skills and surgical conditions, anatomy, pathology, clinical examination, radiographic findings, surgical approach, and postoperative complications. These steps will help address knowledge gaps and promote intern readiness in this cohort of individuals.

Impact of the COVID-19 pandemic on neuro-oncology outcomes.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) pandemic has uprooted healthcare systems worldwide, disrupting care and increasing dependence on alternative forms of health care delivery. It is yet to be determined how the pandemic affected neuro-oncology patient outcomes, given that the majority of even "elective" neurosurgical oncology procedures are time-sensitive. This study quantifies changes in neuro-oncological care during the height of the pandemic and investigates patient outcomes in 2020 compared to a historical control. METHODS: We performed a retrospective review of patients with malignant brain tumor diagnoses who were seen at our institution between March 13 and May 1 of 2020 and 2019. Alterations in care, including shift from in-person to telehealth, delays in evaluation and intervention, and treatment modifications were evaluated. These variables were analyzed with respect to brain tumor control and mortality. RESULTS: 112 patients from 2020 to 166 patients from 2019 were included. There was no significant difference in outcomes between the cohorts, despite significantly more treatment delays (p = 0.0160) and use of telehealth (p < 0.0001) in 2020. Patients in 2020 who utilized telehealth visits had significantly more stable tumor control than those who had office visits (p = 0.0124), consistent with appropriate use of in-person visits for patients with progression. CONCLUSIONS: Our study showed that use of telehealth and selective alterations in neuro-oncological care during the COVID-19 pandemic did not lead to adverse patient outcomes. This suggests that adaptive physician-led changes were successful and may inform management during the ongoing pandemic, especially with the emergence of the Delta variant.

The World of Neurosurgery Reimagined Post COVID-19: Crisis ↔ Opportunities.

The COVID-19 pandemic has impacted neurosurgery in unforeseeable ways. Neurosurgical patient care, research, and education have undergone extraordinary modifications as medicine and mankind have adapted to overcome the challenges posed by this pandemic. Some changes will disappear as the situation slowly recovers to a prepandemic status quo. Others will remain: This pandemic has sparked some long-overdue systemic transformations across all levels of medicine, including in neurosurgery, that will be beneficial in the future. In this paper, we present some of the challenges faced across different levels of neurosurgical clinical care, research, and education, the changes that followed, and how some of these modifications have transformed into opportunities for improvement and growth in the future.

Updates on Surgical Management and Advances for Brain Tumors.

PURPOSE OF REVIEW: This review summarizes the modern approach to surgical management of malignant brain tumors, highlighting new technology and multimodal treatment paradigms. RECENT FINDINGS: Outcomes in patients with glioblastoma are strongly correlated with extent of initial surgical resection. Intraoperative MRI, 5-ALA, and neuronavigation are surgical tools that can help achieve a maximal safe resection. Stereotactic radiosurgery and brachytherapy can be used to enhance local control for brain metastases in conjunction with surgery, while combinatorial approaches are increasingly employed in patients with multiple metastases. Advances in surgical techniques allow for minimally invasive approaches, including the use of tubular retractors, endoscopes, and laser interstitial thermal therapy. Primary and metastatic brain tumors require a multimodal, multidisciplinary approach to treatment. Surgical resection can be paired with radiation for metastases to maximize tumor control, expanding systemic options. Technological innovations have improved the safety of surgical resection, while expanding the surgical options and indications for treatment.

Single molecule fate of HIV-1 envelope reveals late-stage viral lattice incorporation.

Human immunodeficiency virus type 1 (HIV-1) assembly occurs on the inner leaflet of the host cell plasma membrane, incorporating the essential viral envelope glycoprotein (Env) within a budding lattice of HIV-1 Gag structural proteins. The mechanism by which Env incorporates into viral particles remains poorly understood. To determine the mechanism of recruitment of Env to assembly sites, we interrogate the subviral angular distribution of Env on cell-associated virus using multicolor, three-dimensional (3D) superresolution microscopy. We demonstrate that, in a manner dependent on cell type and on the long cytoplasmic tail of Env, the distribution of Env is biased toward the necks of cell-associated particles. We postulate that this neck-biased distribution is regulated by vesicular retention and steric complementarity of Env during independent Gag lattice formation.