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Abstract Background Alzheimer’s disease (AD) is the most common neurogenerative disorder without effective treatments. Defects in mitochondrial complex I are thought to contribute to AD pathogenesis. The aim of this study is to explore whether a novel gene therapy transducing yeast complex I gene NDI1 can be used to treat AD with severely reduced complex I function in cell and animal models. Methods The differentiated human neural cells were induced by Aβ1–42 to establish the AD cell model, and adeno-associated virus serotype 9 (AAV9) was used to transduce yeast NDI1 into the cell model. Aβ1–42 was injected into the hippocampus area of the brain to establish the AD mouse model. AAV9-NDI1 was injected stereotaxically into the hippocampus area to test the therapeutic effect. Results The expressed yeast complex I had an ameliorating effect on the defective function of human complex I and cellular pathological characteristics in the AD cell model. Furthermore, AAV9-NDI1 gene therapy in the hippocampus had a therapeutic effect on various aspects of mitochondrial function, histopathological characteristics and neurological defects in the AD mouse model. In addition, AAV9-NDI1 injection into the hippocampus of normal mice did not cause any adverse effect. Conclusions Compensating mitochondrial complex I function with yeast NDI1 is effective for gene therapy in Aβ-induced AD cell and mouse models. The results of this study offer a novel strategy and approach for treating AD types characterized by complex I abnormalities.

Abstract Objective This study aimed to investigate the clinical features, pathogenic gene variants, and potential genotype–phenotype correlations in Chinese patients with hereditary spherocytosis (HS). Methods Retrospective analysis of clinical data and molecular genetic characteristics was conducted on patients diagnosed with HS at Jiangxi Provincial Children's Hospital, the Second Affiliated Hospital of Nanchang University, Pingxiang People's Hospital and The Third People's Hospital of Jingdezhen between November 2017 and June 2023. Statistical analyses were performed to compare and analyze the red blood cell (RBC), hemoglobin (HB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) data between and within groups based on different mutations and age groups (

Photointiators have been commercially applied in ultra-violet photocuring ink, varnish, coating, lacquers since 1970s. The significant advantages of efficient, energy-saving and environmental-friendly make them more and more popular in automobile industry, package industry, etc. Photointiators can reach foodstuff by vapour or diffusion from the food contact layer of the package. Although UV ink is just printed in the outer surface of the package, the residue photointiators can transfer to the inner surface by “set-off” effect. Different photointiator has different chemical and physical properties, and shows different response by different testing instrument. In this study, two methods of liquid chromatography time-of-flight mass spectrometry (LC-QTOF MS) and gas chromatography triple quadrupole mass spectrometry (GC-MS/MS) were developed for determination of migration for 23 photoinitiators in food contact coating. The response of the photointiators by two methods was compared for method selection. For the LC-QTOF MS method, an Hypersil GOLD AQ C18 column was utilized and 0.1% formic acid water-methanol was used as mobile phase. QTOF MS was performed by electrospray ion source positive ion mode (ESI+) and mutiple reaction monitor high resolution (MRM HR) mode. Simple dilution with acidified methanol was used for migration solution pretreatment and internal standard method was used for quantification. The limits of detection are from 0.0025 to 0.01 mg/kg. Recoveries range from 60.9% to 124%, and the relative standard deviations (RSDs) are between 0.9% and 11.6%. For GC-MS/MS method, a CD-5 column was used, and the MS/MS was operated under MRM mode. Liquid-liquid extraction with n-hexane was used for migration solution pretreatment and internal standard method was also used for quantification. The limits of detection range from 0.0004 to 0.002 mg/kg. The recoveries range from 77.0% to 128%, with RSDs are between 0.4% and 8.1%. Migration solution of 13 batches of metal coating samples were tested, while 5 of them are positive of photoinitiaor TPO or 2,4-diethyl-9H-thioxanthen-9-one, while the maximum detection value of photoinitiaor TPO is 0.0502 mg/kg, the detection values of 2,4-diethyl-9H-thioxanthen-9-one are all less than 0.002 mg/kg. The two methods are easy, sensitive and accuracy, which can determine the migration of photointiators in food contact coating.

Abstract Background The progression of osteoporosis (OP) can dramatically increase the risk of fractures, which seriously disturb the life of elderly individuals. Specific protein 1 (SP1) is involved in OP progression. However, the mechanism by which SP1 regulates OP progression remains unclear. Objective This study investigated the mechanism underlying the function of SP1 in OP. Methods SAMP6 mice were used to establish an in vivo model of age-dependent OP, and BALB/c mice were used as controls. BMSCs were extracted from two subtypes of mice. Hematoxylin and eosin staining were performed to mark the intramedullary trabecular bone structure to evaluate histological changes. ChIP assay was used to assess the targeted regulation between SP1 and miR-133a-3p. The binding sites between MAPK3 and miR-133a-3p were verified using a dual-luciferase reporter assay. The mRNA levels of miR-133a-3p and MAPK3 were detected using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The protein expression of SP1, MAPK3, Colla1, OCN, and Runx2 was examined using Western blotting. Alkaline phosphatase (ALP) kit and Alizarin Red S staining were used to investigate ALP activity and mineralized nodules, respectively. Results The levels of SP1 and miR-133a-3p were upregulated, whereas the expression of MAPK3 was downregulated in BMSCs from SAMP6 mice, and miR-133a-3p inhibitor accelerated osteogenic differentiation in BMSCs. SP1 directly targeted miR-133a-3p, and MAPK3 was the downstream mRNA of miR-133a-3p. Mechanically, SP1 accelerated osteogenic differentiation in BMSCs via transcriptional mediation of the miR-133a-3p/MAPK3 axis. Conclusion SP1 regulates osteogenic differentiation by mediating the miR-133a-3p/MAPK3 axis, which would shed new light on strategies for treating senile OP.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

In general, carriers are designed to deliver pharmaceutical (featuring small drug‐molecules) and biopharmaceutical (featuring large‐molecule drugs, e.g., antibodies, proteins, etc.) active ingredients and platform that is capable of transporting nanoparticles is rare. Herein, the fabrication of a supramolecular carrier with a nano‐grid structure for the entrapment of liposomes and exosomes is reported. The nano‐grid particles (NGP) are made of cyclodextrins as elementary units which are widely used to load drugs through host–guest inclusion complexes, whilst its secondary structure further formed the NGP tertiary architectures, enabling the entrapment of nanoparticles. The NGP features stimuli responsiveness, tunable surface charge, and good biocompatibility. The entrapped liposomes in NGP present enhanced distribution in lungs and extended duration of action in mice. And elongated release profiles for over 14 days is obtained for exosomes—making one‐of‐its‐kind unique platform to load and deliver nanoparticles.

