BACKGROUND:Pilon fractures are historically associated with suboptimal outcomes. No long-term Australian data is available on patient-reported outcomes. We hypothesised that pilon fracture long-term outcomes are inferior to Australian population norms. METHODS:A 14-year retrospective study was conducted in a Level-1 trauma centre on AO/OTA type-B/C fractures. Type-A fractures, skeletally immature, interpreter requirement and primary amputation were excluded. Demographics, injury characteristics, management and complications were collected. The primary outcome was SF-36 with adjusted Australian norms. RESULTS:From 127 eligible patients, 73 were included in the study (age: 46 ± 17 years; 50 [69%] males) with 8.7 ± 3.9 years follow-up. Management included ORIF 46 (61%), external fixation (EF) with staged ORIF 17 (23%), definitive EF 4 (5%) and 8 (11%) non-operative. Further surgical intervention was required in 25 (34%) patients, with the majority for hardware removal (14 [19%]). Compared with Australian SF-36 norms, the mean Physical Component Score was lower (44.7 ± 8.9 vs. 50.3, p ≤ 0.001) whereas the Mental Component Score (51.2 ± 12.5 vs. 51.2, p = 0.24) was not. Median return to work was 4.5 months (IQR 5), with 47 (87%) of the 54 employed pre-injury working at 12 months. Two (3.7%) patients did not return to work and 24 (44%) returned at a reduced capacity. CONCLUSION:This study provides a contemporary reference for pilon fractures managed in Australia. Outcomes were favourable when compared internationally. These patients are likely to resume employment, often at reduced capacity, while experiencing moderate long-term impacts to their physical well-being due to persistent pain.

Abstract Background: Pancreatic cancer portends a very poor prognosis. It is the third leading cause of cancer deaths in the United States. African Americans have a 50- 90% increased incidence of pancreatic cancer in comparison to other racial groups. 20% of patients with pancreatic cancer present with early-stage disease and will have a median overall survival of 2.5 years if able to undergo surgical resection. There is a desperate need to discover novel ways of treating pancreatic cancer. Understanding of the microbiome may be informative to overcoming chemotherapy resistance, toxicity and improving outcomes and disparities. The aim of this study is to (1) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment response and (2) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment toxicity in a diverse patient population. Methods: Patients with resectable or borderline resectable pancreatic cancer who are enrolled in a multi-site clinical trial (NCT03483038) receiving neoadjuvant NEO-Nali-IRI (oxaliplatin, liposomal irinotecan and 5- FU) followed by surgical resection were asked to provide serial microbiome collections of saliva, urine, blood, and stool with a dietary log during the following four (or five) time points: at baseline, mid-therapy (after C4), at completion of chemotherapy (after C8), after radiation if applicable, and at 4-6 weeks post-operative. Participants were given stool collection kits during clinic visits for home sample acquisition. All stool samples were mailed to the University of Florida Health Cancer Center Microbiome Biorepository. Saliva, urine and blood were collected during clinic visits. Demographics, stage, medical history and concurrent medications including antimicrobics and probiotics, chemotherapy dose-reductions, delays, discontinuations, adverse events, safety adverse events, attribution of causality, and hospitalizations were obtained. Outcomes include imaging response using RECIST criteria, CA 19-9 trend, development of metastatic disease, and the ability to proceed to definitive surgical resection. DNA will be extracted from stool and analyzed using 16S rRNA sequencing methods to determine signatures and biodiversity. Descriptive statistics and correlative analysis will be reported. Continuous and categorical variables will be compared with Student’s t-test and Chi-squared test. Multiple groups will be compared by ANOVA. Kaplan-Meier logistic regression will be performed to compare outcomes between the different microbiota groupings. Conclusion: Serial microbiome collection from a multi-site clinical trial is feasible during neoadjuvant chemotherapy for pancreatic cancer and can increase the diversity of the sample population. Citation Format: Sherise C. Rogers, Ibrahim Nassour, Ryan Thomas, Ilyas Sahin, Brian Ramnaraign, Karen Russell, Steven Hughes, Kathryn Hitchcock, Omar Kayaleh, Anita Turk, Ji-Hyun Lee, David DeRemer, Carmen Allegra, Thomas George. Feasibility of serial microbiome collection in a multi-site neoadjuvant pancreatic cancer clinical trial allowing for a diverse patient population [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr PR018.

