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Morshed Khandaker,1 Melville B Vaughan,2 Tracy L Morris,3 Jeremiah J White,1 Zhaotong Meng1 1Department of Engineering and Physics, 2Department of Biology, 3Department of Mathematics and Statistics, University of Central Oklahoma, Edmond, OK, USA Abstract: The most common bone cement material used clinically today for orthopedic surgery is poly(methyl methacrylate) (PMMA). Conventional PMMA bone cement has several mechanical, thermal, and biological disadvantages. To overcome these problems, researchers have investigated combinations of PMMA bone cement and several bioactive particles (micrometers to nanometers in size), such as magnesium oxide, hydroxyapatite, chitosan, barium sulfate, and silica. A study comparing the effect of these individual additives on the mechanical, thermal, and cell functional properties of PMMA would be important to enable selection of suitable additives and design improved PMMA cement for orthopedic applications. Therefore, the goal of this study was to determine the effect of inclusion of magnesium oxide, hydroxyapatite, chitosan, barium sulfate, and silica additives in PMMA on the mechanical, thermal, and cell functional performance of PMMA. American Society for Testing and Materials standard three-point bend flexural and fracture tests were conducted to determine the flexural strength, flexural modulus, and fracture toughness of the different PMMA samples. A custom-made temperature measurement system was used to determine maximum curing temperature and the time needed for each PMMA sample to reach its maximum curing temperature. Osteoblast adhesion and proliferation experiments were performed to determine cell viability using the different PMMA cements. We found that flexural strength and fracture toughness were significantly greater for PMMA specimens that incorporated silica than for the other specimens. All additives prolonged the time taken to reach maximum curing temperature and significantly improved cell adhesion of the PMMA samples. The results of this study could be useful for improving the union of implant-PMMA or bone-PMMA interfaces by incorporating nanoparticles into PMMA cement for orthopedic and orthodontic applications. Keywords: poly(methyl methacrylate), magnesium oxide, hydroxyapatite, chitosan, barium sulfate, silica, flexural strength, fracture toughness, curing temperature, cell viability

The shifts in hospitals from single-site functionally organized university and community hospitals to multilayered, mega institutions have had dramatic effects on social work practice. Through this longitudinal research we examine, using a strengths perspective and qualitative interviews, the strategies social workers in 22 hospitals across Ontario, Canada, utilized to survive and thrive. The findings identify the importance of clearly articulating one's value to the organization, staying current, and being flexible. [ABSTRACT FROM AUTHOR]

Objective: Gamma Knife radiosurgery (GKRS) is a treatment option for refractory trigeminal neuralgia (TN). However, there is a paucity of data regarding the effectiveness of GKRS for relapsing TN following microvascular decompression (MVD). The aim of this study was to characterize the response rate, complications, pain relief durability, and predictors of pain relapse for salvage GKRS following MVD for TN., Methods: A retrospective study of all patients who received GKRS for Burchiel type 1 TN (TN1) or type 2 TN (TN2) pain at Wake Forest University School of Medicine was conducted. Pain was measured using the Barrow Neurological Institute (BNI) pain intensity score. After an initial pain response of BNI scores I-III, a BNI score of IV or V constituted relapse. Durability of pain relief was characterized using the Kaplan-Meier estimator. Predictors of relapse were investigated using Cox regression models. Statistical significance was set at p < 0.05., Results: Of 2065 patients with TN1 or TN2, 59 had GKRS post-MVD. Forty-nine (83.1%) of these patients experienced a BNI pain score of I-III at the first follow-up post-GKRS. The median time to relapse was 1.75 years; freedom rates from relapse were 77%, 45.9%, and 30.7% at 1, 2, and 5 years, respectively. Radiofrequency ablation prior to MVD significantly decreased the likelihood of an initial response to salvage GKRS (Fisher's exact test, p = 0.02). After controlling for baseline and clinical characteristics, facial numbness significantly decreased the likelihood of pain relapse (Cox regression, HR 0.15, 95% CI 0.03-0.73; p = 0.01). Conversely, a worse initial pain response significantly increased the likelihood of pain relapse (Cox regression, HR 3.64, 95% CI 1.02-12.95; p = 0.04). Pain relapse within 24 months of the original MVD did not predict durability of pain relief following salvage GKRS (Cox regression, HR 0.94, 95% CI 0.40-2.22; p = 0.89). The overall toxicity rate of salvage GKRS was 35.6%., Conclusions: Salvage GKRS presents an effective, noninvasive option for recurring TN after MVD, with a comparable response rate to primary GKRS or MVD, and a favorable complications profile relative to salvage MVD. Patients with postoperative facial numbness and a better initial pain response may experience more durable pain relief following salvage GKRS.

