Recent Advances in Light Penetration Depth for Postharvest Quality Evaluation of Fruits and Vegetables.

Light penetration depth, as a characteristic parameter reflecting light attenuation and transmission in biological tissues, has been applied in nondestructive detection of fruits and vegetables. Recently, with emergence of new optical detection technologies, researchers have begun to explore methods evaluating optical properties of double-layer or even multilayer fruit and vegetable tissues due to the differences between peel and pulp in the chemical composition and physical properties, which has gradually promoted studies on light penetration depth. A series of demonstrated research on light penetration depth could ensure the accuracy of the optical information obtained from each layer of tissue, which is beneficial to enhance detection accuracy for quality assessment of fruits and vegetables. Therefore, the aim of this review is to give detailed outlines about the theory and principle of light penetration depth based on several emerging optical detection technologies and to focus primarily on its applications in the field of quality evaluation of fruits and vegetables, its future applicability in fruits and vegetables and the challenges it may face in the future.

WRKY75 regulates anthocyanin accumulation in juvenile citrus tissues.

The anthocyanin accumulation in juvenile tissues can enhance the ornamental value, attract pollinators, and help improve abiotic stress. Although transcriptional regulation studies of anthocyanin have been relatively extensive, there are few reports on the mechanism of anthocyanin accumulation in young tissues. This study reveals that many juvenile citrus tissues (flowers, leaves, and pericarp) undergo transient accumulation of anthocyanins, exhibiting a red coloration. Using weighted gene co-expression network analysis (WGCNA) identified CitWRKY75 as a candidate gene. After detecting the expression levels of CitWRKY75 in various citrus juvenile tissues, the expression trend of CitWRKY75 was highly consistent with the red exhibiting and fading. Overexpression of CitWRKY75 in tobacco significantly increased the anthocyanin content. LUC and yeast one-hybrid assay demonstrated that CitWRKY75 could bind to the promoter of CitRuby1(encoding the key transcription factor promoting anthocyanin accumulation) and promote its expression. Finally, comparing the expression levels of CitWRKY75 and CitRuby1 in the late development stage of blood orange found that CitWRKY75 was not the main regulatory factor for anthocyanin accumulation in the later stage. This study used reverse genetics to identify a transcription factor, CitWRKY75, upstream of CitRuby1, which promotes anthocyanin accumulation in citrus juvenile tissues. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01490-9.

Integrated prenatal and postnatal management for neonates with transposition of the great arteries: thirteen-year experience at a single center.

BACKGROUND: Transposition of the great arteries (TGA) is the most common cyanotic congenital heart defect in neonates but with low prenatal detection rate. This study sought to review the prenatal diagnosis, associated abnormalities, and mid-term postnatal outcomes of fetuses with TGA and investigate the integrated prenatal and postnatal management for TGA neonates. METHODS: A total of 134 infants prenatally diagnosed with TGA in Guangdong Provincial People's Hospital, China, from January 2009 to December 2022 were included in the study. The prenatal ultrasound data and neonatal records were reviewed to assess the accuracy of prenatal diagnosis. Univariate and multivariate logistic and Cox analyses were used to identify risk factors associated with prognosis in such individuals. RESULTS: The population originated from 40 cities in 10 provinces in China, with integrated antenatal and postnatal management rate reaching 94.0% (126/134) and a high accuracy rate (99.3%) of prenatal primary diagnosis. The median period of follow-up was 1.6 [interquartile range (IQR) 0.1-4.3] years. There were 3 (2.2%) postnatal deaths, 118 (88.1%) patients undergoing arterial switch operation (ASO), 3 (2.2%) undergoing Rastelli operations and 5 (3.7%) doing stage operations. Of 118 patients receiving ASO, the major morbidity occurred in 64 patients (54.2%), and right ventricular outflow tract obstruction (RVOTO) in 31 (26.3%). In the multivariate logistic analysis, gestational ages at birth (OR = 0.953, 95% CI 0.910-0.991; p = 0.025) and cardiopulmonary bypass (CPB) time (OR = 1.010, 95% CI 1.000-1.030; p = 0.038) were identified as independent risk factors associated with major morbidity. In the Cox multivariate analysis, aortic cross-clamping time (HR = 1.030, 95% CI 1.000-1.050; p = 0.017) was identified as independent risk factor associated with RVOTO. CONCLUSION: Earlier gestational ages at birth and longer CPB time are significantly associated with increased morbidity. Integrated prenatal and postnatal management is recommended for patients with prenatal diagnosis of TGA.