Objective: The objective of this study was to pinpoint pathogenic genes and assess the mutagenic pathogenicity in two pediatric patients with hereditary spherocytosis.Methods: We utilized whole-exome sequencing (WES) for individual analysis (case 1) and family-based trio analysis (case 2). The significance of the intronic mutation was validated through a Minigene splicing assay and supported by subsequent in vitro experiments.Results: Both probands received a diagnosis of hereditary spherocytosis. WES identified a novel ANK1 c.1504-9G>A mutation in both patients, causing the retention of seven nucleotides at the 5′ end of intron 13, as substantiated by the Minigene assay. This variant results in a premature stop codon and the production of a truncated protein. In vitro studies indicated a reduced expression of the ANK1 gene.Conclusion: The novel ANK1 c.1504-9G>A variant is established as the causative factor for hereditary spherocytosis, with the c.1504-9G site functioning as a splicing receptor.

Abstract Background Virtual nurse-led care models designed with health care professionals (HCPs) and patients may support addressing unmet prostate cancer (PCa) survivor needs. Within this context, we aimed to better understand the optimal design of a service model for a proposed nurse-led PCa follow-up care platform (Ned Nurse). Methods A qualitative descriptive study exploring follow-up and virtual care experiences to inform a nurse-led virtual clinic (Ned Nurse) with an a priori convenience sample of 10 HCPs and 10 patients. We provide a health ecosystem readiness checklist mapping facilitators onto CFIR and Proctor’s implementation outcomes. Results We show that barriers within the current standard of care include: fragmented follow-up, patient uncertainty, and long, persisting wait times despite telemedicine modalities. Participants indicate that a nurse-led clinic should be scoped to coordinate care and support patient self-management, with digital literacy considerations. Conclusion A nurse-led follow-up care model for PCa is seen by HCPs as acceptable, feasible, and appropriate for care delivery. Patients value its potential to provide role clarity, reinforce continuity of care, enhance mental health support, and increase access to timely and targeted care. These findings inform design, development, and implementation strategies for digital health interventions within complex settings, revealing opportunities to optimally situate these interventions to improve care.

Abstract Background Knee joint pain has been demonstrated to be a separate risk factor for falling. A common pain site in the knee, anterior knee pain(AKP), is believed to be associated with early knee osteoarthritis (KOA).This study investigated the relationship between falls and AKP in people with or at risk for KOA. Methods Four years of follow-up data from the Osteoarthritis Initiative cohort trial, a large-scale, multicenter observational investigation, were analyzed in this study. A patellar quadriceps tenderness/tendinitis knee exam was performed to evaluate AKP. Falls were self-reported. The associations between falls (recurrent falls: ≥2 falls/year; any falls: ≥1 fall(s)/year) and AKP were analyzed using the generalized estimation equation of repeated logistic regression and adjusted for confounding variables. Results The study analyzed data from 3,318 participants, split into two groups: those with AKP (720 participants) and those without AKP (2,598 participants). The primary outcome of the study, which focused on repeated falls, revealed that participants with AKP were 1.27 times more likely to experience repeated falls compared to those without AKP (95% CI: 1.07–1.52, P = 0.007). However, when considering any falls experienced by an individual as an additional outcome, it is important to note that our findings did not indicate a significant predictive effect of AKP on any falls investigated. Sensitivity analyses, which excluded knee arthroplasty cases, yielded consistent results with the aforementioned findings. Conclusions Older adults with AKP experience a higher frequency of falls compared to those without AKP in individuals diagnosed with KOA or at a high risk of developing KOA.

Gammacoronavirus infectious bronchitis virus (IBV) causes a highly contagious disease in chickens and seriously endangers the poultry industry. The emergence and co-circulation of diverse IBV serotypes and genotypes with distinct pathogenicity worldwide pose a serious challenge to the development of effective intervention measures. In this study, we report the epidemic trends of IBV in China from 2019 to 2023 and a comparative analysis on the antigenic characteristics and pathogenicity of isolates among major prevalent lineages. Phylogenetic and recombination analyses based on the nucleotide sequences of the spike (S) 1 gene clustered a total of 205 isolates into twelve distinct lineages, with GI-19 as a predominant lineage (61.77 ± 4.56%) exhibiting an overall increasing trend over the past five years, and demonstrated that a majority of the variants were derived from gene recombination events. Further characterization of the growth and pathogenic properties of six representative isolates from different lineages classified four out of the six isolates as nephropathogenic types with mortality rates in one-day-old SPF chickens varying from 20–60%, one as a respiratory type with weak virulence, and one as a naturally occurring avirulent strain. Taken together, our findings illuminate the epidemic trends, prevalence, recombination, and pathogenicity of current IBV strains in China, providing key information for further strengthening the surveillance and pathogenicity studies of IBV.

