Exploring the feasibility of pupillometry training and perceptions of potential use for intracranial pressure monitoring in Uganda: A mixed methods study.

INTRODUCTION: Traumatic brain injury (TBI) accounts for the majority of Uganda's neurosurgical disease burden; however, invasive intracranial pressure (ICP) monitoring is infrequently used. Noninvasive monitoring could change the care of patients in such a setting through quick detection of elevated ICP. PURPOSE: Given the novelty of pupillometry in Uganda, this mixed methods study assessed the feasibility of pupillometry for noninvasive ICP monitoring for patients with TBI. METHODS: Twenty-two healthcare workers in Kampala, Uganda received education on pupillometry, practiced using the device on healthy volunteers, and completed interviews discussing pupillometry and its implementation. Interviews were assessed with qualitative analysis, while quantitative analysis evaluated learning time, measurement time, and accuracy of measurements by participants compared to a trainer's measurements. RESULTS: Most participants (79%) reported a positive perception of pupillometry. Participants described the value of pupillometry in the care of patients during examination, monitoring, and intervention delivery. Commonly discussed concerns included pupillometry's cost, understanding, and maintenance needs. Perceived implementation challenges included device availability and contraindications for use. Participants suggested offering continued education and engaging hospital leadership as implementation strategies. During training, the average learning time was 13.5 minutes (IQR 3.5), and the measurement time was 50.6 seconds (IQR 11.8). Paired t-tests to evaluate accuracy showed no statistically significant difference in comparison measurements. CONCLUSION: Pupillometry was considered acceptable for noninvasive ICP monitoring of patients with TBI, and pupillometer use was shown to be feasible during training. However, key concerns would need to be addressed during implementation to aid device utilization.

Lumbar Drain Use during Middle Fossa Approaches for Nonneoplastic Pathology of the Skull Base.

Introduction The middle fossa craniotomy (MFCs) is commonly utilized for spontaneous cerebrospinal fluid (CSF) leaks, encephaloceles, and superior semicircular canal dehiscence (SSCD). This study compares postoperative outcomes of MFCs with and without LD use. Methods A retrospective cohort study of adults over the age of 18 years presenting for the repair of nonneoplastic CSF leak, encephalocele, or SSCD via MFC from 2009 to 2021 was conducted. The main exposure of interest was the placement of an LD. The primary outcome was the presence of postoperative complications (acute/delayed neurologic deficit, meningitis, intracranial hemorrhage, and stroke). Secondary outcomes included operating room (OR) time, length of stay, recurrence, and need for reoperation. Results In total, 172 patients were included, 96 of whom received an LD and 76 who did not. Patients not receiving an LD were more likely to receive intraoperative mannitol ( n = 24, 31.6% vs. n = 16, 16.7%, p = 0.02). On univariate logistic regression, LD placement did not influence overall postoperative complications (OR: 0.38, 95% confidence interval [CI]: 0.05-2.02, p = 0.28), CSF leak recurrence (OR: 0.75, 95% CI: 0.25-2.29, p = 0.61), or need for reoperation (OR: 1.47, 95% CI: 0.48-4.96, p = 0.51). While OR time was shorter for patients not receiving LD (349 ± 71 vs. 372 ± 85 minutes), this difference was not statistically significant ( p = 0.07). Conclusion No difference in postoperative outcomes was observed in patients who had an intraoperative LD placed compared to those without LD. Operative times were increased in the LD cohort, but this difference was not statistically significant. Given the similar outcomes, we conclude that LD is not necessary to facilitate safe MCF for nonneoplastic skull base pathologies.

Resident Salary Compared to Living Wages at United States Training Institutions.