Background and Objectives: Opportunity exists for improved local control rates of grade 2 meningiomas that recur despite maximal surgical resection and adjuvant fractionated radiotherapy. We describe a dose escalation strategy of increasing the total tumor radiation dose by adding a stereotactic radiosurgery (SRS) boost targeting gross disease to fractionated radiotherapy., Methods: A single institution retrospective cohort of patients from 2009-2023 with grade 2 meningioma treated with surgical resection, fractionated radiotherapy, and SRS boost were evaluated for baseline characteristics, local disease control, and adverse events (AE)., Results: Fourteen meningioma patients were included. Ten patients (71.4%) underwent radiosurgery at initial diagnosis, while 4 patients (28.6%) were treated for recurrent disease. The median fractionated dose was 54 Gy, while the median dose for SRS was 7.5 Gy. Among the 13 patients with follow-up available, median follow-up was 34 months. Three patients (23%) had treatment failures, however, none occurred within the SRS volume and two thirds occurred in patients treated for recurrent disease. 18-month PFS was 92.3%, while 18-month overall survival was 100%. Most patients experienced no or mild AEs, however, 3 patients (23%) experienced a high-grade (CTCAE v5.0 grade ≥ 3) AE including radiation necrosis, seizures and cognitive decline., Conclusions: We found 100% in-field local control at three years from an SRS boost to fractionated radiotherapy targeting gross disease with an acceptable toxicity profile, suggesting this may be an effective and improved adjuvant treatment strategy in patients with grade 2 meningioma., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose/objectives: Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease., Methods: Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression., Results: 130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03)., Conclusions: Elucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Choi, D’Agostino, Farris, Abdulhaleem, Hunting, Wang, Smith, Ruiz, Lycan, Petty, Cramer, Tatter, Laxton, White, Li, Su, Whitlow, Xing and Chan.)

Objective: Following resection of posterior superior frontal gyrus (PSFG) tumors, patients can experience supplementary motor area (SMA) syndrome consisting of contralateral hemiapraxia and/or speech apraxia. Given the heterogeneity of PSFG tumors, the authors sought to determine the risk of postoperative deficits and assess predictors of outcomes for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection), regardless of histology., Methods: This was a retrospective single-center cohort study of adult PSFG-region tumors undergoing biopsy or resection by a single surgeon., Results: A total of 106 consecutive patients undergoing 123 procedures (21 biopsies, 102 resections) fulfilled inclusion and exclusion criteria. Anaplastic astrocytomas were the most frequent among resected tumors (39% vs 29%), while glioblastomas were most common among biopsies (38% vs 27%) (p < 0.0001). The biopsy cohort was more likely to have tumor involvement outside the PSFG (90% vs 62%) (p = 0.011), most commonly in the motor cortex (67% vs 31%) (p = 0.005). Seizures were the most common presenting symptom in the resection cohort (p = 0.017), while motor deficits were more common in the biopsy cohort (58% vs 29%) (p < 0.001). Immediate postoperative neurological deficits occurred in 71 cases (58%), but only 3 of the deficits were permanent at 6 months of follow-up (2%). Postoperative SMA syndrome occurred in 48 cases (47%) and was significantly associated with involvement of the motor cortex (p = 0.018) or cingulate gyrus (p = 0.023), which were also significant in multivariate analysis as risk factors for SMA syndrome. However, postoperative SMA syndrome was not significantly associated with overall survival (p = 0.51). There were no perioperative deaths, but corpus callosum involvement (p < 0.001), contrast enhancement (p = 0.003), and glioblastoma pathology (p = 0.038) predicted worse overall survival in patients undergoing resection., Conclusions: Nearly half of all patients undergoing resection of PSFG-region tumors experience a postoperative SMA syndrome. Individuals with corpus callosum and/or motor cortex involvement may be at an increased risk of experiencing SMA syndrome. However, these deficits are usually transient, and the risk of permanent new deficits is very low (3%). Preoperative characteristics including corpus callosum involvement and tumor enhancement-in addition to pathology-might serve as predictors of overall survival within this patient population.

