Coherent multi-transducer ultrasound (CoMTUS) imaging enables the use of multiple arrays as one large effective aperture yielding images with enlarged field-of-view, improved resolution, and higher signal-to-noise ratio. However, creating a large but discontinuous effective aperture increases the grating and sidelobe levels, and generates cross-talk artifacts between arrays. These additional challenges can degrade the contrast of the images obtained through the classic Delay and Sum (DAS) beamforming algorithm. This study investigates the possibility to improve contrast and reduce artifacts in CoMTUS by using an alternative nonlinear beamforming algorithm, the Filtered Delay Multiply and Sum (F-DMAS). We implemented a specific F-DMAS beamforming algorithm for CoMTUS considering the resulting effective aperture and tested its performance in a coherent dual-array system for 2-D imaging. The comparison between CoMTUS images obtained through F-DMAS and DAS was investigated by both simulations and experiments, including in vivo results. For a typical dual-probe configuration, CoMTUS specific F-DMAS was shown to be effective at lowering the sidelobes and the noise floor, resulting in better quality B-mode images with improved sidelobe suppression (first sidelobe amplitude decreased from -13.0 dB to -24.7 dB; side-lobe-to-main-lobe energy ratio decreased from 9.3 dB to 1.9 dB).
Injectable hydrogels are promising biomaterials for tissue engineering applications due to their ability to deliver bioactive compounds or cells with minimal invasiveness. Temperature-responsive in situ gelling hydrogels, which undergo transition from liquid to gel in response to temperature stimuli, are desirable candidates for injectable hydrogels. Elastin-like polypeptides (ELPs) are well-known temperature-responsive biomaterials for cell scaffolds, drug delivery, and tissue engineering, due to their biocompatibility, biodegradability, and tunable mechanical properties. However, due to high hydrophobicity and heterogeneous aggregation, the development of injectable hydrogel-derived ELPs remains limited. In our previous study, we designed coiled-coil unit-bound ELPs (CUBEs) hydrogel systems, which integrate ELPs, a polyaspartic acid (polyD) chain, a functional peptide, and a coiled-coil peptide. In this study, we evaluated the injectability and cell delivery potential of a basic CUBE hydrogel system, called O-CUBE (AVGVP)-D-CL. The O-CUBE protein solution was mixed with human cervical cancer (HeLa) cells, serving as a cell model, and subsequently injected into culture medium pre-warmed to 37 °C to initiate in situ gelation. O-CUBE protein was successfully gelled at an approximately 90 % gelation rate after injection at 37 °C within pH ranges of 6-8. Encapsulated HeLa cells exhibited spheroid morphology, indicating that the hydrogel facilitated cell-cell interactions in three-dimensional culture. Further evaluation using a DNA assay revealed that HeLa cells can survive and proliferate within the hydrogel. These results demonstrate that the CUBE hydrogel system is a promising candidate to deliver cells with minimal invasiveness.
BACKGROUND: Monitoring neurological disorders is crucial for the early detection of neurodegeneration and abnormal neural activity of the human brain. NEW METHODS: This study combines a feature-based random forest (RF) machine learning model with an image-based convolutional neural network (CNN) deep-learning approach, forming a hybrid random forest-convolutional neural network (RF-CNN) model to detect neurological disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD), and epilepsy (Ep) using electroencephalography (EEG) signals. EEG data from 19 channels were segmented into delta, theta, alpha, and beta frequency bands, generating power-based features, spectral topographic maps, and continuous wavelet transform (CWT) based scalograms, as inputs for cerebral pattern analysis. RESULTS: The experimental results demonstrated detection accuracy of 88 % and F1-score of 84.85 % with RF, accuracy of 97.58 % and F1-score of 95.16 % using scalograms, accuracy of 98.39 % and F1-score of 97.64 % using spectral maps, and an outstanding 99.19 % accuracy and 98.32 % F1-score with hybrid RF-CNN model. COMPARISON WITH EXISTING METHODS: Unlike previous models that relied solely on feature-based machine learning or image-based deep learning, this approach enhances disorder detection with greater accuracy by integrating both features and images. Features like power asymmetry increase with cognitive decline, indicating hemispheric imbalance, while a declining cognition index reflects interhemispheric communication loss. Additionally, images including spectral topographic maps and CWT-based scalograms provide a comprehensive view of spatial power distribution and time-frequency characteristics. CONCLUSION: The hybrid RF-CNN approach enhances more reliable analysis of altered non-linear brain dynamics and transitional phases, making it a valuable tool for detecting neurological disorders.