OBJECTIVE: To compare living wages and salaries at US residency programs. SUMMARY BACKGROUND DATA: It is unknown how resident salary compares to living wages across the United States (US). METHODS: Cross-sectional analysis of publicly available resident salary affordability from training centers with post-graduate-year (PGY)-1 through PGY-7 resident compensation for 2022-2023 was compared with the Massachusetts Institute of Technology (MIT) Living-Wage Calculator. Resident salary to living wage ratios were calculated using PGY-4 salary for each family composition. Univariate and multivariable analysis of PGY-4 salary affordability was performed, accounting for proportion of expected living wages to taxes, transportation, housing, healthcare, childcare, and food, as well as unionization and state income-tax. RESULTS: 118 residency programs, representing over 60% of US trainees, were included, 20 (17%) of which were unionized. Single-parent families were unable to earn a living wage until PGY-7. Residents with 1 child in 2-adult (single-income) and 2-adult (dual-income) families earn below living wages until PGY-5 and PGY-3, respectively. Residents with more than 1 child never earn a living wage. Multivariable regression analysis using PGY-4 salary: living wage ratios in single-child, 2-parent homes showed food expense and unionization status were consistent predictors of affordability. Unionization was associated with lower affordability pre-stipend, almost equivalent affordability post-stipend, and lower affordability post-stipend and union dues. CONCLUSIONS: Resident salaries often preclude residents with children from earning a living wage. Unionization is not associated with increased resident affordability in this cross-sectional analysis. All annual reimbursement data should be centrally compiled, and additional stipends should be considered for residents with children.

GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism.

The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion seven-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7 that is transferred to frizzled (FZD) to initiate canonical ß-catenin signaling. GPR124 remains enigmatic: although its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124 and FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function using the mouse deletion mutant Gpr124ΔC. Despite inefficiently expressed GPR124ΔC protein, Gpr124ΔC/ΔC mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124-/- embryonic lethality, forebrain avascularity and hemorrhage. Gpr124ΔC/ΔC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124ΔC protein expression. Furthermore, Gpr124ΔC and the recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124-regulated CNS forebrain angiogenesis and BBB function are exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion seven-pass transmembrane receptors.

Symptom resolution following a repeat concussion within the same athlete.

INTRODUCTION: Repeat sport-related concussion (SRC) is anecdotally associated with prolonged recovery. Few studies have examined repeat concussion within the same athlete. We sought to explore differences in symptom burden and recovery outcomes in an individual athlete's initial and repeat SRC. METHODS: A retrospective within-subject cohort study of athletes aged 12-23 years diagnosed with two separate SRCs from 11/2017-10/2020 was conducted. Primary outcomes were initial symptom severity and time-to-symptom-resolution. Secondary outcomes included return-to-learn (RTL) and return-to-play (RTP) duration. RESULTS: Of 868 athletes seen, 47 athletes presented with repeat concussions. Median time between concussions was 244 days (IQR 136-395). Comparing initial to repeat concussion, no differences were observed in time-to-clinic (4.3 ± 7.3vs.3.7 ± 4.6 days, p = 0.56) or initial PCSS (26.2 ± 25.3 vs. 30.5 ± 24.1, p = 0.32). While a difference was observed in time-to-symptom resolution between initial/repeat concussion (21.2 ± 16.3 vs. 41.7 ± 86.0 days, p = 0.30), this did not reach statistical significance. No significant differences were observed in time-to-RTL (17.8 ± 60.6 vs. 6.0 ± 8.3 days, p = 0.26) and RTP (33.2 ± 44.1 vs. 29.4 ± 39.1 days, p = 0.75). Repeat concussion was not associated with symptom resolution on univariate (HR 1.64, 95% CI 0.96-2.78, p = 0.07) and multivariable (HR 0.85, 95% CI 0.49-1.46, p = 0.55) Cox regression. CONCLUSION: No significant differences in symptom duration and RTP/RTL were seen between initial/repeat concussion.

Techniques to Reduce the Rate of Infection in Surgeries for Cerebrospinal Fluid Shunting in Adults.