The treatment of critical-sized bone defects caused by tumor removal, skeletal injuries, or infections continues to pose a major clinical challenge. A popular potential alternative solution to autologous bone grafts is a tissue-engineered approach that utilizes the combination of mesenchymal stromal/stem cells (MSCs) with synthetic biomaterial scaffolds. This approach aims to support new bone formation by mimicking many of the biochemical and biophysical cues present within native bone. Regrettably, osteocyte cells, crucial for bone maturation and homeostasis, are rarely produced within MSC-seeded scaffolds, thereby restricting the development of fully mature cortical bone from these synthetic implants. In this work, we have constructed a multimodal scaffold by combining electrospun poly(lactic- co -glycolic acid) (PLGA) fibrous scaffolds with poly(ethylene glycol) (PEG)-based hydrogels that mimic the functional unit of cortical bone, osteon (osteon-mimetic) scaffolds. These scaffolds were decorated with a novel bone morphogenic protein-6 (BMP6) peptide (BMP6p) after our findings revealed that the BMP6p drives higher levels of Smad signaling than the full-length protein counterpart, soluble or when bound to the PEG hydrogel backbone. We show that our osteon-mimetic scaffolds, in presenting concentric layers of BMP6p-PEG hydrogel overlaid on MSC-seeded PLGA nanofibers, promoted the rapid formation of osteocyte-like cells with a phenotypic dendritic morphology, producing early osteocyte markers, including E11/gp38 (E11). Maturation of these osteocyte-like cells was further confirmed by the observation of significant dentin matrix protein 1 (DMP1) throughout our bilayered scaffolds after 3 weeks, even when cultured in a medium without dexamethasone (DEX) or any other osteogenic supplements. These results demonstrate that these osteon-mimetic scaffolds, in presenting biochemical and topographical cues reminiscent of the forming osteon, can drive the formation of osteocyte-like cells in vitro from hBMSCs without the need for any osteogenic factor media supplementation.

Human standing balance relies on the continuous monitoring and integration of sensory signals to infer our body's motion and orientation within the environment. However, when sensory information is no longer contextually relevant to balancing the body (e.g., when sensory and motor signals are incongruent), sensory-evoked balance responses are rapidly suppressed, much earlier than any conscious perception of changes in balance control. Here, we used a robotic balance simulator to assess whether associatively learned postural responses are similarly modulated by sensorimotor incongruence and contextual relevance to postural control. Twenty-nine participants in three groups were classically conditioned to generate postural responses to whole-body perturbations when presented with an initially neutral sound cue. During catch and extinction trials, participants received only the auditory stimulus but in different sensorimotor states corresponding to their group: 1) during normal active balance, 2) while immobilized, and 3) throughout periods where the computer subtly removed active control over balance. In the balancing and immobilized states, conditioned responses were either evoked or suppressed, respectively, according to the (in)ability to control movement. Following the immobilized state, conditioned responses were renewed when balance was restored, indicating that conditioning was retained but only expressed when contextually relevant. In contrast, conditioned responses persisted in the computer-controlled state even though there was no causal relationship between motor and sensory signals. These findings suggest that mechanisms responsible for sensory-evoked and conditioned postural responses do not share a single, central contextual inference and assessment of their relevance to postural control, and may instead operate in parallel., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants., Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI., Results: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2)., Conclusion: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG., (© 2024 Wiley Periodicals LLC.)

Objective: Regular reporting on recruitment of women into neurosurgery is a mechanism to track the progress of minority inclusion and diversity. For more than 20 years, half of US medical students have been women, yet a disproportionate minority pursue a career in neurosurgery. The authors previously published data tracking women in neurosurgery for the prior decade from 2000 to 2009, which showed an increasing match rate of women over time, from 18 women matched at the beginning of the decade to 36 matched at the end. They now present updated data on the matriculation of women into neurosurgical residencies across the most recent decade, from 2010 to 2019., Methods: Public databases from the Association of American Medical Colleges were analyzed for applicants to neurosurgical residency from 2010 to 2019. Demographic data for those matched was obtained from the American Medical Association Masterfile and analyzed for year of match and gender. Secondary outcomes included program location, age, and gap year(s) between medical school and residency., Results: Women made up 18.8% (394/2094) of residents matched into neurosurgery from 2010 to 2019, compared to 12% during the previous decade. There was an increase in overall match rate of 2.2% per year (male + female) from 2010 to 2019, representing the predicted need for expansion of the neurosurgical workforce to meet national needs. Women made up the majority of this expansion, rising by 5.5% over the time period (p = 0.002), compared to men increasing by 1.4% over the time period (p = 0.096). The percentage of women applicants who matched was 34.4%, compared to men at 38.6% (p = 0.009). There was no significant difference in gender with regard to age, number of gap years, or program location., Conclusions: The number of women matching into neurosurgery has continued to increase across the last 2 decades. Despite this, there remains significant disparity between the number of men and women matching into neurosurgery. Ongoing mitigation of barriers to recruitment of women into neurosurgery is critical. The authors' data highlight the fact that women are important to fueling the expansion of the neurosurgical workforce.

