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

The Influence of Patient Sex on Outcomes Following One-Stage and Two-Stage Revision for Periprosthetic Joint Infection in Total Joint Arthroplasty

Although females have a higher rate of primary total joint arthroplasty (TJA), males have a higher rate of revision. The literature lacks studies examining the relationship between sex and outcomes following single and two-stage exchange for periprosthetic joint infection (PJI). The purpose of this study was to examine if differences exist in outcomes following revision for chronic PJI between sexes. A retrospective review was performed on all patients with an MSIS confirmed PJI who underwent a single or two-stage exchange at our institution from January 2010 to January 2021. Patient demographics, comorbidity characteristics, and outcomes were collected and compared between males and females. The primary outcome variable was disease-free survival at 1 year following definitive revision. Multivariable logistic regression analysis was performed to determine risk factors for failure. Of the 470 patients meeting final eligibility criteria, 250 were male and 226 were female (2 males and 4 females had a joint infection of either the contralateral side or a different joint and were treated as separate records). Of the patients in the cohort, 80% of the males (200/250) and 80% of the females (181/226) were found to be disease-free at 1-year follow-up (p > 0.99). Multivariable logistic regression analysis showed that nicotine use and diabetes, but not sex, were significant predictors of failure. Our study did not find a relationship between sex and outcome of revision for PJI. Further research is required to determine whether differences exist between males and females in the expression of PJI and outcomes following treatment

Co-Morbidities Are Associated with Increased Cost, Infection Rates, and Duration of Treatment after Primary Achilles Tendon Repair

Category: Sports. Introduction/Purpose: The purpose of this study was to assess the rate of surgical site infection (SSI) and surgical irrigation and debridement (I&D) after primary Achilles tendon repair. Secondary objectives were to assess the potential effect(s) of medical comorbidities on cost and duration of treatment of SSI after Achilles tendon repair. Methods: De-identified patient insurance records within the government and private national insurance orthopaedic datasets were searched between 2005-2012. The Current Procedural Terminology (CPT) code was used to identify primary Achilles tendon repair and I&D. Subsequently, post-operative SSIs and comorbidities were examined by searching corresponding International Classification of Disease Ninth Revision, Clinical Modification (ICD-9-CM) codes. Results: 24,269 primary Achilles tendon repairs were identified. Overall, there was a significantly increased rate of SSI if a medical comorbidity was present at the time of surgery compared to those without a comorbidity (17.96% vs. 5.96%, p < 0.0001). Patients with diabetes and vascular complications had the highest SSI rate (OR 7.85, CI 6.25-9.86, p < 0.001), followed by peripheral vascular disease, diabetes with peripheral neuropathy, history of drug abuse, fluid and electrolyte abnormalities, obesity, and uncomplicated diabetes. There was higher rate of surgical I&D in patients with cardiac arrhythmias and uncomplicated hypertension. There was a significant increase in cost of SSI treatment ($6,004.09 vs.$4,184.62, p=0.006) and duration of treatment (8.41 days vs. 5.54 days, p < 0.001) if a medical comorbidity was present in Achilles tendon patients with SSI. Conclusion: An analysis of a large cohort of patients undergoing Achilles tendon reconstruction revealed that having certain medical comorbidities conferred a significantly greater risk for developing SSI, which increased both the cost of subsequent care and duration of treatment. Furthermore, with the advent of “value”/outcomes based care being linked to reimbursement, SSI is a one measure being used by the Centers for Medicare & Medicaid Services and private insures to determine appropriate orthopaedic care. Thus, patients with modifiable risk factors should be referred for medical management prior to surgery or deferred to a non-operative treatment program to reduce the risk of SSI after Achilles tendon repair

Preparation and validation of the first WHO international genetic reference panel for Fragile X syndrome

Fragile X syndrome is the most common inherited form of mental retardation. It is caused by expansion of a trinucleotide (CGG)n repeat sequence in the 5′ untranslated region of the FMR1 gene, resulting in promoter hypermethylation and suppression of FMR1 transcription. Additionally, pre-mutation alleles in carrier males and females may result in Fragile X tremor ataxia syndrome and primary ovarian insufficiency, respectively. Fragile X is one of the most commonly requested molecular genetic tests worldwide. Quality assessment schemes have identified a wide disparity in allele sizing between laboratories. It is therefore important that clinical laboratories have access to characterized reference materials (RMs) to aid accurate allele sizing and diagnosis. With this in mind, a panel of genotyping RMs for Fragile X syndrome has been developed, which should be stable over many years and available to all diagnostic laboratories. Immortalized cell lines were produced by Epstein–Barr virus transformation of lymphocytes from consenting patients. Genomic DNA was extracted in bulk and RM aliquots were freeze-dried in glass ampoules. Twenty-one laboratories from seventeen countries participated in a collaborative study to assess their suitability. Participants evaluated the samples (blinded, in triplicate) in their routine methods alongside in-house and commercial controls. The panel of five genomic DNA samples was endorsed by the European Society of Human Genetics and approved as an International Standard by the Expert Committee on Biological Standardization at the World Health Organization

Osteochondral Autograft: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle

Background: Treatment guidelines for cartilage lesions of the talus have been based on both low quality and low levels of evidence. Therefore, an international consensus group of experts was convened to collaboratively advance toward consensus opinions on key topics regarding cartilage lesions of the talus. The purpose of this consensus article is to explain the process and delineate the consensus statements derived from this consensus meeting on the use of “osteochondral autograft” for osteochondral lesions of the talus. Methods: Seventy-five international experts in cartilage repair of the ankle representing 25 countries and 1 territory were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 11 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed upon in unanimous fashion within the working groups. A final vote was then held, and the strength of consensus was characterized as follows: consensus, 51% to 74%; strong consensus, 75% to 99%; and unanimous, 100%. Results: A total of 14 statements on osteochondral autograft reached consensus during the 2017 International Consensus Meeting on Cartilage Repair of the Ankle. Two achieved unanimous support, 11 reached strong consensus (greater than 75% agreement), and 1 achieved consensus. All statements reached at least 67% agreement. Conclusions: This international consensus derived from leaders in the field will assist clinicians with osteochondral autograft as a treatment strategy for osteochondral lesions of the talus