Optical coherence tomography of the macular ganglion cell layer in children with neurofibromatosis type 1 is a useful tool in the assessment for optic pathway gliomas.

BACKGROUND: Optic pathway glioma (OPG) is a feared complication to neurofibromatosis type 1 (NF1) since it can cause visual impairment in young children. The main goal of screening is to detect symptomatic OPGs that require treatment. Optical coherence tomography (OCT) has been suggested as a tool for detection of neuro-retinal damage. AIMS: To investigate whether the ganglion cell layer assessed by OCT is a reliable measure to identify and detect relapses of symptomatic OPGs in children with NF1. METHODS: Children (3-6 years) with NF1, with and without known OPG and children with sporadic OPG (S-OPG) resident in the Stockholm area, were invited and followed in a prospective study during a three-year period. Brain magnetic resonance tomography (MRI) had been performed in children with symptoms of OPG. Outcome measures were VA in logMAR, visual field index (VFI), average thicknesses of the ganglion cell-inner plexiform layer (GC-IPL), and peripapillary retinal nerve fiber layer (pRNFL). RESULTS: There were 25 children with MRI-verified OPG and 52 with NF1 without symptomatic OPG. Eyes from NF1 patients without symptoms of OPG showed significantly better results in all four analyzed parameters compared to eyes with NF1-associated OPG. Mean GC-IPL measurements seemed stable and reliable, significantly correlated to pRNFL (correlation coefficient (r) = 0.662, confidence interval (CI) = .507 to .773 p<0.001), VA (r = -0.661, CI = -7.45 to -.551, p<0.001) and VFI (r = 0.644, CI = .452 to .774, p<0.001). GC-IPL measurements were easy to obtain and acquired at considerably younger age than pRNFL (5.6±1.5 vs 6.8±1.3; p<0.001). CONCLUSIONS: The mean GC-IPL thickness could distinguish well between eyes with OPG and eyes without symptomatic OPG in children with NF1. As thinning of GC-IPL assessed with OCT could indicate underlying OPG, it should be included in the screening protocol of children with questionable VA measurements and in particular in children with NF1.

Cognition in children with arachnoid cysts - A five-year follow-up after microneurosurgical fenestration.

BACKGROUND AND PURPOSE: In recent years there has been a re-evaluation regarding the clinical implications of temporal lobe arachnoid cysts (temporal arachnoid cysts) in children. These cysts have often been considered asymptomatic, or if symptomatic, only causing focal neurological symptoms or signs of increased intracranial pressure. However, several studies have more recently reported on cognitive symptoms improving after surgery. This study aimed to evaluate if reported cognitive improvement after surgery of temporal arachnoid cysts were stable after five years. METHOD: Ten consecutive children (m = 14.65; range 12.1-19.415 were assessed cognitively five years after micro-neurosurgical fenestration of a temporal arachnoid cyst. Results were compared to results from their pre- and post-surgical evaluations. Evaluations included the Wechsler-scales, Boston Naming Test (BNT), Rey Auditory Verbal Learning Test (RAVLT), verbal fluency test (FAS) and Rey Complex Figure Test (RCFT). RESULTS: The analysis revealed significant postsurgical improvement compared to baseline on the Wechsler-scales measures of general intelligence (FSIQ), verbal abilities (VCI) and processing speed (PSI). Mean differences after surgery were 8.3 for FSIQ, (p = 0.026), 8.5 for VI (p = < .01) and 9.9 for PSI (p = 0.03). There were no significant differences in mean test results when comparing postsurgical scores with scores five years after surgery, indicating long-term stability of improvements. CONCLUSION: The results indicate that affected cognitive functions in children with temporal arachnoid cysts improve after surgery and that the improvements remain stable five years later. The improvements and long term stability were also consistent with the experience of both parents and children. The findings provide a strong argument for neurosurgical fenestration of temporal arachnoid cysts in children.

The potential of liquid biopsy for detection of the KIAA1549-BRAF fusion in circulating tumor DNA from children with pilocytic astrocytoma.