Abstract Previous studies have suggested that lobe reconnection under stable northward interplanetary magnetic field (IMF) conditions should be continuous. However, to what extent it can be considered as continuous is unknown. Auroral cusp spots have been considered a signature of lobe reconnection. Here, we show that during a cusp spot event continuously observed by the Defense Meteorological Satellite Program for approximately 4 hr under stable IMF conditions, the ground radars recorded multiple intermittent equatorward‐moving radar forms (EMRFs) near local noon and multiple intermittent poleward‐moving radar forms (PMRFs) at post‐noon, each lasting ∼20–30 min. These intermittent EMRFs and PMRFs are suggested to correspond to intermittent lobe reconnections occurring at the cusp's poleward boundary near local noon and the duskside boundary at post‐noon, respectively. These findings challenge the previously held notion of continuous lobe reconnection under stable IMF conditions.

BackgroundCultural adaptations of digital health innovations are a growing field. However, digital health innovations can increase health inequities. While completing exploratory work for the cultural adaptation of the Ned Clinic virtual survivorship app, we identified structural considerations that provided a space to design digitally connected and collective care. ObjectiveThis study used a community-based participatory research and user-centered design process to develop a cultural adaptation of the Ned Clinic app while designing to intervene in structural inequities. MethodsThe design process included primary data collection and qualitative analysis to explore and distill design principles, an iterative design phase with a multidisciplinary team, and a final evaluation phase with participants throughout the design process as a form of member checking and validation. ResultsParticipants indicated that they found the final adapted prototype to be acceptable, appropriate, and feasible for their use. The changes made to adapt the prototype were not specifically culturally Chinese. Instead, we identified ways to strengthen connections between the survivor and their providers; improve accessibility to resources; and honor participants’ desires for relationality, accountability, and care. ConclusionsWe grounded the use of user-centered design to develop a prototype design that supports the acts of caring through digital technology by identifying and designing to resist structures that create health inequities in the lives of this community of survivors. By designing for collective justice, we can provide accessible, feasible, and relational care with digital health through the application of Indigenous and Black feminist ways of being and knowing.

The utilization of peptide-chelated calcium is low due to the influence of factors such as solubility, heat and digestive environmental conditions; therefore, it is crucial to protect, prolong and stabilize this nutrient in order to enhance its efficacy. This study was conducted to prepare corn peptide-chelated calcium microcapsules using β-cyclodextrin (β-CD) as the wall material through an improved ultrasonic-assisted method. The structure, solubility, thermal stability, and in vitro gastrointestinal digestion of these microcapsules were thoroughly investigated and analyzed. The microcapsules were prepared using the following recommended conditions: a chelate concentration of 5 mg/mL, a mass ratio of chelate to β-CD of 1:8 g/g, and a synchronous dual-frequency ultrasound (20/28 kHz) at a power of 75 W, a duty ratio of 20/5 s/s, and a time of 20 min. These specific parameters were carefully selected to ensure the optimal fabrication of the microcapsules. The results showed that the utilization of dual-frequency ultrasound resulted in a significant increase in both the encapsulation rate and yield, which were enhanced by 15.84 % and 15.68 %, respectively, reaching impressive values of 79.17 % and 90.60 %. Moreover, the results of the structure index analysis provided further confirmation that ultrasonic treatment had a significant impact on the structure of the microcapsules, leading to a noticeable reduction in particle size and transformation into nanoparticles. Furthermore, the microcapsules demonstrated excellent solubility within a wide pH range of 2 to 10, with solubility ranging from 93.54 % to 88.68 %. Additionally, these microcapsules exhibited remarkable thermal stability, retaining a minimum of 84.8 % of their stability when exposed to temperatures ranging from 40 to 80 °C. Moreover, during gastric and intestinal digestion, these microcapsules exhibited a high slow-release rate of 44.66 % and 51.6 %, indicating their ability to gradually release calcium contents. The inclusion of dual-frequency ultrasound in the preparation of high calcium microcapsules yielded promising outcomes. Overall, our work presents a novel method for synthesizing corn peptide-chelated calcium microcapsules with desirable properties such as good solubility, excellent thermal stability, and a significant slow-release effect. These microcapsules have the potential to serve as fortified high calcium supplements.

BackgroundProstate cancer (PCa) is the most commonly diagnosed nonskin cancer for Canadian men and has one of the highest 5-year survival rates, straining systems to provide care. Virtual care can be one way to relieve this strain, but survivors’ care needs and technology use are influenced by intersecting social and cultural structures. Cultural adaptation has been posited as an effective method to tailor existing interventions to better serve racialized communities, including Chinese men. However, cultural adaptations may inadvertently draw attention away from addressing structural inequities. ObjectiveThis study used qualitative methods to (1) explore the perceptions and experiences of Chinese Canadian PCa survivors with follow-up and virtual care, and (2) identify implications for the cultural adaptation of a PCa follow-up care app, the Ned (no evidence of disease) Clinic. MethodsAn axiology of relational accountability and a relational paradigm underpinned our phenomenologically informed exploratory-descriptive qualitative study design. A community-based participatory approach was used, informed by cultural safety and user-centered design principles, to invite Chinese Canadian PCa survivors and their caregivers to share their stories. Data were inductively analyzed to explore their unmet needs, common experiences, and levels of digital literacy. ResultsUnmet needs and technology preferences were similar to broader trends within the wider community of PCa survivors. However, participants indicated that they felt uncomfortable, unable to, or ignored when expressing their needs. Responses spoke to a sense of isolation and reflected a reliance on culturally informed coping mechanisms, such as “eating bitterness,” and familial assistance to overcome systemic barriers and gaps in care. Moreover, virtual care was viewed as “better than nothing;” it did not change a perceived lack of focus on improving quality of life or care continuity in survivorship care. Systemic changes were identified as likely to be more effective in improving care delivery and well-being rather than the cultural adaptation of Ned for Chinese Canadians. Participants’ desires for care reflected accessibility issues that were not culturally specific to Chinese Canadians. ConclusionsChinese Canadian survivors are seeking to strengthen their connections in a health care system that provides privacy and accessibility, protects relationality, and promotes transparency, accountability, and responsibility. Designing “trickle-up” adaptations that address structural inequities and emphasize accessibility, relationality, and privacy may be more effective and efficient at improving care than creating cultural adaptations of interventions.