Human cell reprogramming traditionally involves time-intensive, multistage, costly tissue culture polystyrene-based cell culture practices that ultimately produce low numbers of reprogrammed cells of variable quality. Previous studies have shown that very soft 2- and 3-dimensional hydrogel substrates/matrices (of stiffnesses ≤ 1 kPa) can drive ~2× improvements in human cell reprogramming outcomes. Unfortunately, these similarly complex multistage protocols lack intrinsic scalability, and, furthermore, the associated underlying molecular mechanisms remain to be fully elucidated, limiting the potential to further maximize reprogramming outcomes. In screening the largest range of polyacrylamide (pAAm) hydrogels of varying stiffness to date (1 kPa to 1.3 MPa), we have found that a medium stiffness gel (~100 kPa) increased the overall number of reprogrammed cells by up to 10-fold (10×), accelerated reprogramming kinetics, improved both early and late phases of reprogramming, and produced induced pluripotent stem cells (iPSCs) having more naïve characteristics and lower remnant transgene expression, compared to the gold standard tissue culture polystyrene practice. Functionalization of these pAAm hydrogels with poly-l-dopamine enabled, for the first-time, continuous, single-step reprogramming of fibroblasts to iPSCs on hydrogel substrates (noting that even the tissue culture polystyrene practice is a 2-stage process). Comparative RNA sequencing analyses coupled with experimental validation revealed that a novel reprogramming regulator, protein phosphatase and actin regulator 3, up-regulated under the gel condition at a very early time point, was responsible for the observed enhanced reprogramming outcomes. This study provides a novel culture protocol and substrate for continuous hydrogel-based cell reprogramming and previously unattained clarity of the underlying mechanisms via which substrate stiffness modulates reprogramming kinetics and iPSC quality outcomes., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Mohammad Mahfuz et al.)

Objective: The objective of this study was to examine survival outcomes in 136 patients with renal cell carcinoma with metastases to the brain who were treated with radiation combined with immunotherapy or tyrosine kinase inhibitor compared to those who were treated with radiation therapy alone., Methods: The Wake Forest Gamma Knife prospective database was searched for all patients with renal cell carcinoma brain metastases. Outcome measurements included overall survival, determined via the Kaplan-Meier Method, and cumulative incidence of local and distant failure, determined using the Fine Gray competing risks analysis with death as a competing risk for the 136 patients included., Results: Overall survival for the entire population at 6 months, 12 months, and 24 months was 67%, 47% and 30%, respectively. For the TKI (non-immunotherapy-treated) population (n = 37), overall survival was 75%, 61%, and 40% at 6 months, 12 months, and 24 months, respectively. For the immunotherapy-treated population (n = 35), overall survival was 85%, 64%, and 50% at 6 months, 12 months, and 24 months, respectively. Overall survival was significantly increased for patients who received radiation with either immunotherapy or TKI (p < 0.0001)., Conclusion: Prior series of patients with brain metastases of multiple histologies have demonstrated an improvement in the local efficacy of stereotactic radiosurgery when combined with systemic agents. We found that patients treated with targeted agents and patients treated with immunotherapy demonstrated a trend towards improvement over patients treated in the era prior to the advent of either classes of novel therapies., (Copyright © 2024. Published by Elsevier B.V.)

