Surgical outcomes and risk factors for overall mortality in brain arteriovenous malformations patients: a retrospective analysis.

Background: Brain arteriovenous malformations (AVMs) are challenging vascular lesions. Extensive follow-up studies are necessary to refine the therapeutic algorithm, and to improve long-term survival in these patients. The aim of the study was to assess surgical outcomes, and to evaluate overall long-term mortality in patients treated for brain AVMs. Methods: This retrospective single-center study included 191 patients with brain AVMs, admitted between 2012 and 2022. Clinical and angiographical particularities have been analyzed, to identify factors that might influence early outcome and overall long-term mortality. Results: Out of 79 patients undergoing surgery, 51 had ruptured AVMs with total resection achieved in 68 cases (86.1%). Deep venous drainage was associated with incomplete resection. Female sex, admission modified Rankin Scale (mRS) > 2, and eloquent location were independent predictors of poor outcomes. Multiple venous drainage was associated with a higher risk of worsened early outcome. Eloquent brain region involvement, conservative treatment, increasing age, admission mRS > 2, and comorbidities significantly decrease survival in brain AVM patients. Patients treated with interventional treatments had significantly better survival than the conservatively managed ones, when adjusting for age and admission mRS. Conclusion: The study identified female sex, poor neurologic status on admission and eloquence as independent prognostic factors for a negative outcome after surgery. Patients who received interventional treatment had significantly better survival than patients managed conservatively. We recommend employing tailored, proactive management strategies as they significantly enhance long-term survival in brain AVM patients.

A Systematic Review of Laser Photobiomodulation Dosimetry and Treatment Protocols in the Management of Medications-Related Osteonecrosis of the Jaws: A Rationalised Consensus for Future Randomised Controlled Clinical Trials.

Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect of bisphosphates, antiresorptive therapy or antiangiogenic agents that can potentially increase oxidative stress, leading to progressive osteonecrosis of the jaws. Despite the large number of published systematic reviews, there is a lack of potential MRONJ treatment protocols utilising photobiomodulation (PBM) as a single or adjunct therapy for preventive or therapeutic oncology or non-oncology cohort. Hence, this systematic review aimed to evaluate PBM laser efficacy and its dosimetry as a monotherapy or combined with the standard treatments for preventive or therapeutic approach in MRONJ management. The objectives of the review were as follows: (1) to establish PBM dosimetry and treatment protocols for preventive, therapeutic or combined approaches in MRONJ management; (2) to highlight and bridge the literature gaps in MRONJ diagnostics and management; and (3) to suggest rationalised consensus recommendations for future randomised controlled trials (RCTs) through the available evidence-based literature. This review was conducted according to the PRISMA guidelines, and the protocol was registered at PROSPERO under the ID CRD42021238175. A multi-database search was performed to identify articles of clinical studies published from their earliest records until 15 December 2023. The data were extracted from the relevant papers and analysed according to the outcomes selected in this review. In total, 12 out of 126 studies met the eligibility criteria. The striking inconsistent conclusions made by the various authors of the included studies were due to the heterogeneity in the methodology, diagnostic criteria and assessment tools, as well as in the reported outcomes, made it impossible to conduct a meta-analysis. PBM as a single or adjunct treatment modality is effective for MRONJ preventive or therapeutic management, but it was inconclusive to establish a standardised and replicable protocol due to the high risk of bias in a majority of the studies, but it was possible to extrapolate the PBM dosimetry of two studies that were close to the WALT recommended parameters. In conclusion, the authors established suggested rationalised consensus recommendations for future well-designed robust RCTs, utilising PBM as a monotherapy or an adjunct in preventive or therapeutic approach of MRONJ in an oncology and non-oncology cohort. This would pave the path for standardised PBM dosimetry and treatment protocols in MRONJ management.

Postoperative Stroke Following Anterior Cervical Spine Surgery: A Case Report.