BackgroundThe COVID-19 pandemic forced the spread of digital health tools to address limited clinical resources for chronic health management. It also illuminated a population of older patients requiring an informal caregiver (IC) to access this care due to accessibility, technological literacy, or English proficiency concerns. For patients with heart failure (HF), this rapid transition exacerbated the demand on ICs and pushed Canadians toward a dyadic care model where patients and ICs comanage care. Our previous work identified an opportunity to improve this dyadic HF experience through a shared model of dyadic digital health. We call this alternative model of care “Caretown for Medly,” which empowers ICs to concurrently expand patients’ self-care abilities while acknowledging ICs’ eagerness to provide greater support. ObjectiveWe present the systematic design and development of the Caretown for Medly dyadic management module. While HF is the outlined use case, we outline our design methodology and report on 6 core disease-invariant features applied to dyadic shared care for HF management. This work lays the foundation for future usability assessments of Caretown for Medly. MethodsWe conducted a qualitative, human-centered design study based on 25 semistructured interviews with self-identified ICs of loved ones living with HF. Interviews underwent thematic content analysis by 2 coders independently for themes derived deductively (eg, based on the interview guide) and inductively refined. To build the Caretown for Medly model, we (1) leveraged the Knowledge to Action (KTA) framework to translate knowledge into action and (2) borrowed Google Sprint’s ability to quickly “solve big problems and test new ideas,” which has been effective in the medical and digital health spaces. Specifically, we blended these 2 concepts into a new framework called the “KTA Sprint.” ResultsWe identified 6 core disease-invariant features to support ICs in care dyads to provide more effective care while capitalizing on dyadic care’s synergistic benefits. Features were designed for customizability to suit the patient’s condition, informed by stakeholder analysis, corroborated with literature, and vetted through user needs assessments. These features include (1) live reports to enhance data sharing and facilitate appropriate IC support, (2) care cards to enhance guidance on the caregiving role, (3) direct messaging to dissolve the disconnect across the circle of care, (4) medication wallet to improve guidance on managing complex medication regimens, (5) medical events timeline to improve and consolidate management and organization, and (6) caregiver resources to provide disease-specific education and support their self-care. ConclusionsThese disease-invariant features were designed to address ICs’ needs in supporting their care partner. We anticipate that the implementation of these features will empower a shared model of care for chronic disease management through digital health and will improve outcomes for care dyads.

Background: Declining beneficial cardiovascular actions of estradiol (E2) have been associated with disproportionate susceptibility to takotsubo syndrome (TTS) in postmenopausal women. However, the underlying mechanisms between E2 and this marked disproportion remain unclear. SmgGDS (small GTP-binding protein GDP dissociation stimulator), as a key modulator of cardiovascular disease, plays protective roles in reducing oxidative stress and exerts pleiotropic effects of statins. Whether SmgGDS levels are influenced by E2 status and the effect of SmgGDS on sex differences in TTS are poorly understood. Methods: Clinical data were reviewed from TTS inpatients. Echocardiography, immunofluorescence, and immunohistochemistry were performed together with expression analysis to uncover phenotypic and mechanism changes in sex differences in TTS-like wild-type (WT) and SmgGDS ± mice. HL-1 cardiomyocytes were used to further examine and validate molecular mechanisms. Results: In 14 TTS inpatients, TTS had a higher incidence in postmenopausal women as compared to premenopausal women and men. In murine TTS, female WT mice exhibited higher cardiac SmgGDS levels than male WT mice. Ovariectomy reduced SmgGDS expression in female WT mice similar to that observed in male mice, whereas E2 replacement in these ovariectomized (OVX) female mice reversed this effect. The physiological importance of this sex-specific E2-mediated SmgGDS response is underscored by the disparity in cardiac adaptation to isoproterenol (ISO) stimulation between both sexes of WT mice. E2-mediated SmgGDS induction conferred female protection against TTS-like acute cardiac injury involving ferritinophagy-mediated ferroptosis. No such cardioprotection was observed in male WT mice and OVX female. A causal role for SmgGDS in this sex-specific cardioprotective adaptation was indicated, inasmuch as SmgGDS deficiency abolished E2-modulated cardioprotection against ferritinophagy and aggravates TTS progression in both sexes. Consistently, knockdown of SmgGDS in HL-1 cardiomyocytes exacerbated ferroptosis in a ferritinophagy-dependent manner and abrogated the protective role of E2 against ferritinophagy. Mechanistically, our findings revealed that SmgGDS regulated E2-dependent cardioprotective effects via AMPK/mTOR signaling pathway. SmgGDS deficiency abolished E2-conferred protection against ferritinophagy through activating AMPK/mTOR pathway, while treatment with recombinant SmgGDS in HL-1 cells significantly mitigated this pathway-associated ferritinophagy activity. Conclusions: These results demonstrate that SmgGDS is a central mediator of E2-conferred female cardioprotection against ferritinophagy-mediated ferroptosis in TTS.

