Randomized Comparison of a Polymer-Free Sirolimus-Eluting Stent Versus a Polymer-Based Paclitaxel-Eluting Stent in Patients With Diabetes Mellitus The LIPSIA Yukon Trial

ObjectivesThe objective of the study was to assess noninferiority of the polymer-free sirolimus-eluting Yukon Choice stent (Translumina GmbH, Hechingen, Germany) compared with the polymer-based Taxus Liberté stent (Boston Scientific, Natick, Massachusetts) with regard to the primary endpoint, in-stent late lumen loss, at 9 months in patients with diabetes mellitus.BackgroundThe Yukon Choice stent has been evaluated in several randomized controlled trials before, albeit to date, there has been no trial that exclusively enrolled patients with diabetes mellitus.MethodsPatients with diabetes mellitus undergoing percutaneous coronary intervention for clinically significant de novo coronary artery stenosis were randomized 1:1 to receive either the polymer-free sirolimus-eluting Yukon Choice stent or the polymer-based paclitaxel-eluting Taxus Liberté stent.ResultsA total of 240 patients were randomized. Quantitative coronary angiography was available for 79% of patients. Mean in-stent late lumen loss was 0.63 ± 0.62 mm for the Yukon Choice stent and 0.45 ± 0.60 mm for the Taxus Liberté stent. Based on the pre-specified margin, the Yukon Choice stent failed to show noninferiority for the primary endpoint. During follow-up, there were no significant differences between groups regarding death, myocardial infarction, stent thrombosis, target lesion revascularization, target vessel revascularization, or nontarget vessel revascularization.ConclusionsCompared with the Taxus Liberté stent, the polymer-free sirolimus-eluting Yukon Choice stent failed to show noninferiority with regard to the primary endpoint, in-stent late lumen loss, in patients with diabetes mellitus after 9-month follow-up. Both stents showed comparable clinical efficacy and safety. (Yukon Choice Versus Taxus Liberté in Diabetes Mellitus; NCT00368953

Circulating growth/differentiation factor 15 is associated with human CD56 natural killer cell dysfunction and nosocomial infection in severe systemic inflammation

BACKGROUND Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. FINDINGS During systemic inflammation, the expression of the IL-12 receptor β2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor β receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor β2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Risk factors and injury patterns of e-scooter associated injuries in Germany

Abstract Since the introduction of widely available e-scooter rentals in Hamburg, Germany in June of 2019, our emergency department has seen a sharp increase in the amount of e-scooter related injuries. Despite a rising number of studies certain aspects of e-scooter mobility remain unclear. This study examines the various aspects of e-scooter associated injuries with one of the largest cohorts to date. Electronic patient records of emergency department admissions were screened for e-scooter associated injuries between June 2019 and December 2021. Patient demographic data, mechanism of injury, alcohol consumption, helmet usage, sustained injuries and utilized medical resources were recorded. Overall, 268 patients (57% male) with a median age of 30.3 years (IQR 23.3; 40.0) were included. 252 (94%) were e-scooter riders themselves, while 16 (6%) were involved in crashes associated with an e-scooter. Patients in non-rider e-scooter crashes were either cyclists who collided with e-scooter riders or older pedestrians (median age 61.2 years) who tripped over parked e-scooters. While e-scooter riders involved in a crash sustained an impact to the head or face in 58% of cases, those under the influence of alcohol fell on their head or face in 84% of cases. This resulted in a large amount of maxillofacial soft tissue lacerations and fractures. Extremity fractures and dislocations were more often recorded for the upper extremities. This study comprises one of the largest cohorts of e-scooter associated injuries to date. Older pedestrians are at risk to stumble over parked e-scooters. E-scooter crashes with riders who consumed alcohol were associated with more severe injuries, especially to the head and face. Restricted e-scooter parking, enforcement of drunk driving laws for e-scooters, and helmet usage should be recommended

Total Hip Arthroplasty in a Patient with Mucopolysaccharidosis Type IVB

Introduction. Morquio syndrome or mucopolysaccharidosis (MPS) type IV is a rare autosomal recessive lysosomal storage disease, characterized by abnormal metabolism of glycosaminoglycans associated with specific skeletal deformities, also known as dysostosis multiplex. Case Presentation. We present the case of a 23-year-old patient with advanced osteonecrosis of the femoral head (ONFH) on both sides due to Morquio syndrome. A diagnosis of mucopolysaccharidosis type IVB was made after extensive genetic profiling. The patient had the condition for a long time. At 7 years old, the patient was treated with bilateral pelvic Salter’s osteotomy. Afterward, the patient was able to walk freely but could never take part in sports. At 22 years old, pain in the hip increased, and magnetic resonance imaging showed a bilateral femur head necrosis. Hence, the patient underwent cementless total hip arthroplasty (THA). Intraoperatively, a periprosthetic fracture occurred. Therefore, revision surgery with internal fixation was performed on the next day. Postoperatively, a weight-bearing restriction of 20 kg on the left leg was imposed for 6 weeks. The patient made a full recovery and was able to move without residual complaints. Annual orthopedic evaluation in patients treated with surgical intervention is recommended. Discussion. Orthopedic challenges for mucopolysaccharidoses and corresponding bone alterations, known as dysostosis multiplex, involving trunk and limbs with typical radiological findings have been well described. The hip is invariably involved, with dysplasia affecting the femoral neck (coxa valga), femoral epiphysis (loss of sphericity, osteonecrosis), and a flared hypoplastic iliac wing. Symptomatic therapy consists, on the one hand, of a surgical procedure and, on the other hand, a variety of supportive measures. However, the management of joint replacement in lysosomal storage diseases has not been well reported. All patients with MPS should be considered at high risk for surgical intervention requiring anesthesia because of airway and cardiac disease manifestations. In the case of a need for THA, we recommend cemented stem fixation because of the overall poor bone quality in patients with Morquio syndrome