Vascular complications succeeding anterior cervical spine surgery are rare, but their consequences represent a major burden for the patient. Cerebral infarction following anterior cervical discectomy and fusion (ACDF) is uncommon. However, screening for risk factors before surgery should become mandatory. We present the case of a patient with no significant medical history who underwent ACDF for a C5/C6 herniated disc with myelopathy. Although the surgery was uneventful, after the surgery, partial right palpebral ptosis and miosis were noted, suggestive of Horner syndrome. On the fifth postoperative day, the patient experienced left hemiplegia and drowsiness. An emergency CT scan and cerebral MRI revealed ischemia in the right middle cerebral artery territory. The patient was transferred to a neurology center for mechanical thrombectomy, which revealed a complete occlusion of the right internal carotid artery. The procedure had to be halted due to blood extravasation at the internal carotid artery bifurcation to prevent further complications. An angio-CT examination of the cervical arteries exposed a soft atheromatous plaque on the right internal carotid artery, immediately after the bifurcation. Despite the patient having no significant medical history, blood tests indicated dyslipidemia. At the two-month follow-up, the patient remained hemiplegic, with mild dysphasia. Performing carotid and vertebral Doppler ultrasound before cervical spine surgery might be useful, whenever possible, to assess high-risk factors for ischemic events and avoid such debilitating complications.

Natural History and Predictors for Hemorrhage in Supratentorial Brain Arteriovenous Malformations.

Background/Objectives: Approximately half of the patients harboring supratentorial brain arterio-venous malformations (stAVMs) present with hemorrhage, and another considerable proportion suffer from epileptic seizures. An important milestone in the management of this vascular pathology is acknowledging their natural history, especially across long periods of time. The aim of this study was to assess the predictive factors for hemorrhage and for epileptic seizures as presenting symptoms in stAVMs. Methods: We retrospectively analyzed patients with stAVMs admitted to our institution between 2012 and 2022 and evaluated predictive factors for hemorrhage and the risk factors associated with epileptic seizures. Results: The cohort included 169 patients, 78 of them (46.2%) presenting with intracerebral hemorrhage (ICH). Seventy-seven (45.5%) patients suffered from epileptic seizures. The annual hemorrhagic rate was 1.28%/year. Unruptured lesions (p = 0.001, OR 3.1, 95% CI 1.6-6.2), superficial venous drainage (p = 0.007, OR 2.7, 95% CI 1.3-5.7) and large nidus size (p = 0.025, OR 4, 95% CI 1.2-13.5) were independently associated with seizures. Among unruptured lesions, superficial venous drainage (OR 2.6, p = 0.036, 95% CI 1.06-6.3) and frontal/temporal/parietal location (OR 2.7, p = 0.040, 95 CI% 1.04-6.9) significantly increased the risk of seizures as a presenting symptom in multivariate analysis. Patients younger than 18 (p = 0.003, OR 4.5, 95% CI 1.6-12.2), those with AVMs < 3 cm (p = 0.03, OR 2, 95% CI 1.07-3.9) or those with deep located AVMs (p = 0.035, OR 2.3, 95% CI 1.06-5.1) presented statistically more often with ICH in multivariate regression. Small size (HR 1.8, 95% CI 1.09-3, p = 0.022) and exclusively deep venous drainage (HR 2.2, 95% CI 1.2-4, p = 0.009) were independent predictors for ICH, in time-dependent birth-to-diagnosis analysis. After shifting the birth-to-diagnosis curve by 10 years, unique arterial feeder demonstrated a positive correlation with ICH presentation as well. Conclusions: Small AVMs, those with exclusively deep venous drainage, unique arterial feeder or deep location may pose higher hemorrhagic risks for the patient, and therapeutic strategies should be tailored accordingly. When managing unruptured brain AVMs, it is important to consider the risk of developing seizures, in addition to the lifelong risk of hemorrhage, in determining the optimal treatment approach for each patient.

Clinical outcomes of posterior fossa arteriovenous malformations: a single center experience.