Background: Serum vitamin D is associated with hyperuricemia. However, previous studies have been controversial, with limited focus on children and adolescents. Objective: This study aimed to examine the cross-sectional and longitudinal associations between serum vitamin D and serum uric acid (SUA) levels in children and adolescents. Methods: The cross-sectional survey comprised 4777 participants aged 6 to 18 years, while the longitudinal survey involved 1641 participants aged 6 to 12 years, all derived from an ongoing cohort study in Shenzhen, China. Restricted cubic splines were used to visualize the dose–response relationship between vitamin D and SUA and the risk of higher SUA status. Two-segment generalized linear models (GLM) and logistic models were used to assess the association between vitamin D and SUA and higher SUA status, respectively. The longitudinal analysis used GLM. Results: We observed an inverted U-shaped relationship between vitamin D and SUA (p-overall < 0.0001, p-nonlinear = 0.0002), as well as the risk of higher SUA status (p-overall = 0.0054, p-nonlinear = 0.0015), with the vitamin D inflection point at 24.31 and 21.29 ng/mL, respectively. A 10 ng/mL increment in 25(OH)D3 levels, when below 20.92 ng/mL, was associated with a 68% rise in the risk of higher SUA status (OR: 1.68, 95%CI: 1.07–2.66). Conversely, when 25(OH)D3 levels were above or equal to 20.92 ng/mL, a 10 ng/mL increment was associated with a 45% reduction risk of higher SUA status (OR: 0.55, 95%CI: 0.36–0.84). Longitudinal analysis indicated that the annual change of SUA was from −4.80 (β, 95%CI: −10.74, 1.13) to −9.00 (β, 95%CI: −15.03, −2.99) and then to −6.77 (β, 95%CI: −12.83, −0.71, p for trend = 0.0212) μmol/L when increasing the quartile of vitamin D3. Conclusions: An inverse U-shaped relationship was observed between vitamin D and SUA as well as the risk of higher SUA status. Sufficient vitamin D levels appear to play a preventative role against the age-related increase in SUA. Ensuring adequate vitamin D levels may be beneficial in improving uric acid metabolism.

Abstract Background Cross-sectional studies found that frailty was associated with prevalent diabetic microvascular complications (DMC). Longitudinal evidence in this regard is inconclusive and insufficient. We aimed to prospectively evaluate the association of pre-frailty and frailty with DMC in patients with type 2 diabetes (T2D). Methods We included 18,062 adults (mean age 59.4 ± 7.2 years, 37.4% female) with T2D at baseline in the UK Biobank. Frailty was defined using the frailty phenotype according to five components (weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength). DMC, defined as diabetic nephropathy, diabetic neuropathy, or diabetic retinopathy, was identified using hospital inpatient records and death registries. Cox proportional hazard regression models considering competing risks were used to evaluate the associations of frailty phenotype with overall DMC events and subtypes. Results Among all participants, 6101 (33.8%) were classified as non-frail, 10,073 (55.8%) were classified as pre-frail, and 1888 (10.4%) were classified as frail. During a median follow-up of 12.0 years, 3678 DMC cases were documented, including 2213 diabetic nephropathy, 1520 diabetic retinopathy, and 673 diabetic neuropathy events. In the multivariable-adjusted model, compared with participants with non-frail, both pre-frailty and frailty were significantly associated with increased risk of overall DMC (HR 1.10, 95% CI: [1.02, 1.18] for pre-frailty and HR 1.52 [95% CI: 1.36, 1.69] for frailty). Similar results were observed in the subtypes of DMC. For each one-point increase in frailty phenotype score, the risk of overall DMC, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy event increased by 13%, 16%, 10%, and 20%, respectively. Conclusions Both pre-frailty and frailty were associated with an increased risk of DMC in patients with T2D. These findings have important implications for integrating early assessment and surveillance of frailty in diabetes and may favor the identification of at-risk patients.

ObjectiveThis study aimed to explore both impairments in attention function in patients with major depressive disorder (MDD) and the efficacy of escitalopram monotherapy or combination therapy with agomelatine.MethodsA total of 54 patients with MDD and 46 healthy controls (HCs) were included. Patients were treated with escitalopram for 12 weeks; those who presented with severe sleep impairments were also given agomelatine. Participants were evaluated using the Attention Network Test (ANT), which included tests of alerting, orienting, and executive control networks. Concentration, instantaneous memory, and resistance to information interference were tested using the digit span test, and the logical memory test (LMT) was used to evaluate abstract logical thinking. The Hamilton Depression Rating Scale−17 items, Hamilton Anxiety Rating Scale, and Pittsburgh Sleep Quality Index were used to assess depression, anxiety, and sleep quality, respectively. Patients with MDD were assessed at the end of weeks 0, 4, 8, and 12. HCs were assessed once at baseline.ResultsCompared with HCs, patients with MDD showed significantly different alerting, orienting, and executive control functions of attention networks. Treatment with escitalopram alone or combined with agomelatine significantly improved LMT scores at the end of weeks 4, 8, and 12 and restored scores to the level of HCs at the end of week 8. Total Toronto Hospital Test of Alertness scores in patients with MDD increased significantly after 4 weeks of treatment. The ANT executive control reaction time in patients with MDD decreased significantly after 4 weeks of treatment, with this decrease lasting until the end of week 12, but scores did not return to the levels of HCs. Combined treatment with escitalopram and agomelatine led to more improvement in ANT orienting reaction time and was accompanied by a greater reduction of total scores on the Hamilton Depression Rating Scale−17 items and Hamilton Anxiety Rating Scale compared with escitalopram monotherapy.ConclusionsPatients with MDD showed overall impairments in three domains of attention networks as well as the LMT and a test of subjective alertness. Escitalopram monotherapy significantly improved the LMT scores and the executive control function scores in the ANT at the end of the fourth week of treatment, and the improvement was more extensive with combined escitalopram and agomelatine treatment.

