The Management of Tibial Bone Defects: A Multicenter Experience of Hexapod and Ilizarov Frames.

INTRODUCTION: Bone defects may be managed with bone transport or acute shortening and lengthening using circular external fixation devices. We performed a multicenter retrospective cohort study to compare the outcomes between the Ilizarov frames and hexapod frames for the management of bone defects. METHODS: Patients treated for bone defects using either Ilizarov or hexapod frames were included for analysis in two specialist institutions. Primary outcomes were time to consolidation, bone healing index (BHI), and external fixator index (EFI). Radiographic parameters included the medial proximal tibial angle, lateral distal tibial angle, posterior proximal tibial angle, and anterior distal tibial angle. RESULTS: There were 137 hexapods and 90 Ilizarov frames in total. The mean time to follow-up was 3.7 years in the hexapod group and 4.0 years in the Ilizarov group. Hexapods had a significantly lower time to consolidation (253 days versus 449 days) (P < 0.0001) and BHI (59.1 days/cm versus 87.5 days/cm) (P < 0.0001). Hexapods had a significantly better EFI (72.3 days/cm versus 96.1 days/cm) (P = 0.0009). CONCLUSION: Hexapods may confer a significant advantage over Ilizarov frames in the management of bone defects. Time to consolidation, radiographic parameters, BHI, and EFI are all superior in hexapods.

Krackow Suture Technique Effect on Patella Tendon Vascularity: Quantitative MRI Analysis.

OBJECTIVES: To assess the effects of Krackow suture technique on the vascularity of the patellar tendon. METHODS: Six fresh-frozen matched pair cadaveric knee specimens were used. The superficial femoral arteries were cannulated in all knees. The experimental knee underwent an anterior approach, patellar tendon transection from the inferior pole of the patella, 4-strand Krackow stitch placement, patellar tendon repair via 3-bone tunnels, and standard skin closure. The control knee underwent the identical procedure without Krackow stitching. All specimens then underwent precontrast and postcontrast enhanced quantitative magnetic resonance imaging assessment (with gadolinium-based contrast agent). Region of interest analysis was performed to assess for variation in signal enhancement between the experimental and control limbs in various patellar tendon regions and subregions. Latex infusion and anatomical dissection were performed to further evaluate vessel integrity and assess extrinsic vascularity. RESULTS: Quantitative magnetic resonance imaging analysis demonstrated no statistically significant difference in overall arterial contributions. A small but nonsignificant decrease of 7.5% (SD ± 7.1%) in arterial contributions to the entire tendon was observed. Small nonstatistically significant regional decreases throughout the tendon were also detected. In the regional analysis, the largest to smallest decreases in arterial contributions after suture placement were found in the inferomedial, superolateral, lateral, and inferior tendon subregions. In the anatomical dissection, nutrient branches were seen dorsally and posteroinferiorly. CONCLUSION: The vascularity of the patellar tendon was not significantly affected by Krackow suture placement. Analysis demonstrated small and not statistically significant decreases in arterial contributions, suggesting this technique does not significantly compromise arterial perfusion.

Modern Internet Search Analytics and Osseointegration: What are Patients Asking and Reading Online?

