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Abstract Background We recently developed two Bayesian networks, referred to as the Bayesian-Estimated Tools for Survival (BETS) models, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases (BETS-3 and BETS-12, respectively). In this study, we attempted to externally validate the BETS-3 and BETS-12 models using an independent, international dataset. Methods Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centers between 1999 and 2009. These data were applied to the BETS-3 and BETS-12 models, which generated a probability of survival at 3 and 12 months for each patient. Model robustness was assessed using the area under the receiver-operating characteristic curve (AUC). An analysis of incorrect estimations was also performed. Results Our dataset contained 815 records with adequate follow-up information to establish survival at 12 months. All records were missing data including the surgeon’s estimate of survival, which was previously shown to be a first-degree associate of survival in both models. The AUCs for the BETS-3 and BETS-12 models were 0.79 and 0.76, respectively. Incorrect estimations by both models were more commonly optimistic than pessimistic. Conclusions The BETS-3 and BETS-12 models were successfully validated using an independent dataset containing missing data. These models are the first validated tools for accurately estimating postoperative survival in patients with operable skeletal metastases of the extremities and can provide the surgeon with valuable information to support clinical decisions in this patient population.

Background: Quantifying bone mineral density (BMD) on CT using commercial software demonstrates good-to-excellent correlations with dual-energy x-ray absorptiometry (DEXA) results. However, previous techniques to measure Hounsfield units (HUs) within the proximal femur demonstrate less successful correlation with DEXA results. An effective method of measuring HUs of the proximal femur from CT colonoscopy might allow for opportunistic osteoporosis screening.Questions/purposes: (1) Do proximal femur HU measurements from CT colonoscopy correlate with proximal femur DEXA results? (2) How effective is our single HU measurement technique in estimating the likelihood of overall low BMD? (3) Does the relationship between our comprehensive HU measurement and DEXA results change based on age, sex, or time between studies?Methods: This retrospective study investigated the measurement of HU of the femur obtained on CT colonoscopy studies compared with DEXA results. Between 2010 and 2017, five centers performed 9085 CT colonoscopy studies; of those, 277 (3%) also had available DEXA results and were included in this study, whereas 8809 (97%) were excluded for inadequate CT imaging, lack of DEXA screening, or lack of proximal femur DEXA results. The median number of days between CT colonoscopy and DEXA scan was 595 days; no patient was excluded based on time between scans because bone remodeling is a long-term process and this allowed subgroup analysis based on time between scans. Two reviewers performed HU measurements at four points within the proximal femur on the CT colonoscopy imaging and intraclass correlation coefficients were used to evaluate interrater reliability. We used Pearson correlation coefficients to compare the comprehensive (average of eight measurements) and a single HU measurement with each DEXA result-proximal femur BMD, proximal femur T-score, femoral neck BMD, and femoral neck T-score-to identify the best measurement technique within this study. Based on their lowest DEXA T-score, we stratified patients to a diagnosis of osteoporosis, osteopenia, or normal BMD. We then calculated the area under the receiver operator characteristic curves (AUCs) to evaluate the classification ability of a single HU value to identify possible threshold(s) for detecting low BMD. For each subgroup analysis, we calculated Pearson correlation coefficients between DEXA and HUs and evaluated each subgroup's contribution to the overall predictive model using an interaction test in a linear regression model.Results: The Pearson correlation coefficient between both the comprehensive and single HU measurements was highest compared with the proximal femur T-score at 0.75 (95% confidence interval [CI], 0.69-0.80) and 0.74 (95% CI, 0.68-0.79), respectively. Interobserver reliability, measured with intraclass correlation coefficients, for the comprehensive and single HU measurements was 0.97 (95% CI, 0.72-0.99) and 0.96 (95% CI, 0.89-0.98), respectively. Based on DEXA results, 20 patients were osteoporotic, 167 had osteopenia, and 90 patients had normal BMD. The mean comprehensive HU for patients with osteoporosis was 70 ± 30 HUs; for patients with osteopenia, it was 110 ± 36 HUs; and for patients with normal BMD, it was 158 ± 43 HUs (p < 0.001). The AUC of the single HU model was 0.82 (95% CI, 0.77-0.87). A threshold of 214 HUs is 100% sensitive and 59 HUs is 100% specific to identify low BMD; a threshold of 113 HUs provided 73% sensitivity and 76% specificity. When stratified by decade age groups, each decade age group demonstrated a positive correlation between the comprehensive HU and proximal femur T-score, ranging between 0.71 and 0.83 (95% CI, 0.59-0.91). Further subgroup analysis similarly demonstrated a positive correlation between the comprehensive HU and proximal femur T-score when stratified by > 6 months or < 6 months between CT and DEXA (0.75; 95% CI, 0.62-0.84) as well as when stratified by sex (0.70-0.76; 95% CI, 0.48-0.81). The linear regression model demonstrated that the overall positive correlation coefficient between HUs and the proximal femur T-score is not influenced by any subgroup.Conclusions: Our measurement technique provides a reproducible measurement of HUs within the proximal femur HUs on CT colonoscopy. Hounsfield units of the proximal femur based on this technique can predict low BMD. These CT scans are frequently performed before initial DEXA scans are done and therefore may lead to earlier recognition of low BMD. Future research is needed to validate these results in larger studies and to determine if these results can anticipate future fracture risk.Level Of Evidence: Level III, diagnostic study. [ABSTRACT FROM AUTHOR]