The human body is made up of approximately 40 trillion cells in close contact, with the cellular density of individual tissues varying from 1 million to 1 billion cells per cubic centimetre. Interactions between different cell types (termed heterotypic) are thus common in vivo . Communication between cells can take the form of direct cell-cell contact mediated by plasma membrane proteins or through paracrine signalling mediated through the release, diffusion, and receipt of soluble factors. There is currently no systematic method to investigate the relative contributions of these mechanisms to cell behaviour. In this paper, we detail the conception, development and validation of a microfluidic device that allows cell-cell contact and paracrine signalling in defined areas and over a variety of biologically relevant length scales, referred to as the interactome-device or 'I-device'. Importantly, by intrinsic device design features, cells in different regions in the device are exposed to four different interaction types, including a) no heterotypic cell interaction, b) only paracrine signalling, c) only cell-cell direct contact, or d) both forms of interaction (paracrine and cell-cell direct contact) together. The device design was validated by both mathematical modelling and experiments. Perfused stem cell culture over the medium term and the formation of direct contact between cells in the culture chambers was confirmed. The I-device offers significant flexibility, being able to be applied to any combination of adherent cells to determine the relative contributions of different communication mechanisms to cellular outcomes.

The alkaline electrolyzer (AEL) is a promising device for green hydrogen production. However, their energy conversion efficiency is currently limited by the low performance of the electrocatalysts for the hydrogen evolution reaction (HER). As such, the electrocatalyst design for the high-performance HER becomes essential for the advancement of AELs. In this work, we used both hydrogen (H) and hydroxyl (OH) adsorption Gibbs free energy changes as the descriptors to investigate the catalytic HER performance of 1T' transition metal dichalcogenides (TMDs) in an alkaline solution. Our results reveal that the pristine sulfides showed better alkaline HER performance than their selenide counterparts. However, the activities of all pristine 1T' TMDs are too low to dissociate water. To improve the performance of these materials, defect engineering techniques were used to design TMD-based electrocatalysts for effective HER activity. Our density functional theory results demonstrate that introducing single S/Se vacancy defects can improve the reactivities of TMD materials. Yet, the desorption of OH becomes the rate-determining step. Doping defective MoS 2 with late 3d transition metal (TM) atoms, especially Cu, Ni, and Co, can regulate the reactivity of active sites for optimal OH desorption. As a result, the TM-doped defective 1T' MoS 2 can significantly enhance the alkaline HER performance. These findings highlight the potential of defect engineering technologies for the design of TMD-based alkaline HER electrocatalysts., (Creative Commons Attribution license.)

The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported to linearly encode whisker midpoint, but it is unknown whether the paramedian and simplex lobules as well as their target neurons in the cerebellar nuclei also encode whisker kinematics and if so which ones. Elucidating how these kinematics are represented throughout the cerebellar hemisphere is essential for understanding how the cerebellum coordinates multiple sensorimotor modalities. Exploring the cerebellar hemisphere of mice using optogenetic stimulation, we found that whisker movements can be elicited by stimulation of Purkinje cells in not only crus1 and crus2, but also in the paramedian lobule and lobule simplex; activation of cells in the medial paramedian lobule had on average the shortest latency, whereas that of cells in lobule simplex elicited similar kinematics as those in crus1 and crus2. During spontaneous whisking behaviour, simple spike activity correlated in general better with velocity than position of the whiskers, but it varied between protraction and retraction as well as per lobule. The cerebellar nuclei neurons targeted by the Purkinje cells showed similar activity patterns characterized by a wide variety of kinematic signals, yet with a dominance for velocity. Taken together, our data indicate that whisker movements are much more prominently and diversely represented in the cerebellar cortex and nuclei than assumed, highlighting the rich repertoire of cerebellar control in the kinematics of movements that can be engaged during coordination. KEY POINTS: Excitation of Purkinje cells throughout the cerebellar hemispheres induces whisker movement, with the shortest latency and longest duration within the paramedian lobe. Purkinje cells have differential encoding for the fast and slow components of whisking. Purkinje cells encode not only the position but also the velocity of whiskers. Purkinje cells with high sensitivity for whisker velocity are preferentially located in the medial part of lobule simplex, crus1 and lateral paramedian. In the downstream cerebellar nuclei, neurons with high sensitivity for whisker velocity are located at the intersection between the medial and interposed nucleus., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Objective: Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment., Methods: A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time., Results: The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression., Conclusions: The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression., (Copyright © 2023. Published by Elsevier Inc.)