Background: Osseointegration (OI) limb has been performed for over 30 years and is an example of an advance in technology and surgical technique which has led to improvements in patient mobility and quality of life. An increasing number of patients seek information about osseointegration. The aim of this study was to categorise the most frequently asked questions by patients using the Google search engine and the most frequently accessed websites with the highest return on answers. The secondary aims of this study were to assess the quality of the information provided on those websites and to stratify, by category, which websites provide the best quality information. Materials and methods: Ten permutations and conjugations of the word 'osseointegration' were entered into Google. The first fifty 'People also ask' and associated websites by Google's machine learning and natural language processing engine were collected for each search term. The Rothwell classification system of questions by topic (Fact, Value, Policy) and websites by category was used (Commercial, Academic, Medical Practice, Single Surgeon Personal, Government, Social Media). Website quality was assessed using the Journal of the American Medical Association (JAMA) benchmark criteria (Likert-style rating 0-4). Pearson's Chi-squared and Student's t-tests were performed for statistical analysis as appropriate (significance, p < 0.05). Results: The 10 search terms generated 454 questions and referenced 408 websites. Of the 454 questions generated, the most common question categories were fact (70.8%), value (19.2%), and policy (10%). The most common website type was social media (37.4%). The most common question types were technical details (30.4%), specific activity (20.6%), and cost (14.1%). Only 1.6% of questions related to risks and complications. Generally, website quality was poor with 64.1% having a JAMA score of 0 or 1. Websites that were categorised as 'Government' had the highest overall JAMA scores: 71.4% had a score of 4. Conclusion: Based on Google search engine's results, the most commonly asked questions about osteointegration related to technical details, specific activities and cost; only 1.6% related to risks and complications. Interestingly, social media websites represented the highest volume of search result referrals. Overall, the quality of websites was poor with the most factual information coming from governmental websites. How to cite this article: Murphy EP, Sheridan GA, Page BJ, et al. Modern Internet Search Analytics and Osseointegration: What Are Patients Asking and Reading Online? Strategies Trauma Limb Reconstr 2023;18(3):163-168.

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs. METHODS: We retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors. RESULTS: Among patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes. CONCLUSIONS: Routine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

Clinical Considerations to Reduce Saphenous Neurovascular Bundle Injury During Suture Button Fixation of Syndesmosis Injuries.

OBJECTIVE: To document angles, from 2 difference starting points, or danger zones that should be avoided to minimize risk of injury or irritation to the saphenous neurovascular bundle (SNVB) during suture button (SB) fixation for distal tibiofibular syndesmosis injuries. DESIGN: Retrospective imaging study. SETTING: Academic Level 1 trauma center. PATIENTS: Forty-eight randomly selected patients with healthy ankles and computed tomography scans for nonankle diagnoses. MAIN OUTCOME MEASURES: Computed tomography scans and 3D reconstructed images were used to define the angle between the SNVB and 2 different fibular starting points, using the direct lateral (DL) and the posterolateral (PL) starting points. Descriptive analyses were performed to identify angles that should be avoided during suture button fixation. Distances from the SNVB using preset angles of 0, 10, 20, and 30 degrees were analyzed. In addition, the width of the SNVB, the midsubstance angle of the SNVB, and the distance from the 30-degree point to the tibialis anterior were recorded. RESULTS: The mean angle between the SNVB and the standard DL starting point was 13.7 ± 5.0 degrees (P < 0.05), whereas the mean angle using the alternate PL starting point was 17.2 ± 5.3 degrees (P < 0.05). The SNVB width was 5.2 mm [range, 2.6-9.1 mm] (P < 0.05). The distances from the SNVB were greatest for the DL 30-degree group and the PL 0-degree group. CONCLUSIONS: The results document angles that should be avoided when using suture button fixation for syndesmosis injuries. Device characteristics and surgery-related variables may require intraoperative modifications, and knowledge of this anatomical relationship may reduce SNVB injury during those situations. Considering our results, we recommend that surgeons place suture buttons from the DL starting point with a 30-degree trajectory to avoid injuries to the SNVB.

Clinical Outcomes after Transcatheter Aortic Valve Replacement in Cancer Survivors Treated with Ionizing Radiation.