Background: Low-grade gliomas (LGGs) represent children's most prevalent central nervous system tumor, necessitating molecular profiling to diagnose and determine the most suitable treatment. Developing highly sensitive screening techniques for liquid biopsy samples is particularly beneficial, as it enables the early detection and molecular characterization of tumors with minimally invasive samples. Methods: We examined CSF and plasma samples from patients with pilocytic astrocytoma (PA) using custom multiplexed droplet digital polymerase chain reaction (ddPCR) assays based on whole genome sequencing data. These assays included a screening test to analyze BRAF duplication and a targeted assay for the detection of patient-specific KIAA1549::BRAF fusion junction sequences or single nucleotide variants. Results: Our findings revealed that 5 out of 13 individual cerebrospinal fluid (CSF) samples tested positive for circulating tumor DNA (ctDNA). Among these cases, 3 exhibited the KIAA1549::BRAF fusion, which was detected through copy number variation (CNV) analysis (n = 1) or a fusion-specific probe (n = 2), while 1 case each displayed the BRAF V600E mutation and the FGFR1 N577K mutation. Additionally, a quantitative analysis of cell-free DNA (cfDNA) concentrations in PA CSF samples showed that most cases had low cfDNA levels, below the limit of detection of our assay (<1.9 ng). Conclusions: While CNV analysis of CSF samples from LGGs still has some limitations, it has the potential to serve as a valuable complementary tool. Furthermore, it can also be multiplexed with other aberrations, for example, to the BRAF V600 test, to provide important insights into the molecular characteristics of LGGs.

Liquid biopsy guides successful molecular targeted therapy of an inoperable pediatric brainstem neoplasm.

Midline CNS tumors are occasionally inaccessible for surgical biopsies. In these instances, cell-free DNA (cfDNA) may serve as a viable alternative for molecular analysis and identification of targetable mutations. Here, we report a young child with an inoperable brainstem tumor in whom a stereotactic biopsy was deemed unsafe. The tumor progressed on steroids and after radiotherapy the patient developed hydrocephalus and received a ventriculoperitoneal shunt. Droplet digital PCR analysis of cfDNA from an intraoperative cerebrospinal fluid liquid biopsy revealed a BRAF V600 mutation enabling targeted treatment with MEK and BRAF inhibitors. The patient, now on trametinib and dabrafenib for 1 year, has had substantial tumor volume regression and reduction of contrast enhancement on MRIs and is making remarkable clinical progress. This case highlights that in a subset of CNS tumors, access to liquid biopsy analysis may be crucial to identify actionable therapeutic targets that would otherwise go undiscovered.

Simultaneous Ultra-Sensitive Detection of Structural and Single Nucleotide Variants Using Multiplex Droplet Digital PCR in Liquid Biopsies from Children with Medulloblastoma.

Medulloblastoma is a malignant embryonal tumor of the central nervous system (CNS) that mainly affects infants and children. Prognosis is highly variable, and molecular biomarkers for measurable residual disease (MRD) detection are lacking. Analysis of cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) using broad genomic approaches, such as low-coverage whole-genome sequencing, has shown promising prognostic value. However, more sensitive methods are needed for MRD analysis. Here, we show the technical feasibility of capturing medulloblastoma-associated structural variants and point mutations simultaneously in cfDNA using multiplexed droplet digital PCR (ddPCR). Assay sensitivity was assessed with a dilution series of tumor in normal genomic DNA, and the limit of detection was below 100 pg of input DNA for all assays. False positive rates were zero for structural variant assays. Liquid biopsies (CSF and plasma, n = 47) were analyzed from 12 children with medulloblastoma, all with negative CSF cytology. MRD was detected in 75% (9/12) of patients overall. In CSF samples taken before or within 21 days of surgery, MRD was detected in 88% (7/8) of patients with localized disease and in one patient with the metastasized disease. Our results suggest that this approach could expand the utility of ddPCR and complement broader analyses of cfDNA for MRD detection.

Learning Curve Analysis and Adverse Events After Implementation of Neurosurgical Laser Ablation Treatment: A Population-Based Single-Institution Consecutive Series.