Background: Amputations sustained owing to combat-related blast injuries are at high risk for deep infection and development of heterotopic ossification, which can necessitate reoperation and place immense strain on the patient. Surgeons at our institution began use of intrawound antibiotic powder at the time of closure in an effort to decrease the rate of these surgical complications after initial and revision amputations, supported by compelling clinical evidence and animal models of blast injuries. Antibiotic powder may be useful in reducing the risk of these infections, but human studies on this topic thus far have been inconclusive.Purpose: We sought to determine whether administration of intrawound antibiotic powder at the time of closure would (1) decrease the risk of subsequent deep infections of major lower-extremity combat-related amputations, and (2) limit formation and decrease severity of heterotopic ossification common in the combat-related traumatic residual limb.Methods: Between 2009 and 2015, 252 major lower extremity initial and revision amputations were performed by a single surgeon. Revision cases were excluded if performed specifically to address deep infection, leaving 223 amputations (88.5%) for this retrospective analysis. We reviewed medical records to collect patient information, returns to the operating room for subsequent infection, and microbiologic culture results. We also reviewed radiographs taken at least 3 months after surgery to determine the presence and severity of heterotopic ossification using the Walter Reed classification system. We grouped cases according to whether limbs underwent initial or revision amputations, and whether the limbs had a history of a prior infection. Apart from the use of antibiotic powder and duration of followup, the groups did not differ in terms of age, mechanism of injury, or sex. We then calculated the absolute risk reduction for infection and heterotopic ossification and the number needed to treat to prevent an infection.Results: Overall, administration of antibiotic powder resulted in a 13% absolute risk reduction of deep infection (14 of 82 [17%] versus 42 of 141 [30%]; p = 0.03; 95% CI, 0.20%-24.72%). In revision amputation surgery, the absolute risk reduction of infection with antibiotic powder use was 16% overall (eight of 58 versus 17 of 57; 95% CI, 1.21%-30.86%), and 25% for previously infected limbs (eight of 46 versus 14 of 33; 95% CI, 4.93%-45.14%). The number needed to treat to prevent one additional deep infection in amputation surgery is eight in initial amputations, seven in revision amputations, and four for revision amputation surgery on previously infected limbs. With the numbers available, we observed no reduction in the risk of heterotopic ossification with antibiotic powder use, but severity was decreased in the treatment group in terms of the number of residual limbs with moderate or severe heterotopic ossification (three of 12 versus 19 of 34; p = 0.03).Conclusions: Our findings show that administration of intrawound antibiotic powder reduces deep infection in residual limbs of combat amputees, particularly in the setting of revision amputation surgery in apparently aseptic residual limbs at the time of the surgery. Furthermore, administration of antibiotic powder for amputations at time of initial closure decreases the severity of heterotopic ossification formation, providing a low-cost adjunct to decrease the risk of two complications common to amputation surgery.Level of Evidence Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

Introduction: Invasive fungal infections (IFI) are associated with high morbidity and mortality. A better method of risk stratifying trauma patients for combat-related IFI is needed to improve clinical outcomes while minimizing morbidity related to overtreatment. We sought to develop combat-related IFI clinical decision support (CDS) tools to assist providers to make treatment decisions both near the point of injury and subsequently at definitive treatment centers.Materials and Methods: We utilized a training dataset containing information from 227 combat-injured military personnel to build a Bayesian belief network (BBN) to predict the likelihood of developing IFI using information available at the point of initial resuscitation (THEATER model) and in the tertiary care setting (MEDCEN model). After selecting BBN models, external validation used a separate test dataset of 350 wounded warriors. Furthermore, the performance of the BBN models was compared with a "two-rule model" alone (based on physician experience) and combinations of the BBN models plus the two-rule model. The two-rule model contains plausible IFI criteria, but it has not been formally evaluated, and they are not currently actual clinical guidelines.Results: We found receiver operating characteristic areas under the curve (AUC) of 0.70 (95% CI: [0.62, 0.77]) and 0.68 (95% CI: [0.59, 0.76]) for the THEATER and MEDCEN BBN models, respectively, on cross-validation. External validation with the highest AUC BBN models produced THEATER AUC of 0.68 (95% CI: [0.58, 0.78]) and MEDCEN AUC of 0.67 (95% CI: [0.57, 0.78]). With the incorporation of two-rule model in low IFI-prevalence populations, external validation AUC increased to 0.77 (95% CI: [0.69, 0.84]) for the THEATER model and 0.76 (95% CI:[0.68, 0.85]) for the LRMC model. The two-rule model alone has an AUC of 0.72 (95% CI: [0.63, 0.81]).Conclusions: Overall, the IFI tools produced clinically useful, robust models. However, the clinical utility of these models is highly dependent upon the clinician's individual risk tolerance. The threshold probability for optimal clinical use of this CDS tool is currently being evaluated in an ongoing clinical utilization study. CDS tools, such as these, may facilitate early diagnosis of patients with or at risk for IFI, permitting early or prophylactic treatment with the aim of improving outcomes. [ABSTRACT FROM AUTHOR]

ABSTRACT: Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high‐energy penetrating injuries and blast‐related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast‐related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL‐6 (p = 0.01), TNF‐α (p = 0.001), and IFN‐γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post‐operative day (POD)‐7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP‐O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo‐ and chondrogenic genes by POD‐7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD‐1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter‐related mechanisms including anti‐inflammatory, anti‐proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135–1144, 2018. [ABSTRACT FROM AUTHOR]