Low loss (Al)GaAs on an insulator waveguide platform.

In this Letter, we demonstrate a low loss gallium arsenide and aluminum gallium arsenide on an insulator platform by heterogenous integration. The resonators on this platform exhibit record high quality factors up to 1.5×106, corresponding to a propagation loss ∼0.4 dB/cm. For the first time, to the best of our knowledge, the loss of integrated III-V semiconductor on insulator waveguides becomes comparable with that of the silicon-on-insulator waveguides. This Letter should have a significant impact on photonic integrated circuits (PICs) and become an essential building block for the evolving nonlinear PICs and integrated quantum photonic systems in the future.

Heterogeneous silicon photonics sensing for autonomous cars.

Heterogeneous silicon photonics is uniquely positioned to address the photonic sensing needs of upcoming autonomous cars and provide the necessary cost reduction for widespread deployment. This is because it allows for wafer-scale active/passive integration, including optical sources. We present our recent research and the development of interferometric optical gyroscopes and LiDAR sensors. More specifically, we show a fully integrated gyroscope front-end occupying an area of only 4.5 mm2. We also show the first dense pitch optical phased array using heterogeneous phase shifters. The 4 µm pitch heterogeneous phase shifters provide very low V2π of only 0.35-1.4 V across 200 nm, low residual amplitude modulation of only 0.1-0.15 dB for 2π phase shift, extremely low static power consumption (<3 nW), and high speed (> 1 GHz). All of these factors make them ideal for next-generation LiDAR systems that employ optical phased arrays.

On-chip calibration and control of optical phased arrays.

Optical phased arrays (OPAs) are important as they allow beam steering and scanning with no moving parts. As their channel count increases, the complexity of control and calibration becomes challenging. We propose an architecture and algorithm that provide rapid on-chip calibration and are scalable to arbitrary channel counts with significantly reduced chip area and reduced overall complexity compared to previously proposed approaches. The optimized phase shifter tuning algorithm - Deterministic Stochastic Gradient Descent (DSGD) - rapidly converges to the optimal state speeding up the digital-to-analog converter based control of large channel count OPAs.

Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES: Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS: Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS: We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD. CONCLUSIONS: Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.

Polymorphism rs1761667 in the CD36 Gene Is Associated to Changes in Fatty Acid Metabolism and Circulating Endocannabinoid Levels Distinctively in Normal Weight and Obese Subjects.

The multifunctional CD36 scavenger receptor facilitates fatty acid (FA) uptake and oxidation and it has been involved in the pathophysiology related to dysfunctional FA metabolism. The common variant in the CD36 gene, rs1761667 (A/G), whose allele A is characterized by a reduced protein expression, has been associated with taste sensitivity to and preference for fat. We therefore aimed at evaluating whether the CD36 polymorphism may influence fatty acid metabolism and endocannabinoid biosynthesis in normal weight (NW) and obese (OB) subjects. Red blood cell (RBC) fatty acid composition, and plasma endocannabinoid levels were determined. In NW subjects with AA genotype was found a marked reduction of RBC saturated fatty acids and palmitic/linoleic ratio (PA/LA), considered as de novo lipogenesis (DNL) biomarkers. Remarkably, to the reduction of DNL biomarkers corresponded an increase of omega-6 index, an indirect marker of the impact on fatty acid metabolism of dietary omega-6 fatty acids, endocannabinoid levels and a higher waist/hip ratio. The presence of the G allele was instead associated with increased endocannabinoid plasma levels and a trend for increased waist/hip ratio in obese subjects, even though exhibited decreased BMI with respect to those with AA genotype. These data indicate that the CD36 polymorphism, rs1761667, leads to a distinct metabolic pattern in NW and in OB subjects. Therefore, their determination may be crucial in developing personalized therapeutic strategies for ameliorating dyslipidemia and other metabolic disorders.

Integrated broadband Ce:YIG/Si Mach-Zehnder optical isolators with over 100 nm tuning range.

We demonstrate integrated optical isolators with broadband behavior for the standard silicon-on-insulator platform. We achieve over 20 dB of optical isolation across 18 nm of optical bandwidth. The isolator is completely electrically controlled and does not require a permanent magnet. Furthermore, we demonstrate the ability to tune the central operating wavelength of the isolator across 100 nm, which covers the entire S + C telecom bands. These devices show promise for integration in optical systems in which broadband isolation is needed such as wavelength multiplexed systems or optical sensors.

