Background Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TDP-43 proteinopathy. Methods A retrospective-cohort study using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). Results C9P cases had an earlier age of onset (p=0.047), and in the subset of deceased patients, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rankλ2=4.183,p=0.041), and C9P FTLD showed a significantly greater annualized rate of decline in letter fluency (4.5±1.3words/year) than C9N FTLD (1.4±0.8words/year, p=0.023). VBM revealed greater atrophy in the right fronto-insular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathologic analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. Conclusions C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for ALS and FTLD patients.

3D-printed bioactive ceramic scaffolds can restore critical mandibular segmental defects to levels similar to native bone after 8 weeks in an adult rabbit, critical sized, mandibular defect model.

Background: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. Methods: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 μm of dipyridamole (n = 6), 10,000 μm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. Results: Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-μm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-μm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 μm versus 10,000 μm dipyridamole; p = 0.104), and rhBMP-2–coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 μm dipyridamole, and p = 0.938 versus 10,000 μm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. Conclusion: Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.

Dipyridamole significantly improves the calvarial bone regeneration capacity of 3DPBC scaffolds. The most significant difference in bone regeneration was observed centrally within the interface between the 3DPBC scaffold and the dura mater.

Purpose: Autologous bone grafts remain a standard of care for the reconstruction of large bony defects, but limitations persist. We explored the bone regenerative capacity of customized, 3D printed bioactive ceramic (3DBC) scaffolds with Dipyridamole (DIPY), adenosine A2A receptor (A 2A R) indirect agonist known to enhance bone formation. Methods: Critical-sized bony defects (10mm height, 10mm length, full thickness) were created at the mandibular rami of rabbits (n=15). Defects were replaced by a custom-to-defect, 3DBC scaffold composed of β-tricalcium phosphate. Scaffolds were uncoated (control), collagen-coated (COLL), or immersed in 100μM Dipyridamole (DIPY). At t=8 weeks, animals were euthanized and the rami retrieved. Bone growth was assessed exclusively within scaffold pores, and evaluated by microCT/advanced reconstruction software. MicroCT quantification was calculated. Nondecalcified histology was performed. A general linear mixed model was performed to compare group means and 95% confidence intervals (CI). Results: Qualitative analysis did not show an inflammatory response. The control and COLL groups (12.3±8.3% and 6.9±8.3% bone occupancy of free space, respectively) had less bone

Introduction:The COVID-19 pandemic posed unique challenges for breast reconstruction. Many professional organizations initially placed restrictions on breast reconstruction, leading surgeons to conceive innovative protocols for offering breast reconstruction. This study reviewed the current evidence on breast reconstruction during the COVID-19 pandemic to provide guidance for surgeons facing future crises. Methods: The MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews were searched for studies (1) describing implant and autologous breast reconstruction following mastectomy and (2) occurring during or pertaining to the COVID-19 pandemic. Results: Of the 1347 studies identified, 26 were included. Studies discussed type of reconstruction (18, 69%), complications (11, 42%), timing of reconstruction (10, 38%), protocols (10, 38%), COVID-19 screening (7, 27%), and length of hospital stay (7, 27%). The type of reconstruction varied depending on the stage of the pandemic: early on, autologous breast reconstruction was halted to preserve resources, but was later resumed. Within implant-based reconstruction, direct-toimplant was favored over serial tissue expansion. Several protocols were developed, with many emphasizing multidisciplinary collaborations for patient selection, use of specialized measures to reduce risk of COVID-19 transmission, and optimization of same-day discharge. Complication rates following breast reconstruction were similar to pre-pandemic rates. Conclusions: The COVID-19 pandemic has forever changed the landscape of breast reconstruction by raising important questions about delivery of care, cost, and resource utilization. The findings of this review may inform surgeons as they plan for similar future crises or strive for improved patient care and efficacy even during nonpandemic times.

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Background: Mastectomy flap and nipple–areola complex (NAC) ischemia can be devastating complications after nipple-sparing mastectomy (NSM). Predictors of reconstructive failure with major skin envelope ischemia and implications for decision-making remain to be fully elucidated. Methods: All cases of implant-based reconstruction after NSM from 2006 to June 2018 with mastectomy flap necrosis or NAC necrosis requiring debridement were reviewed. Data on patient demographics, operative characteristics, additional complications, and the nature and management of ischemic complications were collected and analyzed. Results: Out of 1045 NSMs, 70 cases (6.7%) had major ischemic complications. Fifty-two cases (74.3% of major ischemic complications) had isolated major mastectomy flap necrosis, 7 (10%) had full NAC necrosis and 11 (15.7%) had both. Five cases (7.1%) underwent implant exchange at the time of debridement and 15 cases (21.4%) required explantation. Explanted cases had significantly lower body mass index (22.3 versus 24.7, P = 0.013) and larger debridement size (49.5 cm 2 versus 17.6 cm 2 , P = 0.0168). Additionally, explanted cases had a higher rate of acellular dermal matrix/mesh (100% versus 45.5%, P < 0.0001), prior radiation (20.0% versus 0%, P = 0.0083), immediate implants (46.7% versus 20.0%, P = 0.0491), major infection (30.0% versus 1.8%, P = 0.028), and both major mastectomy flap/NAC necrosis (33.3% versus 10.9%, P = 0.0494). Conclusions: NSM cases with major ischemia requiring explantation had a lower body mass index and significantly higher rate of preoperative radiation, immediate implant placement, use of acellular dermal matrix/mesh, and concomitant major infection. These variables should be taken into account when discussing risks with patients preoperatively and assessing the quality of mastectomy flaps and subsequent reconstructive choices intraoperatively.