Background: Pancreatic cancer portends a very poor prognosis. It is the third leading cause of cancer deaths in the United States. African Americans have a 50- 90% increased incidence of pancreatic cancer in comparison to other racial groups. 20% of patients with pancreatic cancer present with early-stage disease and will have a median overall survival of 2.5 years if able to undergo surgical resection. There is a desperate need to discover novel ways of treating pancreatic cancer. Understanding of the microbiome may be informative to overcoming chemotherapy resistance, toxicity and improving outcomes and disparities. The aim of this study is to (1) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment response and (2) identify changes in the intestinal microbiota during neoadjuvant treatment of pancreatic ductal adenocarcinoma that correlate with treatment toxicity in a diverse patient population. Methods: Patients with resectable or borderline resectable pancreatic cancer who are enrolled in a multi-site clinical trial (NCT03483038) receiving neoadjuvant NEO-Nali-IRI (oxaliplatin, liposomal irinotecan and 5- FU) followed by surgical resection were asked to provide stool samples and a dietary log during the following four (or five) time points: baseline, mid-therapy (after C4), at completion of chemotherapy (after C8), after radiation if applicable, and at 4-6 weeks post-operative. Participants will be given stool collection kits at clinic visits for home sample acquisition. All samples will be mailed to the University of Florida Health Cancer Center Microbiome Biorepository. Data will be collected regarding demographics, stage, medical history and concurrent medications including antimicrobics and probiotics, chemotherapy dose-reductions, delays, discontinuations, adverse events, safety adverse events, attribution of causality, and hospitalizations. Outcomes will include imaging response using RECIST criteria, CA 19-9 trend, development of metastatic disease, and the ability to proceed to definitive surgical resection. DNA will be extracted from stool and analyzed using 16S rRNA sequencing methods to determine signatures and biodiversity. Descriptive statistics and correlative analysis will be reported. Continuous and categorical variables will be compared with Student’s t-test and Chi-squared test. Multiple groups will be compared by ANOVA. Kaplan-Meier logistic regression will be performed to compare outcomes between the different microbiota groupings. Conclusion: Stool collection from a multi-site clinical trial is feasible during neoadjuvant chemotherapy for pancreatic cancer and can increase diversity of the sample population. Citation Format: Sherise Rogers, Ryan Thomas, Brain Ramnaraign, Ilyas Sahin, Jesus Fabregas, Karen Russell, Steven Hughes, Ibrahim Nassour, Kathyrn Hitchcock, Omar Kayaleh, Anita Turk, Ji-Hyun Lee, David DeRemer, Carmen Allegra, Thomas George. An exploratory analysis of the intestinal microbiome in neoadjuvant chemotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2186.

BACKGROUND:Jones fractures remain a challenging treatment entity in orthopaedics. Biomechanical stresses, including increased fifth metatarsal (5MT) lateral angle deviation (MLAD), are associated with increased fracture and refracture rates. Current fixation techniques produce good outcomes; however, they do not address metatarsal morphology, which can predispose to refracture. This study describes a novel surgical technique and case series utilizing intramedullary screw fixation and distal metatarsal corrective osteotomy for the management of Jones fractures.METHODS:A retrospective case series was undertaken, including 22 consecutive Jones fracture patients operated on by a single surgeon. Patient demographics, imaging, and operative information were obtained, with return to sport/previous function and radiological outcomes, including fracture union being the outcomes of interest. The surgical technique utilizes a distal osteotomy of the 5MT followed by retrograde guidewire and drilling utilizing the osteotomy. A cannulated screw is passed antegrade along the entire length of the 5MT with manual MLAD correction. Autograft or bone substitute (Augment) was then injected at the fracture site.RESULTS:Median age was 30 years (Q1, Q3: 18, 49 years). Median time from injury to operation was 13 weeks (Q1, Q3: 9, 30 weeks), and clinical follow-up period was 37 months (Q1, Q3: 14, 74 months). Radiological union was achieved at a median of 12 weeks (Q1, Q3: 8, 15 weeks) with clinical union at 11 weeks (Q1, Q3: 8, 14 weeks). All but one patient returned to preinjury functional levels, including 6 professional athletes who returned to preinjury national competition. No refractures were identified.CONCLUSION:The technique described in this study is a viable and safe means of managing Jones fractures. The technique may be particularly useful in patients with excessive MLAD.LEVELS OF EVIDENCE:Level IV: Retrospective case series.