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10 -5 ), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model ( Xenopus laevis ) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2 707C>T and CAPN2 1112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis., Competing Interests: M.J.B. and J.X.C. are the editor-in-chief and deputy editor, respectively, of Human Genetics and Genomics Advances and were recused from the editorial handling of this article. J.J.W. is an employee and shareholder of Invitae. M.J.B. is chair of the Scientific Advisory Board of GeneDx. S.M. is on the Hypertrophic Cardiomyopathy Advisory Board of Bristol-Myers Squibb., (© 2023 The Author(s).)

The classification of neuronal subpopulations has significantly advanced, yet its relevance for behavior remains unclear. The highly organized flocculus of the cerebellum, known to fine-tune multi-axial eye movements, is an ideal substrate for the study of potential functions of neuronal subpopulations. Here, we demonstrate that its recently identified subpopulations of 9+ and 9- Purkinje cells exhibit an intermediate Aldolase C expression and electrophysiological profile, providing evidence for a graded continuum of intrinsic properties among PC subpopulations. By identifying and utilizing two Cre-lines that genetically target these floccular domains, we show with high spatial specificity that these subpopulations of Purkinje cells participate in separate micromodules with topographically organized connections. Finally, optogenetic excitation of the respective subpopulations results in movements around the same axis in space, yet with distinct kinematic profiles. These results indicate that Purkinje cell subpopulations integrate in discrete circuits and mediate particular parameters of single movements., (© 2023. The Author(s).)

The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its capacity to bind two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Whether and how PSGs and SV2 may coordinate other proteins for BoNT/A recruitment and internalization remains unknown. Here, we demonstrate that the targeted endocytosis of BoNT/A into synaptic vesicles (SVs) requires a tripartite surface nanocluster. Live-cell super-resolution imaging and electron microscopy of catalytically inactivated BoNT/A wildtype and receptor-binding-deficient mutants in cultured hippocampal neurons demonstrated that BoNT/A must bind coincidentally to a PSG and SV2 to target synaptic vesicles. We reveal that BoNT/A simultaneously interacts with a preassembled PSG-synaptotagmin-1 (Syt1) complex and SV2 on the neuronal plasma membrane, facilitating Syt1-SV2 nanoclustering that controls endocytic sorting of the toxin into synaptic vesicles. Syt1 CRISPRi knockdown suppressed BoNT/A- and BoNT/E-induced neurointoxication as quantified by SNAP-25 cleavage, suggesting that this tripartite nanocluster may be a unifying entry point for selected botulinum neurotoxins that hijack this for synaptic vesicle targeting., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour., (© 2023. The Author(s).)

