A frequency downscaling technique for enhancing the accuracy of analog lock-in amplifier (LIA) architectures in giant magneto-impedance (GMI) sensor applications is presented in this paper. As a ...proof of concept, the proposed method is applied to two different LIA topologies using, respectively, analog and switching-based multiplication for phase-sensitive detection. Specifically, the operation frequency of both the input and the reference signals of the phase-sensitive detector (PSD) block of the LIA is reduced through a subsampling process using sample-and-hold (SH) circuits. A frequency downscaling from 200 kHz, which is the optimal operating frequency of the employed GMI sensor, to 1 kHz has been performed. In this way, the proposed technique exploits the inherent advantages of analog signal multiplication at low frequencies, while the principle of operation of the PSD remains unaltered. The circuits were assembled using discrete components, and the frequency downscaling proposal was experimentally validated by comparing the measurement accuracy with the equivalent conventional circuits. The experimental results revealed that the error in the signal magnitude measurements was reduced by a factor of 8 in the case of the analog multipliers and by a factor of 21 when a PSD based on switched multipliers was used. The error in-phase detection using a two-phase LIA was also reduced by more than 25%.
Lipoprotein(a) is similar to LDL cholesterol but contains apolipoprotein(a). A trial tested the effects of an oligonucleotide drug targeting apo(a) mRNA on lipoprotein(a) concentrations in patients ...with CVD.
Data support lipoprotein(a) (LpLp(a)) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in ...hepatocytes.
The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing.
OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.
Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol ...(LDL-C) goals.
The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH).
In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids.
In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was −21.2% (−59.8 mg/dl) in patients with HoFH and −54.9% (−104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from −19.6% at week 12 to −29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis.
Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.
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In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density ...lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking.
The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE FOURIER Open-Label Extension) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected.
A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 95% CI, 0.75-0.96;
=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 95% CI, 0.68-0.93;
=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 95% CI, 0.60-0.99;
=0.04).
Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation.
URL: https://www.
gov; Unique identifiers: NCT02867813 and NCT03080935.
Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety ...in the long term remains unknown.
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels.
In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted
<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years.
In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns.
URL: https://www.
gov; Unique identifier: NCT01764633.
Atherogenic dyslipidemia (AD), characterized by increased concentrations of apolipoprotein B (ApoB)-containing particles, is often present in individuals with type 2 diabetes mellitus (T2DM). ...Non-high-density lipoprotein cholesterol (non-HDL-C), cholesterol transported by apolipoprotein B (ApoB)-containing particles), and total apoB are considered secondary goals of lipid-lowering therapy to guide treatment of residual cardiovascular risk. The BANTING and BERSON studies demonstrated that evolocumab added to statin therapy reduced atherogenic lipid and lipoproteins concentrations in patients with T2DM.
This post-hoc analysis combined data from two randomized, placebo-controlled trials, BANTING and BERSON, to investigate the effect of evolocumab (140 mg every two weeks Q2W or 420 mg monthly QM) on atherogenic lipid (LDL-C, non-HDL-C, VLDL-C, remnant cholesterol) and lipoproteins (ApoB, lipoprotein(a) (Lpa)), and achievement of 2019 European Society of Cardiology/European Atherosclerosis Society lipid treatment goals in individuals with and without AD.
In individuals with high TGs with (n = 389) and without (n = 196) AD receiving background statin therapy, evolocumab, compared with placebo, substantially reduced the cholesterol levels from all ApoB atherogenic lipoproteins (least squares (LS) mean LDL-C by 66.7% to 74.3%, non-HDL-C by 53.4% to 65.8%, median remnant cholesterol by 28.9% to 34.2%, VLDL-C by 16.1% to 19.6%) and median TGs levels (by 17.5% to 19.6%) at the mean of weeks 10 and 12. LS mean ApoB was significantly reduced by 41.5% to 56.6% at week 12. Results were consistent in diabetic individuals with normal TGs (n = 519). Evolocumab was also associated with a significant reduction in median Lp(a) by 35.0% to 53.9% at the mean of weeks 10 and 12. A majority (74.7% to 79.8%) of evolocumab-treated individuals achieved the goal of both an LDL-C < 1.4 mmol/L and an LDL-C reduction of at least 50%, > 75% achieved non-HDL-C < 2.2 mmol/L at the mean of weeks 10 and 12, and > 67% achieved ApoB < 65 mg/dL at week 12.
