Prenatal diagnosis of a skeletal disorder characterized by rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene: Case report and literature review.

BACKGROUND: The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features. CASE REPORT: A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio-total whole-exome sequencing (Trio-WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio-WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization. CONCLUSIONS: We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio-WES for diagnosis of skeletal dysplasia in fetuses.

Bottom-up Growth of Convex Sphere with Adjustable Cu(0)/Cu(I) Interfaces for Effective C2 Production from CO2 Electroreduction.

One challenge confronting the Cu2O catalysts in the electrocatalysis of carbon dioxide reduction reaction (CO2RR) is the reduction of active Cu(I) species, resulting in low selectivity and quick deactivation. In this study, we for the first time introduce a bottom-up growth of convex sphere with adjustable Cu(0)/Cu(I) interfaces (Cux@Cu2O convex spheres). Interestingly, the interfaces are dynamically modulated by varying hydrothermal time, thus regulating the conversion of C1 and C2 products. In particular, the 4 h hydrothermal treatment applied to Cu0.25@Cu2O convex sphere with the favorable Cu(0)/Cu(I) interface results in the highest selectivity for C2 products (90.5 %). In situ Fourier-transform infrared spectroscopy measurements and density functional theory calculations reveal that the Cu(0)/Cu(I) interface lowers the energy barrier for the production of ethylene and ethanol while increasing the coverage of localized *CO adsorbate for increased dimerization. This work establishes a novel approach for transforming the state of valence-sensitive electrocatalysts into high-value energy-related engineering products.

FPL+: Filtered Pseudo Label-based Unsupervised Cross-Modality Adaptation for 3D Medical Image Segmentation.

Adapting a medical image segmentation model to a new domain is important for improving its cross-domain transferability, and due to the expensive annotation process, Unsupervised Domain Adaptation (UDA) is appealing where only unlabeled images are needed for the adaptation. Existing UDA methods are mainly based on image or feature alignment with adversarial training for regularization, and they are limited by insufficient supervision in the target domain. In this paper, we propose an enhanced Filtered Pseudo Label (FPL+)-based UDA method for 3D medical image segmentation. It first uses cross-domain data augmentation to translate labeled images in the source domain to a dual-domain training set consisting of a pseudo source-domain set and a pseudo target-domain set. To leverage the dual-domain augmented images to train a pseudo label generator, domain-specific batch normalization layers are used to deal with the domain shift while learn the domain-invariant structure features, generating high-quality pseudo labels for target-domain images. We then combine labeled source-domain images and target-domain images with pseudo labels to train a final segmentor, where image-level weighting based on uncertainty estimation and pixel-level weighting based on dual-domain consensus are proposed to mitigate the adverse effect of noisy pseudo labels. Experiments on three public multi-modal datasets for Vestibular Schwannoma, brain tumor and whole heart segmentation show that our method surpassed ten state-of-the-art UDA methods, and it even achieved better results than fully supervised learning in the target domain in some cases.

Virome diversity shaped by genetic evolution and ecological landscape of Haemaphysalis longicornis.

BACKGROUND: Haemaphysalis longicornis is drawing attentions for its geographic invasion, extending population, and emerging disease threat. However, there are still substantial gaps in our knowledge of viral composition in relation to genetic diversity of H. longicornis and ecological factors, which are important for us to understand interactions between virus and vector, as well as between vector and ecological elements. RESULTS: We conducted the meta-transcriptomic sequencing of 136 pools of H. longicornis and identified 508 RNA viruses of 48 viral species, 22 of which have never been reported. Phylogenetic analysis of mitochondrion sequences divided the ticks into two genetic clades, each of which was geographically clustered and significantly associated with ecological factors, including altitude, precipitation, and normalized difference vegetation index. The two clades showed significant difference in virome diversity and shared about one fifth number of viral species that might have evolved to "generalists." Notably, Bandavirus dabieense, the pathogen of severe fever with thrombocytopenia syndrome was only detected in ticks of clade 1, and half number of clade 2-specific viruses were aquatic-animal-associated. CONCLUSIONS: These findings highlight that the virome diversity is shaped by internal genetic evolution and external ecological landscape of H. longicornis and provide the new foundation for promoting the studies on virus-vector-ecology interaction and eventually for evaluating the risk of H. longicornis for transmitting the viruses to humans and animals. Video Abstract.