OBJECTIVE: Cerebrospinal fluid shunt placement is associated with high rates of infection. Multiple standardized protocols, particularly in pediatric populations, have been proposed to mitigate this infection rate. We sought to determine the effectiveness of a standardized shunt infection protocol in a large adult population. METHODS: A retrospective cohort study of adults presenting for primary cerebrospinal fluid shunt placement from 2012 to 2022. The primary outcome of interest was shunt infection. The primary exposure of interest was implementation of the shunt protocol (began October 2015). Secondary exposures of interest included use and type of perioperative antibiotics and total operating room time. RESULTS: In total, 820 patients were included, 140 before protocol implementation and 680 after protocol implementation. The overall number of infections over the study period was 15 (1.8% infection rate), with 8 infections preprotocol (5.7%) and 7 infections during the protocol period (1.0%). The infection protocol was associated with a decreased infection rate (odds rato [OR] 0.18, 95% confidence interval [CI] 0.05-0.58, P = 0.002). Total operating room time (OR 1.38 per 30-minute increase, 95% CI 1.05-1.81, P = 0.021) was associated with increased infection rate. Patients who received antibiotics with primarily gram-positive coverage (cefazolin or equivalent) did not have significantly different odds of shunt infection as patients who received broad-spectrum coverage (OR 2.10, 95% CI 0.56-7.88, P = 0.274). CONCLUSIONS: The implementation of an evidence-based perioperative shunt infection protocol is an effective method to decrease shunt infections. Broad-spectrum perioperative antibiotics may not have greater efficacy than gram-positive only coverage, but more research is required.

Global pediatric craniopharyngioma management modalities and outcomes.

INTRODUCTION: Pediatric craniopharyngioma is a complex pathology, with optimal management involving a multidisciplinary approach and thoughtful care coordination. To date, no studies have compared various treatment modalities and outcomes described in different global regions. We conducted a comprehensive systematic review to compare demographics, clinical presentation, treatment approach and outcomes of children diagnosed with craniopharyngioma globally. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Search terms included "craniopharyngioma" and country-specific terms. Inclusion criteria included full-text studies published between 2000-2022, primarily examining pediatric patients 18-years old or younger diagnosed with craniopharyngioma, and reporting management and outcomes of interest. Data extracted included country of origin, demographical data, initial presentation and treatment modality, and outcomes. Descriptive statistics and between-group comparisons based on country of origin were performed. RESULTS: Of 797 search results, 35 articles were included, mostly originating from high-income countries (HIC) (n = 25, 71.4%). No studies originated from low-income countries (LIC). When comparing HIC to middle-income countries (MIC), no differences in patient demographics were observed. No differences in symptomatology at initial presentation, tumor type, surgical approach or extent of surgical resection were observed. HIC patients undergoing intracystic therapy were more likely to receive bleomycin (n = 48, 85.7%), while the majority of MIC patients received interferon therapy (n = 10, 62.5%). All MIC patients undergoing radiation therapy underwent photon therapy (n = 102). No statistically significant differences were observed in postoperative complications or mean follow-up duration between HIC and MIC (78.1 ± 32.2 vs. 58.5 ± 32.1 months, p = 0.241). CONCLUSION: Pediatric craniopharyngioma presents and is managed similarly across the globe. However, no studies originating from LICs and resource-poor regions examine presentation and management to date, representing a significant knowledge gap that must be addressed to complete the global picture of pediatric craniopharyngioma burden and management.

Is the level of varicella-zoster virus IgG associated with symptomatic status of genital herpes simplex virus infection? A case-control study.