Background: 22q11 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome with broad phenotypic variability, leading to significant morbidity and some mortality. The varied health problems associated with 22q11DS and the evolving phenotype (both medical and developmental/behavioural) across the lifespan can strongly impact the mental health of patients as well as their caregivers. Like caregivers of children with other chronic diseases, caregivers of children with 22q11DS may experience an increased risk of traumatisation and mental health symptoms.Objective: The study’s primary objective was to assess the frequency of traumatic experiences and mental health symptoms among mothers of children with 22q11DS. The secondary objective was to compare their traumatic experiences to those of mothers of children with other neurodevelopmental disorders (NDDs).Method: A total of 71 mothers of children diagnosed with 22q11DS completed an online survey about their mental health symptoms and traumatic experiences. Descriptive statistics were used to summarise the prevalence of their mental health symptoms and traumatic experiences. Logistic regression models were run to compare the traumatic experiences of mothers of children with 22q11DS to those of 335 mothers of children with other neurodevelopmental disorders (NDDs).Results: Many mothers of children with 22q11DS experienced clinically significant mental health symptoms, including depression (39%), anxiety (25%), and post-traumatic stress disorder (PTSD) symptoms (30%). The types of traumatic events experienced by mothers of children with 22q11DS differed from those of mothers of children with other NDDs as they were more likely to observe their child undergoing a medical procedure, a life-threatening surgery, or have been with their child in the intensive care unit.Conclusion: 22q11DS caregivers are likely to require mental health support and trauma-informed care, tailored to the specific needs of this population as they experience different kinds of traumatic events compared to caregivers of children with other NDDS.

Abstract Caring for children with intellectual and developmental disabilities (IDD) can cause an enormous physical and emotional burden, and therefore these parents have an elevated risk to experience mental health problems. The characteristics of current healthcare systems and parents’ responsibilities to care for their children seem to impede their access to mental healthcare. There is so far a lack of instruments to screen for such obstacles. The aim of this study was to develop and validate a scale for measuring barriers to accessing mental healthcare. The Parental Healthcare Barriers Scale (PHBS) was developed on the basis of an extensive literature research, input and discussion from experts and parents with lived experience. A cross-sectional survey was used to collect data from 456 parents of children with IDD. Physical health, mental health, social support, and parenting were measured for concurrent and discriminant validity of the PHBS. The PHBS scale revealed acceptable to good reliability and validity. It consists of four subscales (i.e., support accessibility, personal belief, emotional readiness, and resource availability). The PHBS found parents prioritized their children’s treatments over their own mental health challenges (93.4%), did not have enough time (90.4%), and had financial concerns (85.8%). Parents in rural and remote areas had more limited resources. Findings from our study suggest increasing financial support for the parents seeking mental health services, introducing evidence-based treatments, increasing the availability of healthcare services for parents, and adjusting current services to their needs.

Abstract Polydimethylsiloxane (PDMS) has been widely used in flexible electronics, soft robotics, and bioelectronics. However, the fabrication of PDMS‐based devices has mostly relied on conventional approaches, such as casting and molding, thereby limiting their potential. Here we fabricate PDMS‐based composites with programmable microstructures by direct ink writing and realize their practical functionalities of four‐dimensional (4D) printing. The mechanical, thermomechanical and magnetic properties of the three‐dimensional‐printed composites can be well tailored by using carbon, metal, or ceramic functional fillers. By taking advantage of the printable, flexible, and magnetic PDMS composites, we demonstrate new practical functionalities of 4D printing by designing programmable architectures, including magnetic‐field‐driven battery cases and patchworks, as well as arbitrary morphing ceramic structures. In particular, 4D‐printed batteries are constructed by PDMS‐based battery cases for the first time, which can be actuated via external magnetic field. This study broadens the paradigm of 4D printing for prospective applications, such as implant batteries, biomimetic engineering, and customized biomedical devices.

Forming compact layered nanostructures is key to achieving continuous MXene fibers with electrical and mechanical properties. Here, authors demonstrate ultra-compact high-performance MXene fibers via a controllable synergy of interfacial interactions and thermal drawing-induced stresses.

Abstract The integration of functional fibers into wearable devices by traditional methods is commonly completed in weaving. A new post‐weaving method of integrating fiber devices into textiles is needed to address the challenge of incorporating functional fiber into ready‐made garments without tearing down the clothing and re‐weaving. A 3D printing method to simultaneously fabricate and integrate highly stretchable conductive fiber into ready‐made garments with designed patterns is presented. The fabricated sheath–core fiber consists of a styrene–ethylene–butylene–styrene (SEBS) shell and a Ga–In–Sn alloy liquid metal core. The SEBS shell guarantees the high stretchability (up to 600%) and flexibility, while the liquid metal core offers a high conductivity maintained at large deformation. It is shown that sophisticated patterns, which have millimeter‐level‐resolution that are difficult to be integrated into textiles by weaving, and even more laborious to be incorporated into ready‐made garments, can now be easily modified and implemented into both textiles and ready‐made garments by a time‐saving and low‐cost 3D printing method. Utilizing the electrical characteristics of the fiber in pre‐designed patterns, on‐clothing soft electronics can be printed directly. A printed on‐clothing strain sensor, bending sensor, wireless charging coil, and a touch‐sensing network are demonstrated to show the potential applications in wearable electronics.

The evaluation of rock porosity and the mercury injection capillary pressure (MICP) curve is fundamental for oil and gas exploration and production. Digital rock (DR) technology, incorporating 3D micro-CT imaging and numerical methods, has been widely employed to predict these properties. However, analyzing the pore structure of heterogeneous rocks, such as fractured rocks or glutenite, solely through single-scale DR analysis poses challenges. Existing upscaling methods have limitations in fully representing the complete range of pore structures at different scales, with limited comparison to experimental data. To address this, we propose a novel method that upscales porosity and simulates the MICP curve from nano-scale to core scale by merging results from micro-CT (at resolutions of 35 μm and 2 μm) and SEM (at resolutions of 6.5 nm and 65 nm). We validate the developed DR model by applying it to sandstones, glutenite, and igneous rocks, and achieve excellent agreement between the experimental data and the multi-scale DR model across 67 samples. The results demonstrate that the multi-scale model effectively captures the porosity and pore structures across the entire range. In contrast, the single digital rock (DR) model underestimates the porosity measurements for both homogeneous sandstones and heterogeneous cores. While the MICP model based on a single DR proves suitable for homogeneous rock samples, it introduces noticeable discrepancies when applied to heterogeneous rock samples. The developed multi-scale method significantly enhances the confidence in using DR to assess the pore structure of complex rocks.