Experimental Investigation of Vibration Isolator for Large Aperture Electromagnetic MEMS Micromirror.

The Micro-Electro-Mechanical-System (MEMS) micromirror has shown great advantages in Light Detection and Ranging (LiDAR) for autonomous vehicles. The equipment on vehicles is usually exposed to environmental vibration that may degrade or even destroy the flexure of the micromirror for its delicate structure. In this work, a mechanical low-pass filter (LPF) acting as a vibration isolator for a micromirror is proposed. The research starts with the evaluation of vibration influences on the micromirror by theoretical calculation and simulation. The results illustrate that mechanical load concentrates at the slow flexure of the micromirror as it is excited to resonate in second-order mode (named piston mode) in Z-direction vibration. A specific LPF for the micromirror is designed to attenuate the response to high-frequency vibration, especially around piston mode. The material of the LPF is a beryllium-copper alloy, chosen for its outstanding properties of elasticity, ductility, and fatigue resistance. To measure the mechanical load on the micromirror in practical, the on-chip piezoresistive sensor is utilized and a relevant test setup is built to validate the effect of the LPF. Micromirrors with or without the LPF are both tested under 10 g vibration in the Z-direction. The sensor output of the device with the LPF is 35.9 mV in piston mode, while the device without the LPF is 70.42 mV. The attenuation ratio is 0.51. This result demonstrates that the LPF structure can effectively reduce the stress caused by piston mode vibration.

Effect of Nano Nd2O3 on the Microstructure and High-Temperature Resistance of G@Ni Laser Alloying Coatings on Ti-6Al-4V Alloy.

Titanium and its alloys are widely used in high-end manufacturing fields. However, their low high-temperature oxidation resistance has limited their further application. Recently, laser alloying processing has attracted researchers to improve the surface properties of Ti, for which Ni coated graphite system is an excellent prospect due to its outstanding properties and metallurgical bonding between coating and substrate. In this paper, nanoscaled rare earth oxide Nd2O3 addition was added to Ni coated graphite laser alloying materials to research its influence on the microstructure and high-temperature oxidation resistance of the coating. The results proved that nano-Nd2O3 has an outstanding effect on refining coating microstructures, thus the high-temperature oxidation resistance was improved. Furthermore, with the addition of 1. 5 wt.% nano-Nd2O3, more NiO formed in the oxide film, which effectively strengthened the protective effect of the film. After 100 h of 800 °C oxidation, the oxidation weight gain per unit area of the normal coating was 14.571 mg/cm2, while that of the coating with nano-Nd2O3 addition was 6.244 mg/cm2, further proving that the addition of nano-Nd2O3 substantially improved the high-temperature oxidation properties of the coating.

Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects.

Background: Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis. Methods: Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing. Results: In family A, a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant ZIC3: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants PLD1: c.1132dupA and ZIC3: c.861delG were novel. Conclusion: The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.

Immunoinducible Carbon Dot-Incorporated Hydrogels as a Photothermal-Derived Antigen Depot to Trigger a Robust Antitumor Immune Response.

Immunogenic tumor cell death (ICD) induced by photothermal therapy (PTT) fails to elicit a robust antitumor immune response partially due to its inherent immunosuppressive microenvironment and poor antigen presentation. To address these issues, we developed an immunoinducible carbon dot-incorporated hydrogel (iCD@Gel) through a dynamic covalent Schiff base reaction using mannose-modified aluminum-doped carbon dots (M/A-CDs) as a cross-linking agent. The M/A-CDs possessed superior photothermal conversion efficiency and served as nanocarriers to load cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) for inducing the maturation of dendritic cells (DCs) via mannose receptor-mediated targeting delivery. Upon intratumoral injection, the as-prepared iCD@Gel induced ICD, and damage-associated molecular patterns (DAMPs) were released via photothermal ablation under 808 nm NIR irradiation. Subsequently, the iCD@Gel synergized with the DAMPs to significantly promote the maturation and antigen cross-presentation ability of DCs. This work provides a promising strategy to develop carbon dot-based therapeutic hydrogels for photothermal therapy and immune activation.