Current and Future Concepts for the Treatment of Impaired Fracture Healing

Bone regeneration represents a complex process, of which basic biologic principles have been evolutionarily conserved over a broad range of different species. Bone represents one of few tissues that can heal without forming a fibrous scar and, as such, resembles a unique form of tissue regeneration. Despite a tremendous improvement in surgical techniques in the past decades, impaired bone regeneration including non-unions still affect a significant number of patients with fractures. As impaired bone regeneration is associated with high socio-economic implications, it is an essential clinical need to gain a full understanding of the pathophysiology and identify novel treatment approaches. This review focuses on the clinical implications of impaired bone regeneration, including currently available treatment options. Moreover, recent advances in the understanding of fracture healing are discussed, which have resulted in the identification and development of novel therapeutic approaches for affected patients

CD56^bright NK cells are suppressed in <i>Staphylococcus aureus</i>-induced IFN-γ synthesis after invasive surgery.

<p><b>(A-D)</b> PBMC were isolated from “patients 1” 24 h before (-1) and 1 d (+1), 5 d (+5), and 7 d (+7) after surgery and were stained against CD3 and CD56. <b>(A)</b> Gating strategy of CD3^-CD56^{<b>bright</b>} NK cells among total PBMC. The number indicates the percentage of gated cells in the rectangle. <b>(B)</b> Cumulative data on the percentage of gated CD3^-CD56^{<b>bright</b>} NK cells among total PBMC. <b>(C, D)</b> PBMC were cultured in the presence of <i>S</i>. <i>aureus</i> and cells were stained for intracellular IFN-γ. <b>(C)</b> Representative dot plots of intracellular IFN-γ expression in gated CD3^-CD5^{<b>bright</b>} NK cells isolated before and 1 d after injury. Numbers indicate the percentage of IFN-γ-positive (IFN-γ^<b>+</b>) cells. <b>(D)</b> Cumulative data on the kinetics of IFN-γ^<b>+</b> CD3^-CD56^{<b>bright</b>} NK cells upon exposure to <i>S</i>. <i>aureus</i> before and after injuy. <b>(E)</b> CD56^{<b>bright</b>} NK cells were purified from “patients 2” (n = 11) 1 d before and on day +1 after injury and stimulated with IL-12 and IL-18. The release of IFN-γ into the supernatant was quantified. Results are expressed as scatter plots (median, interquartile range). Statistical differences were tested using the Friedman test (B, D) or the Wilcoxon signed rank test (E). *, p<0.05; **, p<0.01; ***, p<0.001 vs. d-1. iso, isotype control antibodies.</p

Invasive Surgery Impairs the Regulatory Function of Human CD56^bright Natural Killer Cells in Response to <i>Staphylococcus aureus</i>. Suppression of Interferon-γ Synthesis

<div><p>Major surgery increases the risk for infectious complications due to the development of immunosuppression. CD56^bright NK cells play a key role in the defense against bacterial infections through the release of Interferon (IFN) γ upon stimulation with monocyte-derived Interleukin (IL) 12. We investigated whether invasive visceral surgery interferes with the IFN-γ synthesis of human NK cells in response to <i>Staphylococcus aureus</i>. In a prospective pilot study, peripheral blood mononuclear cells (PBMC) were isolated from 53 patients before and 1 to 7 d after elective visceral surgery. The release of IL-12 and IFN-γ from PBMC upon exposure to <i>S</i>. <i>aureus in vitro</i> was quantified. The expression of the IL-12 receptor β1 chain on the surface, the phosphorylation of signal transducer and activator of transcription (STAT) 4, and the synthesis of IFN-γ on/in individual CD56^bright NK cells were investigated using flow cytometry. The modulatory effect of IL-12 on the <i>S</i>. <i>aureus</i>-induced IFN-γ production in CD56^bright NK cells was analyzed. The IFN-γ secretion from purified CD56^bright NK cells was quantified after stimulation with IL-12 and IL-18. After surgery, CD56^bright NK cells among total PBMC were impaired in the release of IFN-γ for at least 5 d. Likewise, the IL-12-induced release of IFN-γ from purified CD56^bright NK cells was abolished. Upon stimulation with <i>S</i>. <i>aureus</i>, PBMC secreted less IL-12 but supplementation with recombinant IL-12 did not restore the capacity of CD56^bright NK cells to produce IFN-γ. CD56^bright NK cells displayed reduced levels of the IL-12Rβ1 chain whereas the phosphorylation of STAT4, the key transcription factor for the <i>Ifng</i> gene was not diminished. In summary, after invasive visceral surgery, CD56^bright NK cells are impaired in <i>S</i>. <i>aureus</i>-induced IFN-γ production and might contribute to the enhanced susceptibility to opportunistic infections.</p></div

Patients’ characteristics.

<p>Quantitative variables are expressed as median (25^th-75^th interquartile range), qualitative variables are provided as number/% of total. Significant differences between both groups were tested using Mann-Whitney and Fisher’s exact test, respectively.</p><p>Patients’ characteristics.</p