Citations

Aims To demonstrate, with concrete examples, the value of in-depth exploration and comparison of data published in National Joint Arthroplasty registry reports. Patients and Methods The author reviewed published current reports of National Joint Arthroplasty registries for findings of current significance to current orthopaedic practice. Results A total of six observations that demonstrate actionable or unexpected findings from joint registries are described. These include: one third to one half of all arthroplasty failures in the first decade occur in the first one to two years; infection rates after arthroplasty have not declined in the last three decades; infection after TKA is more common in men than women; outcomes of TKA are more variable in young compared with older patients; new technologies (uncemented implants and crosslinked polyethylene) have improved results of THA and a real-time shift in use of ceramic femoral heads is occurring in THA. Conclusion These six observations may be used to better understand current practice, stimulate practice improvements or suggest topics for further study. Cite this article: Bone Joint J 2017;99-B(1 Supple A):3–7

ABSTRACTBackground:The association between celiac disease (CD) and eosinophilic esophagitis (EoE) has been the focus of multiple studies with variable results. Both diseases are immune mediated, and dietary triggers play a role in their pathogenesis.Objectives:The aim of the study was to analyze the risk of EoE in children with CD, assess the magnitude of association between CD and EoE in children, and report the characteristics and outcomes of children with both conditions.Methods:We conducted a retrospective study of the Mayo Clinic Electronic medical records between January 1, 1998 and December 31, 2015. Systematic review and meta‐analysis of multiple databases was conducted to include studies reporting on the same association. Random‐effects model was used to report pooled odds ratio (OR) and 95% confidence interval (CI).Results:In this cohort study, of 10,201 children who underwent at least 1 endoscopy, 595 had EoE, and 546 had CD. The risk of having EoE was not increased in children with CD compared to those without CD (OR, 0.29; 95% CI, 0.154–0.545). Nine of 10 children improved with gluten‐free diet, topical glucocorticosteroid, and/or elimination diet. One child lost to follow‐up.Meta‐analysis of 5 studies showed similar results (OR, 0.525; 95% CI, 0.364–0.797). A total of 45 cases in the literature had both CD and EoE (mean age, 10 years; 64% boys; majority presenting with abdominal pain, vomiting, and diarrhea).Conclusions:Based on our cohort and the observational data, the diagnosis of CD in children is not associated with increased risk of EoE.

Abstract Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure). Current guidelines recommend use of natriuretic peptides (N-terminal pro-B type natriuretic peptide) and rest/exercise echocardiography (E/e′ ratio) to make this determination. Data to support this practice are conflicting. Methods: Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24). Results: N-Terminal pro-B type natriuretic peptide levels were below the level considered to exclude disease (≤125 pg/mL) in 18% of subjects with HFpEF. E/e′ ratio was correlated with directly measured pulmonary capillary wedge pressure at rest ( r =0.63, P <0.0001) and during exercise ( r =0.57, P <0.0001). Although specific, current guidelines were poorly sensitive, identifying only 34% to 60% of subjects with invasively proven HFpEF on the basis of resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e′ ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%). Conclusions: Currently proposed HFpEF diagnostic guidelines on the basis of resting data are poorly sensitive. Adding exercise E/e′ data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF on the basis of resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique Identifier: NCT01418248.

Nonalcoholic steatohepatitis (NASH) is a lipotoxic disorder, wherein proinflammatory lipids, such as ceramide and its derivative sphingosine 1-phosphate (S1P), contribute to macrophage-associated liver inflammation. For example, we have previously demonstrated a role for S1P in steatotic hepatocyte-derived S1P-enriched extracellular vesicles in macrophage chemotaxis in vitro. Therefore, we hypothesized that FTY720, an S1P antagonist, would ameliorate NASH by inhibiting proinflammatory monocyte chemotaxis. To test our hypothesis, NASH was established in C57BL/6 male mice by feeding a diet high in fructose, saturated fat, and cholesterol for 22 wk. Then mice received daily intraperitoneal injections of FTY720 for 2 wk before analysis of liver injury, inflammation, and fibrosis. FTY720-treated mice with NASH demonstrated improved liver histology with a significant reduction in hepatocyte ballooning and inflammatory foci. Hepatomegaly was reversed, and liver triglycerides were reduced following FTY720 administration to mice with NASH. Correspondingly, serum ALT levels, hepatic inflammatory macrophage accumulation, and the expression of Ly6C in recruited myeloid cells was reduced in FTY720-treated mice. Hepatic collagen accumulation and expression of α-smooth muscle actin were significantly lowered as well. Body composition, energy consumption and utilization, and hepatic sphingolipid composition remained unchanged following FTY720 administration. FTY720 ameliorates murine nonalcoholic steatohepatitis. Reduction in liver injury and inflammation is associated with a reduction in hepatic macrophage accumulation, likely due to dampened recruitment of circulating myeloid cells into the liver. Nonalcoholic steatohepatitis may be a novel indication for the therapeutic use of FTY720. NEW & NOTEWORTHY There are no approved pharmacologic therapies for nonalcoholic steatohepatitis (NASH), the leading cause of chronic liver disease worldwide. This study describes the use of FTY720, a novel small molecule, for the amelioration of NASH in a mouse model. We demonstrate that 2-wk administration of FTY720 to mice with NASH led to a reduction in liver injury, inflammation, and fibrosis. These data provide a preclinical rationale for studying this drug in human NASH.

Extracellular vesicles (EVs) are membrane-bound vesicles that are released by cells into their extracellular environment, have selective enrichment of specific proteins and RNA, and can mediate intercellular communication. In this review we highlight recent observations of the role of EVs in liver injury, viral hepatitis, alcoholic or nonalcoholic liver disease, biliary tract disease, and liver cancers. Potential applications as markers of diseases or for therapeutic applications are outlined to emphasize the new opportunities that are arising from the study of EVs.