Experimental demonstration of a 24-port packaged multi-microring network-on-chip in silicon photonic platform.

A 24-port packaged multi-microring optical network-on-chip has been tested for simultaneous co- and counter-propagating transmissions at the same wavelength at 10 Gbps. In the co-propagating scenario communications up to five hops with one interfering signal have been tested, together with transmissions impaired by up to three interfering signals. In the counter-propagating scenario the device performance has been investigated exploiting the ring resonators in both shared-source and shared-destination configurations. The spectral characterization is in good agreement with the theoretical results. Bit-error-rate measurements indicate power penalties at BER=10-9 limited to (i) 0.5 dB in the co-propagating scenarios independently from the number of interfering transmissions, (ii) 0.8 dB in the counter-propagating scenario with shared-source configuration, and (iii) 2 dB in the counter-propagating scenario with shared-destination configuration.

Participants with Normal Weight or with Obesity Show Different Relationships of 6-n-Propylthiouracil (PROP) Taster Status with BMI and Plasma Endocannabinoids.

Reduced taste sensitivity to 6-n-propylthiouracil (PROP), a genetic trait regarded as a general index for oral chemosensory perception, has been associated with a calorie-rich food preference and lower circulating endocannabinoid levels in participants with normal weight (NW), which suggests an adaptive mechanism to maintain a lean phenotype. In this study, we assessed whether participants with obesity (OB) show different patterns of plasma endocannabinoids and lipid metabolism biomarkers from those of NW, with further categorization based on their PROP sensitivity. NW and OB were classified by their PROP taster status as non-tasters (NT), medium-tasters (MT) and supertasters (ST). The blood samples were analysed for plasma endocannabinoids, nonesterified fatty acids (NEFA) and retinol, which have been associated to metabolic syndrome. In OB, we found a higher BMI and lower circulating endocannabinoids in ST vs. OB NT. However, OB ST showed lower circulating NEFA and retinol levels, which suggested a more favourable lipid metabolism and body fat distribution than those of OB NT. We confirmed lower plasma endocannabinoid levels in NW NT than in NW ST. These data suggest that PROP taste sensitivity determines metabolic changes and ultimately body mass composition differently in OB and NW.

Efficacy of Lomitapide in the Treatment of Familial Homozygous Hypercholesterolemia: Results of a Real-World Clinical Experience in Italy.

INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is a rare form of inherited dyslipidemia resistant to conventional cholesterol-lowering medications so that lipoprotein apheresis (LA) is usually required. Lomitapide has been approved for the treatment of HoFH. The aim of this study was to evaluate the benefits of lomitapide in HoFH patients followed with the usual clinical care. METHODS: Clinical and biochemical data were retrospectively collected in 15 HoFH patients (10 with mutations in the LDLR gene and 5 in the LDLRAP1 gene) treated for at least 6 months with lomitapide in addition to lipid-lowering therapies (LLT) in different Lipid Clinics across Italy. RESULTS: The mean follow-up period was 32.3 ± 29.7 months. During background therapies, HoFH patients showed a mean LDL-C level of 426.0 ± 204.0 mg/dl. The addition of lomitapide at the average dosage of 19 mg/day lowered LDL-C levels by 68.2 ± 24.8%. At their last visit, 60% of patients showed LDL-C <100 mg/dl and 46.6% <70 mg/dl. During follow-up, 8 of 10 patients receiving LA (80%) stopped this treatment due to marked LDL-C reduction. A wide range (13-95%) of individual LDL-C reduction was observed, but this was not related to genotype. During follow-up, 53.3% of patients reported at least one episode of diarrhea, but none was referred as severe; none had liver transaminase >5× ULN or had to stop treatment due to side effects. A subset of patients was evaluated by liver ultrasound and fibroscan (n = 5) or nuclear magnetic resonance with spectroscopy (MRS) (n = 1) not showing clinical evidence of liver damage. CONCLUSION: In this real-world experience, lomitapide was confirmed to be a very powerful cholesterol-lowering agent in HoFH showing a good safety profile.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.

OBJECTIVE: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? APPROACH AND RESULTS: Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. CONCLUSIONS: PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.

BER evaluation of a low-crosstalk silicon integrated multi-microring network-on-chip.

The operation of an integrated silicon-photonics multi-microring network-on-chip (NoC) is experimentally demonstrated in terms of transmission spectra and bit error rates at 10 Gb/s. The integrated NoC consists of 8 thermally tuned microrings coupled to a central ring. The switching functionalities are tested with concurrent transmissions at both the same and different wavelengths. Experimental results validate the analytical model based on the transfer matrix method. BER measurements show performance up to 10(-9) at 10 Gb/s with limited crosstalk and penalty (below 0.5 dB) induced by an interfering transmission.

Accurate vectorial finite element mode solver for magneto-optic and anisotropic waveguides.

In this work, a dielectric waveguide mode solver is presented considering a general nonreciprocal permittivity tensor. The proposed method allows us to investigate important cases of practical interest in the field of integrated optics, such as magneto-optical isolators and anisotropic waveguides. Unlike the earlier developed mode solver, our approach allows for the precise computation of both forward and backward propagating modes in the nonreciprocal case, ensuring high accuracy and computational efficiency. As a result, the nonreciprocal loss/phase shift can be directly computed, avoiding the use of the perturbation method. To compute the electromagnetic modes, the Rayleigh-Ritz functional is derived for the non-self adjoint case, it is discretized using the node-based finite element method and the penalty function is added to remove the spurious solutions. The resulting quadratic eigenvalue problem is linearized and solved in terms of the propagation constant for a given frequency (i.e., γ-formulation). The main benefits of this formulation are that it avoids the time-consuming iterations and preserves the matrix sparsity. Finally, the method is used to study two examples of integrated optical isolators based on nonreciprocal phase shift and nonreciprocal loss effect, respectively. The developed method is then compared with the perturbation approach and its simplified formulation based on semivectorial approximation.

Silicon-based all-optical multi microring network-on-chip.

An optical multi microring network-on-chip (MMR NoC) is proposed and evaluated through numerical simulations. The network architecture consists of a central resonating microring with local microrings connected to the input/output ports. A mathematical model based on the transfer matrix method is used to assess the MMR NoC performance and to analyze the fabrication tolerances. Results show that the proposed architecture exhibits a limited coherent crosstalk with a bandwidth suitable for 10 Gb/s signals, and it is robust to coupling ratio variations and ring radii fabrication inaccuracies.

Numerical study of high-index-contrast Er:LiNbO3 photonic wire lasers optically pumped at 980 nm.

For the first time [to our best knowledge] a high-index-contrast z-cut Er:LiNbO(3) photonic wire waveguide laser, optically pumped at 980 nm wavelength, is designed for continuous-wave operation. Waveguide modes and laser characteristics are numerically computed using a developed full vectorial finite-element method based tool. In order to maximize the output power of the laser, the active cavity length and output mirror's reflectivity have been optimized, considering different pump power and waveguide background losses. Efficient laser emission is theoretically predicted at 1531 nm wavelength for the fundamental TE mode and a value of threshold pump power as low as 0.2 mW has been computed.

Integrated TE and TM optical circulators on ultra-low-loss silicon nitride platform.

In this paper, we present two four-port optical circulators for TE and TM modes, respectively. Exploiting the recent technological development concerning Ce:YIG pulse laser deposition on silicon nitride platform, we design two integrated circulators, which can be used to implement several functions in integrated optics, such as de-interleavers, input/output amplifier isolators and output laser isolators. The proposed devices combine the benefit of low loss silicon nitride waveguides with the non-reciprocal properties of magneto-optical materials. The ring cross-section has been optimized in order to maximize the non-reciprocal phase shift and finally the scattering coefficients have been computed using the transfer matrix method. The material stability and refractive index regularity of silicon nitride, the small micro-ring footprint, and the high wavelength selectivity make these devices particularly attractive.

Sheep cheese naturally enriched in α-linolenic, conjugated linoleic and vaccenic acids improves the lipid profile and reduces anandamide in the plasma of hypercholesterolaemic subjects.

Intake of dairy fat has long been considered as a risk factor for CVD. Pasture and dietary lipid supplementation have been reported to be reliable strategies in ruminant nutrition, in order to increase the content of α-linolenic acid (ALA), conjugated linoleic acid (CLA) and vaccenic acid (VA), and decrease SFA in milk fat. In the present study, we aimed at verifying whether consumption of a sheep cheese, naturally enriched in ALA, CLA and VA, would modify the plasma lipid and endocannabinoid profiles in mildly hypercholesterolaemic subjects. A total of forty-two adult volunteers (nineteen males and twenty-three females) with diagnosed mildly hypercholesterolaemia (total cholesterol 5·68-7·49 mmol/l) were randomly assigned to eat 90 g/d of a control or enriched cheese for 3 weeks, with a cross-over after 3 weeks of washout. Plasma lipids, endocannabinoids, adipokines and inflammatory markers were measured. The intake of enriched cheese significantly increased the plasma concentrations of CLA, VA, the n-3 fatty acids ALA and EPA, and more remarkably decreased that of the endocannabinoid anandamide. LDL-cholesterol decreased significantly (7%). No changes were detected in the levels of inflammatory markers; however, a significant correlation was found between the plasma levels of anandamide and leptin. The control cheese modified none of the parameters measured. The results obtained do not support the view that intake of dairy fat is detrimental to hypercholesterolaemic subjects. Indeed, they show that a naturally enriched cheese possesses beneficial properties, since it ameliorates the plasma lipid profile, and more remarkably reduces endocannabinoid biosynthesis.

[LDL-apheresis in Sardinia, Italy]. / Dislipidemie: realta' nella regione Sardegna.

A steady increase in mean serum cholesterol levels has been observed in the Sardinian population over the past three decades, probably related to modifications in the diet such as the introduction of fast food; however, the mean serum values are still lowest compared with the other Italian regions. These data clearly contrast with the presence in our area of five LDL-apheresis centers where, in 20 years of activity, over 16,000 treatments were performed in 60 patients, accounting for 30% of LDL-apheresis-treated patients in Italy. The contrast is even more surprising when one considers that Sardinia has a population of only 1.6 million, i.e., 2.8% of the Italian population. A recessive form of familial hypercholesterolemia, called ARH, was recently discovered and studied in the Sardinian population. It has a prevalence of about 1:38,000- 40,000 for homozygous and double heterozygous subjects, who show clinical features similar to those of classical homozygous familial hypercholesterolemia, a disease characterized by autosomal dominant transmission.

Design of transverse electric ring isolators for ultra-low-loss Si3N4 waveguides based on the finite element method.

In this Letter we present the design of a novel (to our best knowledge) integrated TE isolator realized using ultra-low-loss Si(3)N(4) waveguides. The device is made of two straight waveguides coupled to an array of ring resonators including a Ce:YIG garnet grown on their internal side. The analysis demonstrates advantages in loss, isolation, and passband width as the number of rings is increased.

Silicon ring isolators with bonded nonreciprocal magneto-optic garnets.

A ring isolator is demonstrated for the first time by directly bonding a cerium-substituted yttrium iron garnet (Ce:YIG) onto a silicon ring resonator using oxygen plasma enhanced bonding. The silicon waveguide is 600 nm wide and 295 nm thick with 500-nm-thick Ce:YIG on the top to have reasonable nonreciprocal effect and low optical loss. With a radial magnetic field applied to the ring isolator, it exhibits 9-dB isolation at resonance in the 1550 nm wavelength regime.

HELP LDL-apheresis in two cases of familial hypercholesterolemic pregnant women.

We report our experience with selective LDL-apheresis in two women affected by autosomal recessive hypercholesterolemia and heterozygous familial hypercholesterolemia respectively, during pregnancy. To date only a few cases have been reported, because of the rarity of pregnancy in these patients and a hesitation of physicians to perform extracorporeal treatment. One of the patients had severe coronary artery disease, an absolute contraindication for pregnancy. Both patients had extremely elevated lipoprotein values because of their primary dyslipidemia, pregnancy-related modification of their lipid profile, and mandatory discontinuation of lipid-lowering drugs. In both cases the use of the Heparin-induced Extracorporeal Lipoprotein Precipitation (HELP) therapy improved the clinical situation and resulted in a good outcome for both mother and fetus.