Physics-Informed Masked Autoencoder for active sparse imaging.

Imaging technology based on detecting individual photons has seen tremendous progress in recent years, with broad applications in autonomous driving, biomedical imaging, astronomical observation, and more. Comparing with conventional methods, however, it takes much longer time and relies on sparse and noisy photon-counting data to form an image. Here we introduce Physics-Informed Masked Autoencoder (PI-MAE) as a fast and efficient approach for data acquisition and image reconstruction through hardware implementation of the MAE (Masked Autoencoder). We examine its performance on a single-photon LiDAR system when trained on digitally masked MNIST data. Our results show that, with 1.8 × 10 - 6 or less detected photons per pulse and down to 9 detected photons per pixel, it achieves high-quality image reconstruction on unseen object classes with 90% physical masking. Our results highlight PI-MAE as a viable hardware accelerator for significantly improving the performance of single-photon imaging systems in photon-starving applications.

Exploring bioactive compounds in chickpea and bean aquafaba: Insights from glycomics and peptidomics analyses.

The objective of this study was to identify bioactive oligosaccharides and peptides in the cooking water of chickpeas and common beans, known as aquafaba. The oligosaccharides stachyose, raffinose and verbascose were quantified by high-performance anion-exchange chromatography; 78 and 67 additional oligosaccharides were identified in chickpea and common bean aquafaba, respectively, by LC-MS/MS. Chickpea aquafaba uniquely harbored ciceritol and other methyl-inositol-containing oligosaccharides. In prebiotic growth assays, chickpea aquafaba oligosaccharides were differentially utilized, promoting growth of Limosilactobacillus reuteri DSM 20016 and Bifidobacterium longum subsp. infantis ATCC 15697, but not Lacticaseibacillus rhamnosus GG. Dimethyl labeling, along with LC-MS/MS, effectively differentiated α- and γ-glutamyl peptides, revealing the presence of several γ-glutamyl peptides known to possess kokumi and anti-inflammatory activities, including γ-Glu-Phe and γ-Glu-Tyr in chickpeas aquafaba and γ-Glu-S-methyl-Cys and γ-Glu-Leu in beans aquafaba. This work uncovered unique bioactive peptides and oligosaccharides in aquafaba, helping promote its valorization, food system sustainability, and future health-promoting claims.

Study on Effect of Surface Micro-Texture of Cemented Carbide on Tribological Properties of Bovine Cortical Bone.

In bone-milling surgical procedures, the intense friction between the tool and bone material often results in high cutting temperatures, leading to the thermal necrosis of bone cells. This paper aims to investigate the effect of micro-texture on the tribological properties of YG8 cemented carbide in contact with bone. The main objective is to guide the design of tool surface microstructures to reduce frictional heat generation. To minimize experimental consumables and save time, numerical simulations are first conducted to determine the optimal machining depth for the texture. Subsequently, micro-textures with different shapes and pitches are prepared on the surface of YG8 cemented carbide. These textured samples are paired with bovine cortical bone pins featuring various bone unit arrangements, and friction and wear tests are conducted under physiological saline lubrication. The experimental results indicate that the appropriate shape and pitch of the micro-texture can minimize the coefficient of friction. The parallel arrangement of bone units exhibits a lower coefficient of friction compared to the vertical arrangement. This study holds significant implications for the design and fabrication of future micro-texture milling cutters.

Non-contact elasticity contrast imaging using photon counting.

