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Background: The impact of intense low-density lipoprotein cholesterol (LDL-C) reduction using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on profiles of platelet reactivity has yet to be explored., Aims: Our aim was to investigate the effects of the PCSK9 inhibitor, evolocumab, on platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) on clopidogrel treatment., Methods: This was a prospective, randomised, double-blind, placebo-controlled pharmacodynamic study in patients with ASCVD on clopidogrel treatment and with LDL-C levels ≥70 mg/dL despite a maximally tolerated statin dose. Patients were stratified according to levels of platelet reactivity using VerifyNow P2Y 12 reactivity units (PRU) into high platelet reactivity (HPR; PRU >208) or normal platelet reactivity (NPR; PRU >85 and ≤208). Each cohort was randomised to receive evolocumab 420 mg or placebo. The primary endpoint was the difference in PRU at 30 days., Results: A total of 84 patients (HPR, n=37 [19 evolocumab vs 18 placebo]; NPR, n=47 [22 evolocumab vs 25 placebo]) were included. Evolocumab significantly reduced LDL-C compared to placebo at 14 (p<0.001) and 30 (p=0.001) days. At 14 days, PRU levels were significantly lower with evolocumab compared to placebo in the HPR (218.2±29.7 vs 246.6±35.2; p=0.017), but not in the NPR cohort (141.2±42.8 vs 148.2±41.7; p=0.578). At 30 days, there were no significant differences in PRU in the HPR (219.3±38.3 vs 240.9±51.8; p=0.161) or NPR (141.5±54.3 vs 158.6±40.8; p=0.229) cohorts., Conclusions: Compared to placebo, evolocumab in adjunct to statin therapy did not significantly reduce platelet reactivity at 30 days in ASCVD patients on clopidogrel treatment despite intense LDL-C reduction. ClinicalTrials.gov: NCT03096288.

Competing Interests: Competing interests: None declared.

Previous reviews have reported virtual reality (VR) to be an effective method to treat pain. This scoping review examines the state of the science for VR and pain both generally and by pain type (acute and chronic) related to types of mechanisms, dosage, effectiveness, and adverse events (AEs). We searched online databases PubMed, Web of Science, PsychInfo, and CINAHL from 2010 to 2020 and included studies from peer reviewed journals that examined people with pain, (excluding pain-free participants) with a primary outcome measuring pain. We assessed studies for risk of bias using PEDro criteria. We described data through counts and percentages. Significant results were determined through P-values. We found 70 studies representing 4105 people; 46 acute pain studies (65.7%), 22 chronic pain studies (31.4%), and 2 (2.9%) "both." The most common VR mechanism was distraction (78.6%) then embodiment (17.1%). However, distraction was the mechanism for 97.8% acute pain studies while embodiment was more common for chronic pain (54.5%). Dosage of VR was inconsistently reported and varied considerably. VR treatment groups showed significant improvements in pain, particularly for intensity of pain (72.1%) and quality of pain (75.0%). Few studies examined AEs. Limitations of this review include only examining last 10 years of articles and that many studies were missing data. VR appears to be an effective intervention to address both acute and chronic pain. Research evaluating VR mechanisms, dosage, and AEs is warranted, as is further work in under-served populations (children for chronic pain and older adults) as the current evidence is largely limited to adult populations with pain., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Several platelet function tests (PFT) are available to assess the pharmacodynamic (PD) effects of P2Y 12 inhibitors. However, there are technical variances between PFT, and P2Y 12 inhibitors differ in pharmacological properties. Manufactures of PFT recommend a time-frame within which assessments needs to be executed. However, if the timing from blood sampling to processing affects PD results is unknown. We conducted a prospective study assessing the impact of timing from blood sampling to processing on PD measures using three different PFT. We studied 60 aspirin-treated patients with coronary artery disease (CAD) on maintenance P2Y 12 inhibiting therapy [clopidogrel 75 mg/day (n=20), prasugrel 10 mg/day (n=20) and ticagrelor 90 mg bid (n=20)]. PD assessments (trough levels) were performed by VerifyNow P2Y12 (VN), light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) at 30 minutes, 2 and 4 hours post-sampling; VASP was also performed at 24 hours. P2Y 12 reaction units (PRU) by VN significantly decreased over time with all P2Y 12 inhibitors (clopidogrel p<0.001; prasugrel p=0.016; ticagrelor p<0.001). PRU at 30 minutes and 2 hours were similar, but decreased at 4 hours. LTA showed consistent findings with VN. Conversely, PD measures as assessed by VASP were stable over time (p>0.1 for all P2Y 12 inhibitors). In conclusion, in CAD patients on maintenance therapy with P2Y 12 inhibitors, timing from blood sampling to processing significantly influences PD measures as assessed by VN and LTA, but not by VASP.

