Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Učinak ketoprofena ili vrućice na farmakokinetiku cefepima u ovaca.

The pharmacokinetics of cefepime (20 mg/kg) were studied following intramuscular administration of cefepime alone, co-administered with ketoprofen (3 mg/kg) and in a febrile state (Escherichia coli LPS induced) in sheep. The concentration of cefepime in the serum was detected by High Performance Liquid Chromatography. Following single dose intravenous administration of cefepime, elimination half life (2.50 ± 0.05 h), the area under the curve (143.48± 7.36 μg.h/mL), body clearance (0.14 ± 0.01 L/h/kg) and volume of distribution (0.51 ± 0.03 L/kg) were determined. Following a single dose intramuscular administration of cefepime alone, peak serum concentration (28.76 ± 0.54 μg/mL) was obtained at 0.75 h. The absorption half life (t1/2Kα), volume of distribution (Vdarea), total body clearance (ClB) and elimination half life (t1/2β) of cefepime were 0.16 ± 0.01 h, 1.02 ± 0.08 L/kg, 0.13 ± 0.01 L/h/kg and 5.31 ± 0.23 h, respectively. Following co-administration of ketoprofen (30.74 ± 1.22 μg/mL) and in a febrile condition, a higher peak serum concentration of cefepime (39.68 ± 1.13 μg/mL) was observed at 0.75 h and 1 h, respectively. However, no significant changes were reported in other pharmacokinetic parameters following co administration of cefepime with ketoprofen. In a febrile state, absorption half life, area under the curve and bioavailability were significantly increased while the volume of distribution and clearance of cefepime were significantly decreased following intramuscular administration. Cefepime pharmacokinetic data (20 mg/kg) generated from the present study suggest that the drug may be administered with ketoprofen, and in febrile conditions in sheep, the drug may be given intramuscularly at 24 h intervals to combat susceptible bacterial infections.Istražena je farmakokinetika cefepima (20 mg/kg) nakon njegove intramuskularne primjene s ketoprofenom (3 mg/kg) u tijeku vrućice u ovaca izazvane lipopolisaharidima bakterije Escherichia coli. Koncentracija cefepima u serumu bila je određivana tekućinskom kromatografijom. Nakon jednokratne intravenske primjene poluživot njegova izlučivanja iznosio je 2,50 ± 0,05 h, površina ispod koncentracijske krivulje bila je 143,48 ± 7,36 μg.h/mL, ukupni tjelesni klirens iznosio je 0,14 ± 0,01 L/h/kg, a volumen raspodjele 0,51 ± 0,03 L/kg. Nakon jednokratne intramuskularne primjene samo cefepima vršna koncentracija u serumu iznosila je 28,76 ± 0,54 μg/mL nakon 0,75 h. Poluživot apsorpcije (t1/2Kα) iznosio je 0,16 ± 0,01 h, volumen raspodjele (Vdarea) 1,02 ± 0,08 L/kg, ukupni klirens iz organizma (ClB) 0,13 ± 0,01 L/h/kg te poluživot izlučivanja (t1/2β) 5,31 ± 0,23 h. Nakon istodobne primjene ketoprofena (30,74 ± 1,22 μg/mL) u uvjetima izazvane vrućice ustanovljena je veća vršna koncentracija cefepima (39,68 ± 1,13 mg/mL) u razdoblju od 0,75 h odnosno 1 sata. Vrijednosti ostalih farmakokinetičkih pokazatelja nisu se značajno promijenile poslije istodobne primjene cefepima s ketoprofenom. Poluživot apsorpcije, površina ispod koncentracijske krivulje i biološka raspoloživost bili su značajno povišeni, dok su volumen raspodjele i klirens cefepima bili značajno sniženi nakon intramuskularne primjene u febrilnih životinja. Farmakokinetičke značajke cefepima (20 mg/kg) proizašle iz ovog istraživanja upućuju na zaključak da se on u ovaca može primijeniti s ketoprofenom i u febrilnim stanjima. Može se primijeniti intramuskularno u razmaku od 24 sata za liječenje bolesti uzrokovanih bakterijama osjetljivima na cefepim