BACKGROUND: Posterior fossa arterio-venous malformations (pfAVMs) are challenging lesions due to the anatomical particularities of the posterior fossa, and the high incidence of hemorrhagic presentation. The two most important goals when treating AVMs are preserving neurological function and preventing rupture, or a second hemorrhage. The aim of this study was to analyze the clinical and imaging features of pfAVMs to identify the factors that influence the prognosis of these patients. METHODS: We conducted a single-center retrospective observational study that included patients treated at our institution with pfAVMs between January 1997 and December 2021. RESULTS: A total of 48 patients were included. A good modified Rankin score (mRS) was observed in 33 cases (69%) at presentation. Thirty-four patients (71%) presented with a ruptured AVM. Out of these, 19 patients (40%) had intraventricular hemorrhage. Microsurgical resection was performed in 33 cases (69%), while in the other cases, the patients opted for conservative management (7 cases, 15%), stereotactic radiosurgery (SRS) (6 cases, 12%), or endovascular treatment (2 cases, 4%). Patients ≤ 30 years old were more prone to hemorrhagic presentation (OR: 5.23; 95% CI: 1.42-17.19; p = 0.024) and this remained an independent risk factor for rupture after multivariate analysis as well (OR: 4.81; 95% CI: 1.07-21.53; p = 0.040). Following multivariate analysis, the only factor independently associated with poor prognosis in the surgically treated subgroup was a poor clinical status (mRS 3-5) at admission (OR: 96.14; 95% CI: 5.15-1793.9; p = 0.002). CONCLUSIONS: Management of posterior fossa AVMs is challenging, and patients who present with ruptured AVMs often have a poor clinical status at admission leading to a poor prognosis. Therefore, proper and timely management of these patients is essential.

A Novel Therapeutic Approach of 980 nm Photobiomodulation Delivered with Flattop Beam Profile in Management of Recurrent Aphthous Stomatitis in Paediatrics and Adolescents-A Case Series with 3-Month Follow-Up.

Background/Objectives: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal lesions and a very debilitating lesion, especially in paediatric and adolescent patients. The current pharmacotherapy offers a pain relief but not without side effects, and therefore photobiomodulation (PBM) can be an alternative therapy. To the authors' best knowledge, no published study has explored the efficacy of λ 980 nm laser PBM in the management of all RAS subtypes in paediatric and adolescent patients, and therefore, this prospective observational clinical study was conducted to bridge this gap by evaluating λ 980 nm laser PBM efficacy in symptomatic RAS management in paediatric and adolescent patients. The objectives were to evaluate (1) pain intensity alleviation; (2) wound healing rate; (3) wound size closure; (4) a complete resolution; (5) evidence of recurrence; and (6) patients' treatment satisfaction. Methods: The study's variables were assessed at the following timepoints: T0: pre-treatment; T1: immediately after first PBM session; T2: 5 hours (h) post first PBM session (via telephone call); T3: immediately after second PBM session (three days post first PBM session); T4: three-day follow-up (after complete PBM treatments); T5: two-week follow-up; and T6: three-month follow-up. The following PBM dosimetry and treatment protocols were employed: λ 980 nm; 300 mW; 60 s; 18 J; CW; flattop beam profile of 1 cm2 spot size; 18 J/cm2; and twice-a-week irradiation (72 h interval). Results: At T1, significant immediate pain intensity relief was reported. 33.33% recorded "4" and 66.67% reported "5" on the quantitative numeric pain intensity scale (NPIS), and this continued to improve significantly (83.33%) at T2. All the subjects reported "0" on the NPIS at T3, T4, T5 and T6. There was a significant reduction in the lesion surface area (>50% complete healing) at T3 compared to T0. Complete healing (100%) with no evidence of scarring and lesion recurrence observed at T4, T5 and T6. Very good patients' satisfaction was reported at all timepoints. Conclusions: This is the first report demonstrating λ980 nm efficacy in all RAS subtype management in paediatric and adolescent patients with a 3-month follow-up, whereby its PBM dosimetry and treatment protocols were effective from scientific and practical standpoints, and hence multicentre RCTs with large data are warranted to validate its reproducibility and to enrich the knowledge of PBM application in all RAS subtypes.

Leptomeningeal Dissemination Complicated With Acute Tetraplegia From a Supratentorial Multicentric Isocitrate Dehydrogenase (IDH)-Wildtype Glioblastoma: A Case Report.

Glioblastoma (GBM) is a major concern for neurosurgeons and oncologists, being a malignant tumor with a high recurrence rate and reduced survival. Leptomeningeal dissemination (LMD) of GBM is rare and difficult to diagnose due to the low rate of cellular detection in the cerebrospinal fluid and clinical and imaging similarities with fungal and tuberculous meningitis. We report the case of a 25-year-old female patient suffering from multicentric GBM who developed hydrocephalus and extensive LMD three months after surgery for a left frontal parafalcine cerebral GBM isocitrate dehydrogenase (IDH)-wildtype.