OBJECTIVE AND METHODS: We conducted a retrospective review of the first 30 patients treated with stereotactic laser ablation (SLA) at our institution since the introduction of the technique in September 2019. We aimed to analyze our initial results and potential learning curve by investigating precision and lesion coverage and assessing the frequency and nature of adverse events according to the Landriel-Ibanez classification for neurosurgical complications. RESULTS: Indications were de novo gliomas (23%), recurrent gliomas (57%), and epileptogenic foci (20%). There was a trend toward improvement of lesion coverage and target deviation, and a statistically significant improvement in entry point deviation, over time. Four patients (13.3%) experienced a new neurological deficit, where three patients had transient and one patient had permanent deficits, respectively. Our results show a learning curve on precision measures over the first 30 cases. Based on our results the technique can safely be implemented at centers with experience in stereotaxy.

Laser interstitial thermal therapy using the Leksell Stereotactic System and a diagnostic MRI suite: how I do it.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a stereotactic neurosurgical procedure used to treat neoplastic and epileptogenic lesions in the brain. A variety of advanced technological instruments such as frameless navigation systems, robotics, and intraoperative MRI are often described in this context, although the surgical procedure can also be performed using a standard stereotactic setup and a diagnostic MRI suite. METHODS: We report on our experience and a surgical technique using a Leksell stereotactic frame and a diagnostic MRI suite to perform LITT. CONCLUSION: LITT can be safely performed using the Leksell frame and a diagnostic MRI suite, making the technique available even to neuro-oncology centers without advanced technological setup.

Percutaneously inserted ventriculo-ureteral shunt as a salvage treatment in paediatric hydrocephalus: a technical note.

BACKGROUND: Hydrocephalus is a challenge for paediatric neurosurgeons. When the abdominal cavity and heart fail as diversion sites for cerebrospinal fluid (CSF), many of the otherwise used alternative diversion sites are not feasible due to the smaller physical body size of children and infants. Using the urinary system as a site of diversion has been described in adults primarily. OBJECTIVE: To describe a minimally invasive procedure to percutaneously access the ureter for placement of a distal catheter in the treatment of paediatric hydrocephalus. METHODS: A percutaneous ultrasound-assisted technique was used to access the renal pelvis for catheter placement into the distal ureter. RESULTS: Fifteen months after the surgery, the child has a stable neurological condition and adequately managed hydrocephalus. CONCLUSION: The urinary tract should be considered a viable option for CSF diversion in complex paediatric hydrocephalus. A multidisciplinary approach consisting of interventional radiologists, urologists and neurosurgeons should be involved in the evaluation of potential candidates.

Global neurosurgery over a 60-year period: Conceptual foundations, time reference, emerging Co-ordinates and prospects for collaborative interventions in low and middle income countries.

Introduction: We evaluated salient initiatives invested in global neurosurgery over a 60-year period. Research question: What are the Phases, Achievements, Challenges, and Lessons of Global Neurosurgery. Methods: A 60-year retrospective study from 1960 to 2020 analyzing the major phases, lessons, and progress notes. We reviewed the foundational need questions and innovated tools used to answer them. Results: Three phases defining our study period were identified. In the early phase, birthing academic units and the onset of individual volunteerism were dominant concepts. The 2nd phase is summarized by the rise of volunteerism and surgical camps.The third phase is heralded by advocacy and strategies for achieving care equity. The defining moment is the Lancet commission for global surgery summit in 2015. Lessons include the need for evaluation of the resources of recipient and donor locations using novel global surgery tools. Conclusion: Global neurosurgery over the 60-year study period is summarized by indelible touchstones of personal and group efforts as well as triumphs derived from innovations in the face of formidable challenges.

[Epilepsy surgery seems underutilized in Sweden]. / Epilepsikirurgin är underutny­­ttjad ­ fler bör hänvisas till utredning.