BACKGROUND: Nurse retention and wellbeing have reached alarmingly low levels in recent years and health systems globally are searching for large-scale systemic solutions to reduce nurse burnout, improve wellbeing, and increase job satisfaction and retention while simultaneously enhancing patient care quality and safety. OBJECTIVE: To evaluate whether a minimum nurse staffing policy intervention in Queensland Australia improved nurse wellbeing, intentions to leave employment, and patient safety. METHODS: This is a quasi-experimental intervention study in which we compared nurse outcomes, patient safety measures, quality of care indicators, and operational failures among 27 hospitals subject to a minimum nurse staffing policy (i.e. intervention hospitals) and 41 hospitals not subject to the policy (i.e. comparison hospitals) at two points in time: prior to implementation of the policy (i.e. baseline) and two years after implementation (i.e. post-implementation). Percentages of nurses with unfavorable outcomes and unfavorable ratings of quality of care and patient safety are reported for intervention and comparison hospitals at baseline and post-implementation of the staffing policy. Fixed effects logistic regression models evaluated the interaction between the intervention effect and the post-implementation period to report the impact of the staffing policy on outcomes. RESULTS: The minimum nurse staffing policy intervention was associated with improvements in staffing, nurse wellbeing and job outcomes, and quality of care and patient safety in the intervention hospitals. Nurses in intervention hospitals had 24 % lower odds of high burnout (OR 0.76, 95 % CI 0.61-0.94, p < 0.05) and 27 % lower odds of job dissatisfaction (OR 0.73, 95 % CI 0.59-0.91, p < 0.01) at post-implementation relative to the baseline; no statistically significant differences in these outcomes were found among comparison hospitals. Job dissatisfaction with workload, professional development, autonomy at work, and work schedule all declined significantly in intervention hospitals and worsened over time in comparison hospitals. Nurse work environment scores improved in the intervention hospitals and worsened in the comparison hospitals. Quality of care, patient safety, and operational failures markedly improved in the intervention hospitals and generally worsened in the comparison hospitals. CONCLUSIONS: The quasi-experimental study design gives policymakers and hospital administrators strong confidence that minimum nurse staffing policy interventions can result in more favorable work environments for nurses, better job outcomes including lower nurse burnout and job dissatisfaction, and improvements in quality of care and safety for patients.
OBJECTIVES: Although ADHD has its roots in childhood, significant symptoms persist into adulthood for more than half of individuals. Adults with ADHD are heterogeneous in terms of symptom presentations, impairment domains, and relative strengths. Consequently, it is essential to better understand the diverse self-perceptions and experiences of adults with ADHD; qualitative methods are a valuable complement to quantitative work in this area. Our aim is to provide a scoping review of qualitative studies on adults with ADHD to articulate the current status of the field and establish future research directions. METHOD: We review 41 studies, separating findings into four subpopulations: (1) adults with childhood ADHD, (2) college students with ADHD, (3) adults diagnosed with ADHD in adulthood, and (4) other studies (unspecified age of diagnosis). RESULTS: Qualitative research on all four subgroups identifies recurring themes: substance use, decisions about medication for ADHD, perceived domains of impairment, factors that promote or hinder success, and concerns about identity and stigma. Notably, the relative emphasis of each theme varies as a function of sample type. Specifically, qualitative research among adults with a childhood ADHD diagnosis focuses principally on substance use and treatment desistance, whereas studies of individuals diagnosed with ADHD as adults often examine emotional responses to receiving the diagnosis. For college students with ADHD, themes frequently relate to struggles with the increased independence demanded by post-secondary educational environments and the adoption of accommodations or coping strategies. For future studies of adult ADHD, we highlight key domains for which mixed-methods strategies will be critical: (a) similarities and differences between multiple reporters of functioning, (b) willingness to receive treatment, (c) women, (d) participants from diverse racial and ethnic groups, and (e) middle age and older adults. CONCLUSION: In all, we highlight the value of qualitative and mixed-methods approaches to ensure that research captures the beliefs, intentions, experiences, emotions, and self-perspectives of people with ADHD.
