Parasagittal Dural Space and Cerebrospinal Fluid (CSF) Changes Across the Lifespan in Healthy Adults: Implications for Glymphatic Flow

Background: Recent studies have suggested the importance of a glymphatic clearance pathway for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of this pathway is the anatomic region surrounding the superior sagittal sinus, which has been hypothesized to encompass lymphatic vessels. This so-called parasagittal dural (PSD) space likely plays a physiologically significant role at the distal intracranial component of the human glymphatic circuit, yet owing to the relative novelty of this discovery, fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. Methods: We tested the hypotheses that volumetric magnetic resonance imaging (MRI) measures of the PSD space (i) are directly related to cerebrospinal fluid (CSF) flow at the cerebral aqueduct, and (ii) increase with age. Healthy participants (n=62; age range = 20-83 years) provided informed, written consent and multi-modal 3 Tesla MRI was performed including phase contrast assessment of the CSF flow through the aqueduct of Sylvius, T1-weighted and T2-weighted MRI for tissue volume and PSD assessment. Standard anatomical and cognitive testing were applied to confirm inclusion criteria. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flux (significance criteria: two-sided p<0.05). Results: A significant enlargement of PSD volume in relation to normal aging (p<0.001, Spearman’s- =0.6), CSF volume (p<0.001, Spearman’s- =0.6) and bulk CSF flux through the aqueduct of Sylvius (anterograde and retrograde, p<0.001) were observed. The elevation in PSD volume was not significantly related to changes in tissue volume (p=0.11 and p=0.24 for gray and white matter, respectively). Findings are consistent with PSD volume increasing with age and bulk CSF flux.Conclusions: The findings of this study are two folds, first they highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Second, that PSD volume increases with age, and relates to bulk CSF volume and flux. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

CT for estimating adequacy of lymph node dissection in patients with squamous cell carcinoma of the head and neck

Background Indices obtained from lymph node dissection specimens, specifically lymph node yield (LNY) and lymph node ratio (LNR), have prognostic significance in the setting of head and neck squamous cell carcinoma (HNSCCa). However, there are currently no validated tools to estimate adequacy of planned lymph node dissection using preoperative data. The present study sought to evaluate CT-derived estimates of lymphatic tissue volumes as a preoperative tool to guide cervical node dissection. Methods Fifteen cervical lymph node dissections were performed in 14 subjects with HNSCCa. Preoperative CT-derived estimates of lymphatic tissue volumes were compared with gross pathology tissue volume estimates and pathologically-determined LNY. Results Resected tissue volume (calculated using the triaxial ellipsoid method) correlates with CT-derived preoperative lymphatic volume estimates (r = 0.74, p = 0.003) while LNY does not(r = − 0.12, p = 0.67). When excluding pathologically enlarged lymph nodes (“refined” data), a negative correlation was observed between refined CT-derived volume estimates and refined LNY (r = − 0.65, p = 0.009). Conclusion In the setting of cervical lymph node dissection, CT-derived lymphatic volume estimates correlate with resected tissue volume, but refined CT-derived volume estimates correlate negatively with refined LNY. Trial registration Retrospectively registered. Level of evidence 4

Hard Tissue Volume Stability Effect beyond the Bony Envelope of a Three-Dimensional Preformed Titanium Mesh with Two Different Collagen Barrier Membranes on Peri-Implant Dehiscence Defects in the Anterior Maxilla: A Randomized Clinical Trial

This single-blinded, randomized, controlled study aimed to clinically and radiographically evaluate hard tissue volume stability beyond the bony envelope using three-dimensional preformed titanium mesh (3D-PFTM) for peri-implant dehiscence defects in the anterior maxilla. A total of 28 patients who wished to undergo implant surgery combined with guided bone regeneration (GBR) after extraction of a single maxillary anterior tooth were randomly assigned to two groups depending on the type of collagen membrane used, additionally with the 3D-PFTM—test (n = 14, cross-linked collagen membrane; CCM) and control (n = 14, non-cross-linked collagen membrane; NCCM) groups. Each implant was evaluated radiographically using CBCT at baseline, immediately after surgery, and at 6 months postoperatively. The relative position and distances from the bony envelope to the outlines of the augmented ridge were further determined immediately after GBR and 6 months after healing. At the platform level, the mean horizontal hard tissue gain (HG) at all the sites was 2.35 ± 0.68 mm at 6 months postoperatively. The mean HG rate was 84.25% ± 14.19% in the CCM group and 82.56% ± 13.04% in the NCCM group, but the difference was not significant between the groups. In all cases, HG was maintained beyond the bony envelope even after 6 months of GBR. This study suggests that 3D-PFTM should be considered a valuable option for GBR for peri-implant dehiscence defects in the anterior maxilla. In addition, 3D-PFTM may confer predictable hard tissue volume stability even after the healing period of hard tissue augmented outside the bony envelope by GBR.

Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel–Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study

ABSTRACT Purpose PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Methods Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Results Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Endothelial Cell PHD2-HIF1α-PFKFB3 Contributes to Right Ventricle Vascular Adaptation in Pulmonary Hypertension

Background: Humans and animals with pulmonary hypertension (PH) show right ventricular (RV) capillary growth, which positively correlates with overall RV hypertrophy. However, molecular drivers of RV vascular augmentation in PH are unknown. Prolyl hydroxylase (PHD2) is a regulator of hypoxia-inducible factors (HIFs), which transcriptionally activates several proangiogenic genes, including the glycolytic enzyme PFKFB3. We hypothesized that a signaling axis of PHD2-HIF1α-PFKFB3 contributes to adaptive coupling between the RV vasculature and tissue volume to maintain appropriate vascular density in PH. Methods and Results: We used design-based stereology to analyze endothelial cell (EC) proliferation and the absolute length of the vascular network in the RV free wall, relative to the tissue volume in mice challenged with hypoxic PH. We observed increased RV EC proliferation starting after 6 hours of hypoxia challenge. Using parabiotic mice, we found no evidence for a contribution of circulating EC precursors to the RV vascular network. Mice with transgenic deletion or pharmacologic inhibition of PHD2, HIF1α, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. Conclusions: PHD2-HIF1α-PFKFB3 contributes to structural coupling between the RV vascular length and tissue volume in hypoxic mice, consistent with homeostatic mechanisms which maintain appropriate vascular density. Activating this pathway could help augment the RV vasculature and preserve RV substrate delivery in PH, as an approach to promote RV function.

Epicardial adipose tissue is associated with cardiorespiratory fitness and hemodynamics among Japanese individuals of various ages and of both sexes

Epicardial adipose tissue may affect hemodynamics and cardiorespiratory fitness as it is a metabolically active visceral adipose tissue and a source of inflammatory bioactive substances that can substantially modulate cardiovascular morphology and function. However, the associations between epicardial adipose tissue and hemodynamics and cardiorespiratory fitness remain unclear. This cross-sectional study aimed to examine the association between epicardial adipose tissue volume and hemodynamics, and cardiorespiratory fitness among Japanese individuals of various ages and of both sexes. Epicardial adipose tissue volume was measured in 120 participants (age, 21–85 years) by cardiac magnetic resonance imaging. To evaluate cardiorespiratory fitness, peak oxygen uptake was measured by cardiopulmonary exercise testing. Peak cardiac output and arteriovenous oxygen difference were calculated by impedance cardiography. The epicardial adipose tissue volume was significantly increased in middle-aged and older women. The epicardial adipose tissue volume was significantly and negatively correlated to peak cardiac output and peak oxygen uptake, regardless of age and sex; furthermore, epicardial adipose tissue showed a strong negative correlation with peak heart rate. Epicardial adipose tissue and peak cardiac output were significantly associated (β = -0.359, 95% confidence interval, -0.119 to -0.049, p < 0.001), even after multivariate adjustment (R2 = 0.778). However, in the multiple regression analysis with peak oxygen uptake as a dependent variable, the epicardial adipose tissue volume was not an independent predictor. These data suggest that increased epicardial adipose tissue volume may be correlated with decreased peak oxygen uptake, which might have mediated the abnormal hemodynamics among Japanese people of various ages and of both sexes. Interventions targeting epicardial adipose tissue could potentially improve hemodynamics and cardiorespiratory fitness.