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death in the United States. Our group and others have demonstrated that the intestinal microbiota accelerates pancreatic carcinogenesis. The relationship of intestinal bacteria, immune response, and PDAC development is unclear. To that end, we investigated the role of intestinal bacterial soluble factors in modulating the immune environment of PDAC and its progression. Methods: Mice intestinal microbiota was depleted with wide-spectrum antibiotics. The human PDAC cell line, L3.6pl, was heterotopically implanted into Rag1-/- mice, while the syngeneic murine PDAC cell line, Pan02, was orthotopically implanted into the pancreas of C57Bl/6 mice. Tumor and pancreas infiltrated natural killer (NK) cells were quantitated by flow cytometry. In vivo NK cell depletion was attained by intraperitoneal injection of anti-Asialo-GM1 antibody twice weekly. Germ-free (GF) and conventionally housed Rag1-/- mice stool was cultured and bacteria-free supernatant extracted. The ability of these bacteria-free supernatants to regulate NK-92mi cell cytotoxicity and migration was tested in vitro by flow cytometry and a Transwell assay, respectively. Results: Compared to microbiota-intact Rag1-/- mice, microbiota depletion yielded 74% smaller tumors (p<0.05) with a 1.5-fold increase in PDAC infiltrating NK cells (p<0.001). Confirmation by immunohistochemistry demonstrated a 6.5-fold increase in NK cell tumor infiltration in microbiota-depleted mice (p<0.0001). Notably, a 3-fold increase of intrapancreatic NK cells in GF Rag1-/- mice versus conventionally housed mice was noted, suggesting that bacteria regulate immune cell trafficking. Antibody-mediated NK cell depletion with concomitant microbiota depletion increased PDAC tumor growth, negating the antitumor phenotype of microbiota depletion alone in both immunodeficient Rag1-/- (2.8-fold increase; p<0.05) and immunocompetent C57Bl/6 mice (2.4-fold increase; p<0.05). Quantitative PCR revealed 9-fold higher IFN-gamma gene expression in PDAC xenografts of microbiota-depleted mice versus microbiota-intact (p<0.05). Cell-free stool bacteria culture supernatant from conventionally housed Rag1-/- mice, but not from GF mice, inhibited NK-92mi cell migration by 26% (p<0.05) and cytotoxicity against L3.6pl cells by 51% (p<0.01). Compared to NK-92mi cells exposed to cultured stool supernatant from GF Rag1-/- mice, SPF cultured stool supernatant resulted in decreased gene expression associated with activation/recruitment of NK cells including FASLG, CCL18, IL-13, CXCR2, CCL4, and increased expression associated with inhibition of NK cell activity including CCR1 and IL-6. Conclusion: These findings suggest that intestinal bacteria modulate PDAC development through suppression of NK cell recruitment and activation, a phenomenon potentially mediated by yet to be identified small molecules. Citation Format: Qin Yu, Mark Beveridge, Ryan Thomas, Christian Jobin. Intestinal microbiota mediates pancreatic carcinogenesis through modulation of tumor infiltrating natural killer cells [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B05.

Critical Care Medicine: January 2020 - Volume 48 - Issue 1 - p 759 doi: 10.1097/01.ccm.0000648172.61303.e0

OBJECTIVES:The goal of this analysis was to examine the comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention among patients aged less than 60 years. METHODS:We performed a multicenter, retrospective analysis of all cardiac revascularization procedures from 2005 to 2015 among 7 medical centers. Inclusion criteria were age less than 60 years and 70% stenosis or greater in 1 or more major coronary artery distribution. Exclusion criteria were left main 50% or greater, ST-elevation myocardial infarction, emergency status, and prior revascularization procedure. After applying inclusion and exclusion criteria, the final study cohort included 1945 patients who underwent cardiac surgery and 2938 patients who underwent percutaneous coronary intervention. The primary end point was all-cause mortality stratified by revascularization strategy. Secondary end points included stroke, repeat revascularization, and 30-day mortality. We used inverse probability weighting to balance differences among the groups. RESULTS:After adjustment, there was no significant difference in 30-day mortality (surgery: 0.8%; percutaneous coronary intervention: 0.7%, P = .86) for patients with multivessel disease. Patients undergoing surgery had a higher risk of stroke (1.3% [n = 25] vs 0.07% [n = 2], P < .001). Overall, surgery was associated with superior 10-year survival compared with percutaneous coronary intervention (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88; P = .002). Repeat procedures occurred in 13.4% (n = 270) of the surgery group and 36.4% (n = 1068) of the percutaneous coronary intervention group, with both groups mostly undergoing percutaneous coronary intervention as their second operation. Accounting for death as a competing risk, at 10 years, surgery resulted in a lower cumulative incidence of repeat revascularization compared with percutaneous coronary intervention (subdistribution hazard ratio, 0.34; 95% confidence interval, 0.28-0.40; P < .001). CONCLUSIONS:Among patients aged less than 60 years with 2-vessel disease that includes the left anterior descending or 3-vessel coronary artery disease, surgery was associated with greater long-term survival and decreased risk of repeat revascularization.