Significance: Tissues' biomechanical properties, such as elasticity, are related to tissue health. Optical coherence elastography produces images of tissues based on their elasticity, but its performance is constrained by the laser power used, working distance, and excitation methods. Aim: We develop a new method to reconstruct the elasticity contrast image over a long working distance, with only low-intensity illumination, and by non-contact acoustic wave excitation. Approach: We combine single-photon vibrometry and quantum parametric mode sorting (QPMS) to measure the oscillating backscattered signals at a single-photon level and derive the phantoms' relative elasticity. Results: We test our system on tissue-mimicking phantoms consisting of contrast sections with different concentrations and thus stiffness. Our results show that as the driving acoustic frequency is swept, the phantoms' vibrational responses are mapped onto the photon-counting histograms from which their mechanical properties-including elasticity-can be derived. Through lateral and longitudinal laser scanning at a fixed frequency, a contrast image based on samples' elasticity can be reliably reconstructed upon photon level signals. Conclusions: We demonstrated the reliability of QPMS-based elasticity contrast imaging of agar phantoms in a long working distance, low-intensity environment. This technique has the potential for in-depth images of real biological tissue and provides a new approach to elastography research and applications.

Photon counting Raman spectroscopy: a benchmarking study vs surface plasmon enhancement.

We demonstrate a single-photon counting Raman spectroscope and benchmark it against conventional and surface-enhanced Raman spectroscopy. For direct comparison without ambiguity, we use the same solutions of Rhodamine 6G and a common optical setup with either a spectrometer or an acousto-optic tunable filter, whereas the surface enhancement is realized with immobilized Ag nanoparticles. Our results find that the single photon counting significantly elevates the detection sensitivity by up to eight orders of magnitude, arriving at a comparable level of surface-enhanced Raman spectroscopy. Another significant advantage is with the time-resolving measurement, where we demonstrate time-gated and time-correlated single-photon counting with sub-nanosecond resolution. It offers insights into the samples' transient responses and enables the isolation of Raman scattering from fluorescence signals.

Invertible all-optical logic gate on chip.

We demonstrate an invertible all-optical gate on chip, with the roles of control and signal switchable by slightly adjusting their relative arrival time at the gate. It is based on the quantum Zeno blockade (QZB) driven by sum-frequency generation (SFG) in a periodically poled lithium niobate microring resonator. For two nearly identical nanosecond pulses, the later arriving pulse is modulated by the earlier arriving one, resulting in 2.4 and 3.9 power extinction between the two, respectively, when their peak powers are 1 mW and 2 mW, respectively. Our results, while to be improved and enriched, herald a new, to the best of our knowledge, paradigm of logical gates and circuits for exotic applications.

Engineered plants provide a photosynthetic platform for the production of diverse human milk oligosaccharides.

Human milk oligosaccharides (HMOs) are a diverse class of carbohydrates which support the health and development of infants. The vast health benefits of HMOs have made them a commercial target for microbial production; however, producing the approximately 200 structurally diverse HMOs at scale has proved difficult. Here we produce a diversity of HMOs by leveraging the robust carbohydrate anabolism of plants. This diversity includes high-value and complex HMOs, such as lacto-N-fucopentaose I. HMOs produced in transgenic plants provided strong bifidogenic properties, indicating their ability to serve as a prebiotic supplement with potential applications in adult and infant health. Technoeconomic analyses demonstrate that producing HMOs in plants provides a path to the large-scale production of specific HMOs at lower prices than microbial production platforms. Our work demonstrates the promise in leveraging plants for the low-cost and sustainable production of HMOs.

Broadband frequency comb generation through cascaded quadratic nonlinearity in thin-film lithium niobate microresonators.