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Not AvailableSoft rot is a devastating disease of aloe and the infected plants developed symptoms of rotting tissues from collar region upwards. Aloe plants artificially inoculated with a Dickeya spp. (reported earlier as the causal agent) at the root zone but did not develop the disease symptoms, eliminating the possibility of pathogen to entering through roots. Besides, a Fusarium spp. was repeatedly isolated from collar regions of the naturally infected plants. Further, it was established that lesions produced due to fungal infection predisposed the subsequent infection of the bacterial pathogen. Sequencing results and phylogenetic analysis based on three partial genes of bacteria (dnaX, icdA and mdh) and fungus (ITS, TEF-1α and RPB-2) confirmed the identity of pathogens as Dickeya zeae and Fusarium falciforme, respectively. An artificial inoculation technique was developed for quick screening of aloe germplasm for resistance of bacterium. Among 40 accessions screened, none was found resistant, however, F. falciforme failed to produce lesion on two accessions (Guj4 and Raj3), consequently making them resistant to soft rot disease upon combined inoculation with both the pathogens. Besides the genetic constituent, rapid rotting was observed at 35 ◦C but not at and below the 15 ◦C temperature. In planta, the bacterium concentration increased gradually with the rise of incubation temperature between 15 and 35 ◦C. The present study suggests possible management aspects of the problem through (i) exploiting host resistance and (ii) escaping post–harvest decay by storing and transporting aloe leaves at temperatures ≤ 15 ◦C and (iii) avoidance of water stagnation in field.Not Availabl

Co-design of a patient experience survey for arthritis central intake: an example of meaningful patient engagement in healthcare design

Abstract Background To describe the process of patient engagement to co-design a patient experience survey for people with arthritis referred to central intake. Methods We used a participatory design to engage with patients to co-design a patient experience survey that comprised three connected phases: 1) Identifying the needs of patients with arthritis, 2) Developing a set of key performance indicators, and 3) Determining the survey items for the patient experience survey. Results Patient recommendations for high quality healthcare care means support to manage arthritis, to live a meaningful life by providing the right knowledge, professional support, and professional relationship. The concept of integrated care was a core requirement from the patients’ perspective for the delivery of high quality arthritis care. Patients experience with care was ranked in the top 10 of 28 Key Performance Indicators for the evaluation of central intake, with 95% of stakeholders rating it as 9/10 for importance. A stakeholder team, including Patient and Community Engagement Researchers (PaCER), mapped and rated 41 survey items from four validated surveys. The final patient experience survey had 23 items. Conclusion The process of patient engagement to co-design a patient experience survey, for people with arthritis, identified aspects of care that had not been previously recognized. The linear organization of frameworks used to report patient engagement in research does not always capture the complexity of reality. Additional resources of cost, time and expertise for patient engagement in co-design activity are recognized and should be included, where possible, to ensure high quality data is captured

42GHz ECRH assisted Plasma Breakdown in tokamak SST-1

In SST-1, 42GHz ECRH system has been commissioned to carry out breakdown and heating experiments at 0.75T and 1.5T operating toroidal magnetic fields. The 42GHz ECRH system consists of high power microwave source Gyrotron capable to deliver 500kW microwave power for 500ms duration, approximately 20 meter long transmission line and a mirror based launcher. The ECRH power in fundamental O-mode & second harmonic X-mode is launched from low field side (radial port) of the tokamak. At 0.75T operation, approximately 300 kW ECH power is launched in second harmonic X-mode and successful ECRH assisted breakdown is achieved at low loop_voltage ~ 3V. The ECRH power is launched around 45ms prior to loop voltage. The hydrogen pressure in tokamak is maintained ~ 1×10-5mbar and the pre-ionized density is ~ 4×1012/cc. At 1.5T operating toroidal magnetic field, the ECH power is launched in fundamental O-mode. The ECH power at fundamental harmonic is varied from 100 kW to 250 kW and successful breakdown is achieved in all ECRH shots. In fundamental harmonic there is no delay in breakdown while at second harmonic ~ 40ms delay is observed, which is normal in case of second harmonic ECRH assisted breakdown