Interface Engineering in 2D/2D Heterogeneous Photocatalysts.

Assembling different 2D nanomaterials into heterostructures with strong interfacial interactions presents a promising approach for novel artificial photocatalytic materials. Chemically implementing the 2D nanomaterials' construction/stacking modes to regulate different interfaces can extend their functionalities and achieve good performance. Herein, based on different fundamental principles and photochemical processes, multiple construction modes (e.g., face-to-face, edge-to-face, interface-to-face, edge-to-edge) are overviewed systematically with emphasis on the relationships between their interfacial characteristics (e.g., point, linear, planar), synthetic strategies (e.g., in situ growth, ex situ assembly), and enhanced applications to achieve precise regulation. Meanwhile, recent efforts for enhancing photocatalytic performances of 2D/2D heterostructures are summarized from the critical factors of enhancing visible light absorption, accelerating charge transfer/separation, and introducing novel active sites. Notably, the crucial roles of surface defects, cocatalysts, and surface modification for photocatalytic performance optimization of 2D/2D heterostructures are also discussed based on the synergistic effect of optimization engineering and heterogeneous interfaces. Finally, perspectives and challenges are proposed to emphasize future opportunities for expanding 2D/2D heterostructures for photocatalysis.

Generalized minimum error entropy Kalman filter for non-Gaussian noise.

Error entropy is a well-known learning criterion in information theoretic learning (ITL), and it has already been applied to a wide range of fields. However, the shape of error entropy cannot be changed freely since its kernel function is the Gaussian kernel function, which causes the error entropy-based algorithm to handle only some specific kinds of noises. Benefiting from the property that the generalized Gaussian kernel function is free to adjust its shape, a novel Kalman-type filter algorithm based on the generalized minimum error entropy (GMEEKF) criterion is derived. Moreover, the mean error behavior, mean square error behavior, and computational complexity of the GMEEKF algorithm are analyzed. Finally, several simulations and experiments are performed to demonstrate the performance of the GMEEKF algorithm in comparison with the existing Kalman-type filter algorithms.

Influence of Scanning Speed on the Microstructure and Wear Resistance of Laser Alloying Coatings on Ti-6Al-4V Substrate.

Laser alloying has attracted significant attentions due to the advantages of high processing precision, good controllability and low heat effects on the substrate. However, the complexity of laser alloying requires further attentions on its processing parameters. This study aims at improving the wear resistance of the Ti-6Al-4V substrate by means of laser surface alloying with Ni-coated graphite (G@Ni). The effect of laser scanning speed is explored. The result suggests that the coating has a high surface quality and excellent metallurgical bonding with the substrate. NiTi and NiTi2 have a eutectic microstructure as well as in the TiC ceramic-reinforced phase as dendrites distribute in the γ-Ni matrix of the coatings. At higher scanning speeds, the lower energy density and shorter existence time of the molten pool refines the microstructure of the coating, improving its microhardness. At the scanning speed of 15 mm/s, the coating has the lowest wear weight loss due to its high microhardness and dense structure. This paper explores the influence of scanning speed on the microstructure and properties of the coatings, expanding the application of laser alloying on the surface modification of Ti-6Al-4V alloys.

NiCrBSi Coatings Fabricated on 45 Steel Using Large Spot Laser Cladding.