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas., Competing Interests: Declaration of interests M.B.: NIH/NINDS grant R01NS117641, advisory board membership and grant (Varian Medical Systems), consulting (MRIMath). L.E.: Instituto de Salud Carlos III grant PI22/00069. T.L.-J.: an Asociación Española Contra el Cáncer grant. G.R.H.: NIH/NIBIB grant (P41-EB032840-01). J.S.B.-S.: NIH/NCI grants to Case Western Reserve University School of Medicine. J.P.M.: MOU between OSU Radiation Oncology and OSU Center for Biostatistics. R.B.J.: NIH grants. A.W.: MOU between OSU Radiation Oncology and OSU Biomedical Informatics. T.A.C.: grants (PGDX, Pfizer, AstraZeneca, Illumina, NysnoBio); royalties (PGDX); consulting (Illumina, NysnoBio, Pfizer, BMS, Merck, LG Chem); patents (TMB as predictor of immunotherapy response); stock (Griststone Bio, Nysno Bio). A.N.: consulting (Daiichi-Sankyo, NGK, SparkPlug) to his institution; $2,000 as honoraria. M.W.: grants (Apogenix, Merck, Sharp & Dohme, Merck [EMD], Philogen, Quercis); consulting (Adastra, Medac, Merck [EMD], Nerviano Medical Sciences, Novartis); honoraria (Bristol Meyer Squibb, Medac, Merck, Sharp & Dohme); Data Safety Monitoring Board or Advisory Board (Orbus and Philogen); leadership (EORTC). R.G.W.: grant 70-3163-Wi 3 (German Cancer Aid). S.O.: grant (Cordia Therapeutics, Dainippon-Sumitomo, Pharmaceuticals, Otsuka Assay Inc.); royalties (ASAHI Genomics, Qiagen); consulting (Cordia Therapeutics, Kan Research Institute, Novartis Pharmaceuticals); honoraria (MSD Japan, Kyowa Hakko Kirin, Pfizer); stocks (ASAHI Genomics, Cordia Therapeutics, Rebirthell). M.M.: NIH grants (R01NS092597, DP1NS111132, P50CA165962), grants from Kleberg Foundation Cancer Research, Ludwig Fund for Cancer Research; consulting (Cygnal Therapeutics); honoraria for lectures. C.R.M. and F.B.F.: NIH grant (R01CA258248). F.B.F.: NIH grant (R01NS080939). D.R.M.: clinical trials support (INTELLANCE-1 study [M13-813], CCTG CE.8 [EORTC-1709-BTG], INDIGO study [AG-881], Abbvie, Celgene, Agios [now Servier])., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinocerebellar ataxias are neurodegenerative diseases, the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells, the principal neurons of the cerebellar cortex, are the main cells affected in these disorders, but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of Purkinje cells dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to Purkinje cells dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1 (SCA1). Spatiotemporal characterization of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of Purkinje cells intrinsic excitability, which was followed by atrophy of Purkinje cells dendrite arborization and aberrant glutamatergic signalling, finally leading to disruption of Purkinje cells innervation of climbing fibres and loss of intrinsic plasticity of Purkinje cells. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of climbing fibre degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Airway foreign body can be a life-threatening issue in pediatric and adult patients, and the majority of these patients will first present to the emergency department., Objective: This article provides a narrative review of the diagnosis and management of airway foreign bodies for the emergency clinician., Discussion: Foreign bodies in the upper and lower airways are potentially life threatening. This affects all age groups but is more common in pediatric patients. A history of a witnessed ingestion or aspiration event should raise the clinical suspicion for an aspirated foreign body. Patients with upper-airway foreign bodies are more likely to present in respiratory distress when compared with lower-airway foreign bodies, which often present with more subtle signs. Stridor, drooling, and wheezing suggest respiratory distress, but the presenting clinical picture is often unclear and may only include a cough. Immediate intervention is required in the patient with hemodynamic instability or respiratory distress. Airway management including laryngoscopy, fiberoptic bronchoscopy, and cricothyrotomy may be needed in these patients, with the emphasis on removing the obstructing foreign body and securing the airway. Specialist consultation can assist in retrieving the foreign body and managing the airway. If the patient is stable, imaging and specialist consultation for potential operating room intervention should be considered., Conclusions: An understanding of the presentation, evaluation, and management of the patient with an airway foreign body is essential for emergency clinicians., (Published by Elsevier Inc.)

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays., Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF., Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P  = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression ( β  = 1.849, P  = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P  = .01)., Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Dystonia is a neurological disease that is currently ranked as the third most common motor disorder. Patients exhibit repetitive and sometimes sustained muscle contractions that cause limb and body twisting and abnormal postures that impair movement. Deep brain stimulation (DBS) of the basal ganglia and thalamus can be used to improve motor function when other treatment options fail. Recently, the cerebellum has garnered interest as a DBS target for treating dystonia and other motor disorders. Here, we describe a procedure for targeting DBS electrodes to the interposed cerebellar nuclei to correct motor dysfunction in a mouse model with dystonia. Targeting cerebellar outflow pathways with neuromodulation opens new possibilities for using the expansive connectivity of the cerebellum to treat motor and non-motor diseases., (© 2023. Springer Nature Switzerland AG.)