BACKGROUND: Improved cancer survival in patients treated with thoracic ionizing radiation (XRT) has resulted in unanticipated surge of aortic stenosis. Transcatheter aortic valve replacement (TAVR) has revolutionized the management of severe aortic stenosis. However, long-term clinical outcomes in radiation-exposed cohorts undergoing TAVR are unknown. We compared the all-cause mortality and major adverse cardiac events (MACE) in patients with prior chest XRT (C-XRT) undergoing TAVR. METHODS: This is an observational cohort study in subjects who underwent TAVR for symptomatic severe aortic stenosis from 2012 to 2017 in a tertiary care referral center. We examined the all-cause mortality and MACE using cox proportional hazard analysis to identify the clinical predictors of survival in the cohort of patients who had a history of prior C-XRT for malignancy. RESULTS: Of the 610 patients who underwent TAVR for symptomatic severe aortic stenosis, 75 had prior C-XRT. The majority of C-XRT patients had prior breast cancer (44%) followed by Hodgkin's lymphoma (31%), with the median time from XRT to TAVR of 19.0 years. During a mean follow up of 17.1 months after TAVR, all-cause mortality was 17%. Those with prior C-XRT had higher all-cause mortality (XRT: 29%; non-XRT:15%, p<0.01) and MACE (XRT: 57%; non-XRT: 27%, p<0.001) after TAVR. Patients with prior XRT had a higher incidence of atrial fibrillation (XRT: 48 %; non-XRT: 2.4%, p<0.01) and high-grade heart block (XRT: 20%; non-XRT: 9.1%, p=0.007) requiring pacemaker implant after TAVR. On multivariate cox proportional hazard analysis, prior XRT (HR: 2.07, p=0.003), poor renal function (HR: 1.29, p<0.001) and post-operative anemia requiring transfusion (HR: 1.16, p:0.001) were the strongest predictors of reduced survival. CONCLUSIONS: Cancer survivors with prior C- XRT have higher incidence of all-cause mortality and MACE after TAVR. Careful patient selection and follow-up strategies are needed to improve outcomes.

A novel method of acromioclavicular joint separation fixation using a knotless dog bone technique.

Acromioclavicular (AC) joint separations are common in both sports and trauma injuries. Many surgical options exist for fixation of these injuries. Although the suture button has become popular, it has a moderately high complication rate. The most common complication is the loss of reduction, but another common complication is knot-related pain. This article outlines a method of suture button fixation that addresses both of these complications with a novel knotless construct using TightRopes.

Revascularization of chronic hibernating myocardium stimulates myocyte proliferation and partially reverses chronic adaptations to ischemia.

BACKGROUND: The time course and extent of recovery after revascularization of viable dysfunctional myocardium are variable. Although fibrosis is a major determinant, myocyte structural and molecular remodeling may also play important roles. OBJECTIVES: This study sought to determine whether persistent myocyte loss and/or irreversibility of protein changes that develop in hibernating myocardium have an impact on functional recovery in the absence of infarction. METHODS: Swine implanted with a chronic left anterior descending artery (LAD) stenosis to produce hibernating myocardium underwent percutaneous revascularization, with serial functional recovery evaluated for 1 month (n = 12). Myocardial tissue was evaluated to assess myocyte size, nuclear density, and proliferation indexes in comparison with those of normal animals and nonrevascularized controls. Proteomic analysis by 2-dimensional differential in-gel electrophoresis was used to determine the reversibility of molecular adaptations of hibernating myocytes. RESULTS: At 3 months, physiological features of hibernating myocardium were confirmed, with depressed LAD wall thickening and no significant infarction. Revascularization normalized LAD flow reserve, with no immediate change in LAD wall thickening. Regional LAD wall thickening slowly improved but remained depressed 1 month post-percutaneous coronary intervention. Surprisingly, revascularization was associated with histological evidence of myocytes re-entering the growth phase of the cell cycle and increases in the number of c-Kit(+) cells. Myocyte nuclear density returned to normal, whereas regional myocyte hypertrophy regressed. Proteomic analysis demonstrated heterogeneous effects of revascularization. Up-regulated stress and cytoskeletal proteins normalized, whereas reduced contractile and metabolic proteins persisted. CONCLUSIONS: Delayed recovery of hibernating myocardium in the absence of scar may reflect persistent reductions in the amounts of contractile and metabolic proteins. Although revascularization appeared to stimulate myocyte proliferation, the persistence of small immature myocytes may have contributed to delayed functional recovery.