Feasibility and Safety of Adopting a New Approach in Delivering a 450 nm Blue Laser with a Flattop Beam Profile in Vital Tooth Whitening. A Clinical Case Series with an 8-Month Follow-Up.

A prospective observational case series included six patients who presented with discoloured upper and lower teeth extending from the right second premolar to the left second premolar. The photoactivation dosimetry and treatment protocol were as follows: λ 450 nm, 1 W, CW; flattop beam profile; 1 cm2; 15 J/spot; 10 irradiated spots; an irradiation time of 15 s/spot; three whitening cycles in a single session. Blanc One ULTRA+ was the bleaching agent. A visual analogue scale (VAS) was utilised to evaluate the pain intensity and dental hypersensitivity during treatment immediately after complete treatment (T1), 24 h (T2), and 8 h (T3) postoperatively, and at an 8-month follow-up timepoint (T4), whereas the dental colour shade change was assessed using the VITA colour shade guide pre-treatment (T0), T1, and T4. The Gingival index and modified Wong Baker faces scale were utilised to evaluate gingival inflammation and patients' treatment satisfaction, respectively. Our findings revealed a reduction in the dental colour shade of the six cases between 2 and 10- fold (average of 3.5-fold) at T1 and maintained at T4, indicating significant improvement in the colour shade change with optimal outcomes. The percentage of this improvement for all the patients was ranged between 16.6% and 33.3%. At all timepoints, a "0" score was provided for pain intensity, dental hypersensitivity, and gingival inflammation. Our study demonstrates the feasibility and safety of a λ 450 nm laser delivered with a flattop handpiece to achieve optimal whitening outcomes without adverse effects. This offers a useful guide for dental clinicians for vital in-office tooth whitening. Extensive clinical studies with large data are warranted to validate our study protocol.

Nonisolated diaphragmatic hernia in Simpson-Golabi-Behmel syndrome.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. METHOD: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. RESULTS: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. CONCLUSION: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life.

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.

CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10-12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

Systematic discovery of in vivo phosphorylation networks.

Protein kinases control cellular decision processes by phosphorylating specific substrates. Thousands of in vivo phosphorylation sites have been identified, mostly by proteome-wide mapping. However, systematically matching these sites to specific kinases is presently infeasible, due to limited specificity of consensus motifs, and the influence of contextual factors, such as protein scaffolds, localization, and expression, on cellular substrate specificity. We have developed an approach (NetworKIN) that augments motif-based predictions with the network context of kinases and phosphoproteins. The latter provides 60%-80% of the computational capability to assign in vivo substrate specificity. NetworKIN pinpoints kinases responsible for specific phosphorylations and yields a 2.5-fold improvement in the accuracy with which phosphorylation networks can be constructed. Applying this approach to DNA damage signaling, we show that 53BP1 and Rad50 are phosphorylated by CDK1 and ATM, respectively. We describe a scalable strategy to evaluate predictions, which suggests that BCLAF1 is a GSK-3 substrate.

A sensitive flow cytometry-based cytotoxic T-lymphocyte assay through detection of cleaved caspase 3 in target cells.

We describe a highly sensitive flow cytometry-based CTL assay using the cleavage of caspase 3 in target cells as a readout. The assay involved labeling of cells with a cell tracker dye and staining permeabilized cells with an antibody recognizing cleaved caspase 3. The assay proved to be robust and reliable in measuring antigen-specific CTL activity in a number of human and murine systems, including MLR, human peptide-specific T-cell responses induced in vitro, and CTL responses following immunization of mice with viral and peptide vaccines. The assay was found to yield comparable results as 51Cr-release, but with markedly higher sensitivity. When compared to detection of antigen-specific T cells via HLA tetramer/pentamer-based methods of T-cell staining in HIV gag peptide-specific human T cell lines the caspase 3 cleavage readout assay exhibited a comparable level of sensitivity with detection of CTL function at antigen-specific T-cell frequencies of 1:15,000 or lower. A similar level of sensitivity was obtained when murine CTL assays were performed with MLR in which effector cells were highly diluted with naïve syngeneic spleen cells. Our results indicate that the caspase 3 cleavage assay may be a powerful tool to measure antigen-specific CTL responses in human vaccine trials and in pre-clinical animal models of CTL function at both high and low effector cell frequencies.