BACKGROUND AND OBJECTIVE: Following Neoadjuvant Chemotherapy (NAC), there exists a probability of changes occurring in the Human Epidermal Growth Factor Receptor 2 (HER2) status. If these changes are not promptly addressed, it could hinder the timely adjustment of treatment plans, thereby affecting the optimal management of breast cancer. Consequently, the accurate prediction of HER2 status changes holds significant clinical value, underscoring the need for a model capable of precisely forecasting these alterations. METHODS: In this paper, we elucidate the intricacies surrounding HER2 status changes, and propose a deep learning architecture combined with radiomics techniques, named as Ultrasound Radiomics Attention Network (URAN), to predict HER2 status changes. Firstly, radiomics technology is used to extract ultrasound image features to provide rich and comprehensive medical information. Secondly, HER2 Key Feature Selection (HKFS) network is constructed for retain crucial features relevant to HER2 status change. Thirdly, we design Max and Average Attention and Excitation (MAAE) network to adjust the model's focus on different key features. Finally, a fully connected neural network is utilized to predict HER2 status changes. The code to reproduce our experiments can be found at https://github.com/didadiuouo/URAN. RESULTS: Our research was carried out using genuine ultrasound images sourced from hospitals. On this dataset, URAN outperformed both state-of-the-art and traditional methods in predicting HER2 status changes, achieving an accuracy of 0.8679 and an AUC of 0.8328 (95% CI: 0.77-0.90). Comparative experiments on the public BUS_UCLM dataset further demonstrated URAN's superiority, attaining an accuracy of 0.9283 and an AUC of 0.9161 (95% CI: 0.91-0.92). Additionally, we undertook rigorously crafted ablation studies, which validated the logicality and effectiveness of the radiomics techniques, as well as the HKFS and MAAE modules integrated within the URAN model. The results pertaining to specific HER2 statuses indicate that URAN exhibits superior accuracy in predicting changes in HER2 status characterized by low expression and IHC scores of 2+ or below. Furthermore, we examined the radiomics attributes of ultrasound images and discovered that various wavelet transform features significantly impacted the changes in HER2 status. CONCLUSIONS: We have developed a URAN method for predicting HER2 status changes that combines radiomics techniques and deep learning. URAN model have better predictive performance compared to other competing algorithms, and can mine key radiomics features related to HER2 status changes.
In recent years, phased array ultrasonic testing (PAUT) has gradually been substituted by approaches such as the Total Focusing Method (TFM), which use the Full Matrix Capture (FMC) acquisition scheme. Phase Coherence Imaging (PCI) has been proposed to mitigate the problems associated with amplitude-based TFM. PCI also holds high potential for dramatically simpler and far more affordable instruments as it only requires the phase of signals. However, in the context of PCI and in a scenario where the amplitude is not acquired, point-like scatterers would easily be identified due to their diffractive nature, while specular reflectors would not be detectable, as specular information is only captured by a specific group of elements known as sub-apertures (SA). In this paper, specular wave paths are analyzed to predict and choose the suitable emitting and receiving SA that are sensitive to specular reflections. The work demonstrates the effectiveness of the proposed method for revealing specular information by comparing PCI images of notches with the corresponding pairs of side-drilled holes (SDH) at their extremities. Results on two fatigue cracks are also presented as more realistic scenarios, and show that, while PCI highlights diffuse reflections, selecting the right SA on PCI mainly exhibit specular reflections, and reduce the image quality owing to the fact that the number of active elements in the aperture is reduced. When dedicated PCI instruments are present, the proposed method should be included in the inspection workflow to obtain images. PCI may not only be a complementary solution to amplitude imaging, but indeed, a solution in its own right. Finally, as Vector Coherence Factor (VCF) imaging can be achieved using binary acquisitions, this method allows to obtain images very similar to those from TFM should one wish to use simplified instruments.