Background and aims: Childhood and adolescence are critical periods for linear growth and preventing stunting. Current evidence indicates that dietary protein intake in children and adolescents is often two to three times higher than the recommendations in many regions worldwide. However, few studies have focused on the association between high protein intake and linear growth and stunting in this population. We aim to investigate this association in children and adolescents aged 6 to 18 years in a population with relatively high protein consumption. Methods: We conducted a large cross-sectional study involving 3299 participants from Shenzhen, a modern metropolis of China. Protein intake, including total protein, animal protein, and plant protein, was evaluated by a food-frequency questionnaire and expressed as grams per kilogram of body weight per day (g·kg−1·d−1) and as a percentage of total energy intake (%E). The primary outcomes were body height and height-for-age Z score (HAZ). Generalized linear models and logistic regression analyses were employed to examine the associations between protein intake and outcomes. We also conducted stratified analyses across different genders and pubertal stages in the aforementioned associations. Results: The mean protein intake was 1.81 g·kg−1·d−1 (17% E). After adjusting for serum calcium, zinc, vitamin D3, vitamin A levels, birth outcomes, lifestyle, and parental characteristics, each standard deviation increase of 1 in protein intake (0.64 kg−1·d−1) is found to be associated with a −5.78 cm change in body height (95% CI: −6.12, −5.45) and a −0.79 change in HAZ (95% CI: −0.84, −0.74). Consistent results were observed when protein intake was expressed as %E or specifically as animal or plant protein. Moreover, the relationship between protein intake and linear growth remained consistent across genders in different pubertal stages, similar to that of the overall participants. Conclusions: Our findings highlight the potential hazards of high protein intake on linear growth in children and adolescents. Caution should be exercised when promoting increased protein consumption in children and adolescents who already have a high intake of protein.

At present, phenolic acid derivatives and triazole derivatives have a good antifungal effect, which has attracted widespread attention. A series of novel phenolic acid triazole derivatives were synthesized, and their structures were characterized by IR, MS, NMR, and X-ray crystal diffraction. Compound methyl 4-(2-bromoethoxy)benzoate, methyl 4-(2-(1H-1,2,4-triazol-1-yl) ethoxy)benzoate, 4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)benzoic acid and 4-(2-(1H-1,2,4-triazol-1-yl) ethoxy)-3-methoxybenzoic acid crystallize in the monoclinic system with space group P21/n, the monoclinic system with space group P21, the monoclinic system with space group P21 and the orthorhombic system with space group Pca21, respectively. At a concentration of 100 μg/mL and 200 μg/mL, the antifungal activity against seven plant pathogen fungi was determined. Compound methyl 4-(2-bromoethoxy)benzoate has the best inhibitory effect on Rhizoctonia solani AG1, and the inhibitory rate reached 88.6% at 200 μg/mL. The inhibitory rates of compound methyl 4-(2-(1H-1,2,4-triazol-1-yl) ethoxy)benzoate against Fusarium moniliforme and Sphaeropsis sapinea at a concentration of 200 μg/mL were 76.1% and 75.4%, respectively, which were better than that of carbendazim.

Highlights 1. The recyclable high-efficiency Hap@BC was prepared for U(VI) removal. 2. The adsorption capacity for U(VI) of Hap@BC-10% achieved 834.8 mg/g. 3. The U(VI) extraction efficiency reached 99.9% in dynamic adsorption. 4. The interaction mechanism between U(VI) and Hap@BC was clearly expounded.

Background: Drug-induced liver injury (DILI) is a potentially serious adverse drug reaction. Due to the lack of definite etiology, specific clinical manifestations, and diagnostic methods, its prediction and diagnosis are challenging. Elderly individuals are deemed to be at high risk for DILI due to abnormal pharmacokinetics, aging tissue repair function, comorbidities, and taking multiple drugs. This study aimed to identify the clinical characteristics and explore the risk factors associated with the severity of illness in elderly patients with DILI.Methods: In the present study, the clinical characteristics at the time of liver biopsy of consecutive patients with biopsy-proven DILI who presented at our hospital from June 2005 to September 2022 were evaluated. Hepatic inflammation and fibrosis were assessed according to the Scheuer scoring system. The presence of autoimmunity was considered if IgG level >1.1 × ULN (1826 mg/dL), or high titer (>1:80) of ANA, or SMA.Results: In total, 441 patients were enrolled, and the median age was 63.3 years (IQR, 61.0–66.0); 122 (27.7%), 195 (44.2%), or 124 (28.1%) were classified as having minor, moderate, or severe hepatic inflammation, respectively; and 188 (42.6%), 210 (47.6%) or 43 (9.8%) patients presented minor, significant fibrosis or cirrhosis, respectively. Female sex (73.5%) and the cholestatic pattern (47.6%) were dominant in elderly DILI patients. Autoimmunity existed in 201 patients (45.6%). Comorbidities were not directly associated with the severity of DILI. PLT (OR: 0.994, 95% CI: 0.991–0.997; p < 0.001), AST (OR: 1.001, 95% CI: 1.000–1.003, p = 0.012), TBIL (OR: 1.006, 95% CI: 1.003–1.010, p < 0.001), and autoimmunity (OR: 1.831, 95% CI: 1.258–2.672, p = 0.002) were associated with the degree of hepatic inflammation. Meanwhile, PLT (OR: 0.990, 95% CI: 0.986–0.993, p < 0.001), TBIL (OR: 1.004, 95% CI: 1.000–1.007, p = 0.028), age (OR: 1.123, 95% CI: 1.067–1.183, p < 0.001), and autoimmunity (OR: 1.760, 95% CI: 1.191–2.608, p = 0.005) were associated with the stage of hepatic fibrosis.Conclusion: This study revealed that the presence of autoimmunity represents a more serious illness state of DILI, deserving more intensive monitoring and progressive treatment.