There has been an interesting series of commentaries based on the initial paper by Pan et al. 1–4 I note with interest the suggestion by Binks et al 4 that to preserve the infrapatellar fat pad (IPFP) and perform later arthroscopic resection on a case by case basis may be a viable option for management of anterior knee pain (AKP) after total knee arthroplasty (TKA). This is contrary to the solution offered by Han et …

Women undergoing percutaneous coronary interventions (PCI) have a higher risk of access site bleeding and vascular complications (ASB/VC) than men. The impact of various bleeding avoidance strategies (BAS) on sex differences in PCI related bleeding is not well studied. Patients (n=42,101)

BACKGROUND:Arthroscopic knee surgery is a common technique used in Australia. Post-operative pain is common and can lead to delayed discharge and impair early mobilization. Use of local anaesthesia can reduce pain while avoiding systemic side effects. This systematic review and meta-analysis aimed to establish the use of tramadol as an adjunct to intra-articular local anaesthetic infiltration in knee arthroscopy in the current literature.METHODS:Two independent reviewers performed a systematic search of four databases, where 24 articles were identified with six studies (four high-quality and two low-quality randomized controlled trials), with a total of 334 patients were included for analysis. RevMan 5.3 software (The Nordic Cochrane Centre, Copenhagen, Denmark) was used to perform the data analysis. The studies included focused on outcomes such as pain scores, breakthrough analgesia, total analgesia, time to discharge and adverse events related to the use of tramadol as an adjunctive therapy.RESULTS:This study found that using tramadol as an adjunct to intra-articular local anaesthetic infiltration in arthroscopic knee surgery reduced post-operative pain and increased time to breakthrough analgesia without an increase in side effects.CONCLUSION:This meta-analysis suggests that tramadol is an efficacious adjunct for use in intra-articular local anaesthetic infiltration following arthroscopic knee surgery.

Background: Opioid analgesia is commonly employed in the postoperative period. Opioids have a well-documented side effect profile. Their administration is made difficult following major abdominal surgery in those patients intolerant of oral intake. Furthermore, efforts are required to reduce the contribution of prescription opioids to the global illicit drug epidemic. Buprenorphine is thought to have a lesser side effect profile than morphine, is available in sublingual form and has a reduced risk of addiction. This study aims to compare the effectiveness and side effect profile of buprenorphine against morphine in managing pain following major abdominal surgery. Methods: Five databases were searched up to May 2019. Randomized controlled trials comparing articles comparing buprenorphine with morphine post-major abdominal were included. Major abdominal surgery included operations on the abdominal wall, abdominal cavity or abdominal organs with an expected duration greater than 60 minutes. Postoperative pain and opioid-related adverse events, such as respiratory depression and sedation, were meta-analyzed. Results: Eleven studies with a combined pool of 764 patients were included. Buprenorphine provided improved analgesia from 6 to 12 hours postoperatively (P=0.0003). Pain and analgesia use were otherwise equivalent with buprenorphine and morphine use up to 48 hours postoperatively. There was no discrepancy in respiratory depression, sedation, nausea, vomiting, dizziness or hypotension. Conclusions: Buprenorphine is non-inferior to morphine in managing pain following major abdominal surgery. Opioid-related side effects were unaltered. Further study is required to analyse rates of addiction. The study was hindered by the number of relevant studies and the age of included data.

Background: Female sex is associated with increased risk of procedure related bleeding and vascular complications (VC). The effect of radial approach on sex based differences in bleeding/ VC remains speculated. Methods: We studied 42101 (11997 w; 30104 m) consecutive patients undergoing PCI from