OBJECTIVE: To evaluate the prevalence of reporting guideline and clinical trial registration requirements in the "instructions for authors" pages of pediatric journals since a previously completed 2010 publication. STUDY DESIGN: This cross-sectional study analyzed 100 peer-reviewed pediatric journals identified through the 2021 Scopus CiteSource tool. Two investigators independently reviewed journals' "instructions for authors" pages on December 10, 2023, for references to the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network, International Committee of Medical Journal Editors, specific reporting guidelines, and clinical trial registration requirements. RESULTS: Among the 100 journals analyzed, 33% (33/100) did not reference any specific reporting guidelines. Of the 98 journals assessed for clinical trial registration, 43% (42/98) failed to mention study registration. EQUATOR Network guidelines were mentioned by 39% (39/100) of journals, and ICMJE was referenced by 68% (68/100). CONSORT and PRISMA were the most cited reporting guidelines, mentioned by 52% (51/98) and 41% (41/100) of journals, respectively. In contrast, 95% (94/99) of journals did not reference meta-analysis of observational studies in epidemiology, and 99% (99/100) omitted quality of reporting of meta-analyses. CONCLUSION: Pediatric journals inadequately endorse reporting guidelines and clinical trial registration in their author instructions. These tools are critical for improving research quality, transparency, and reproducibility. Pediatric journals should strengthen publication policies to mandate these practices. Further research is needed to explore barriers and incentives for adoption to enhance integration into clinical research.
BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH), caused by the rupture of intracranial aneurysms, is a devastating cerebrovascular event with high mortality and disability. However, effective diagnostic biomarkers and therapeutic targets remain limited. METHODS: We combined 4D label-free quantitative proteomics with transcriptomic datasets (GSE122897, GSE36791, GSE73378) for integrative analysis. Weighted Gene Co-expression Network Analysis (WGCNA) identified key gene modules. Functional enrichment (GO, KEGG) and GeneMANIA interaction networks were constructed. A diagnostic model was built using 113 machine learning algorithm combinations and validated across multiple datasets. Immune infiltration was evaluated by CIBERSORT. Gene Set Enrichment Analysis (GSEA) explored underlying biological processes. A nomogram was developed using the "rms" package. Experimental aSAH models were established in vivo and in vitro to validate candidate gene expression and function via qPCR, Western blot, immunofluorescence, and immunohistochemistry. AAV-mediated gene modulation and primary cortical neuron cultures were used for mechanistic validation. RESULTS: CALR was identified as a key diagnostic biomarker through WGCNA and machine learning. The diagnostic model demonstrated high accuracy (AUC > 0.85). CALR was significantly associated with immune cell infiltration and endoplasmic reticulum stress. In vivo, AAV-mediated CALR overexpression attenuated neuronal damage in SAH mice. In vitro, CALR exerted neuroprotective effects on primary neurons under SAH conditions. CONCLUSION: CALR serves as a promising diagnostic and therapeutic target in aneurysmal subarachnoid hemorrhage. This study highlights the role of multi-omics and machine learning in uncovering novel mechanisms and targets in cerebrovascular diseases.