BACKGROUND: Herpes simplex virus (HSV) is a common infection, affecting the majority of the population by age of 50. Recurrent symptomatic outbreaks, experienced by a minority, have significant psychological and psychosexual effects. The varicella zoster virus (VZV), resembling HSV, shows potential for a functional cure via vaccination. This study seeks to investigate if there is an association between low VZV antibody levels and recurrent HSV outbreaks. METHODS: A total of 110 patients with symptomatic and asymptomatic HSV were recruited during their sexual health screen. Serum samples were collected between Aug 2019 - July 2022; breaks in the study occurred due to COVID. The primary outcome measure was the serological status of HSV and VZV IgG titre level. RESULTS: The average age was 37.3 years (range 21-65 years). For people with asymptomatic genital HSV2 the average VZV IgG titre was 2373.9 IU/mL (n = 17); and 1219.0 IU/mL for the symptomatic group (n = 67); p ≤ 0.00001), with similar results for HSV1. CONCLUSION: There is a strong association between average higher varicella-zoster virus (VZV) IgG level and being an asymptomatic carrier of herpes simplex sirus (HSV)1&2. A feasibility study to assess the use of the VZV vaccine as a treatment of HSV is planned.

A Mixed-Methods Assessment of the Feasibility of Conducting Neurosurgical Clinical Research in Uganda.

BACKGROUND: Clinical research is necessary to evaluate neurosurgical interventions, yet clinical trials are conducted less frequently in low- and middle-income countries. Because specific barriers, facilitating factors, and strategies for neurosurgical clinical research in Uganda have not been previously identified, this study evaluated neurosurgical providers' perspectives on clinical research and documentation patterns of neurosurgical variables at Mulago National Referral Hospital. METHODS: Retrospective review of 166 neurosurgical patient charts assessed the frequency of documentation of key variables. Twenty-two providers working in neurosurgery participated in 6 focus group discussions with qualitative analysis utilizing the framework method. RESULTS: Chart review showed that primary diagnosis (99.4%), pupil light response (97.6%), and computed tomography scan results (93.3%) were documented for most patients. Cranial nerve exam (61.5%), pupil size (69.9%), and time to neurosurgical intervention (45%) were documented less frequently. On average, Glasgow Coma Scale was documented for 86.6% of days hospitalized, while vital signs were documented for 12.3%. In most focus group discussions, participants identified follow-up, financing, recruitment, time, approval, and sociocultural factors as research barriers. Participants described how the current health workforce facilitates successful research. To improve research capacity, suggested strategies focused on research networks, data collection, leadership, participant recruitment, infrastructure, and implementation. CONCLUSIONS: At Mulago National Referral Hospital, there was variability in the frequency of documentation of neurosurgical variables, which may impact data collection for future studies. While multiple barriers were identified, sociocultural, financing, and time barriers greatly impacted neurosurgical clinical research. Despite that, identified facilitating factors and strategies could be utilized to support neurosurgical research capacity growth.

Endothelial SARS-CoV-2 infection is not the underlying cause of COVID-19-associated vascular pathology in mice.

Endothelial damage and vascular pathology have been recognized as major features of COVID-19 since the beginning of the pandemic. Two main theories regarding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages endothelial cells and causes vascular pathology have been proposed: direct viral infection of endothelial cells or indirect damage mediated by circulating inflammatory molecules and immune mechanisms. However, these proposed mechanisms remain largely untested in vivo. In the present study, we utilized a set of new mouse genetic tools developed in our lab to test both the necessity and sufficiency of endothelial human angiotensin-converting enzyme 2 (hACE2) in COVID-19 pathogenesis. Our results demonstrate that endothelial ACE2 and direct infection of vascular endothelial cells do not contribute significantly to the diverse vascular pathology associated with COVID-19.

Endothelial SARS-CoV-2 infection is not the underlying cause of COVID19-associated vascular pathology in mice.

Endothelial damage and vascular pathology have been recognized as major features of COVID-19 since the beginning of the pandemic. Two main theories regarding how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) damages endothelial cells and causes vascular pathology have been proposed: direct viral infection of endothelial cells or indirect damage mediated by circulating inflammatory molecules and immune mechanisms. However, these proposed mechanisms remain largely untested in vivo. Here, we utilized a set of new mouse genetic tools 1 developed in our lab to test both the necessity and sufficiency of endothelial human angiotensin-converting enzyme 2 (hACE2) in COVID19 pathogenesis. Our results demonstrate that endothelial ACE2 and direct infection of vascular endothelial cells does not contribute significantly to the diverse vascular pathology associated with COVID-19.

