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Cranioplasty using Hydroxyapatite prosthesis is a conceptually simple procedure, but it may harbor several challenges for the surgeons. Several papers in the literature deal with cranioplasty using porous hydroxyapatite. The results are not homogeneous both because of the variability of the patients treated but also because Hydroxyapatite requires a more careful surgical technique to achieve maximum performance. The aim of the present study is to offer an insight of a single institution, multidisciplinary experience with custom-made Hydroxyapatite cranioplasty with surgical tips and tricks based on personal opinion and literature evidence. We will provide an overview of all the fundamental steps we believe to be useful to optimize surgical outcomes, including preoperative planning of cranioplasty; as cranioplasty flap/soft tissue coverage planning, infectious prophylaxis, patient positioning, incisional patterns, tissue dissection, primary bone demolition, and preparation of the craniectomy margins before implant positioning. The authors will also discuss methods for dural suspension, implant fixation and anchorage, margins polishing, drainage, suturing, and dressing. Cranioplasty using hydroxyapatite prosthesis is a valuable alternative for skull reconstruction with heterologous implants, and in our opinion a multidisciplinary approach integrating plastic surgeons and neurosurgeons' specific skills can facilitate surgical planning, reducing complications and allowing to achieve better functional and aesthetic results., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Notch and its ligands play a critical role in rheumatoid arthritis (RA) pathogenesis. Hence, studies were conducted to delineate the functional significance of the Notch pathway in RA synovial tissue (ST) cells and the influence of RA therapies on their expression. Morphological studies reveal that JAG1, DLL4, and Notch1 are highly enriched in RA ST lining and sublining CD68 + CD14 + MΦs. JAG1 and DLL4 transcription is jointly upregulated in RA MΦs reprogrammed by TLR4/5 ligation and TNF, whereas Syntenin-1 exposure expands JAG1, DLL4, and Notch1 expression levels in these cells. Single-cell RNA-seq data exhibit that JAG1 and Notch3 are overexpressed on all fibroblast-like synoviocyte (FLS) subpopulations, in parallel, JAG2, DLL1, and Notch1 expression levels are modest on RA FLS and are predominately potentiated by TLR4 ligation. Intriguingly, JAG1, DLL1/4, and Notch1/3 are presented on RA endothelial cells, and their expression is mutually reconfigured by TLR4/5 ligation in the endothelium. Synovial JAG1/JAG2/DLL1 or Notch1/3 transcriptomes were unchanged in patients who received disease-modifying anti-rheumatic drugs (DMARDs) or IL-6R Ab therapy regardless of disease activity score. Uniquely, RA MΦs and endothelial cells rewired by IL-6 displayed DLL4 transcriptional upregulation, and IL-6R antibody treatment disrupted RA ST DLL4 transcription in good responders compared to non-responders or moderate responders. Nevertheless, the JAG1/JAG2/DLL1/DLL4 transcriptome was diminished in anti-TNF good responders with myeloid pathotype and was unaltered in the fibroid pathotype except for DLL4. Taken together, our findings suggest that RA myeloid Notch ligands can serve as markers for anti-TNF responsiveness and trans-activate Notch receptors expressed on RA FLS and/or endothelial cells., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1β, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy., (© 2023. The Author(s), under exclusive licence to CSI and USTC.)

