What is the significance of the extensive variability observed in individual members of a single-cell phenotype? This question is particularly relevant to the highly differentiated organization of the brain. In this study, for the first time, we analyze the in vivo variability within a neuronal phenotype in terms of input type. We developed a large-scale geneexpression data set from several hundred single brainstem neurons selected on the basis of their specific synaptic input types. The results show a surprising organizational structure in which neuronal variability aligned with input type along a continuum of sub-phenotypes and corresponding gene regulatory modules. Correlations between these regulatory modules and specific cellular states were stratified by synaptic input type. Moreover, we found that the phenotype gradient and correlated regulatory modules were maintained across subjects. As these specific cellular states are a function of the inputs received, the stability of these states represents ''attractor''-like states along a dynamic landscape that is influenced and shaped by inputs, enabling distinct state-dependent functional responses. We interpret the phenotype gradient as arising from analog tuning of underlying regulatory networks driven by distinct inputs to individual cells. Our results change the way we understand how a phenotypic population supports robust biological function by integrating the environmental experience of individual cells. Our results provide an explanation of the functional significance of the pervasive variability observed within a cell type and are broadly applicable to understanding the relationship between cellular input history and cell phenotype within all tissues.

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Background Avascular necrosis is a delayed complication of proximal humerus fractures that increases the likelihood of poor clinical outcomes. CT scans are routinely performed to guide proximal humerus fracture management. We hypothesized iodine concentration on post-contrast dual energy CT scans identifies subjects who develop avascular necrosis and ischemia due to compromised blood flow. Materials and methods 55 patients with proximal humerus fractures enrolled between 2014 and 2017 underwent clinical, radiographic and contrast enhanced dual energy CT assessment. Iodine densities of the humeral head and the glenoid (control) were measured on CT. Subjects managed with open reduction internal fixation or conservatively (non-surgical) were followed for up to two years for radiographic evidence of avascular necrosis. Arthroplasty subjects underwent histopathologic evaluation for ischemia of the resected humeral head. Results 17 of 55 subjects (30.9%) were treated conservatively, 21 (38.2%) underwent open reduction internal fixation and 17 of 55 (30.9%) underwent arthroplasty. Of the 38 subjects treated conservatively or with ORIF, 20 (52.6%) completed 12 months of follow up and 14 (36.8%) 24 months of follow up. At 12 months follow up, two of 20 subjects (10%) and at 24 months 3 of 14 subjects (21.4%) developed avascular necrosis. At 12 months, the mean humerus/glenoid iodine ratio was 1.05 (standard deviation 0.24) in subjects with AVN compared to 0.91 (0.24) in those who did not. At 24 months, subjects with avascular necrosis had a mean humerus/glenoid iodine concentration ratio of 1.06 (0.17) compared to 0.924 (0.21) in those who did not. Of 17 arthroplasty subjects, 2 had severe ischemia and an iodine ratio of 1.08 (0.30); 5 had focal ischemia and a ratio of 1.00 (0.36); and 8 no ischemia and a ratio of 0.83 (0.08). Conclusions Quantifying iodine using dual energy CT in subjects with proximal humerus fractures is technically feasible. Preliminary data suggest higher humeral head iodine concentration may increase risk of avascular necrosis; however, future studies must enroll and follow enough subjects managed with open reduction internal fixation or conservatively for two or more years to provide statistically significant results. Trial Registrations NCT02170545 registered June 23, 2014, ClinicalTrials.gov.

Pelvic soft tissue sarcomas are rare tumors often presenting larger than other soft tissue sarcomas and can extend into the thigh through various anatomic routes. Surgical resection is the main modality of curative treatment. En bloc tumor excision with wide, negative margins may reduce the risk of local recurrence. Soft tissue sarcomas extending through the obturator foramen create unique challenges to operative management. This case report describes 2 cases of lipomatous lesions that extend through the obturator foramen, presenting as dumbbell-shaped lesions with large intra- and extrapelvis portions. One possible surgical approach performed in both patients is detailed with long-term follow-up. Postoperatively, 1 incidence of infection was reported. Functional outcomes were acceptable, with full restoration of ambulation without assistive devices in both cases and no hernia observed. Oncologic outcomes included locoregional recurrence in 1 patient at 24 months outside the radiation field. The ideal primary treatment for all localized soft tissue sarcomas, including those extending through the obturator foramen, is resection. However, the unique subgroup of obturator ring soft tissue sarcomas has undefined outcomes and complications. The authors' goal was to achieve en bloc resection with wide negative margins while preserving ipsilateral limb function. The surgical approach described in this case study offers a description of feasibility and discussion of theoretical and observed complications.

Background Salvage reverse shoulder arthroplasty (RSA) for failed proximal humerus fractures (PHFs) fixation and hemiarthroplasty (HA) may maximize outcomes in the absence of tuberosity healing or a chronically torn rotator cuff. The purpose of this systematic review was to examine the improvement in clinical outcomes for patients after revision RSA was performed for failed PHFs fixation or HA. Methods An electronic database search of SCOPUS, PubMed, Embase, MEDLINE, SPORTDiscus, CINAHL, and ClinicalTrials.gov was performed. A meta-analysis was carried out to determine weighted mean outcome differences between two primary intervention cohorts (failed fixation: open reduction and internal fixation, intramedullary nail, or K-wire vs. failed HA). Results Fifteen studies were included (primary fixation: 208 patients; HA: 162 patients). Patients improved meaningfully in all clinical outcomes after revision surgery (constant: 18.5–48.3; abduction: 44–95; forward flexion: 47–107; external rotation: 5–10), with a 16.2% complication and 9.4% revision rate. The failed fixation group performed significantly better than the failed HA group in postoperative constant (fixation: 53.3 vs. HA: 45.1, p = 0.016) and shoulder abduction (fixation: 102 vs. HA: 87, p = 0.026). Conclusions RSA is a successful revision intervention for primary PHF operative failures with the greatest benefit for failures of primary fixation versus HA.