What's luck got to do with it? A generative model for examining the role of stochasticity in age-at-death, with implications for bioarchaeology.

INTRODUCTION: The role of "luck" in determining individual exposure to health insults is a critical component of the processes that shape age-at-death distributions in mortality samples but is difficult to address using traditional bioarcheological analysis of skeletal materials. The present study introduces a computer simulation approach to modeling stochasticity's contribution to the mortality schedule of a simulated cohort. METHODS: The present study employs an agent-based model of 15,100 individuals across a 120 year period to examine the predictive value of birth frailty on age-at-death when varying the likelihood of exposure to health insults. RESULTS: Birth frailty, when accounting for varying exposure likelihood scenarios, was found to account for 18.7% of the observed variation in individual age-at-death. Analysis stratified by exposure likelihood demonstrated that birth frailty alone explains 10.2%-12.1% of the variation observed across exposure likelihood scenarios, with the stochasticity associated with exposure to health insults (i.e., severity of health insult) and mortality likelihood driving the majority of variation observed. CONCLUSIONS: Stochasticity of stressor exposure and intrinsic stressor severity are underappreciated but powerful drivers of mortality in this simulation. This study demonstrates the potential value of simulation modeling for bioarchaeological research.

Delayed skin grafting protocol following Integra™ application for non-radiated scalp reconstruction for decreased wound depth and improved contour.

The clinical use of Integra™ has expanded to include scalp reconstruction since its FDA approval in 1996. Integra™, or dermal regeneration template, can be utilized in patients who are elderly with multiple medical comorbidities. Well-established Integra™ techniques utilize skin grafting 1-2 weeks following evidence of template vascularity. Most studies show the time to graft placement as <30 days, with almost all <52 days. No single article proposes a time frame for applying STSG after neodermis regeneration. Therefore, we aimed to describe our protocol to define a time frame for delaying scalp reconstruction with STSG following dermal regeneration. Over the last several years, the senior author has utilized a delayed reconstruction with skin grafting method where-in Integra™ is applied to either debrided bone or exposed pericranium in selected patients, and allowed to mature for ~6 weeks before performing skin grafting. The results have been predictable, reproducible, and have yielded high levels of patient and provider satisfaction due to the improved contour cosmesis. In this pictorial essay, the authors' novel protocol is detailed.

Assessing the association of skeletal indicators of stress with mean age-at-death in sub-adults.

OBJECTIVES: The present study investigated the association of skeletal indicator of stress presence with mean age-at-death as a means of understanding whether commonly studied indicators are indeed indicative of increased frailty. MATERIALS AND METHODS: Using a medieval Gaelic population from Ballyhanna (Co. Donegal), the present study assessed the association between skeletal indicators of stress and mean age-at-death using the Kaplan-Meier survival function with log rank test to determine whether these indicators were associated with younger age-at-death, and therefore increased frailty, in sub-adults only (0 to 18 years, N = 139) and through comparison to an all-ages cohort (N = 318). RESULTS: Only linear enamel hypoplasia was found to be associated with significantly decreased survivorship across the all-ages cohort but, conversely, was associated with increased survivorship when analysis was restricted to sub-adults. All other indicators assessed were associated with increased age-at-death for both all-age cohorts and sub-adult cohorts (cribra orbitalia), increased age-at-death when assessing all ages only (porotic hyperostosis and healed periosteal lesions); or were sufficiently rare in adults to prevent comparative analysis (stunting and micronutrient deficiency). Increased survivorship in individuals with higher numbers of co-morbid skeletal indicators was observed for both sub-adults alone and all age cohort. DISCUSSION: These findings suggest that these commonly recorded skeletal indicators may be more accurately viewed simply as records of stressor exposure and subsequent survival only, rather than providing evidence that these sub-adults are frailer than their similarly aged-at-death peers. Thus, the demographic and sociocultural context is essential to the interpretation of observed skeletal indicators of stress.

Impact of Perioperative Dexamethasone on Hospital Length of Stay and Glycemic Control in Patients With Type 2 Diabetes Undergoing Total Hip Arthroplasty.

