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THIS thesis describes the development of a positionable waveguide array realized in a silicon nitride / silicon dioxide (Si3N4 core / SiO2 cladding) photonic platform. The positionable waveguide array is the heart of a novel alignment approach for high precision multi-channel chip-to-chip interconnects. This alignment approach enables submicron accurate alignment of an Indium Phosphide (InP) Photonic Integrated Circuit (PIC) and a TriPleX interposer chip. Mechanically flexible waveguides with integrated alignment functionality are realized within the TriPleX interposer chip. Compared to competing alignment approaches, the proposed concept targets higher accuracy and precision and allows for an increased level of automation to lower assembly time and cost. The final alignment of the waveguides is achieved in two stages. In the first stage, both chips are flip-chip bonded on a common substrate. The result of this first stage is a coarse alignment of the waveguides of both chips, as well as mechanical fixation and electrical connection of both chips. In the second stage, integrated alignment functionality of the positionable waveguide array within the TriPleX interposer chip is used to optimally align the interposer waveguides with the waveguides of the InP PIC. Once aligned, the alignment function of the positionable waveguide array has served its purpose and the positionable waveguide array is mechanically fixed, providing an optimal alignment for the lifetime of the PIC.

BackgroundMajor depressive disorder (MDD) has a high personal and socio-economic burden and more than 60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.MethodsPolygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).ResultsNo significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.DiscussionWe identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.

The Screening for Osteoporosis in Older Women for the Prevention of Fracture (SCOOP) study was a community-based screening intervention in women aged 70 to 85 years in the United Kingdom. In the screening arm, licensed osteoporosis treatments were recommended in women identified to be at high risk of hip fracture using the FRAX risk assessment tool (including bone mineral density measurement). In the control arm, standard care was provided. Screening led to a 28% reduction in hip fractures over 5 years. In this planned post hoc analysis, we wished to examine for interactions between screening effectiveness on fracture outcome (any, osteoporotic, and hip fractures) on the one hand and baseline FRAX 10-year probability of hip fracture on the other. All analyses were conducted on an intention-to-treat basis, based on the group to which women were randomized, irrespective of whether screening was completed. Of 12,483 eligible participants, 6233 women were randomized to screening, with treatment recommended in 898 (14.4%). No evidence of an effect or interaction was observed for the outcomes of any fracture or osteoporotic fracture. In the screening arm, 54 fewer hip fractures were observed than in the control arm (164 versus 218, 2.6% versus 3.5%), and commensurate with treatment being targeted to those at highest hip fracture risk, the effect on hip fracture increased with baseline FRAX hip fracture probability (p = 0.021 for interaction); for example, at the 10th percentile of baseline FRAX hip probability (2.6%), there was no evidence that hip fractures were reduced (hazard ratio [HR] = 0.93; 95% confidence interval [CI] 0.71 to 1.23), but at the 90th percentile (16.6%), there was a 33% reduction (HR = 0.67; 95% CI 0.53 to 0.84). Prior fracture and parental history of hip fracture positively influenced screening effectiveness on hip fracture risk. We conclude that women at high risk of hip fracture based on FRAX probability are responsive to appropriate osteoporosis management. © 2018 American Society for Bone and Mineral Research.

This paper reports on the progress related to a multichannel photonic alignment concept, which aims to achieve submicrometer alignment of the waveguides of two photonic integrated circuits (PICs). The concept consists of two steps: chip-to-chip positioning and fixing provide a coarse alignment after which waveguide-to-waveguide positioning and fixing result in a fine alignment. For the waveguide-to-waveguide alignment, mechanically flexible waveguides are used. Positioning of the waveguides is performed by integrated MEMS actuators. The flexible waveguides and the actuators are both integrated in one of the PICs. This paper reports on the fabrication and the mechanical characterization of the suspended waveguide structures. The flexible waveguide array is created in a PIC which is based on TriPleX technology, i.e. a silicon nitride (Si 3 N 4 ) core encapsulated in a silicon dioxide (SiO 2 ) cladding. The realized flexible waveguide structures consist of parallel cantilevered waveguide beams and a crossbar that connects the free ends of the waveguide beams. The fabrication of suspended structures consisting of a thick, i.e. 15 µm, TriPleX layer stack is challenged by the compressive mean stress in the SiO 2 . We have developed a fabrication method for the reliable release of flexible TriPleX structures, resulting in a 96% yield of cantilever beams. The realized suspended waveguide arrays have a natural out-of-plane deformation, which is studied using white light interferometry. Suspended waveguide beams reveal a downward slope at the base of the beams close to 0:5_. In addition to this slope, the beams have a concave upward profile. The constant curvature over the length of the waveguide beams is measured to range from 0:2 µm to 0:8 µm. The profiles measured over the length of the crossbars do not seem to follow a circular curvature. The variation in deflection within crossbars is measured to be smaller than 0:2 µm.