Coronary Subclavian Steal Syndrome: An Unusual Cause of Angina in a Post-CABG Patient.

Coronary subclavian steal syndrome is a rare complication of coronary artery bypass grafting surgery (CABG) when a left internal mammary artery (LIMA) graft is utilized. This syndrome is characterized by retrograde flow from the LIMA to the left subclavian artery (SA) when a proximal left SA stenosis is present. We describe a unique case of an elderly male who underwent CABG 6 years ago who presented with prolonged chest pain, mildly elevated troponins, and unequal pulses in his arms. A CTA of the chest demonstrated a severely calcified occluded proximal left SA jeopardizing his LIMA graft. Subclavian angiography was performed with an attempt to revascularize the patient's occluded left SA which was unsuccessful. We referred the patient for nuclear stress testing which demonstrated a moderate size area of anterior ischemia on imaging; the patient exercised to a fair exercise capacity of 7 METS with no chest pain and no ECG changes. Subsequent coronary angiography showed severe native three-vessel coronary artery disease with intermittent retrograde blood flow from the LIMA to the left SA distal to the occlusion, jeopardizing perfusion to the left anterior descending (LAD) coronary artery distribution. He declined further options for revascularization and was discharged with medical management.

Reproducible ion-current-based approach for 24-plex comparison of the tissue proteomes of hibernating versus normal myocardium in swine models.

Hibernating myocardium is an adaptive response to repetitive myocardial ischemia that is clinically common, but the mechanism of adaptation is poorly understood. Here we compared the proteomes of hibernating versus normal myocardium in a porcine model with 24 biological replicates. Using the ion-current-based proteomic strategy optimized in this study to expand upon previous proteomic work, we identified differentially expressed proteins in new molecular pathways of cardiovascular interest. The methodological strategy includes efficient extraction with detergent cocktail; precipitation/digestion procedure with high, quantitative peptide recovery; reproducible nano-LC/MS analysis on a long, heated column packed with small particles; and quantification based on ion-current peak areas. Under the optimized conditions, high efficiency and reproducibility were achieved for each step, which enabled a reliable comparison of 24 the myocardial samples. To achieve confident discovery of differentially regulated proteins in hibernating myocardium, we used highly stringent criteria to define "quantifiable proteins". These included the filtering criteria of low peptide FDR and S/N > 10 for peptide ion currents, and each protein was quantified independently from ≥2 distinct peptides. For a broad methodological validation, the quantitative results were compared with a parallel, well-validated 2D-DIGE analysis of the same model. Excellent agreement between the two orthogonal methods was observed (R = 0.74), and the ion-current-based method quantified almost one order of magnitude more proteins. In hibernating myocardium, 225 significantly altered proteins were discovered with a low false-discovery rate (∼3%). These proteins are involved in biological processes including metabolism, apoptosis, stress response, contraction, cytoskeleton, transcription, and translation. This provides compelling evidence that hibernating myocardium adapts to chronic ischemia. The major metabolic mechanisms include a down-regulation of mitochondrial respiration and an increase in glycolysis. Meanwhile, cardioprotective and cytoskeletal proteins are increased, while cardiomyocyte contractile proteins are reduced. These intrinsic adaptations to regional ischemia maintain long-term cardiomyocyte viability at the expense of contractile function.

The physiological significance of a coronary stenosis differentially affects contractility and mitochondrial function in viable chronically dysfunctional myocardium.