Fetal skin in early to mid gestation exhibits scar-free wound healing, however, it loses the regenerative capacity in late gestation and adulthood, where fibrosis predominates. Human keratinocytes (hKCs) and human fibroblasts (hFBs) play critical roles in this process, with early- to mid- gestational hKCs enhancing hFB proliferation and migration. MicroRNAs (miRNAs) regulate wound healing, but their roles in scarless repair remains incompletely disclosed. We isolated hKCs from mid- (22-23 weeks) and late- gestational (33-36 weeks) fetal skin and performed miRNA sequencing (miRNA-seq), identifying seq-14465_x69 as a novel miRNA highly expressed in mid gestation. Bioinformatics and dual-luciferase reporter assays predicted and validated its targeting of TGF-β/SMADs pathway genes. Functional assays including cell proliferation, migration, and a murine full-thickness wound model determined its effects on proliferation, migration, and fibrosis during wound healing. Seq-14465_x69 suppressed TGF-β2, TGF-βR2, and SMAD3, enhanced hFBs migration while reducing collagen I deposition, and drove accelerated wound closure. Our study revealed seq-14465_x69 as a key miRNA promoting scarless healing by modulating TGF-β/SMADs signaling and extracellular matrix (ECM) remodeling, offering a potential therapeutic target for anti-fibrotic wound management.
Mollusks, beyond their critical significance in aquaculture, have long been recognized as sentinel species for monitoring chemical contaminants in aquatic ecosystems. This study presents a comprehensive assessment of polycyclic aromatic hydrocarbons (PAHs) in an intensive coastal aquaculture area, encompassing their multimedia distribution, tissue-specific accumulation, bioaccumulation dynamics, partitioning behavior, and associated health risks. Among the 16 analyzed PAHs, 15 were detected in inshore seawater, while all 16 were quantified in intertidal sediment and mollusks. Low molecular weight PAHs were the most prevalent congeners. The average ∑16PAHs were 235.2 ng L in inshore seawater and 124.8 ng g dry weight (dw) in intertidal sediment, while the levels reached 249.5 ng g dw in muscles and 608.9 ng g dw in viscera in mollusks. PAH concentrations were significantly higher in mollusk viscera than in muscles. Among inshore species, infauna bivalves accumulated more PAHs than attached bivalves and epifauna gastropods. Intertidal mollusks generally exhibited higher PAH levels than inshore species. The significant inverse linear correlation between log BSAF and log Kow of PAHs indicated reduced bioavailability of high-ring PAHs in mollusks. Estimated non-carcinogenic and carcinogenic risks remained well below safety thresholds, suggesting that the health risks of PAHs through mollusk consumption were within acceptable limits. Safety thresholds for daily intake of mollusks were established at 607 g for viscera and 1573 g for muscles, highlighting the need to limit viscera consumption. The findings emphasize the critical necessity of monitoring PAH accumulation in mollusks, given their major role in human dietary exposure to environmental contaminants.