Since ancient history, men have been attempting to intervene when skull trauma occurs. The majority of traumas were always linked to war injuries, and in the modern era, the culprit was reached during World War I. Cranial traumas in wartime were very common, and consequently, physicians in wartime became particularly interested in the subject of cranial traumatology. In the following text, we want to bring to light the experience of some of the pioneers of cranial surgery in Italy during the First Great War. In fact before the war, very few medical officers had received training in central nervous system surgery. In addition, the surgical instruments for that clinical activity were inadequate and obsolete, but to deal with the medical emergency that had arisen on the front lines, the Italian government established Battlefield Medical Schools. And it is also from the reports and lectures of surgeons working on the front lines that the next generations of neurosurgeons were able to develop this surgical field into the complex and well-established surgical specialty that it is today., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Burr holes in the cranial vault are usually made during trephination for craniotomy or drainage of chronic subdural hematomas. The resulting cranial defect might bring to unsatisfactory esthetic outcome. In the current study the authors report clinical data regarding a cohort of patients who were treated with 3 different types of burr hole covers; autologous bone dust from skull trephination, and 2 different types of cylindric plug made out of porous hydroxyapatite in order to evaluate medium and long-term esthetic and radiological outcomes. Twenty patients were consecutively enrolled in the study and in each patient all 3 types of materials were used to cover different holes. Clinical and radiological outcomes at 6 and 12 months, were analyzed for all 3 types of plugs in terms of thickness of the graft coaptation of margins, remodeling, fractures, mobilization, and contour irregularities. In all craniotomy holes filled with autologous bone dust the authors have observed partial or complete bone reabsorption at 1 year and in 60% of the cases a visible and palpable cranial vault contour irregularity was reported. Both types of bone substitutes gave satisfactory results, comparable to autologous bone dust at 6 months and superior at 12 months, especially in terms of thickness and esthetic appearance. Hydroxyapatite plugs have shown better esthetic and biomechanical results and higher patients' satisfaction compared to autologous bone dust while not giving any additional complications., Competing Interests: A.N. is consultant for FinCeramica. The remaining authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Background and Purpose: Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored., Methods: Data from an ongoing international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included., Results: Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6 months, 8/10 of surgical CVST-VITT who survived admission were functionally independent., Conclusions: Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Retrospective cohort study., Objective: The authors' goal was to clarify whether a bone substitute combined with antibiotics might gain a hold in spinal surgery as a preventive treatment for early infections (EIs)., Background: A relatively infrequent but severe complication in spinal surgery is the occurrence of EIs., Methods: The authors retrospectively compared a population undergoing posterolateral fusion with Mg-enriched hydroxyapatite paste mixed with 60 mg rifampicin powder, with a matched population treated with autologous bone without antibiotics. A total of 30 patients from 2020 to 2021 were included in our study. We estimated EI's relative risk and the number needed to treat. Statistical analyses were performed using the R statistical package v3.4.1 (http://www.r-project.org)., Results: No early infections occurred in the population treated with antibiotic-combined bone substitutes, compared with 6.7% of patients treated with autologous bone without antibiotics. The relative risk of EIs was 0.33 ( P=. 49; 95% CI = 0.01-7.58) and the number needed to treat was 15., Conclusions: The results support the hypothesis that combining bone substitutes with antibiotics may decrease the risk of EIs and could be a viable option to improve spinal surgery outcomes. However, a larger sample size would be needed to confirm the benefit of rifampicin-combined Mg-enriched hydroxyapatite substitutes over autologous bone for surgical site infection prevention., Level of Evidence: Level 3., Competing Interests: The authors declare they have no financial or other conflict of interests in relation to this research and its publication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA., Methods: RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape., Results: Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14 + CD86 + GLUT1 + MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80 + iNOS + RAPTOR + MΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1 -/- animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation., Conclusion: The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

To improve solid spinal fusion while avoiding the morbidity associated with autograft harvesting procedures, numerous alternatives have been investigated, including allograft, demineralized bone matrix (DBM), cell-based therapies and growth factors (i.e., bone morphogenetic proteins, platelet concentrates), and ceramic-based biomaterials. Even though all of these approaches have the potential to improve the outcome of spinal fusion procedures, most of them have not yet been validated by evidence-based clinical results, and thus they are not strongly advisable for clinical use, in addition to being particularly expensive. Here, we give an overview of the current clinical evidence for bone graft alternatives for spine surgery procedures. We will also evaluate the pros and cons of their use and briefly review the more relevant literature.

Abstract: Cranioplasty is a common neurosurgical procedure performed to reconstruct cranial defects. The most common cranioplasty materials used today can be divided into 2 types: autologous bone and bone substitutes, such as polyetheretherketone, titanium mesh, poly-methyl methacrylate, and Hydroxyapatite (HA). Infection represents one of the most feared complications, ranging from 2.3% to 20%. Early implant infections occur within 30 days from the operation and are mostly due to pathogens from the skin and the paranasal cavity. The authors aim to demonstrate the efficacy of our preoperative antibiotic immersion protocol of custom-made HA prosthesis, to prevent early implant infections. The authors compare this population to cranioplasties without preoperative antibiotic elution and those with anonstandardized antibiotic elution. The authors retrospectively analyzed data from patients referred to 6 different hospitals in northern Italy, in the period 2000 to 2020. Inclusion criteria were patients requiring reconstruction of thecal bone with HA prosthesis after post-traumatic decompressive surgery; age more than 18 years; detailed patient history and clinical data; and follow-up of minimum 6 months. A total of 77 cranioplasties were included in the study, along with 120 retrospective cases in comparison. Infections occurred in 2.6% of cranioplasties with antibiotic immersion compared to 7.8% of cranioplasties without. Even if nonsignificant, these results support our hypothesis that pretreatment of HA implants with antibiotic appears to prevent cranioplasty infections and could be a viable option to improve cranioplasty outcomes in the future., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)