The reversibility of viable dysfunctional myocardium after revascularization is variable and the reasons for this are unknown. Using 2D-DIGE, we tested the hypothesis that this could reflect the extent of molecular remodeling of myocardial tissue in the absence of infarction. Swine with a progressive left anterior descending (LAD) stenosis were studied 2 months (n = 18) or 3 months (n = 22) post-instrumentation. Coronary flow reserve (vasodilated/rest) was severely reduced at 2 months (LAD 2.6 ± 0.4 versus 5.1 ± 0.4 in normal, p < 0.05) and became critically impaired after 3 months (LAD 1.1 ± 0.2, p < 0.05 vs. 2 months). Despite progression in stenosis severity, reductions in wall thickening at 2 months (LAD 37 ± 4% vs. remote 86 ± 9%, p < 0.05) were unchanged at 3 months (LAD 32 ± 3%, p = ns). Contractile dysfunction was primarily related to reductions (LAD/normal) in contractile proteins which were not affected by stenosis severity (e.g., troponin T, 2 months 0.82 ± 0.03 vs. 0.74 ± 0.03 at 3 months, p-ns). In contrast, mitochondrial function and proteins were normal at 2 months but declined with progression to a critical stenosis (state 3 respiration at 3 months 145 ± 13 vs. 216 ± 5 ng-atoms O2 mg(-1) min(-1) at 2 months, p < 0.05). In a similar fashion, increases in stress (e.g., αB-crystalline 2.13 ± 0.2 vs. 1.17 ± 0.13 at 2 months, p < 0.05) and cytoskeletal proteins (e.g., desmin 1.63 ± 0.12 vs. 1.24 ± 0.10 at 2 months, p < 0.05) only developed with more advanced remodeling from a critical stenosis. We conclude that similar degrees of chronic contractile dysfunction can have diverse intrinsic molecular adaptations to ischemia. This spectrum of adaptations may underlie variability in the time course and extent of reversibility in viable chronically dysfunctional myocardium after revascularization.

Combinatorial peptide ligand library treatment followed by a dual-enzyme, dual-activation approach on a nanoflow liquid chromatography/orbitrap/electron transfer dissociation system for comprehensive analysis of swine plasma proteome.

The plasma proteome holds enormous clinical potential, yet an in-depth analysis of the plasma proteome remains a daunting challenge due to its high complexity and the extremely wide dynamic range in protein concentrations. Furthermore, existing antibody-based approaches for depleting high-abundance proteins are not adaptable to the analysis of the animal plasma proteome, which is often essential for experimental pathology/pharmacology. Here we describe a highly comprehensive method for the investigation of the animal plasma proteome which employs an optimized combinatorial peptide ligand library (CPLL) treatment to reduce the protein concentration dynamic range and a dual-enzyme, dual-activation strategy to achieve high proteomic coverage. The CPLL treatment enriched the lower abundance proteins by >100-fold when the samples were loaded in moderately denaturing conditions with multiple loading-washing cycles. The native and the CPLL-treated plasma were digested in parallel by two enzymes (trypsin and GluC) carrying orthogonal specificities. By performing this differential proteolysis, the proteome coverage is improved where peptides produced by only one enzyme are poorly detectable. Digests were fractionated with high-resolution strong cation exchange chromatography and then resolved on a long, heated nano liquid chromatography column. MS analysis was performed on a linear triple quadrupole/orbitrap with two complementary activation methods (collisionally induced dissociation (CID) and electron transfer dissociation). We applied this optimized strategy to investigate the plasma proteome from swine, a prominent animal model for cardiovascular diseases (CVDs). This large-scale analysis results in identification of a total of 3421 unique proteins, spanning a concentration range of 9-10 orders of magnitude. The proteins were identified under a set of commonly accepted criteria, including a precursor mass error of <15 ppm, Xcorr cutoffs, and ≥2 unique peptides at a peptide probability of ≥95% and a protein probability of ≥99%, and the peptide false-positive rate of the data set was 1.8% as estimated by searching the reversed database. CPLL treatment resulted in 55% more identified proteins over those from native plasma; moreover, compared with using only trypsin and CID, the dual-enzyme/activation approach enabled the identification of 2.6-fold more proteins and substantially higher sequence coverage for most individual proteins. Further analysis revealed 657 proteins as significantly associated with CVDs (p < 0.05), which constitute five CVD-related pathways. This study represents the first in-depth investigation of a nonhuman plasma proteome, and the strategy developed here is adaptable to the comprehensive analysis of other highly complex proteomes.