Broadband frequency comb generation through cascaded quadratic nonlinearity remains experimentally untapped in free-space cavities with bulk χ(2) materials mainly due to the high threshold power and restricted ability of dispersion engineering. Thin-film lithium niobate (LN) is a good platform for nonlinear optics due to the tight mode confinement in a nano-dimensional waveguide, the ease of dispersion engineering, large quadratic nonlinearities, and flexible phase matching via periodic poling. Here we demonstrate broadband frequency comb generation through dispersion engineering in a thin-film LN microresonator. Bandwidths of 150 nm (80 nm) and 25 nm (12 nm) for center wavelengths at 1560 and 780 nm are achieved, respectively, in a cavity-enhanced second-harmonic generation (doubly resonant optical parametric oscillator). Our demonstration paves the way for pure quadratic soliton generation, which is a great complement to dissipative Kerr soliton frequency combs for extended interesting nonlinear applications.

How do probiotics alleviate constipation? A narrative review of mechanisms.

Constipation is a common gastrointestinal condition, which may occur at any age and affects countless people. The search for new treatments for constipation is ongoing as current drug treatments fail to provide fully satisfactory results. In recent years, probiotics have attracted much attention because of their demonstrated therapeutic efficacy and fewer side effects than pharmaceutical products. Many studies attempted to answer the question of how probiotics can alleviate constipation. It has been shown that different probiotic strains can alleviate constipation by different mechanisms. The mechanisms on probiotics in relieving constipation were associated with various aspects, including regulation of the gut microbiota composition, the level of short-chain fatty acids, aquaporin expression levels, neurotransmitters and hormone levels, inflammation, the intestinal environmental metabolic status, neurotrophic factor levels and the body's antioxidant levels. This paper summarizes the perception of the mechanisms on probiotics in relieving constipation and provides some suggestions on new research directions.

Molecular mechanism of wedelolactone inhibits high glucose-induced human retinal vascular endothelial cells injury through regulating miR-190 expression.

To investigate the effects and molecular mechanisms of wedelolactone (WEL) on high glucose-induced injury of human retinal vascular endothelial cells (HRECs). The cell injury model was established by incubating HRECs with 30 mmol/L glucose for 24 hour. HRECs were divided into control (Con) group, high glucose (HG) group, HG + WEL-low dose (L) group, HG + WEL-medium dose (M), HG + WEL-high dose (H) group, HG + miR-NC group, HG + miR-190 group, HG + WEL + antimiR-NC group, HG + WEL + antimiR-190 group. The kit detects cellular reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) content; cell apoptosis was analyzed by flow cytometry; miR-190 expression was detected by real-time quantitative PCR (RT-qPCR). Compared with Con group, the levels of ROS and MDA in the HG group were significantly increased (P < .01), the SOD activity and the expression of miR-190 expression were significantly decreased (P < .05), and the apoptosis rate was significantly increased (P < .01). Compared with HG group, the levels of ROS and MDA in HG + WEL-L group, HG + WEL-M group and HG + WEL-H group were significantly decreased (P < .05), SOD activity and miR-190 expression were significantly increased (P < .05), and apoptosis rate was significantly reduced (P < .05). Compared with the HG + miR-NC group, the levels of ROS and MDA in HG + miR-190 group were significantly reduced (P < .01), SOD activity was significantly increased (P < .01), and apoptosis rate was significantly reduced (P < .05). Compared with the HG + WEL + antimiR-NC group, the ROS level and MDA content in the HG + WEL + antimiR-190 group were significantly increased (P < .05), SOD activity was significantly decreased (P < .05), and apoptosis rate was significantly increased (P < .05). Wedelolactone can attenuate high glucose-induced HRECs apoptosis and oxidative stress by up-regulating miR-190 expression.

A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer.

BACKGROUND: Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer. RESULTS: An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies. CONCLUSION: We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer.

LRFNet: A real-time medical image fusion method guided by detail information.