Ni35 coatings were fabricated on 45 steel using a CO2 laser at various parameters. A relatively large spot (10 mm diameter) was adopted, which was beneficial to the coating quality and the cladding efficiency. The cross-sectional geometry, phase constituent, and microstructure of the coatings were investigated. With a lower specific energy, coating height increased, while coating width, melted depth, dilution rate, width to height ratio and contact angle decreased. Ni35 coating primarily consisted of γ-Ni, FeNi3, Ni3B, Cr23C6, and Cr5B3. Dendrites with flower-like, fishbone-like, pearl-like, and column-like morphologies were observed. The fraction of flower-like dendrites increased gradually with the decrease in scanning velocity due to the dendrite growth direction evolution. With the decrease in scanning velocity, the microstructure of the heat-affected zone transformed from martensite to martensite + sorbite and finally sorbite. The maximum microhardness of the Ni35 coating reached 451.8 HV0.2, which was about double that of the substrate (220 HV0.2).

Microstructure and Wear Resistance of a Composite Coating Prepared by Laser Alloying with Ni-Coated Graphite on Ti-6Al-4V Alloy.

Titanium alloys are widely used in high-tech fields, while its disadvantages such as low hardness, high coefficient of friction and poor wear resistance have restricted its applications. This study focuses on improving the friction and wear resistance of Ti-6Al-4V titanium alloys by means of laser surface alloying with Ni-coated graphite (G@Ni). The results suggest that Ni acts as a protective layer to hinder the direct contact and reaction of C and Ti in the molten pool. A part of graphite is unmelted and finally remains to form a self-lubricating wear-resistant composite coating with a compact structure. The average hardness of the coating is approximately four times that of the substrate owing to the TiC hard phase and compact microstructures as the reinforcing phase. The residual graphite in the coating plays a friction-reduction role during the wear test. The wear resistance is increased to 8.53 times that of the substrate according to wear mass loss. This study can effectively enhance the performance and expand the application of the titanium alloys by improving the wear resistance and reducing the friction.

SO2- and H2O-Tolerant Catalytic Reduction of NOx at a Low Temperature via Engineering Polymeric VOx Species by CeO2.

Selective catalytic reduction (SCR) of NOx over V2O5-based oxide catalysts has been widely used, but it is still a challenge to efficiently reduce NOx at low temperatures under SO2 and H2O co-existence. Herein, SO2- and H2O-tolerant catalytic reduction of NOx at a low temperature has been originally demonstrated via engineering polymeric VOx species by CeO2. The polymeric VOx species were tactfully engineered on Ce-V2O5 composite active sites via the surface occupation effect of Ce, and the obtained catalysts exhibited remarkable low-temperature activity and strong SO2 and H2O tolerance at 250 °C. The strong interaction between Ce and V species induced the electron transfer from V to Ce and tuned the SCR reaction via the E-R pathway between the NH4+/NH3 species and gaseous NO. In the presence of SO2 and H2O, the polymeric VOx species had not been hardly influenced, while the formation of sulfate species on Ce sites not only promoted the adsorption of NH4+ species and the reaction between gaseous NO and NH4+ but also facilitated the decomposition of ammonium bisulfate through weakening the strong bond between HSO4- and NH4+. This work provided a new strategy for SO2- and H2O-tolerant catalytic reduction of NOx at a low temperature.

Associations between prepregnancy body mass index, gestational weight gain, and pregnancy outcomes in women with twin pregnancies: A five-year prospective study.