上游刺激因子2（USF2）已被确定为多种癌症中的致癌因子；然而，其在肺癌发病机制中的确切生物学功能和潜在分子机制仍有待充分阐明。在本研究中，我们发现USF2在肺腺癌（LUAD）组织和细胞中显著上调。敲低USF2可抑制A549细胞增殖和侵袭并诱导细胞凋亡。USF2的过表达促进A549细胞中的异常脂质代谢，甘油三酯、胆固醇和游离脂肪酸水平升高、脂肪酸合酶水平上调以及酰基辅酶A氧化酶1水平下调证明了这一点。机制上，USF2直接结合过氧化物酶体生物发生因子3（PEX3）的启动子以驱动其转录激活。上调的PEX3通过与溶质载体家族25成员17（SLC25A17）相互作用上调其蛋白水平，从而促进LUAD细胞中的异常脂质代谢。敲低PEX3可逆转USF2过表达对A549细胞的影响。此外，SLC25A17的过表达通过激活janus激酶2/信号转导和转录激活因子3（JAK2/STAT3）途径加剧A549细胞中的脂质积累，而JAK2抑制剂AG490可消除这种作用。最后，通过将转染了sh-USF2慢病毒载体的A549细胞皮下注射到裸鼠中建立了异种移植肿瘤模型。结果表明，敲低USF2可抑制异种移植小鼠中的异常脂质代谢和肿瘤生长。总之，我们的研究表明，USF2过表达通过促进PEX3转录激活增强SLC25A17介导的JAK2/STAT3信号传导，从而加剧A549细胞中的异常脂质代谢并加速LUAD进展。
Cyanobacteria convert CO into valuable compounds using solar energy, making them ideal for sustainable isobutene production, a key precursor for fuels and chemicals. This study aimed to enhance isobutene production in engineered Synechocystis sp. PCC 6803 strains: Syn-RnKICD, which produes isobutene from α-ketoisocaproate via Rattus norvegicus α-ketoisocaproate dioxygenase (RnKICD), and Syn-F336V, a mutant RnKICD variant with a phenylalanine to valine substitution at position 336 showing improved isobutene production. We investigated the effects of varying culture conditions, including light intensity, inorganic carbon, and nitrogen on isobutene production. Nitrogen limitation emerged as a critical factor, improving yields to 112 µg L OD by reducing growth and redirecting carbon toward isobutene synthesis. However, prolonged nitrogen limitation ultimately reduced productivity. To address this limitation, we employed a polyvinyl alcohol-sodium alginate (PVA-SA) hydrogel, crosslinked with B(OH) and Ca to entrap cells. This approach restricted growth while maintaining cell viability and isobutene productivity. Optimizing crosslinking parameters such as time, pH, and the hydrogel-to-cell mass ratio improved bead stability under bicarbonate and nitrate supply. This strategy extended cell viability and isobutene productivity in Syn-RnKICD and Syn-F336V by nearly a month, increasing yields by 60 % and 80 %, respectively, compared to suspension cells, achieving a maximum yield of 94 mg/g DW at 744 h and reaching a highest production rate of 1 mg/g DW/h at 264 h. This study underscores the importance of optimizing environmental conditions for isobutene production in Synechocystis and highlights the effectiveness of PVA-SA cell entrapment as a biocatalyst platform for sustained chemical production.
Forty-three compounds, including nine undescribed compounds, five iridoids (patrirupesins A-E, 1-5) and four bis-iridoids (patrirupesins F-I, 6-9), were isolated from the EtOAc-soluble fraction of the aerial parts of Patrinia rupestris (Pall.) Dufr., and their structures were elucidated based on Mass spectrometry and NMR spectroscopy. The absolute configuration of patrirupesins A-E (1-5) and I (9) was determined by experimental and calculated electronic circular dichroism (ECD). In addition, patrirupesin E (5), patrirupesin H (8), 8,9-didehydro-7-hydroxydolichodial (17), 5,6-epoxy-3-hydroxy-7-megastigmen-9-one (19), iso-seco-tanapartholide (24) and 3-hydroxy-2-methyl-4-(3-oxoprop-1-en-2-yl)cyclopent-1-enecarbaldehyde (43) showed in vitro anti-inflammatory activity on NO production in RAW 264.7 cells stimulated by lipopolysaccharide (LPS) with IC values of 9.32 ± 3.83, 4.63 ± 1.23, 8.31 ± 4.05, 17.23 ± 5.19, 8.30 ± 6.17 and 27.38 ± 4.69 μM, respectively.