Epilepsy surgery should be considered for individuals with drug-resistant focal epilepsy. The pre-surgical evaluation is highly multi-disciplinary and performed by a team consisting of neurologists, neurophysiologists, neurosurgeons, neuroradiologists, neuropsychologists, biomedical scientists, speech-language pathologists and nursing staff. The evaluation comprises of a meticulous medical history with focus on seizure semiology, a 3 Tesla MRI, ictal video-EEG, neuropsychological evaluation and sometimes also MEG, nTMS, fMRI, PET or SISCOM/ictal SPECT. Occasionally, invasive monitoring with intracranial electrodes is necessary. Surgical options in treatment of epilepsy range from open resections of epileptogenic areas to focal ablations and neurostimulation. There is evidence of epilepsy surgery being an effective treatment in carefully selected cases. Epilepsy surgery seems underutilized in Sweden and referrals for epilepsy surgery work-up need to increase.

Filum terminale transection in pediatric tethered cord syndrome: a single center, population-based, cohort study of 95 cases.

PURPOSE: The purpose of this study was to evaluate outcome following surgical transection of filum terminale (FT) in symptomatic and asymptomatic pediatric patients with radiological findings consistent with tethered cord syndrome (TCS). METHODS: Patients < 17 years who underwent untethering surgery between 2007 and 2018 were screened for eligibility. Those who had undergone primary transection of the FT, and had preoperative radiological findings of fatty filum, thickened FT, or low-lying conus, below the pedicles of L2, were included. The cohort was divided into symptomatic and asymptomatic depending on clinical presentation. Surgical complications and functional outcome was recorded. RESULTS: In total, 95 patients were included, of whom 62 were symptomatic. In symptomatic patients, the main indications for radiological evaluation were scoliosis (29%) and motor symptoms (19%). In asymptomatic patients, skin stigmata (76%) were the most common finding. Fatty or thick FT was the most common radiographic finding, seen in 61% of symptomatic and 79% of asymptomatic cases. All patients underwent transection of the FT and were followed for a median of 1.8 years. A postoperative complication occurred in 12%, all Ibanez type Ib and managed without invasive treatment. For the symptomatic cohort, significant improvement was seen for both urodynamic assessment (48% improved, p = 0.002) and sensorimotor function (42% improved, p < 0.001). CONCLUSIONS: Neurological improvement or halted deterioration was seen in the majority of symptomatic cases. Asymptomatic patients did not experience any severe complications. Filum transection should be offered to symptomatic and asymptomatic patients upon diagnosis of fatty filum, thickened FT, or low-lying conus.

Optical Coherence Tomography Identifies Visual Pathway Involvement Earlier than Visual Function Tests in Children with MRI-Verified Optic Pathway Gliomas.

This study investigates whether optical coherence tomography (OCT) could add useful information in the examination of children with optic pathway glioma (OPG) at high risk of developing vision loss. For this purpose, the relationship between ganglion cell-inner plexiform layer (GC-IPL) thickness and visual function, evaluated with tests of visual acuity (VA) and visual field (VF), as well as tumor site according to magnetic resonance imaging (MRI), were examined in a geographically defined group of children with OPG. METHODS: Children aged <18 years with OPG underwent ophthalmic examination including VA, VF (Zeiss HFA perimetry) and OCT imaging (Zeiss Cirrus HD-OCT). RESULTS: Out of 51 patients included, 45 provided 77 eyes with MRI-verified OPG, and 19 patients provided 25 eyes without OPG. Significant correlations were found between GC-IPL, VF and VA (p < 0.001). The GC-IPL pattern loss corresponded in 95% to VF defects and in 92% to MRI findings. CONCLUSIONS: Our study indicates that GC-IPL measures could serve as an early marker of vision-threatening changes related to OPG and as a valuable link between MRI and visual function tests. Thinning of GC-IPL and differences in topography between eyes are strong indicators of and predictive of vision loss related to OPG.

Pilot application of Lecture-Panel-Discussion Model (LPDM) in global collaborative neurosurgical education: a novel training paradigm innovated by the Swedish African Neurosurgery Collaboration.

BACKGROUND: Disruptions in global surgery educational routines by the COVID-19 pandemic have elicited demands for alternative formats for rendering qualitative neurosurgical education. This study presents application of a novel model of online neurosurgical course, the Lecture-Panel-Discussion Model (LPDM). METHODS: This is a cross-sectional survey of participants who attended the Swedish African Neurosurgery Collaboration (SANC)-100A course. Participants evaluated the course through an online self-administered questionnaire using a 5-point Likert scale ranging from very poor-1, poor-2, average (fair)-3, good-4, to excellent-5. SANC-100A comprises a tripod of Lectures, Panel review, and interactive case Discussion. This model (LPDM) was innovated by SANC and applied at the Enugu International Neurosurgery course in February 2021. RESULTS: There were 71 attendees, 19 were course faculty, while 52 were participants. Thirty-five attended from Nigeria, 11 from Sweden, 3 from Malawi, 2 from Senegal, and 1 from the UK. Among 44 participants who completed the questionnaire, there were 9 fellows and 35 residents. The overall median course Likert rating was 4.65 ± 0.1. The median overall rating for course events was similar between day 1 (Likert score = 4.45) and day 2 (Likert score = 4.55), U = 55, Z score = 1.10, P = 0.27. The median rating for lectures was 4.50 ± 0.2 and varied from 4.40 on day 1 to 4.55 on day 2. The median rating for panel review was 4.60 ± 0.1 and varied from 4.55 on day 1 to 4.65 on day 2. Interactive case discussions were rated 4.80 on both course days. There was a significant variability in the rating profiles of the course tripod: U = 24.5, P = 0.03. Fifty-one (98%) participants believe LPDM was COVID-19-compliant, while 90% believe the course was beneficial to training and practice. CONCLUSION: Initial application of LPDM is rewarded with both high acceptance and high rating among participants.

Improved cephalic index following early cranial vault remodeling in patients with isolated nonsyndromic sagittal synostosis.

OBJECTIVE: Isolated nonsyndromic sagittal synostosis (SS) is the most common form of craniosynostosis in children, accounting for approximately 60% of all craniosynostoses. The typical cranial measurement used to define and follow SS is the cephalic index (CI). Several surgical techniques have been suggested, but agreement on type and timing of surgery is lacking. This study aimed to evaluate the authors' institutional experience of surgically treating SS using a modified subtotal cranial vault remodeling technique in a population-based cohort. Special attention was directed toward the effect of patient age at time of surgery on long-term CI outcome. METHODS: A retrospective analysis was conducted on all patients with isolated nonsyndromic SS who were surgically treated from 2003 to 2011. Data from electronic medical records were gathered. Eighty-two patients with SS were identified, 77 fulfilled inclusion criteria, and 72 had sufficient follow-up data and were included. CI during follow-up after surgery was investigated with ANOVA and a linear mixed model. RESULTS: In total, 72 patients were analyzed, consisting of 16 females (22%) and 56 males (78%). The mean ± SD age at surgery was 4.1 ± 3.1 months. Blood transfusions were received by 81% of patients (26% intraoperatively, 64% postoperatively, 9% both). The mean ± SD time in the pediatric ICU was 1.1 ± 0.25 days, and the mean ± SD total hospital length of stay was 4.6 ± 2.0 days. No patient required reoperation. The mean ± SD CI increased from 69 ± 3 to 87 ± 5 for patients who underwent surgery before 45 days of age. Surgery resulted in a larger increase in CI for patients who underwent surgery at a younger age compared with older patients (p < 0.05, Tukey's HSD test). In the comparison of patients who underwent surgery before 45 days of age with patients who underwent surgery at 45-90, 90-180, and more than 180 days of age, the linear mixed model estimated a long-term loss of CI of 3.0, 5.5, and 7.4 points, respectively. CONCLUSIONS: The modified subtotal cranial vault remodeling technique used in this study significantly improved CI in patients with SS. The best results were achieved when surgery was performed early in life.

Should neurosurgeons continue to work in the absence of personal protective equipment during the COVID-19 era?

The COVID-19 pandemic has resulted in a widespread shortage of personal protective equipment (PPE). Many healthcare workers, including neurosurgeons, have expressed concern about how to safely and adequately perform their medical responsibilities in these challenging circumstances. One of these concerns revolves around the pressing question: should providers continue to work in the absence of adequate PPE? Although the first peak of the COVID-19 crisis seems to have subsided and supply of PPE has increased, concerns about insufficient PPE availability remain. Inconsistent supply, limited efficacy, and continued high demand for PPE, combined with the continued threat of a second COVID-19 wave, mean that the issues surrounding PPE availability remain unresolved, including a duty to work. This paper offers an ethical investigation of whether neurosurgeons should perform their professional responsibilities with limited availability of PPE. We evaluate ethical considerations and conflicting duties and thereby hope to facilitate providers in making a well-considered personal and moral decision about this challenging issue.

Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy.

PURPOSE: Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy. METHOD: We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77C>T; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079G>A; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77C>T) in the CHRNB2 gene. RESULTS: We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4ß2 (wild-type), α4ß2-Thr26Met (homozygote), and α4ß2/ß2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation. CONCLUSIONS: This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.

Ethical triage during the COVID-19 pandemic: a toolkit for neurosurgical resource allocation.

BACKGROUND: The COVID-19 pandemic confronts healthcare workers, including neurosurgeons, with difficult choices regarding which patients to treat. METHODS: In order to assist ethical triage, this article gives an overview of the main considerations and ethical principles relevant when allocating resources in times of scarcity. RESULTS: We discuss a framework employing four principles: prioritizing the worst off, maximizing benefits, treating patients equally, and promoting instrumental value. We furthermore discuss the role of age and comorbidity in triage and highlight some principles that may seem intuitive but should not form a basis for triage. CONCLUSIONS: This overview is presented on behalf of the European Association of Neurosurgical Societies and can be used as a toolkit for neurosurgeons faced with ethical dilemmas when triaging patients in times of scarcity.

Cognition in Children with Arachnoid Cysts.

BACKGROUND: This study aims to evaluate if children with temporal arachnoid cysts (AC) have cognitive symptoms and if neurosurgery improves these. METHODS: A prospective case series study including consecutive pediatric patients with temporal AC. The children underwent neuroradiology, neuroopthalmologic evaluation, and a standard electroencephalography (EEG). Additionally, a neuropsychologist performed a standardized set of evaluations, with a one-year follow-up consisting of Weschler Intelligence Scale for Children version IV (WISC-IV), FAS (for verbal fluency), Boston Naming Test (BNT, for visual naming ability) and NEPSY-II (Developmental NEuroPSYchological Assessment) for verbal memory. RESULTS: Fifteen children, 9 boys and 6 girls, were evaluated and 11 underwent surgery. The Full Scale IQ subscore (FSIQ) improved from M = 84.8 to M = 93.0 (p = 0.005). The preoperative Verbal Comprehension Index (VCI) was in the low average range (M = 86.7), improving to a level within the average range (M = 94.7, p = 0.001). Preoperative Perceptual Speed Index (PSI) was in the below average range (M = 81.5), improving to a level within the average range (M = 92.5, p = 0.004). CONCLUSION: ACs are a common finding in a pediatric neurosurgical setting. Our data suggest that some temporal AC have a negative effect on general cognitive ability and that this impairment can be improved by surgery. We suggest a standardized evaluation, including comprehensive and validated neuropsychological assessment tools, to thoroughly assess symptoms as well as the postoperative outcome.

Vascular complications in pediatric craniopharyngioma patients: a case-based update.

PURPOSE: Craniopharyngiomas remain a challenging entity for neurosurgeons because of their deep-seated, midline location, and intimate relationship with critical neurovascular structures. With high long-term survival rates, patients with craniopharyngioma are likely to experience significant late morbidity related to both disease and therapy. METHOD AND RESULTS: In this paper, we present two cases of late vascular complications after multi-modal treatment of craniopharyngioma. CONCLUSION: Available data suggests that pediatric patients with craniopharyngioma represent a particularly vulnerable group.