1. Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR
Javier Escaned, et al. Eur Heart J. 2021 Dec 1;42(45):4624-4634. doi: 10.1093/eurheartj/ehab702.
Aims: Patients at high bleeding risk (HBR) represent a prevalent subgroup among those undergoing percutaneous coronary intervention (PCI). Early aspirin discontinuation after a short course of dual antiplatelet therapy (DAPT) has emerged as a bleeding avoidance strategy. The aim of this study was to assess the effects of ticagrelor monotherapy after 3-month DAPT in a contemporary HBR population. Methods and results: This prespecified analysis of the TWILIGHT trial evaluated the treatment effects of early aspirin withdrawal followed by ticagrelor monotherapy in HBR patients undergoing PCI with drug-eluting stents. After 3 months of ticagrelor plus aspirin, event-free patients were randomized to 12 months of aspirin or placebo in addition to ticagrelor. A total of 1064 (17.2%) met the Academic Research Consortium definition for HBR. Ticagrelor monotherapy reduced the incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding compared with ticagrelor plus aspirin in HBR (6.3% vs. 11.4%; hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.35-0.82) and non-HBR patients (3.5% vs. 5.9%; HR 0.59, 95% CI 0.46-0.77) with similar relative (Pinteraction = 0.67) but a trend towards greater absolute risk reduction in the former [-5.1% vs. -2.3%; difference in absolute risk differences (ARDs) -2.8%, 95% CI -6.4% to 0.8%, P = 0.130]. A similar pattern was observed for more severe BARC 3 or 5 bleeding with a larger absolute risk reduction in HBR patients (-3.5% vs. -0.5%; difference in ARDs -3.0%, 95% CI -5.2% to -0.8%, P = 0.008). There was no significant difference in the key secondary endpoint of death, myocardial infarction, or stroke between treatment arms, irrespective of HBR status. Conclusions: Among HBR patients undergoing PCI who completed 3-month DAPT without experiencing major adverse events, aspirin discontinuation followed by ticagrelor monotherapy significantly reduced bleeding without increasing ischaemic events, compared with ticagrelor plus aspirin. The absolute risk reduction in major bleeding was larger in HBR than non-HBR patients.
2. Isokinetic knee strength and proprioception before and after anterior cruciate ligament reconstruction: A comparison between home-based and supervised rehabilitation
Jong-Min Lim, Jae-Jin Cho, Tae-Yeong Kim, Bum-Chul Yoon J Back Musculoskelet Rehabil. 2019;32(3):421-429. doi: 10.3233/BMR-181237.
Background: Rehabilitation after anterior cruciate ligament (ACL) reconstruction focuses on restoring knee deficiencies and function. However, the extent of the clinician's direct supervision that is required to recover knee function is unknown. Objective: To investigate differences in isokinetic knee strength improvement, endurance, and proprioception between home-based (HBR) and supervised rehabilitation (SR). Methods: Thirty participants were randomly allocated to each group after reconstruction. Isokinetic knee strength and proprioception were measured using the Biodex multi-joint and stability systems, respectively, before and after intervention. Results: The SR group showed a significant improvement from baseline, but not the HBR group (SR group, from 1.94 ± 1.44 to 1.02 ± 0.92, p< 0.05; HBR group, from 1.69 ± 0.88 to 1.61 ± 0.90, p> 0.05). There was a significant effect of exercise type on proprioception scores after controlling for pretest values (p< 0.05). No significant difference in isokinetic knee strength was observed between the groups. Conclusions: HBR recovered knee strength as effectively as the SR, but SR was more effective than HBR for the recovery of proprioception and functional knee movement. This result indicates that guidance from health professionals play an important role in enhancing proprioception for patients following ACL reconstruction.
3. Unimolecular HBr and HF Elimination Reactions of Vibrationally Excited C2H5CH2Br and C2D5CHFBr: Identification of the 1,1-HBr Elimination Reaction from C2D5CHFBr and Search for the C2D5(F)C:HBr Adduct
Timothy M Brown, Blanton R Gillespie, Mallory M Rothrock, Anthony J Ranieri, Melinda K Schueneman, George L Heard, Donald W Setser, Bert E Holmes J Phys Chem A. 2019 Oct 17;123(41):8776-8786. doi: 10.1021/acs.jpca.9b07029. Epub 2019 Oct 3.
Chemical activation experiments and computational methods have been used to study the unimolecular reactions of C2H5CH2Br and C2D5CHFBr with 90 and 93 kcal mol-1 of vibrational energy, respectively. The four-centered elimination reactions of HBr and DBr are the dominant reactions; however, 2,1-DF, 1,1-HBr, and 1,1-HF reactions are also observed from C2D5CHFBr. The main focus was to search for the role of the C2D5(F)C:HBr adduct in the 1,1-HBr elimination for comparison with carbene adducts in 1,1-HX(Y) elimination from RCHXY (X,Y = Cl and F) molecules. Models of transition states and molecules from electronic structure calculations were used in statistical calculations of the rate constants to assign threshold energies for each reaction based on the experimental rate constants. The threshold energy for 2,1-HBr elimination from 1-bromopropane is 50 kcal mol-1, which is in basic agreement with thermal activation experiments. Comparison of the 2,1-DBr and 2,1-HBr rate constants permits discussion of the kinetic isotope effects and the effect of F atom substitution on the threshold energy for 2,1-HBr elimination. Although CD3CD═CDF from 1,1-HBr elimination of C2D5CHFBr followed by D atom migration is an experimentally observed product, dissociation of the C2D5(F)C:HBr adduct may be the rate-limiting step rather than crossing the barrier associated with the transition state for 1,1-HBr elimination. The calculated dissociation energies of C2H5(X)C:HF adducts are 9.9, 9.3, and 9.0 kcal mol-1 for X = F, Cl, and Br, and the values for C2H5(F)C:HX are 9.9, 6.4, and ~4.9 kcal mol-1.