BACKGROUND: The purpose of this project was to investigate the relationship between prepregnancy body mass index (ppBMI), gestational weight gain (GWG), and pregnancy outcomes in women with twin pregnancies. METHODS: A prospective cohort of 369 women with dichorionic diamniotic twin pregnancies was recruited from 2016 to 2020. According to ppBMI using Chinese BMI classifications, they were categorized into the underweight (BMI < 18.5 kg/m2 ), normal (BMI 18.5-23.9 kg/m2 ), and overweight and obese (BMI ≥ 24 kg/m2 ) groups. In each ppBMI group, they were divided into two subgroups based on the presence or absence of the complications such as gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and small for gestational age (SGA). The outcomes including GDM, HDP, and SGA were compared among three ppBMI groups, and the associations of GWG with these outcomes within each ppBMI category were analyzed. RESULTS: Twin-pregnant women with overweight and obesity were at increased risks of HDP (aOR = 4.417 [95% CI = 1.826-9.415]) and SGA (2.288 [1.102-4.751]), whereas underweight women were prone to deliver SGA newborns (2.466 [1.157-5.254]). Women with GDM gained less weight during pregnancy than those without GDM within each ppBMI category. For overweight and obese women, greater GWG increased the incidence of HDP (1.235 [1.016-1.500]) and decreased the risk of SGA (0.818 [0.702-0.953]). CONCLUSIONS: Both ppBMI and GWG in twin-pregnant women were strongly associated with HDP and SGA, but not GDM.

Investigation of the Contact Characteristics of Silicon-Gold in an Anodic Bonding Structure.

Anodic bonding is broadly utilized to realize the structure support and electrical connection in the process of fabrication and packaging of MEMS devices, and the mechanical and electrical characteristics of the bonded interface of structure exhibit a significant impact on the stability and reliability of devices. For the anodic bonding structure, including the gold electrode of micro accelerometers, the elastic/plastic contact model of a gold-silicon rough surface is established based on Hertz contact theory to gain the contact area and force of Gauss surface bonding. The trans-scale finite element model of a silicon-gold glass structure is built in Workbench through the reconstruction of Gauss surface net by the reverse engineering technique. The translation load is added to mimic the process of contact to acquire the contact behaviors through the coupling of mechanical and electrical fields, and then the change law of contact resistance is obtained. Finally, the measurement shows a good agreement between the experimental results, theoretical analysis and simulation, which indicates there is almost no change of resistance when the surface gap is less than 20 nm and the resistance is less than 5Ω, while the resistance changes rapidly after the gap exceeds 20 nm.

Effect of interval between oocyte retrieval and resuscitation embryo transfer on pregnancy outcomes.

Objectives: Resuscitation transfer of embryos after elective cryopreservation has been widely applied in in vitro fertilization-embryo transfer (IVF-ET) therapy for human infertility or sterility owing to higher embryo implantation rates. This method separates oocyte retrieval from embryo transfer. The optimal time for frozen embryo transfer (FET) remains unknown. Therefore, this study mainly compares the advantages and disadvantages of delayed FET and immediate FET through retrospective analysis. Methods: We analyzed real world data of patients who underwent resuscitation transplantation between October 2019 and July 2021 at the Reproductive Center of Chengdu Jinjiang Hospital for Women's and Children's Health. Propensity score matching was applied to control potential confounding factors. A total of 5,549 patients who received at least one FET were analyzed. Patients undergoing transplantation within 60 days of oocyte retrieval were included in the immediate FET group (n = 1,265) and those undergoing transplantation > 60 days after retrieval were included in the delayed FET group (n = 4,284). Results: Live birth rates between the two groups were comparable (45.25% vs. 45.76%, p = 0.757). Moreover, no difference was observed in the rates of biochemical pregnancy (64.50% vs. 66.80%), clinical pregnancy (55.24% vs. 56.83%), ectopic pregnancy (1.47% vs. 1.39%), early miscarriage (14.41% vs. 16.20%), late miscarriage (2.21% vs. 2.09%), singleton premature delivery (16.67% vs. 18.29%), and neonatal deformity (1.97% vs. 1.80%). After stratifying the patients based on the type of embryo transferred, number of embryos transferred, FET protocol, and good prognosis criteria, live birth rates remained comparable between the two groups (p > 0.05). Conclusion: Pregnancy outcomes were comparable between the immediate and delayed FET groups.

Graphene-Based Biosensors with High Sensitivity for Detection of Ovarian Cancer Cells.