Patients with type 2 diabetes mellitus (T2DM) have impaired clopidogrel-induced antiplatelet effects, which may be in part attributed to their reduced sensitivity to insulin and consequently, results in upregulation of the P2Y12 signalling pathway. It has been hypothesised that insulin sensitising strategies may enhance clopidogrel-mediated P2Y12 inhibitory effects. The aim of this pilot pharmacodynamics (PD) study was to assess the impact of pioglitazone on clopidogrel-mediated P2Y12 inhibitory effects in patients with T2DM. This was a prospective, randomised, double-blind, placebo-controlled, cross-over PD study. Patients with T2DM and stable coronary artery disease on maintenance aspirin and clopidogrel were randomised to receive either pioglitazone 30 mg or matching placebo daily for 14 days. PD assessments were measured at baseline, 14 days after randomisation, at the end of the wash-out period, and 14 days after cross-over. The primary endpoint measure was maximal platelet aggregation (MPA) to 20 μM adenosine diphosphate (ADP) as assessed by light transmittance aggregometry (LTA). Flow cytometric analysis of vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI), and VerifyNow P2Y12 testing were also performed. A total of 15 randomised patients completed the study. MPA to 20 μM ADP (primary endpoint) was not significantly different with pioglitazone compared with placebo (49.53 ± 4.76 vs. 52.52 ± 3.89%; p = 0.594). Similarly, other PD measures did not differ significantly between the groups. In conclusion, in patients with T2DM on maintenance aspirin and clopidogrel therapy, the adjunctive use of pioglitazone does not result in enhanced inhibition of platelet P2Y12 mediated signalling.

Cilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilator-stimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.

Background: Patients with small coronary arteries are at high risk for complications after percutaneous coronary intervention (PCI). The objective of our study was to investigate the correlation between angiography, intravascular ultrasound (IVUS), and fractional flow reserve (FFR) in patients with moderate stenoses in small (<2.8 mm) coronary arteries., Methods and Results: Sixty consecutive patients, of 800 scheduled for PCI during the study period, were prospectively enrolled in the study. The FFR was measured after a 2-minute infusion of adenosine. For the preprocedural assessments, 60 patients underwent an FFR measurement, 56 underwent an IVUS, and 60 underwent an angiography; for the postprocedural assessments, 22 patients underwent an FFR measurement, 18 underwent an IVUS, and 22 underwent an angiography. The jeopardy score for the target vessel was calculated. Data were analyzed by an independent core laboratory. Patients with an FFR >0.75 were deferred from PCI. Patients were stratified in 2 groups according to their FFR values (< or =0.75 vs >0.75) and were followed for 1 year. Significant (FFR < or =0.75) coronary stenosis was observed in only 35% of the patients. The mean preprocedural FFR values were 0.79 +/- 0.13 for the overall population, 0.64 +/- 0.08 for the patients with an FFR < or =0.75, and 0.87 +/- 0.06 for the patients with an FFR >0.75. There was no correlation between angiography, IVUS, and FFR. The jeopardy score was inversely correlated with FFR (R = -0.32). Only a third of the patients with optimal stenting defined by IVUS achieved an FFR >0.90. After 1 year, 24% of the patients with an FFR < or =0.75 required a repeat PCI. There was no occurrence of myocardial infarction or death, and only 2.6% of the patients deferred from PCI required revascularization., Conclusion: Anatomical parameters are limited in determining the hemodynamic significance of small coronary disease. Most moderate stenoses in small coronaries could be safely deferred from PCI based on FFR.

Unlabelled: Graft disease remains a therapeutic challenge. Procedural complications and unsatisfactory patency rates are realized with both percutaneous intervention and repeat coronary artery bypass graft (CABG) surgery. The efficacy of sirolimus-eluting stents (SES) for the treatment of de novo coronary artery disease has been established, but the use of this technology to treat bypass graft disease remains undefined. The aim of this study was to evaluate the safety and feasibility of SES to treat patients with high-risk bypass graft disease., Methods: The compassionate use of SES (SECURE) study included patients with recurrent coronary disease and no acceptable alternative available treatment, including brachytherapy or CABG. Outcomes from 76 patients (n = 94 lesions) with graft lesions treated with SES in the U.S. were compared with the outcomes of 176 patients (n = 311 lesions) with only native vessels. IVUS follow-up was performed at 8 months in 14 patients with graft SES treatment., Results: In-hospital outcomes were similar between both groups, with 99% of patients discharged without adverse events. The incidence of target vessel failure including death, MI, and TVR at 12 months in the bypass graft group (55.3%) was similar to that observed in the native vessel group (45.5%, p = 0.17). Intimal hyperplasia (IH) measured by IVUS was 11.8 +/- 16.5%; 50% of patients with graft SES had < 1% IH at 8 months., Conclusion: Implantation of SES in high-risk patients with recurrent bypass graft disease is feasible. SES represents a future.

Intracoronary brachytherapy has become the current treatment of choice for patients with in-stent restenosis (ISR). The aim of the present study was to determine whether plaque extraction using debulking techniques prior to brachytherapy would improve the outcomes of patients with ISR. Patients enrolled into the START (n = 476) and START-40 (n = 205) trials were divided into four subgroups according to their treatment assignments: debulking-radiation, debulking-placebo, balloon angioplasty (BA) radiation, and BA placebo. Patients were further divided according to their ISR lesion length: all lesions, > 15 mm, and > 19 mm. Restenosis rates were higher in placebo, nonradiated lesions undergoing debulking (52.7%) vs. BA alone (38.5%; P = 0.04). Postprocedural minimal lumen diameter (MLD) was similar among the subgroups. Outcomes were similar between debulking and BA within each therapeutic arm. MLD after debulking radiation was greater in patients with ISR > 15 mm (post-MLD was 1.9 vs. 1.7 mm; P = 0.06) but not in the placebo. Debulking radiation patients had greater MLD at follow-up, but restenosis (23.5% after debulking vs. 32.7% BA alone) and late loss (0.3 mm in both subgroups) were not statistically different. There was a trend toward higher mortality among debulked patients (3.7%) compared to BA alone (0.8%). In patients with ISR > 19 mm, four patients died following debulking radiation as compared to no death after BA (P = 0.05). Our results do not support the strategy of plaque extraction prior to intracoronary beta-radiation for ISR., (Copyright 2003 Wiley-Liss, Inc.)

Intracoronary ultrasound (IVUS) facilitates optimal stent deployment in the treatment of coronary artery disease, which may favorably improve long-term outcome after stenting. Complications associated with IVUS include coronary vasospasm and rarely more serious adverse events such as vessel perforation or stent deformation. We report an IVUS catheter tip entrapment within a self-deploying nitinol stent., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: Augmentation cystoplasty has become a primary form of bladder management in children with a noncompliant bladder. Excellent urinary drainage is required for anastomotic healing and the removal of mucous buildup. Suprapubic drainage traditionally involves a Malecot catheter, although poor irrigation and dislodgment of this type of catheter are well-known complications. We report the placement of an intravesical Jackson-Pratt drain for urinary diversion in augmented bladders., Materials and Methods: We reviewed our use of an intravesical Jackson-Pratt drain for urinary diversion between 1995 and 1999 in 17 patients. Postoperative catheter drainage and irrigation characteristics were assessed as well as catheter related complications., Results: Average patient age was 13 years (range 3 to 27). The majority of patients underwent ileal (11) or sigmoid (4) cystoplasty and 1 each underwent composite and ureteral cystoplasty. Drains remained in place an average of 27 days (range 6 to 57). All patients had excellent drainage during the postoperative period. Irrigation was subjectively easier than with a Malecot catheter. Average cost of a latex-free Malecot catheter was 2.7-fold that of a Jackson-Pratt drain. No catheters became nonfunctional before removal, although 1 was inadvertently pulled during patient transfer., Conclusions: A Jackson-Pratt drain provides excellent urinary drainage in patients undergoing augmentation cystoplasty. Multiple openings along the tube seem to improve irrigation in contrast to the single opening in a Malecot catheter, which often aspirates a region of the augmented bladder. The ready availability, decreased cost, ease of irrigation, increased pliability with decreased chance of dislodgment and lack of latex make an intravesical Jackson-Pratt drain a superior choice for augmented neurogenic bladder.

Objective: To determine the nasopharyngeal colonization rate of penicillin-susceptible and penicillin-resistant strains of Streptococcus pneumoniae in young children, and to assess its relationship with the incidence of otitis media., Design: Observational study in 215 children younger than 6 years of age who received care in the Vanderbilt Vaccine Clinic from September 1, 1992, to August 31, 1993., Results: Of 842 nasopharyngeal cultures obtained, results for 44% of the cultures were positive for S. pneumoniae; 73% of the isolates were serotypes 6, 14, 19, or 23. Younger children had significantly higher rates of pneumococcal colonization than older children, with a peak at 1 year of age. By microdilution susceptibility testing, 37% of the cultures with positive results were intermediately or highly resistant to penicillin. Significantly more serotype 19 and 23 isolates were penicillin resistant than organisms of other serotypes. Children younger than 2 years of age had a twofold higher percentage of resistant isolates than those older than 2 years of age. A significant association was noted between nasopharyngeal carriage of S. pneumoniae and acute otitis media (p = 0.0002); however, the incidence of acute otitis media did not differ significantly between children colonized with penicillin-susceptible or penicillin-resistant strains. Unresolved otitis media was diagnosed more often in children who were colonized with resistant organisms than in children colonized with susceptible strains (p = 0.04)., Conclusions: There was a high rate of nasopharyngeal carriage of penicillin-resistant S. pneumoniae in this population of young children. Nasopharyngeal colonization was associated with an increased incidence of acute otitis media, and penicillin resistance was associated with an increased incidence of unresolved otitis media.