Multimodal medical image fusion (MMIF) technology plays a crucial role in medical diagnosis and treatment by integrating different images to obtain fusion images with comprehensive information. Deep learning-based fusion methods have demonstrated superior performance, but some of them still encounter challenges such as imbalanced retention of color and texture information and low fusion efficiency. To alleviate the above issues, this paper presents a real-time MMIF method, called a lightweight residual fusion network. First, a feature extraction framework with three branches is designed. Two independent branches are used to fully extract brightness and texture information. The fusion branch enables different modal information to be interactively fused at a shallow level, thereby better retaining brightness and texture information. Furthermore, a lightweight residual unit is designed to replace the conventional residual convolution in the model, thereby improving the fusion efficiency and reducing the overall model size by approximately 5 times. Finally, considering that the high-frequency image decomposed by the wavelet transform contains abundant edge and texture information, an adaptive strategy is proposed for assigning weights to the loss function based on the information content in the high-frequency image. This strategy effectively guides the model toward preserving intricate details. The experimental results on MRI and functional images demonstrate that the proposed method exhibits superior fusion performance and efficiency compared to alternative approaches. The code of LRFNet is available at https://github.com/HeDan-11/LRFNet.

An accurate calculation method for inductor air gap length in high power DC-DC converters.

High-power inductors are fundamental components in high-power DC-DC converters, with their performance being a crucial metric of converter efficiency. This paper presents an in-depth analysis of a novel calculation method for the air gap length in such inductors. Taking into account the effects of air gap diffusion and the winding magnetic field, an expression for the air gap diffusion radius is derived, focusing on a distributed air gap structure. Furthermore, models for calculating the air gap and winding reluctance are developed, grounded in electromagnetic field theory. An equivalent magnetic circuit model, formulated based on Kirchhoff's second law, facilitates the proposed method for air gap length calculation. This study also involves the development of 3D models for both discrete and decoupled integrated inductors. The comparison between simulation outcomes and calculated air gap lengths indicates a maximum error of less than 8%, with the minimum error being as low as - 0.79%. Compared with traditional methods, the calculation method proposed in this paper has significant advantages. Additionally, the discrepancy between calculated values and experimental measurements is found to be 1.11%. These results validate the accuracy and applicability of the theoretical analysis and calculation method, underscoring their significance in the design and optimization of high-power DC-DC converters.

Osteoarthritis versus psoriasis arthritis: Physiopathology, cellular signaling, and therapeutic strategies.

Osteoarthritis and psoriasis arthritis are two degenerative forms of arthritis that share similar yet also different manifestations at the histological, cellular, and clinical levels. Rheumatologists have marked them as two entirely distinct arthropathies. Given recent discoveries in disease initiation and progression, potential mechanisms, cellular signaling pathways, and ongoing clinical therapeutics, there are now more opportunities for discovering osteoarthritis drugs. This review summarized the osteoarthritis and psoriasis arthritis signaling pathways, crosstalk between BMP, WNT, TGF-ß, VEGF, TLR, and FGF signaling pathways, biomarkers, and anatomical pathologies. Through bench research, we demonstrated that regenerative medicine is a promising alternative for treating osteoarthritis by highlighting significant scientific discoveries on entheses, multiple signaling blockers, and novel molecules such as immunoglobulin new antigen receptors targeted for potential drug evaluation. Furthermore, we offered valuable therapeutic approaches with a multidisciplinary strategy to treat patients with osteoarthritis or psoriasis arthritis in the coming future in the clinic.

Performance and mechanism of benzene adsorption on ZnCl2 one-step modified corn cob biochar.