The accurate understanding of the origin of overpressure is the basis of formation pressure research and the core work of determining the distribution of formation pore pressure in drilling design. The deep water area of Baiyun Sag in the Pearl River Mouth Basin in the northern margin of the South China Sea has been proved to be a hydrocarbon rich depression. In recent years, overpressure has been encountered in the middle and deep layers, but the geological origin of the overpressure in the deep water area are still unclear. Therefore, the pore pressure profile of the Baiyun Sag was evaluated using the data of drilling and seismic velocity, and the relationship between overpressure and the generation mechanism was established. Most of the surrounding and shallow strata of Baiyun Sag show normal pressure, while the middle and deep strata generally show overpressure, with the maximum pressure coefficient up to 1.55. The overpressure zone mainly develops from the middle of Zhujiang Formation to the upper member of Enping Formation. The mudstone resistivity and density values of the two typical Wells deviated from the normal trend. The density showed a constant trend with the increase of depth, while the resistivity showed a certain degree of reversal. The upper layer of the overpressure zone showed abnormally high resistivity values, corresponding to the overgland and transition zone formed by high carbonate content. There is no obvious increase of porosity in the overpressured sandstone strata of Baiyun sag, which does not have the characteristics of undercompaction. The velocity in the overpressure section of the two Wells varies greatly, and the density is basically unchanged or slightly decreased. It is concluded that the overpressure is caused by fluid expansion from hydrocarbon-generation. The large-scale and long-term fluid expansion caused by hydrocarbon generation and expulsion of source rocks provides the power source for the formation of overpressure in Baiyun sag. The distribution of effective source rocks has a controlling effect on the distribution range of overpressure. The tight sandstone strata in the Zhuhai, Wenchang and Enping formations become the cover layer of the overpressure system in the longitudinal direction.

Rheumatoid arthritis is considered a chronic systemic autoimmune disorder that may cause joint destruction. Triptolide, an active component isolated from Tripterygium wilfordii Hook.f., is considered to have promising potential for clinical use in treating rheumatoid arthritis. However, its clinical application has been limited by the narrow therapeutic window, side effects associated with plasma drug fluctuations, low oral bioavailability, and poor patient compliance with the long and frequent dosing regimen. An extended drug release preparation may address these limitations. The aim of this work was therefore to develop, formulate and optimize sustained release triptolide microspheres with poly (lactide-co-glycolide) (PLGA). Triptolide-loaded microspheres were prepared using PLGA as the matrix polymer, dichloromethane as the oil phase, and polyvinyl alcohol (PVA) as the matrix forming emulsifier. An oil-in-water (O/W) emulsion solvent evaporation technique was utilized to prepare the microspheres. Surface response methodology (RSM) coupled with central composite design (CCD) was used to optimize the formulation and a total of twenty formulations were prepared. PVA concentration (X1), PLGA concentration (X2), and theoretical drug content (X3) were selected as independent variables; and drug content (Y1), encapsulation efficiency (Y2), mean diameter (Y3) and the initial release during the first day (Y4) were taken as the response variables. The optimized formulation showed mean diameter of 42.36 μm, drug content of 7.96%, encapsulation efficiency of 80.16% and an initial release of 14.48%. The prepared microspheres exhibited a sustained release profile of triptolide in vitro over 4 weeks, which was wellfitted with a Korsmeyer-Peppas equation. However, the initial drug release (~14%) of triptolide-loaded microspheres was very high and should be specifically investigated in future studies. The results indicate that long-term sustained release microspheres of triptolide can be considered a strategy to overcome the low bioavailability and poor patient compliance with conventional triptolide tablets. The issue of initial burst release and in vivo evaluations should be specifically investigated in the future.

High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20 weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.

An intriguing Brønsted acid-catalyzed 1,6-hydrophosphination of in situ generated propargylic para-quinone methides (p-QMs) and aza-para-quinone methides (aza-p-QMs) with H-phosphorus oxides via dehydration/1,6-addition under ultrasonic irradiation is described. This methodology provides a rapid and green approach for the construction of diarylmethyl phosphorus oxides bearing phosphorus-substituted quaternary carbon centers in high yields (up to 98% yield) within merely 5 ​min. This environmentally benign protocol represents a unique example of 1,6-conjugate additions of propargylic p-QMs and aza-p-QMs for site-selective C–P bond formation in an operationally simple and atom-economical manner. The use of readily available Brønsted acid catalyst, operationally simplicity, high yields, and high atom economy make this protocol very facile, practical, easily scaled-up and environmentally friendly.

The heart requires a large and constant supply of energy that is mainly the result of an efficient metabolic machinery that converges on mitochondrial oxidative metabolism to maintain its continuous mechanical work. Perturbations in these metabolic processes may therefore affect energy generation and contractile function directly. Metabolism characteristics in takotsubo syndrome (TTS) reveals several metabolic alterations called metabolic remodeling, including the hyperactivity of sympathetic metabolism, derangements of substrate utilization, effector subcellular dysfunction and systemic metabolic disorders, ultimately contributing to the progression of the disease and the development of a persistent and long-term heart failure (HF) phenotype. In this review, we explore the current literature investigating the pathological metabolic alterations in TTS. Although the metabolic dysfunction in takotsubo hearts is initially recognized as a myocardial metabolic inflexibility, we suggest that the widespread alterations of systemic metabolism with complex interplay between the heart and peripheral tissues rather than just cardiometabolic disorders per se account for long-term maladaptive metabolic, functional and structural impairment under this condition. Therapeutic strategies with the recent evidence from small clinical and animal researches, especially for targeting substrate utilization and/or oxidative stress, might be promising tools to improve the outcome of patients with TTS beyond that achieved with traditional sympathetic inhibition and symptomatic therapies.