Systematic Review Examining the Reporting of Race and Ethnicity in Sport-Related Concussion Studies.

OBJECTIVE: Sport-related concussion (SRC) is an evolving public health concern among youth athletes. Despite emerging evidence that race/ethnicity are important factors in determining concussion outcomes, studies examining race/ethnicity are limited. We conducted a systematic review to: 1) determine the prevalence of SRC studies that report race/ethnicity of their participants, 2) describe how race/ethnicity are used within each study, and 3) assess predictive factors for reporting of race/ethnicity. DATA SOURCES: PubMed/Embase/PsycINFO/CINAHL databases. STUDY SELECTION: Study inclusion criteria were: 1) primary/peer-reviewed research 2) related to the diagnosis/treatment/recovery of SRC 3) involving school-aged athletes (ages 5-25) 4) with ≥ 25 participants. The search was performed 03/2021 and included only studies published after 03/2013. DATA EXTRACTION: For each article, we looked at whether race/ethnicity were reported, and if so, which races/ethnicities were mentioned. For each race/ethnicity mentioned, we extracted the corresponding sample size and how they were used as variables in the study. DATA SYNTHESIS: Of 4,583 studies screened, 854 articles met inclusion criteria. Of the included articles, 132 (15.5%) reported race of their sample and 65 (7.6%) reported ethnicity, whereas 721 (84.4%) reported neither. When examining the demographic characteristics of the 132 studies that reported race, 69.8% of athletes were reported to be White. Additionally, 79.5% of these studies solely used race as a demographic descriptor as opposed to as a main exposure or covariate of interest. Studies published more recently were more likely to report race. Further, specific study/journal topics and geographic location of the authors were more likely to report race. CONCLUSIONS: Reporting of race/ethnicity is limited in current SRC literature. Future studies should improve the reporting of race/ethnicity, diversify study samples by focusing on enrolling athletes from underrepresented groups, and consider the potential impact of race/ethnicity as social determinants of health on risk factors, recovery, and long-term sequelae after SRC.

Predicting early versus late recovery from sport-related concussion using decision tree analysis.

OBJECTIVE: Accurately predicting early (≤ 14 days) versus typical (15-27 days) or delayed (≥ 28 days) recovery from sport-related concussion (SRC) may allow for improved resource utilization and precision in planning and carrying out rehabilitation. In this study, the authors sought to develop an algorithm that enables accurate differentiation of recovery periods and duration after SRC. The authors hypothesized that data regarding initial symptom burden as quantified by a Post-Concussion Symptom Scale (PCSS) score, time to presentation, and number of prior concussions would be the most useful for analyzing predictive factors for concussion recovery duration. METHODS: A retrospective case-control study was conducted to assess the primary outcome of days to clinical recovery following SRC in pediatric patients. Data from patients 12-18 years old presenting within 28 days of injury to an SRC clinic between November 11, 2017, and October 10, 2020, were analyzed. Patients with positive evidence of injury on head imaging or incomplete records were excluded. The primary outcome was duration of clinical recovery, grouped as early (≤ 14 days), typical (15-27 days), or delayed (≥ 28 days). Recovery was defined as follows: 1) symptom resolution or return to baseline, or 2) initiation of graduated return to play. CHAID (chi-square automatic interaction detection) analysis was used to optimize a decision tree based on 16 input factors, including age, sex, initial PCSS score, time to clinic presentation, number of prior concussions, and presence of defined symptom clusters. The cohort was randomized into training (70%) and test (30%) samples for algorithm validation. RESULTS: A total of 493 patients met the inclusion criteria (mean age 15.7 ± 1.5 years, 68.2% male, 70.0% White). The median time to presentation was 5 days (IQR 2-10 days). Most patients (52.3%) recovered within 14 days of injury, 21.5% recovered within 15-27 days, and 26.2% had a recovery period of 28 days or longer. The variables most predictive of recovery were initial PCSS score (cutoffs ≤ 6, 7-28, or ≥ 29), time to presentation (≤ 7 vs > 7 days), or prior concussions (0 vs ≥ 1). The model accurately discriminated between early versus typical or delayed recovery duration groupings (area under the curve 0.80, Youden index 0.44), and correctly classified > 90% of patients who recovered early. CONCLUSIONS: This novel three-factor predictive tool enabled accurate discrimination of early versus typical or delayed SRC recovery to better allocate resources, counsel patients, and make timely referrals.