Purpose: This study aimed to evaluate effects of perioperative dexamethasone on hospital length of stay (LOS) and glycemic control for patients with type 2 diabetes mellitus undergoing total hip arthroplasty (THA). Methods: We performed retrospective case review of THA performed in adults (≥18 years old) with type 2 diabetes at Springfield Memorial Hospital (Springfield, IL) immediately before (2013), during (2014), and after (2015) publication of consensus guidelines for use of perioperative dexamethasone. Hospital LOS was the primary endpoint. Capillary blood glucose by hospital day, proportion of patients treated with insulin, and median insulin dose by hospital day were secondary endpoints. Results: A total of 209 patients were included: 109 not dosed with dexamethasone ("no dexamethasone"), and 100 treated with perioperative dexamethasone. The most common dose of dexamethasone was 4 mg (63% of patients). Mean (95% CI) reduction in adjusted hospital LOS for dexamethasone-treated patients, compared to controls, was -2.8 (-3.7 to -1.9) days for all patients, -1.6 (-2.7 to -0.5) days for those with arthritis as the indication for THA, and -4.0 (-5.9 to -2.1) days for those with fracture as indication for THA (P<0.001 for all). Glycemic control measured by median capillary blood glucose was no different or slightly better in the dexamethasone group than the no dexamethasone group, except for postoperative day 1 among patients treated with insulin prior to surgery. Conclusions: Perioperative dexamethasone significantly reduces hospital LOS for patients with type 2 diabetes undergoing THA, with modest effects on hyperglycemia.

Long segment spinal reconstruction of C3-T1 utilizing single strut fibula free flap following debridement and corpectomy for chronic osteomyelitis.

Cervical vertebral osteomyelitis (CVO) is a complex destructive pathology that presents as a significant challenge to reconstructive surgeons. Advanced cases of CVO involving neurologic deficits, spinal column instability, or refractory infection require surgical intervention with bony debridement and decompression followed by spinal reconstruction, realignment, and stabilization. Reconstruction of the spine is typically performed through an anterior approach with or without posterior instrumentation. Restoration of the anterior spinal column can be performed with titanium or PEEK cages, allograft bone or vascularized autograft bone. Anterior spine reconstruction using vascularized osseous free flaps has been well documented in the medical literature; however, to our knowledge, we report the largest osteomyelitic anterior cervical spine defect that has been reconstructed using a single strut osseous free flap. This was a complex case of cervical osteomyelitis in a patient with prior C4-C7 anterior cervical corpectomy and fusion who presented with instrumentation failure and septicemia. Anterior column reconstruction required a vascularized fibular strut spanning six vertebral levels from C3-T1, as well as a trapezius myocutaneous pedicled flap for posterior soft tissue coverage.

Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4.

The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416-26. ©2016 AACR.

Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis.

The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tumors, presenting opportunities for the study of combinatorial therapies.

An integrative view on sex differences in brain tumors.

Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations.

CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma.

Medulloblastoma prognosis tends to be poor, despite aggressive therapy, but defining molecular subgroups may identify patients who could benefit from targeted therapies. This study used human gene array and associated clinical data to identify a new molecular subgroup of medulloblastoma characterized by coactivation of the Sonic hedgehog (SHH) and CXCR4 pathways. SHH-CXCR4 tumors were more common in the youngest patients where they were associated with desmoplastic histology. In contrast to tumors activating SHH but not CXCR4, coactivated tumors exhibited greater expression of Math1 and cyclin D1. Treatment with the CXCR4 antagonist AMD3100 inhibited cyclin D1 expression and maximal tumor growth in vivo. Mechanistic investigations revealed that SHH activation stimulated CXCR4 cell surface localization and effector signaling activity, whereas SHH absence caused CXCR4 to assume an intracellular localization. Taken together, our findings define a new medulloblastoma subgroup characterized by a functional interaction between the SHH and CXCR4 pathways, and they provide a rationale to clinically evaluate combined inhibition of SHH and CXCR4 for medulloblastoma treatment.