Systemic mastocytosis (SM) is a rare disease characterized by aggregation of mast cells in the skin or extracutaneous organs. Disease subtypes range from cutaneous to systemic mastocytosis with highly malignant forms, indolent systemic mastocytosis (ISM) being the most frequent subtype. In ISM, mast cells infiltrate bone marrow, with some patients developing osteoporosis and fractures. However, fractures do not occur in all ISM patients. In this retrospective one-center study, we analyzed data from patients evaluated for osteoporosis diagnosed with ISM according to WHO criteria between 2006 and 2019. ISM patients (n = 42) comprised 76.2 % women (n = 32), had a mean age of 52.2 ± 12 years, and presented with skin lesions in 80.5 % (n = 33). Osteoporosis was diagnosed in 42 % (n = 15) according to the WHO definition (T-score ≤ -2.5). Fractures were either peripheral in 19 % (n = 8), or to the spine in 43 % (n = 18); both fracture types presented in 14 % (n = 6). All fracture types correlated to femoral BMD T-scores. The presence of the somatic gain-of-function mutation in the KIT receptor tyrosine kinase (KIT-mutation) in bone biopsy was associated with a significantly greater number of fractures (p = 0.024) and correlated to the number of vertebral fractures in individual patients (p = 0.03). Neither tryptase levels, postmenopausal status, nor bone turnover markers were indicators of an increase in vertebral or peripheral fractures in ISM patients. Smoking was associated with more fractures, however the effect disappeared dependent on KIT-mutation. Those with skin lesions had better femoral BMD T-scores (right femur: -1.05 ± 0.99 vs -2.26 ± 0.59, p = 0.008; right femoral neck: -1.21 ± 0.99 vs -2.22 ± 0.55, p = 0.0023). In conclusion, we demonstrate the influence of the KIT-mutation on the severity of fractures in osteoporosis patients with the final diagnosis of ISM. Our results suggest that, in the presence of the KIT-mutation in ISM patients without skin lesions, the timely onset of anti-osteoporotic treatment might be of value.
Global demands for energy-neutral wastewater treatment drive innovation in sustainable nitrogen removal. A single-biofilm membrane biofilm reactor (MBfR) was constructed for efficient aerobic methane oxidation coupled with simultaneous ammonia oxidation and denitrification (AME-AOD). Through meticulous refinement in aspects such as membrane materials and gas-to-feed ratios, the best-performing biofilm achieved a high total nitrogen (TN) removal efficiency of 97 % ± 2 %. The system ultimately reduced TN from 51.6 ± 0.7 mg l to approximately 5 mg l within 16 h with a methane conversion efficiency of 30.0 ± 0.9 mg-CH/mg-N. From startup, the biofilm supported stable coexistence of aerobic and anoxic processes, with gene abundances related to nitrification and denitrification increasing by 1.6-fold and 1.2-fold, respectively. After long-term operation, ecological niche differentiation enabled coexistence and synergistic interaction of methanotrophs, anaerobic ammonium oxidation (anammox), denitrifiers, and nitrifiers within each layer of the biofilm. Overall, this study offers a new strategy to advance sustainable mainstream nitrogen removal in wastewater.
Syndecans are a family of four-member transmembrane heparan sulfate proteoglycans that bind to various extracellular biomolecules, such as Wnt ligands, via their heparan sulfate chains, thereby controlling a variety of cellular processes. When dysregulated, syndecans can affect tumorigenesis and cancer progression by modulating key signaling pathways involved in the regulation of biological functions. Aberrant activation of Wnt/β-catenin signaling is a hallmark of many human tumors, including breast cancer. Studying the interplay between syndecans and Wnt signaling in human cancers is beneficial for identifying new therapeutic strategies, understanding tumor behavior and improving patient outcomes. Syndecan-2 is predominantly expressed by mesenchymal cells, and its overexpression in tumors of epithelial origin appears to induce aggressive behavior. Here, by measuring β-catenin cytoplasmic stabilization and transcriptional activity, we show that syndecan-2 expression significantly enhances the sensitivity of HEK293T cells and BT-20 triple-negative breast cancer cells to Wnt3a-induced activation of Wnt/β-catenin signaling. In addition, CRISPR/Cas9-mediated deletion of SDC2, the gene encoding syndecan-2, reduced β-catenin transcriptional activity in BT-20 cells in response to Wnt3a stimulation. This reduction was rescued by the re-expression of SDC2. Collectively, our results demonstrate that syndecan-2 is a positive regulator of canonical Wnt signaling. These results also suggest that syndecan-2 is a potential clinical target for inhibiting the progression of some human cancers.