Investigation of Factors Contributing to Racial Differences in Sport-Related Concussion Outcomes.

OBJECTIVE: Following sport-related concussion (SRC), early studies have demonstrated racial differences in time to clinical recovery; however, these differences have not been fully explained. We sought to further explore these associations by considering possible mediating/moderating factors. METHODS: Data from patients aged 12-18 years diagnosed with SRC from November 2017 to October 2020 were analyzed. Those missing key data, lost to follow-up, or missing race were excluded. The exposure of interest was race, dichotomized as Black/White. The primary outcome was time to clinical recovery (days from injury until the patient was either deemed recovered by an SRC provider or symptom score returned to baseline or zero.) RESULTS: A total of 389 (82%) White and 87 (18%) Black athletes with SRC were included. Black athletes more frequently reported no SRC history (83% vs. 67%, P = 0.006) and lower symptom burden at presentation (median total Post-Concussion Symptom Scale 11 vs. 23, P < 0.001) than White athletes. Black athletes achieved earlier clinical recovery (hazard ratio [HR] = 1.35, 95% CI 1.03-1.77, P = 0.030), which remained significant (HR = 1.32, 95% CI 1.002-1.73, P = 0.048) after adjusting for confounders associated with recovery but not race. A third model adding the initial Post-Concussion Symptom Scale score nullified the association between race/recovery (HR = 1.12, 95% CI 0.85-1.48, P = 0.410). Adding prior concussion history further reduced the association between race/recovery (HR = 1.01, 95% CI 0.77-1.34, P = 0.925). CONCLUSIONS: Overall, Black athletes initially presented with fewer concussion symptoms than White athletes, despite no difference in time to clinic. Black athletes achieved earlier clinical recovery following SRC, a difference explained by differences in initial symptom burden and self-reported concussion history. These crucial differences may stem from cultural/psychologic/organic factors.

Transforaminal Lumbar Interbody Fusion Versus Posterolateral Fusion Alone in the Treatment of Grade 1 Degenerative Spondylolisthesis.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) and posterolateral fusion (PLF) alone are two operations performed to treat degenerative lumbar spondylolisthesis. To date, it is unclear which operation leads to better outcomes. OBJECTIVE: To compare TLIF vs PLF alone regarding long-term reoperation rates, complications, and patient-reported outcome measures (PROMs) in patients with degenerative grade 1 spondylolisthesis. METHODS: A retrospective cohort study using prospectively collected data between October 2010 and May 2021 was undertaken. Inclusion criteria were patients aged 18 years or older with grade 1 degenerative spondylolisthesis undergoing elective, single-level, open posterior lumbar decompression and instrumented fusion with ≥1-year follow-up. The primary exposure was presence of TLIF vs PLF without interbody fusion. The primary outcome was reoperation. Secondary outcomes included complications, readmission, discharge disposition, return to work, and PROMs at 3 and 12 months postoperatively, including Numeric Rating Scale-Back/Leg and Oswestry Disability Index. Minimum clinically important difference of PROMs was set at 30% improvement from baseline. RESULTS: Of 546 patients, 373 (68.3%) underwent TLIF and 173 underwent (31.7%) PLF. Median follow-up was 6.1 years (IQR = 3.6-9.0), with 339 (62.1%) >5-year follow-up. Multivariable logistic regression showed that patients undergoing TLIF had a lower odds of reoperation compared with PLF alone (odds ratio = 0.23, 95% CI = 0.54-0.99, P = .048). Among patients with >5-year follow-up, the same trend was seen (odds ratio = 0.15, 95% CI = 0.03-0.95, P = .045). No differences were observed in 90-day complications ( P = .487) and readmission rates ( P = .230) or minimum clinically important difference PROMs. CONCLUSION: In a retrospective cohort study from a prospectively maintained registry, patients with grade 1 degenerative spondylolisthesis undergoing TLIF had significantly lower long-term reoperation rates than those undergoing PLF.

Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection.

Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires in vivo models. Here, we report humanized ACE2-floxed mice in which hACE2 is expressed from the mouse Ace2 locus in a manner that confers lethal disease and permits cell-specific, Cre-mediated loss of function, and LSL-hACE2 mice in which hACE2 is expressed from the Rosa26 locus enabling cell-specific, Cre-mediated gain of function. Following exposure to SARS-CoV-2, hACE2-floxed mice experienced lethal cachexia, pulmonary infiltrates, intravascular thrombosis and hypoxemia-hallmarks of severe COVID-19. Cre-mediated loss and gain of hACE2 demonstrate that neuronal infection confers lethal cachexia, hypoxemia, and respiratory failure in the absence of lung epithelial infection. In this series of genetic experiments, we demonstrate that ACE2 is absolutely and cell-autonomously required for SARS-CoV-2 infection in the olfactory epithelium, brain, and lung across diverse cell types. Therapies inhibiting or blocking ACE2 at these different sites are likely to be an effective strategy towards preventing severe COVID-19.

Association between preoperative hematologic markers and aggressive behavior in meningiomas.

INTRODUCTION: Meningiomas have varying degrees of aggressive behavior. Some systemic hematologic makers are associated with malignancy, but their value in predicting aggressive meningioma behavior is not fully understood. OBJECTIVE: To evaluate the association between preoperative markers such as neutrophil-lymphocyte ratio (NLR), neutrophil-monocyte ratio (NMR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), and prognostic nutritional index (PNI), and diagnostic and prognostic factors including WHO grade, proliferation index, presence of edema on preoperative MRI, and tumor recurrence. METHODS: A retrospective review of patients treated between 2000 and 2019 with a preoperative complete blood count (CBC) differential lab draw before intracranial meningioma resection was conducted. All preoperative steroid dosages were converted to dexamethasone equivalents. Primary outcomes included presence/absence of perilesional edema, WHO grade, Ki-67/MIB-index, and recurrence. Univariate and multivariable regression analyses were conducted. RESULTS: A total of 209 meningioma patients were included. Of these, 143 (68 %) were WHO grade I, 61 (29 %) grade II and 5 (2 %) were grade III. Recurrence was reported in 19 (9.1 %) tumors. No hematologic markers were associated with recurrence. In separate multivariable logistic analyses, no biomarkers were associated with perilesional edema or WHO grade. MLR was associated with higher MIB-index (p = 0.018, OR 6.57, 95 % CI 1.37-30.91). CONCLUSION: Most hematologic markers were not associated with meningioma invasiveness, grade, proliferative index, or aggressiveness. Preoperative MLR was associated with high proliferation index in patients undergoing surgery for intracranial meningioma. Higher MLR could be a surrogate for meningioma proliferation and has potential to be used as an adjunct for risk-stratifying meningiomas.

Which Approach Leads to More Reoperations in Single-Level, Open, Posterior Lumbar Fusion: Transforaminal Lumbar Interbody Fusion or Posterolateral Fusion Alone?

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) and posterolateral fusion (PLF) without an interbody device are two common approaches for single-level, open posterior fusion. Presently, it is unknown whether one of these operations leads to better outcomes. We sought to compare reoperation, complication, and readmission rates between TLIF and PLF for patients undergoing elective single-level, open, posterior lumbar fusion. METHODS: A single-center, retrospective cohort study utilizing prospectively collected data was performed. Inclusion criteria were patients undergoing elective single-level, open, posterior lumbar decompression and fusion between October 2010 and April 2021 with at least 1-year follow-up. The two comparison groups were TLIF vs PLF alone without interbody. The primary outcome was need for reoperation at most recent follow-up. Secondary outcomes included 90-day complication and readmission rates. Univariate and multivariable logistic regression analyses were performed. RESULTS: A total of 850 patients were included, 591 (69.5%) of whom underwent TLIF and 259 (30.5%) of whom underwent PLF. Median follow-up was 6.1 years (interquartile range 3.7-8.9). No significant difference was found in overall reoperation rates (12.4% vs 13.9%, P = 0.534). When stratified by <5-year follow-up (n = 231 TLIF, n = 85 PLF; 37.2%) and ≥5-year follow-up (n = 360 TLIF, n = 174 PLF; 62.8%), no significant differences were seen in either cohort (<5 years: n = 24 TLIF vs n = 9 PLF, P = 0.959; 5+ years: n = 49 TLIF vs n = 27 PLF, P = 0.555). On multivariable logistic regression analysis, the presence of interbody fusion was not associated with reoperation (OR 2.26, 95% CI 0.66-7.74, P = 0.194). CLINICAL RELEVANCE: For patients undergoing elective single-level, open, posterior lumbar fusion without isthmic spondylolisthesis, no differences were seen in reoperation rates at long-term follow-up. Similar 90-day complication and readmission rates were seen. These results suggest that in degenerative lumbar spine disease without isthmic spondylolisthesis, TLIF and PLF achieved similar outcomes.

Conditional Recurrence-Free Survival After Surgical Resection of Meningioma.

BACKGROUND: Recurrence after meningioma resection warrants serial surveillance imaging, but little evidence guides the optimal time interval between imaging studies/surveillance duration. OBJECTIVE: To describe recurrence-free survival (RFS) after meningioma resection, conditioned to short-term RFS. METHODS: A retrospective cohort study for adults presenting for meningioma resection from 2000 to 2018 was conducted. The primary outcome was postoperative follow-up RFS. Conditional RFS Kaplan-Meier analysis was performed at 1, 2, 3, 5, and 10 years, conditioned to 6-month and 12-month RFS. RFS probabilities conditioned to 6-month RFS were estimated in subgroups, stratified by World Health Organization grade, extent of resection, and need for postoperative radiation. RESULTS: In total, 723 patients were included. Median age at surgery was 57.4 years (IQR = 47.2-67.2). Median follow-up was 23.5 months (IQR = 12.3-47.8). Recurrence was observed in 90 patients (12%), with median time to recurrence of 14.4 months (IQR = 10.3-37.1). Conditioned to 6-month postoperative RFS, patients had 90.3% probability of remaining recurrence-free at 2 years and 69.4% at 10 years. Subgroup analysis conditioned to 6-month RFS demonstrated grade 1 meningiomas undergoing gross total resection (GTR) had 96.0% probability of RFS at 1 year and 82.8% at 5 years, whereas those undergoing non-GTR had 94.5% and 79.9% probability, respectively. RFS probability was 78.8% at 5 years for non-grade 1 meningiomas undergoing GTR, compared with 69.7% for non-grade 1 meningiomas undergoing non-GTR. Patients with non-grade 1 meningiomas undergoing upfront radiation had a 1-year RFS of 90.1% and 5-year RFS of 51.7%. CONCLUSION: Recurrence risk after meningioma resection after an initial recurrence-free period is reported, with high-risk subgroups identified. These results can inform objective shared decision-making for optimal follow-up.