New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Arthroscopic-Assisted Core Decompression for Osteonecrosis of the Femoral Head

The management of pre-collapse osteonecrosis of the femoral head is controversial. Core decompression is a technique that theoretically decreases the intraosseous pressure of the femoral head, resulting in a local vascularized healing response. Its efficacy has been shown in delaying early subchondral collapse. We describe the technique of arthroscopic-assisted core decompression of the femoral head for osteonecrosis. The advantages of this technique include evaluation of the presence or absence of articular cartilage injury, subchondral collapse, and guidance during reaming and curettage. It also allows the ability to address any concomitant soft-tissue or bony pathology associated with or in addition to the osteonecrotic lesion

Routine Complete Capsular Closure During Hip Arthroscopy

The utility of hip arthroscopy has recently progressed beyond diagnostic to therapeutic purposes addressing central and peripheral compartment pathologies. Capsulotomy provides freedom of visualization and instrumentation. The contribution to hip stability of both dynamic and static hip structures is not fully understood. However, both basic science biomechanical and clinical outcome studies have exhibited a relevant role of the capsule in hip stability. Though rare, iatrogenic post-arthroscopy subluxation and dislocation have been reported. Therefore many surgeons have cautioned against aggressive capsulotomy or capsulectomy without repair, because of the potential for precipitation of iatrogenic hip instability. We typically perform a “T” capsulotomy and recommend complete capsular closure in conjunction with labral repair and osseous femoral and acetabular treatment. A safe, efficient, and effective method to accomplish complete capsular closure is presented to reduce iatrogenic postoperative hip instability

Arthroscopic Bony Bankart Fixation Using a Modified Sugaya Technique

Arthroscopic fixation of bony Bankart lesions in the setting of anterior shoulder instability has had successful long-term results. Key factors such as patient positioning, portal placement, visualization, mobilization of bony/soft tissues, and anatomic reduction and fixation are crucial to yield such results. We present a modified Sugaya technique that is reproducible and based on such key principles. This technique facilitates ease of anchor and suture placement to allow for anatomic reduction and fixation

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. © 2022, The Author(s)

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)