Evolocumab effectively reduced LDL-C, non-HDL-C, ApoB, Lp(a), and remnant cholesterol in individuals with T2DM with and without AD. Evolocumab Q2W or QM enabled most individuals at high/very-high cardiovascular disease risk to achieve their LDL-C, non-HDL-C, and ApoB recommended goals.
IMPORTANCE: The 5-item Sick, Control, One, Fat, Food (SCOFF) questionnaire is the most widely used screening measure for eating disorders. However, no previous systematic review and meta-analysis ...determined the proportion of disordered eating among children and adolescents. OBJECTIVE: To establish the proportion among children and adolescents of disordered eating as assessed with the SCOFF tool. DATA SOURCES: Four databases were systematically searched (PubMed, Scopus, Web of Science, and the Cochrane Library) with date limits from January 1999 to November 2022. STUDY SELECTION: Studies were required to meet the following criteria: (1) participants: studies of community samples of children and adolescents aged 6 to 18 years and (2) outcome: disordered eating assessed by the SCOFF questionnaire. The exclusion criteria included (1) studies conducted with young people who had a diagnosis of physical or mental disorders; (2) studies that were published before 1999 because the SCOFF questionnaire was designed in that year; (3) studies in which data were collected during COVID-19 because they could introduce selection bias; (4) studies based on data from the same surveys/studies to avoid duplication; and (5) systematic reviews and/or meta-analyses and qualitative and case studies. DATA EXTRACTION AND SYNTHESIS: A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. MAIN OUTCOMES AND MEASURES: Proportion of disordered eating among children and adolescents assessed with the SCOFF tool. RESULTS: Thirty-two studies, including 63 181 participants, from 16 countries were included in this systematic review and meta-analysis. The overall proportion of children and adolescents with disordered eating was 22.36% (95% CI, 18.84%-26.09%; P < .001; n = 63 181) (I2 = 98.58%). Girls were significantly more likely to report disordered eating (30.03%; 95% CI, 25.61%-34.65%; n = 27 548) than boys (16.98%; 95% CI, 13.46%-20.81%; n = 26 170) (P < .001). Disordered eating became more elevated with increasing age (B, 0.03; 95% CI, 0-0.06; P = .049) and body mass index (B, 0.03; 95% CI, 0.01-0.05; P < .001). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, the available evidence from 32 studies comprising large samples from 16 countries showed that 22% of children and adolescents showed disordered eating according to the SCOFF tool. Proportion of disordered eating was further elevated among girls, as well as with increasing age and body mass index. These high figures are concerning from a public health perspective and highlight the need to implement strategies for preventing eating disorders.
Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed.
The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by ...serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model.
Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume ECV quantification). A control group was sacrificed after the initial CMR.
The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage.
T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.
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We present a new technique allowing the fabrication of large modal count photonic lanterns for space-division multiplexing applications. We demonstrate mode-selective photonic lanterns supporting 10 ...and 15 spatial channels by using graded-index fibres and microstructured templates. These templates are a versatile approach to position the graded-index fibres in the required geometry for efficient mode sampling and conversion. Thus, providing an effective scalable method for large number of spatial modes in a repeatable manner. Further, we demonstrate the efficiency and functionality of our photonic lanterns for optical communications. Our results show low insertion and mode dependent losses, as well as enhanced mode selectivity when spliced to few mode transmission fibres. These photonic lantern mode multiplexers are an enabling technology for future ultra-high capacity optical transmission systems.
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