This paper proposes and tests a design of electro-thermal bimorph actuators for alignment of flexible photonic waveguides fabricated in 16 μm thick SiO2. The actuators are for use in a novel alignment concept for multi-port photonic integrated circuits (PICs), in which the fine alignment is taken care of by positioning of suspended, mechanically flexible waveguide beams on one or more of the PICs. The design parameters of the bimorph actuator allow to tune both the initial relative position of the waveguide end-facets, and the motion range of the actuators. Bimorph actuators have been fabricated and characterized. The maximum out-of-plane deflection of the bimorph actuator (with 720 μm-long poly-Si) can reach 18:5 μm with 126:42mW, sufficient for the proposed application.

This paper reports on the progress related to a multichannel photonic alignment concept, aiming for sub-micrometer precision in the alignment of the waveguides of two photonic integrated circuits (PICs). The concept consists of two steps: chip-to-chip positioning and chip bonding provide a coarse alignment after which waveguide-to-waveguide positioning and fixing result in a fine alignment. For the waveguide-to-waveguide alignment, an alignment functionality is developed and integrated in one of the PICs, consisting of mechanically flexible waveguides and MEMS actuators. This paper reports on the fabrication and characterization of a mechanically flexible waveguide array that can be positioned by two out-of-plane actuators. Thermal actuators are integrated with mechanically flexible waveguide beams to enable positioning them with high precision. By adding a poly-Si pattern on top of SiO2 beams, an out-of-plane bimorph actuator can be realized. An analytical model enables estimating the curvature and the deflection of a single bimorph beam. Acquiring a small initial deflection while having a large motion range of the actuator proves to have conflicting demands on the poly-Si/SiO2 thickness ratio. In this paper, we show that suspended waveguide arrays with integrated alignment functionality have an initial deflection- they curl up- due to residual stress in the materials. The actuators can be operated using a driving voltage between 0V to 45V, corresponding to ∼50mW. Using higher voltages brings the risk of permanently changing the material properties of the heaters. The actuators can accomplish an out-of-plane crossbar translation up to 6.5 μm at ∼50mW as well as a rotation around the propagation direction of the light ranging from -0:1° to 0.1°. At a constant actuation power of ∼50mW, the crossbar shows a drift in vertical deflection of 0.16 μm over a time of 30 min.

Fully automated, high precision, cost-effective assembly technology for photonic packages remains one of the main challenges in photonic component manufacturing. Next to the cost aspect the most demanding assembly task for multiport photonic integrated circuits (PICs) is the high-precision (±0.1 μm) alignment and fixing required for optical I/O in InP PICs, even with waveguide spot size conversion. In a European research initiative - PHASTFlex - we develop and investigate an innovative, novel assembly concept, in which the waveguides in a matching TriPleX interposer PIC are released during fabrication to make them movable. After assembly of both chips by flip-chip bonding on a common carrier, TriPleX based actuators and clamping functions position and fix the flexible waveguides with the required accuracy.

This paper proposes a microfabrication process for the reliable release of SiO2 beam structures. These structures are intended to be utilized in SiO2 photonic MEMS. A major fabrication challenge is the release of thick (>10 ?m) SiO2 structures with high yield. A single mask process is developed based on temporary reinforcement of the SiO2 structure. A supporting layer of Si functions as a reinforcing layer during etching and release, thereby enabling a high fabrication yield. Furthermore, the process allows to create structures of which the final Si support thickness is configurable from tens of micrometers to zero, thereby providing additional design freedom. The fabrication process is tested on a silicon wafer with a ?15 ?m thick thermal oxide layer. The obtained suspended structures are mechanically characterized. Two deformation effects can be distinguished: a curvature of the beam and a slope at the base of the beam. These effects are caused by the compressive mean stress and the gradient stress in the thermal SiO2. The curvature of the SiO2–Si beams corresponds to a concave downward profile while the SiO2 beams without supporting Si reveal a small curvature in the opposite direction (concave upward). The slope at the base is approximately ?0.5° for the SiO2 beams and between ?0.5° and 0° for the SiO2–Si beams. The acquired bending stiffness of long SiO2 beams is in the newton per meter range (e.g. 0.8 N m?1 for a cantilever measuring 1000 ?m in length and 13 ?m in width).