The role of revascularization versus medical therapy in patients with type 2 diabetes mellitus and coronary artery disease.

Patients with type 2 diabetes mellitus (T2DM) are at increased risk for cardiovascular clinical events, adverse nonfatal outcomes, and death. There has been considerable improvement in the medical management of patients with T2DM in an attempt to alter the metabolic cascade that is triggered by insulin resistance. Recent trials have demonstrated that medical management of patients with diabetes mellitus and stable coronary artery disease (CAD) is equivalent to revascularization in terms of morality benefit and rates of major adverse cardiovascular events, particularly in patients who do not have extensive CAD. Nonetheless, in those diabetic patients with additional high-risk features including left main disease, reduced left ventricular ejection fraction (LVEF), severe ischemia, or acute coronary syndrome, revascularization remains the best treatment option. Although the evidence still supports coronary artery bypass grafting (CABG) as the standard of care for revascularization of diabetic patients with multivessel CAD and/or reduced LVEF, percutaneous coronary intervention (PCI) with drug-eluting stents (DES) has resulted in at least partial closure of the gap in benefit between surgery and catheter-based intervention. Ongoing trials of diabetic patients with CAD randomized to PCI or CABG will help further elucidate the role of PCI with DES as a potential revascularization option for this patient population.

Medical therapy in acute coronary syndromes: which medicines and at what doses?

Acute coronary syndrome (ACS) occurs when plaque rupture in a coronary artery is superimposed with thrombus formation. This accounts for 1.7 million hospital admissions in the United States annually and significant morbidity and mortality. Although there are advantages to an invasive approach to treating patients with ACS, the role of medical therapy is vital as an adjunctive treatment to reperfusion therapies and in stabilizing ruptured plaques and modifying the metabolic milieu that predisposes to plaque formation and rupture. This article reviews the most important drug classes for medical treatment of ACS patients, as well as optimal doses. This is an exciting time to be involved in the field of cardiovascular medicine, as we continue to see profound improvement from medical therapy in the morbidity and mortality associated with ACS.

Reductions in mitochondrial O(2) consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium.

We performed the present study to determine whether hibernating myocardium is chronically protected from ischemia. Myocardial tissue was rapidly excised from hibernating left anterior descending coronary regions (systolic wall thickening = 2.8 +/- 0.2 vs. 5.4 +/- 0.3 mm in remote myocardium), and high-energy phosphates were quantified by HPLC during simulated ischemia in vitro (37 degrees C). At baseline, ATP (20.1 +/- 1.0 vs. 26.7 +/- 2.1 micromol/g dry wt, P < 0.05), ADP (8.1 +/- 0.4 vs. 10.3 +/- 0.8 micromol/g, P < 0.05), and total adenine nucleotides (31.2 +/- 1.3 vs. 40.1 +/- 2.9 micromol/g, P < 0.05) were depressed compared with normal myocardium, whereas total creatine, creatine phosphate, and ATP-to-ADP ratios were unchanged. During simulated ischemia, there was a marked attenuation of ATP depletion (5.6 +/- 0.9 vs. 13.7 +/- 1.7 micromol/g at 20 min in control, P < 0.05) and mitochondrial respiration [145 +/- 13 vs. 187 +/- 11 ng atoms O(2).mg protein(-1).min(-1) in control (state 3), P < 0.05], whereas lactate accumulation was unaffected. These in vitro changes were accompanied by protection of the hibernating heart from acute stunning during demand-induced ischemia. Thus, despite contractile dysfunction at rest, hibernating myocardium is ischemia tolerant, with reduced mitochondrial respiration and slowing of ATP depletion during simulated ischemia, which may maintain myocyte viability.