Ovarian cancer has the highest mortality rate in the world. Therefore, it is urgent but still challenging to develop an efficient circulating tumor cell (CTC) detection method to sensitively detect ovarian cancer. To address such issues, herein, for the first time, we present a novel CTC detection method for ovarian cancer cells by designing sensitive and rapid graphene-based biosensors. This graphene-based sensor, consisting of a cell pool and two electrodes, can be prepared by a conventional chip fabrication process. It demonstrates high-sensitivity detection even for several ovarian cancer cells by comparing the electrical signal before and after adding cell solution. Moreover, the graphene-based biosensors can perform rapid detection with good repeatability. This suggests that this novel method is possible to use for the early detection of ovarian cancer with very low CTC cell concentration. This work provides a novel and quick strategy to detect ovarian cancer and further judge or predict the risk of the transfer of ovarian cancer.

A Clinical Study on the Treatment of Children's Short Stature with Auxiliary Comprehensive Management Combined with Growth Patch.

OBJECTIVE: To explore the clinical effect of auxiliary comprehensive management combined with growth patch in the treatment of childhood idiopathic short stature (ISS). METHODS: From September 2017 to December 2019, 120 children with ISS who met the selection criteria were collected. Random number table method divided them into 2 groups: one group was given auxiliary comprehensive management and recorded as the routine group (n = 60), and the other group was given auxiliary comprehensive management and combined growth patch treatment and recorded as the combination group (n = 60). The course of treatment was 12 months. The effects of the two methods on children's height, bone age, body weight, and insulin-like growth factor (IGF)-1 and IGF-binding protein (IGFBP)-3 levels were compared. RESULTS: There was no statistical difference between the two groups in baseline height, genetic height, baseline bone age, baseline body weight, and body weight before and after treatment (P > 0.05). After treatment, the heights of the two groups were higher than before for the same group, the height growth values and predicted adult height of the combination group were higher than those of the routine group, and the predicted adult height of the combination group was higher than the genetic height of the same group (P < 0.001). There was no statistical difference in IGF-1 and IGFBP-3 levels before treatment between the two groups (P > 0.05). The levels of IGF-1 and IGFBP-3 after treatment in the two groups were higher than those in the same group before treatment, and the combination group was higher than that in the routine group (P < 0.05). CONCLUSION: On the basis of auxiliary comprehensive management, combined with growth patch for the treatment of children with ISS, it can effectively increase the height of the children, improve the levels of serum IGF-1 and IGFBP-3, and have significant clinical effects, which is beneficial to the healthy growth of the children.

Design of a high-performance non-linear gradient coil for diffusion weighted MRI of the breast.

Diffusion-weighted imaging (DWI) in the female breast is a magnetic resonance imaging (MRI) technique that complements clinical routine protocols, and that might provide an independent diagnostic value for specific clinical tasks in breast imaging. To further improve specificity of DWI in the breast, stronger and faster diffusion weighting is advantageous. Here, a dedicated gradient coil is designed, targeted at diffusion weighting in the female breast, with the peak gradient magnitude exceeding that of the current clinical MR scanners by an order of a magnitude. Design of application-tailored gradient coils in MRI has recently attracted increased attention. With the target application in mind, the gradient coil is designed on an irregularly shaped semi-open current-carrying surface. Due to the coil former closely fitting the non-spherical target region, non-linear encoding fields become particularly advantageous for achieving locally exceptionally high gradient strengths. As breast tissue has a predominantly isotropic cellular microstructure, the direction of the diffusion-weighting gradient may be allowed to vary within the target volume. However, due to the quadratic dependency of the b-factor on the gradient strength, variation of the gradient magnitude should be carefully controlled. To achieve the above design goals the corresponding multi-objective optimization problem is reformulated as a constrained optimization, allowing for flexible and precise control of the coil properties. A novel constraint is proposed, limiting gradient magnitude variation within every slice while allowing for variations in both the direction of the gradient within the slice and the magnitude across the slices. These innovations enable the design of a unilateral coil for diffusion weighting in the female breast with local gradient strengths exceeding 1 T/m with highly homogeneous diffusion weighting for imaging in the coronal slice orientation.