Objectives: To assess the difference in survival and neurological outcomes between endotracheal tube (ETT) intubation and supraglottic airway (SGA) devices used during out-of-hospital cardiac arrest (OHCA). Methods: A systematic search of five databases was performed by two independent reviewers until September 2018. Included studies reported on (1) OHCA or cardiopulmonary resuscitation, and (2) endotracheal intubation versus supraglottic airway device intubation. Exclusion criteria (1) stimulation studies, (2) selectively included/excluded patients, (3) in-hospital cardiac arrest. Odds Ratios (OR) with random effect modelling was used. Primary outcomes: (1) return of spontaneous circulation (ROSC), (2) survival to hospital admission, (3) survival to hospital discharge, (4) discharge with a neurologically intact state. Results: Twenty-nine studies (n=539,146) showed that overall, ETT use resulted in a heterogeneous, but significant increase in ROSC (OR=1.44; 95% CI=1.27 to 1.63; I-2=91%; pb 0.00001) and survival to admission (OR=1.36; 95% CI=1.12 to 1.66; I-2=91%; p=0.002). There was no significant difference in survival to discharge or neurological outcome (p > 0.0125). On sensitivity analysis of RCTs, there was no significant difference in ROSC, survival to admission, survival to discharge or neurological outcome (p > 0.0125). On analysis of automated chest compression, without heterogeneity, ETT provided a significant increase in ROSC (OR = 1.55; 95% CI = 1.20 to 2.00; I-2 =0%; p = 0.0009) and survival to admission (OR = 2.16; 95% CI = 1.54 to 3.02; I-2 = 0%; p < 0.00001). Conclusions: The overall heterogeneous benefit in survivalwith ETTwas not replicated in the low risk RCTs, with no significant difference in survival or neurological outcome. In the presence of automated chest compressions, ETT intubation may result in survival benefits. (c) 2018 Elsevier Inc. All rights reserved.

The infiltration of local anesthetic has been shown to reduce postoperative pain in knee arthroscopy. Several studies have shown that the addition of agents such as magnesium and nonsteroidal antiinflammatory drugs (NSAIDs) result in an increased time to first analgesia and overall reduction in pain. The aim of this systematic review and meta-analysis was to determine whether the addition of an alpha-2 agonist (A2A) to intra-articular local anesthetic, results in a reduction in postoperative pain. Four major databases were systematically searched for relevant randomized controlled trials (RCTs) up to July 2017. RCTs containing a control group receiving a local anesthetic and an intervention group receiving the same with the addition of an A2A were included in the review. The included studies were assessed for level of evidence and risk of bias. The data were then analyzed both qualitatively and where appropriate by meta-analysis. We reviewed 12 RCTs including 603 patients. We found that the addition of an A2A resulted in a significant reduction in postoperative pain up to 24 hours. The addition of the A2A increased time to first analgesia request by 258.85 minutes (p < 0.00001). Total 24-hour analgesia consumption was analyzed qualitatively with all included studies showing a significant reduction in total analgesia requirement. Interestingly, none of the studies found an increase in side effects associated with the A2A. This study provides strong evidence for the use of A2As as a means to reduce postoperative pain post arthroscopic knee surgery, without a corresponding increase in side effects.

however this did not result in elevated plasma concentrations or systemic toxicity.The authors of this study hypothesised that LIA may actually be preferable to FNB due to the ease and availability of LIA

Hypoxaemia increases the risk of cardiac arrest and mortality during intubation. The reduced physiological reserve and reduced efficacy of pre-oxygenation in intensive care patients makes their intubation particularly dangerous. Apnoeic oxygenation is a promising means of preventing hypoxaemia in this setting. We sought to ascertain whether apnoeic oxygenation reduces the incidence of hypoxaemia when used during endotracheal intubation in the intensive care unit (ICU). A systematic review of five databases for all relevant studies published up to November 2016 was performed. Eligible studies investigated apnoeic oxygenation during intubation in the ICU, irrespective of design. All studies were assessed for risk of bias and level of evidence. A meta-analysis was performed on all data using Revman 5.3. Six studies including 518 patients were retrieved. The study found level 1 evidence of a significant reduction in the incidence of critical desaturation (RR = 0.69, CI = 0.48-1.00, p = 0.05) and a significant increase in the lowest SpO2 value by 2.83% (CI = 2.28-3.38, p < 0.00001). There was a significant reduction in ICU stay (WMD = -2.89, 95%CI = -3.25 to -2.51, p < 0.00001). There was no significant difference between groups regarding mortality (RR = 0.77, 95%CI = 0.59-1.03, p = 0.08), first pass intubation success (RR = 1.17, 95%CI = 0.67 to 2.03, p = 0.58), arrhythmia during intubation (RR = 0.58, 95%CI = 0.08 to 4.29, p = 0.60), cardiac arrest during intubation (RR = 0.33, 95%CI = 0.01 to 7.84, p = 0.49) and duration of ventilation (WMD = -1.97, 95%CI = -5.89 to 1.95, p = 0.32). Apnoeic oxygenation reduces patient hypoxaemia during intubation performed in the ICU. This meta-analysis found evidence that apnoeic oxygenation may significantly reduce the incidence of critical desaturation and significantly raises the minimum recorded SpO2 in this setting. We recommend apnoeic oxygenation be incorporated into ICU intubation protocol.

Hypothesis: Distance to a PCI hospital will impact the treatment and outcome of patients presenting with ST elevation myocardial infarction (STEMI). Methods: We studied all STEMI patients treated w...

The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS.