Rapid Campimetry in glaucoma - correspondence with standard perimetry and OCT.

The Rapid Campimetry (RC), a kinetic visual field test proved to reliably detect visual field defects within the central 10° degrees, the most crucial part for visual acuity and quality of life, affected even at very early stages of glaucoma, within a short measurement epoch, ~ 1 min. This study aims to further investigate RC correspondence with standard tests in glaucoma, namely standard automated perimetry (SAP) and optical coherence tomography (OCT) within 10° of visual field (VF). For this purpose, we included 41 participants, [21 glaucoma (GLA, mean age: 65.9 ± 12.4; 12 preperimetric eyes and 11 with VF defects) and 20 healthy controls (HC; mean age: 65.0 ± 10.3); 20 eyes]. At first, we compared the rate of detection/exclusion of VF defects in RC vs. SAP. Then, for those with VF defects (11 eyes), we investigated the 68-pointwise correspondence of 10 - 2 layout of RC and SAP. For functional and structural (SF) correspondence, pointwise correspondence of RC, SAP vs. OCTmacula [ macular ganglion cell thickness (GCL)] was also performed. Further, we compared sector-based correspondence of RC, SAP vs. OCTmacula accounting for GCL displacement at the fovea as well as sector-based correspondence with OCTdisc [peripapillary retinal nerve fiber layer thickness (pRNFL)]. Agreement estimates were reported along with Cohen Kappa ([Formula: see text]) statistic. For overall performance, RC and SAP showed 100% agreement ([Formula: see text]) for the exclusion of VF defects (HC and preperimetric GLA) and for detection of VF defects [11 eyes of 9 GLA, ([Formula: see text]]. Further, RC outperformed SAP in detection of arcuate scotomas, 7 vs. 5, respectively. Pointwise correspondence of VF defects (11 eyes), RC-SAP agreement reached 90% accuracy ([Formula: see text]). For SF correspondence, RC [SAP] showed 62% [69%] pointwise agreement with OCTmacula, ([Formula: see text]). For macular sector-based correspondence, SF correspondence improved and reached 83% [83%] agreement, ([Formula: see text]). For OCTdisc sector-based analysis, SF correspondence was highest, 100% [100%] agreement, ([Formula: see text]). Rapid Campimetry gave reproducible results in comparison to SAP and OCT with high potential as a screening VF method given its short testing duration, ~ 1 min in screening mode, and compatibility with telemedicine technologies upon future optimization and automation.

DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells.

Epigenetic mechanisms stabilize gene expression patterns during CD8+ T cell differentiation. Although adoptive transfer of virus-specific T cells is clinically applied to reduce the risk of virus infection or reactivation in immunocompromised individuals, the DNA methylation pattern of virus-specific CD8+ T cells is largely unknown. Hence, we here performed whole-genome bisulfite sequencing of cytomegalovirus-specific human CD8+ T cells and found that they display a unique DNA methylation pattern consisting of 79 differentially methylated regions (DMRs) when compared to memory CD8+ T cells. Among the top demethylated DMRs in cytomegalovirus-specific CD8+ T cells was TBKBP1, coding for TBK-binding protein 1 that can interact with TANK-binding kinase 1 (TBK1) and mediate pro-inflammatory responses in innate immune cells downstream of intracellular virus sensing. Since TBKBP1 has not yet been reported in T cells, we aimed to unravel its role in virus-specific CD8+ T cells. TBKBP1 demethylation in terminal effector CD8+ T cells correlated with higher TBKBP1 expression at both mRNA and protein level, independent of alternative splicing of TBKBP1 transcripts. Notably, the distinct DNA methylation patterns in CD8+ T cell subsets was stable upon long-term in vitro culture. TBKBP1 overexpression resulted in enhanced TBK1 phosphorylation upon stimulation of CD8+ T cells and significantly improved their virus neutralization capacity. Collectively, our data demonstrate that TBKBP1 modulates virus-specific CD8+ T cell responses and could be exploited as therapeutic target to improve adoptive T cell therapies.

The development of children's and adults' use of kinematic cues for visual anticipation and verbal prediction of action.

Expectations about how others' actions unfold in the future are crucial for our everyday social interactions. The current study examined the development of the use of kinematic cues for action anticipation and prediction in 3-year-olds, 4-year-olds, 10-year-olds, and adults in two experiments. Participants observed a hand repeatedly reaching for either a close or far object. The motor kinematics of the hand varied depending on whether the hand reached for the close or far object. We assessed whether participants would use kinematic cues to visually anticipate (Experiment 1; N=98) and verbally predict (Experiment 2; N=80) which object the hand was going to grasp. We found that only adults, but not 3- to 10-year-olds, based their visual anticipations on kinematic cues (Experiment 1). This speaks against claims that action anticipations are based on simulating others' motor processes and instead provides evidence that anticipations are based on perceptual mechanisms. Interestingly, 10-year-olds used kinematic cues to correctly verbally predict the target object, and 4-year-olds learned to do so over the trials (Experiment 2). Thus, kinematic cues are used earlier in life for explicit action predictions than for visual action anticipations. This adds to a recent debate on whether or not an implicit understanding of others' actions precedes their ability to verbally reason about the same actions.

CD19-CAR T-cell therapy induces deep tissue depletion of B cells.

OBJECTIVES: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo. METHODS: Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages. RESULTS: Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19+ and CD20+ B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells. DISCUSSION: This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.

New Biomarkers for Renal Transporter-Mediated Drug-Drug Interactions: Metabolomic Effects of Cimetidine, Probenecid, Verapamil, and Rifampin in Humans.

The inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug-drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE- or OAT-mediated DDIs. For OCT2/MATEs, 5-amino valeric acid betaine (median log2-fold change of estimated renal elimination: -3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7-methyluric acid and cinnamoylglycine (median log2-fold changes -3.10 and -1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter-mediated DDIs.

Rapid campimetry - a novel robust kinetic approach for visual field screening in glaucoma.

Purpose: To investigate the robustness and variability of a novel kinetic visual field (VF) screening method termed rapid campimetry (RC). Methods: In RC visual field (VF) screening is enabled via kinetic-based testing on any computer (10°/4.7 s at 40-cm viewing distance) and high contrast in a dark room (1 cd/cm2). In experiment (1): 30 participants [20 healthy participants (HC), 5 glaucoma patients (GLA) and 5 patients with cataract (CAT)] were included to test the intra-session variability (fatigue effect) and the following effects on RC: room illumination (140 cd/m2), ±3 D refractive errors, media opacity. In experiment (2): Inter-session variability (1-3 weeks apart) was assessed in 10 HC and 10 GLA. Since RC detects absolute scotomas, the outcome measure was the size of physiological (blindspot) and pathological (glaucoma) scotomas in degrees. A repeated measures ANOVA was employed in experiment 1 and intraclass correlation (ICC) in experiment 2. Results: Neither the size of the blindspot nor the VF defects differed significantly between the different testing conditions. For intra-session variability, the average bias of blindspot size was -0.6 ± 2.5°, limits of agreement (LOA), in comparison to 0.3 ± 1.5° for VF defects, both with ICC of 0.86 and 0.93, respectively. For the inter-session repeatability, the average bias and LOA for blindspot size was 0.2 ± 3.85° in comparison 1.6 ± 3.1° for VF defects, both with ICC of 0.87 and 0.91, respectively. Conclusion: RC was robust to suboptimal testing VF conditions and showed good-to-excellent reliability between VF testing visits holding high potential for teleophthalmology.

Advancements and challenges in CAR T cell therapy in autoimmune diseases.

Chimeric antigen receptor (CAR) T cells are highly effective at targeting and eliminating cells of the B cell lineage. CAR T cell therapy has become a standard-of-care treatment for patients with relapsed or refractory B cell malignancies. In addition, the administration of genetically modified T cells with the capacity to deplete B cells and/or plasma cells has tremendous therapeutic potential in autoimmune diseases. In the past few years, CD19-based and B cell maturation antigen (BCMA)-based CAR T cell therapies have been applied to various B cell-mediated autoimmune diseases including systemic lupus erythematosus, idiopathic inflammatory myopathy, systemic sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis and multiple sclerosis. The scientific rationale behind this approach is that deep depletion of B cells, including autoreactive B cell clones, could restore normal immune function, referred to as an immune reset. In this Review, we discuss important aspects of CAR T cell therapy in autoimmune disease, including considerations relating to patient selection, safety, efficacy and medical management. These considerations are based on the early experiences of CAR T cell therapy in autoimmune diseases, and as the field of CAR T cell therapy in autoimmune diseases continues to rapidly evolve, these issues will remain subject to ongoing refinement and adaptation.

Fear of cancer progression and the quality of sexual life of female cancer patients in Romania.

Introduction: As cancer survival rates increase, it has become crucial to pay attention to the long-term quality of life of survivors, including sexual functioning. The quality of sexual life and fear of cancer progression are often unmet needs, significantly impacting cancer patients' overall quality of life. In this study, we investigate these factors in Romanian female cancer patients and highlight their relationship with mental health and demographic variables. Methods: This study included 242 Romanian female cancer patients who completed questionnaires assessing sexual functioning (EORTC QLQ-SHQ22), fear of cancer progression (FoP-Q), depression (PHQ-9), and anxiety (GAD-7). We examined these relationships using descriptive, exploratory, and regression analyses. Results: Around 50% of patients reported impairments in sexual satisfaction and pain during sex. Lower sexual satisfaction increased sexual dysfunction, and heightened fear of cancer progression (FCP) were associated with depression, anxiety, younger age, lower education, rural residence, and unmarried status. Discussion: This study reveals a complex interplay between sexual health, fear of cancer progression, and psychological well-being among female cancer survivors in Romania. Addressing sexual concerns, providing psychoeducation, promoting coping with the fear of progression, and utilizing interdisciplinary interventions are essential to improving these patients' overall quality of life. These findings underscore the need for integrated care approaches that consider both physical and psychological dimensions of cancer survivorship.

Fabian Müller.

Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department of Medicine 5 (Hematology and Oncology), University Hospital Erlangen, Germany.

Selective CAR T cell-mediated B cell depletion suppresses IFN signature in SLE.

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell-mediated depletion of B cells in patients with SLE. The resulting data sets not only confirm a selective CAR T cell-mediated reset of the B cell response but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type I IFN signaling. Our current data, thus, provide evidence for a causal relationship between the B cell response and the increased IFN signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.

[CAR T-cell therapy in rheumatology-What we know so far?] / CAR-T-Zell-Therapie in der Rheumatologie ­ Was wissen wir bisher?

Autoreactive B­cells play a key role in the pathogenesis of autoimmune diseases, such systemic lupus erythematosus (SLE). An efficient depletion of B­cells therefore plays a special role in autoimmune diseases, especially in cases with a severe course of the disease. Treatment with chimeric antigen receptor (CAR) T­cells, which was originally developed for the treatment of B­cell lymphomas and leukemias, provides the possibility to deplete B­cells even in deep tissues. The initial results from case series with this procedure for SLE, myositis and systemic sclerosis were very positive. This review article gives an overview of the course, mechanism of action, results so far and the research agenda of CAR T­cell therapy in autoimmune diseases.

Epigenetic signature and key transcriptional regulators of human antigen-specific type 1 regulatory T cells.

Human adaptive immunity is orchestrated by effector and regulatory T (Treg) cells. Natural Tregs arise in the thymus where they are shaped to recognize self-antigens, while type 1 Tregs or Tr1 cells are induced from conventional peripheral CD4 + T cells in response to peripheral antigens, such as alloantigens and allergens. Tr1 cells have been developed as a potential therapy for inducing antigen-specific tolerance, because they can be rapidly differentiated in vitro in response to a target antigen. However, the epigenetic landscape and the identity of transcription factors (TFs) that regulate differentiation, phenotype, and functions of human antigen-specific Tr1 cells is largely unknown, hindering Tr1 research and broader clinical development. Here, we reveal the unique epigenetic signature of antigen-specific Tr1 cells, and TFs that regulate their differentiation, phenotype and function. We showed that in vitro induced antigen-specific Tr1 cells are distinct both clonally and transcriptionally from natural Tregs and other conventional CD4 + T cells on a single-cell level. An integrative analysis of Tr1 cell epigenome and transcriptome identified a TF signature unique to antigen-specific Tr1 cells, and predicted that IRF4, BATF, and MAF act as their transcriptional regulators. Using functional genomics, we showed that each of these TFs play a non-redundant role in regulating Tr1 cell differentiation, suppressive function, and expression of co-inhibitory and cytotoxic proteins. By using the Tr1-specific TF signature as a molecular fingerprint, we tracked Tr1 cells in peripheral blood of recipients of allogeneic hematopoietic stem cell transplantation treated with adoptive Tr1 cell therapy. Furthermore, the same signature identified Tr1 cells in resident CD4 + T cells in solid tumors. Altogether, these results reveal the epigenetic signature and the key transcriptional regulators of human Tr1 cells. These data will guide mechanistic studies of human Tr1 cell biology and the development and optimization of adoptive Tr1 cell therapies.

CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up.

BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).

Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma.

PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee.

Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.

Approaches for bridging therapy prior to chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic B-lineage leukaemia in children and young adults.

The ongoing development of immunotherapies, including chimeric antigen receptor (CAR) T cells, has revolutionized cancer treatment. In paediatric relapsed/refractory B-lineage acute leukaemia antiCD19-CARs induced impressive initial response rates, with event-free survival plateauing at 30-50% in long-term follow-up data. During the interval between diagnosis of relapse or refractoriness and CAR T cell infusion, patients require a bridging therapy. To date, this therapy has consisted of highly variable approaches based on local experience. Here, in an European collaborative effort of paediatric and adult haematologists, we summarise current knowledge with the aim of establishing a guidance for bridging therapy. This includes treatment strategies for different patient subgroups, the advantages and disadvantages of low- and highintensity regimens, and the potential impact of bridging therapy on outcome after CAR T cell infusion. This guidance is a step towards a cross-institutional harmonization of bridging therapy, including personalized approaches. This will allow better comparability of clinical data and increase the level of evidence for the treatment of children and young adults with relapsed/refractory B-lineage ALL until CAR T cell infusion.

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality.

ABSTRACT: Cytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post-CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

Selective dehydrogenation of ammonia borane to polycondensated BN rings catalysed by ruthenium olefin complexes.

Dehydrogenation of ammonia borane to well-defined products is an important but challenging reaction. A dinuclear ruthenium complex with a Ru-Ru bond bearing a diazadiene (dad) unit and olefins as non-innocent ligands catalyzes the highly selective formation of conjugated polycondensed borazine oligomers (BxNxHy), predominantly B21N21H18, the BN analogue of superbenzene.