Purpose: Data on the efficacy and safety of stereotactic radiosurgery (SRS) for treatment of radiation-induced meningiomas (RIMs) are limited., Methods: A single institution database of Cobalt-60 SRS cases from 08/1999 to 10/2020 was reviewed. Radiation-induced meningiomas were identified using Cahan's criteria. Endpoints included overall survival (OS), progression free survival (PFS), local control (LC), treatment failure, and treatment toxicity. Univariate and multivariate analyses were performed using cox proportional hazard models., Results: A total of 29 patients with 86 RIM lesions were identified. Median follow-up after SRS was 59 months. The median dose prescribed to the 50% isodose line was 14 Gy (range 12-20 Gy). The actuarial 5-yr OS and PFS were 96% and 68%, respectively. Patients treated for recurrent RIMs had a significantly lower PFS (45% vs 94% at 3 yr, p < 0.005) than patients treated in the upfront setting. Patients with presumed or WHO grade I RIMs had a significantly greater PFS (3-year PFS 96% vs 20%) than patients with WHO grade II RIMs (p < 0.005). On a per-lesion basis, local control (LC) at 1-, 3-, and 5-yrs was 82%, 76%, 74%, respectively. On multivariate analysis, female gender was associated with improved LC (p < 0.001), while marginal doses > 14 Gy were associated with worse local control (p < 0.001). Grade I-III toxicity following treatment was 9.0%., Conclusions: Stereotactic radiosurgery is a safe and effective treatment option for radiographic RIMs, WHO grade I RIMs, or lesions treated in the upfront setting. WHO grade II lesions and recurrent lesions are at increased risk for disease progression., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival., Methods: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS., Results: A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS ( P  = .19), primary cancer distribution ( P  = .80), and the number of metastases at first SRS ( P  = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control ( P  = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up., Conclusion: Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type., Competing Interests: Dr Stephen Tatter: Arbor Pharmaceuticals, research support, Monteris Medical Inc., research support. Dr Michael Chan: Monteris Medical Inc., speaker. The remainder of the authors declares no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cerebellar learning is expressed as upbound or downbound changes in simple spike activity of Purkinje cell subpopulations, but the underlying mechanism remains enigmatic. By visualizing murine Purkinje cells with different molecular identities, we demonstrate that the potential for induction of long-term depression is prominent in downbound and minimal in the upbound subpopulation. These differential propensities depend on the expression profile, but not on the synaptic inputs, of the individual Purkinje cell involved, highlighting the functional relevance of intrinsic properties for memory formation., (© 2022. The Author(s).)

Purpose: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero., Methods: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF)., Results: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03)., Conclusion: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intimate partner violence (IPV) has been implicated in HIV acquisition and worse HIV outcomes. Limited research focuses on the experiences of Black gay and bisexual men. Using data from cross-sectional surveys in Baltimore, Maryland, and Jackson, Mississippi, we analyzed the association between IPV victimization and HIV-related outcomes among 629 adult Black gay and bisexual men, among whom 53% self-reported a negative result at last HIV test. 40% of participants reported lifetime physical, sexual, and/or psychological IPV victimization, and 24% past-year victimization. Recent and lifetime IPV were associated with recent clinical diagnosis of STI (adjPrR: 1.44; 95%CI: 1.08-1.92) and ART medication interruptions (adjPrR: 1.59; 95%CI: 1.25-2.01), respectively. Physical IPV was inversely associated with current PrEP use (adjPrR: 0.35; 95%CI: 0.13-0.90). Recent IPV was independently correlated with depression symptomatology (adjPrR: 2.36; 95%CI: 1.61-3.47) and hazardous alcohol use (adjPrR: 1.93; 95%CI: 1.42-2.61), with evidence of interactions. IPV-HIV relationships were intersected by internalized stigma, housing instability, poverty, and lack of insurance. Tailored IPV services are urgently needed for comprehensive HIV services for Black gay and bisexual men in the U.S., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Laser interstitial thermal therapy (LITT) is an emerging treatment modality for both primary brain tumors and metastases. We report initial outcomes after LITT for metastatic brain tumors across 3 sites at our institution and discuss potential strategies for optimal patient selection and outcomes., Methods: International Classification of Diseases, Ninth Revision and Tenth Revision codes were used to identify patients with malignant brain tumors treated via LITT across all 3 Mayo Clinic sites with at least 6 months follow-up. Local control was based on radiologic and clinical evidence. Overall survival was measured from time of receiving LITT until death or end of the study period., Results: Twenty-three patients were treated for progression of a single (n = 21) or multiple (n = 2) previously radiated metastatic lesions and/or radiation necrosis. Median age was 56 years (interquartile range, 47-66.5 years). LITT achieved local control of the lesion in most patients with metastatic tumors or radiation necrosis (n = 18; 81.8%) for the duration of follow-up. One patient did not have local control data available. Thirteen (56.5%) patients remained alive at the end of the study period. No other patients died of their treated disease during the study period; 5 of 10 deaths were attributable to central nervous system progression outside the treated lesion. Although median survival for this cohort has not yet been reached, the current median survival is 16 months (interquartile range, 12-48.5 months) after LITT for metastatic/radiation necrosis lesions., Conclusions: LITT was associated with sustained local control in 81.8% of patients treated for radiographic progression of metastatic central nervous system disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)