Utilizing cost-effective corn cob, zinc chloride-modified biochar was synthesized through one-step method for benzene adsorption from air. Study on impregnation ratio impact showed optimal benzene adsorption at ZnCl2:CC ratio of 1.5:1, with capacity reaching 170.53 mg g-1. Characterization using BET, SEM, FTIR, and XPS was conducted. BET results indicated specific surface area of Zn1.5BC at 1260.63 m2 g-1 and maximum pore volume of 0.546 m3 g-1. SEM analysis revealed microporous-mesoporous structure in Zn1.5BC, marking significant improvement over original biomass. DFT pore size distribution and FTIR analysis suggested post-modification dehydration and elimination reactions, leading to volatile compound release, functional group reduction, and pore widening. XPS analysis showed decrease in O = C-OH content with increased impregnation ratio, enhancing biochar's π-π electron diffusion for benzene. Langmuir isotherm and pseudo-second-order kinetic models effectively described experimental data, indicating multilayer benzene adsorption on biochar controlled by complex physicochemical adsorption and pore diffusion. Adsorption condition assessment, including adsorption temperature (20-120 â„ƒ) and benzene concentration in inlet phase (159.73-383.36 mg L-1), was performed. Yoon-Nelson model fitting indicated adsorption site loss at higher temperatures and reduced capture ability due to increased adsorbate molecule kinetic energy. Higher adsorbate concentrations aided adsorption molecule diffusion to biochar surface and internal pores, increasing adsorption rate and shortening equilibrium time. Overall, zinc chloride-modified biochar facilitates benzene adsorption through pore filling and π-π interactions, with pore filling as primary mechanism. Produced biochar shows excellent regeneration properties and reusability.

Bifunctional Square-Planar NiO4 Coordination of Topotactic LaNiO2.0 Films for Efficient Oxygen Evolution Reaction.

The high-efficient and low-cost oxygen evolution reaction (OER) is decisive for applications of oxide catalysts in metal-air batteries, electrolytic cells, and energy-storage technologies. Delicate regulations of active surface and catalytic reaction pathway of oxide materials principally determine thermodynamic energy barrier and kinetic rate during catalytic reactions, and thus have crucial impacts on OER performance. Herein, a synergistic modulation of catalytically active surface and reaction pathway through facile topotactic transformations switching from perovskite (PV) LaNiO3.0 film to infinite-layer (IL) LaNiO2.0 film is demonstrated, which absolutely contributes to improving OER performance. The square-planar NiO4 coordination of IL-LaNiO2.0 brings about more electrochemically active metal (Ni+ ) sites on the film surface. Meanwhile, the oxygen-deficient driven PV- IL topotactic transformations lead to a reaction pathway converted from absorbate evolution mechanism to lattice-oxygen-mediated mechanism (LOM). The non-concerted proton-electron transfer of LOM pathway, evidenced by the pH-dependent OER kinetics, further boosts the OER activity of IL-LaNiO2.0 films. These findings will advance the in-depth understanding of catalytic mechanisms and open new possibilities for developing highly active perovskite-derived oxide catalysts.

Insisting on help, facing challenges, and maintaining balance: The lived experiences of caregivers raising a child with developmental delay in the remote islands of Kinmen.

PURPOSE: To explore the lived experiences of the caregivers of children with developmental delay (DD) on the remote island of Kinmen, Taiwan. DESIGN AND METHODS: This descriptive phenomenological study included 14 caregivers of 16 children with DD recruited from Kinmen, Taiwan. Data were collected from September 2020 to February 2021 with face-to-face semi-structured interviews, which were transcribed verbatim and analyzed using thematic analysis. RESULTS: Twelve caregivers were mothers; there was one father and one grandmother. Their mean age was 37.93 ± 5.17 years. The mean age of the children was 3.90 ± 1.49 years; 11 were male (69%). As we began our study, the COVID-19 pandemic occurred, which influenced two of the three themes: (1) focusing on their child's delayed development, which involved seeking a diagnosis and blaming themselves; (2) facing barriers to caring a child with DD on a remote island, which included ostracization of their child and limited off-island medical resources, especially during COVID-19; and (3) maintaining a healthy life balance, which involved protecting their child from physical or spiritual harm, including exposure to COVID-19, and reflecting on their strengths. CONCLUSIONS: Our findings highlight the challenges of caring for a child with DD in the Kinmen islands of Taiwan, and the impact of the COVID-19 pandemic. PRACTICAL IMPLICATIONS: Healthcare professionals are encouraged to provide caregivers of children with DD living in remote, island communities an opportunity to share their caregiving experiences and provide strategies for obtaining medical care, which could help reduce caregiver burden.