Kuroshio-Oyashio Extension (KOE) region is an ideal natural laboratory for investigating microbial community dynamics due to its frequent nutrient exchanges. However, comprehensive spatiotemporal investigations of microbial communities in this region remain limited. We conducted a systematic research examining microbial community variations across space and time through integrated physicochemical analysis and high-throughput sequencing of 54 surface water samples collected from 33 stations during three consecutive summer seasons (2021-2023). The results demonstrated an increasing trend in species richness from Cold Water Area (CWA) to Warm Water Area (WWA), while species diversity showed no significant spatiotemporal trends. The nMDS analysis indicated that the microbial communities in mixed area were more similar to those in WWA during 2022 and 2023. There were significant spatial and temporal differences in the structure and composition of microbial communities, with spatial differences being particularly pronounced. Proteobacteria (range: 61.64%-76.39%), Bacteroidota (range: 8.09%-10.74%), Cyanobacteria (range: 5.51%-19.05%), and Verrucomicrobiota (range: 0.95%-7.24%) were the dominant phylum. Spatially and temporally, dominant genera such as Vibrio, Alteromonas, Pseudoalteromonas, Prochlorococcus_MIT9313, Alcanivorax, and Synechococcus_CC9902 exhibited dynamic shifts in abundance. Spearman correlation analysis and Mantel tests indicated that temperature, salinity, density and conductivity were key environmental factors. Co-occurrence network analysis showed that microbial interactions were dominated by positive correlations. The complex interplay of geographic location, environmental parameters, microbial interactions, and ocean current patterns collectively governed the microbial distribution within KOE region. This research significantly enhances our understanding of the mechanisms underlying microbial community construction and maintenance in KOE region.
BACKGROUND: The gut-liver axis, pivotal in managing glucose balance and insulin responsiveness, is central to the development of type 2 diabetes mellitus (T2DM). Research has highlighted the regulatory effects of dietary alpha-linolenic acid (ALA), but it remains unclear how ALA modulates gut microbiota and liver inflammation in T2DM. PURPOSE: This study aimed to systematically investigate ALA's influence on liver inflammation, intestinal barrier integrity, gut microbial composition, and metabolic homeostasis in T2DM, with a focus on the underlying molecular mechanisms. STUDY DESIGN: A dual-model approach was employed using both db/db mouse model and the SCZ/NA-induced T2DM rat model to ensure robust species and model validation. METHODS: Animals received oral ALA supplementation, followed by assessments of glucose tolerance, insulin sensitivity, hepatic histology, and inflammatory markers. Intestinal barrier function, permeability, and systemic LPS levels were evaluated. Mechanistic analysis focused on the GPR120-NF-κB/NLRP3 signaling pathway. Multi-omics profiling including fecal metagenomics, SCFA quantification, and plasma metabolomics were conducted to assess gut microbiota and host metabolic responses. RESULTS: Our results revealed that ALA therapy significantly mitigated insulin resistance and glucose intolerance in db/db mice. Histopathological analysis revealed a decrease in hepatic steatosis following ALA administration, alongside a reduction in inflammatory markers indicative of T2DM. Importantly, our findings demonstrated that ALA mitigates liver inflammation by inhibiting the NF-κB/NLRP3 pathway, possibly via its interaction with GPR120. Beyond this, augmenting ALA bolstered intestinal integrity, minimized permeability, curbed lipopolysaccharide leakage, and suppressed pro-inflammatory cytokine expression within the intestines. Significantly, an integrated multi-omics investigation, encompassing fecal metagenomic sequencing, SCFA evaluation, and plasma non-targeted metabolomics, disclosed a potent correlation between ALA's hypoglycemic efficacy and the modulation of gut microbial community structure, elevation of SCFA synthesis, and enhancement of metabolic signatures. CONCLUSION: Our study's initial insights indicated that dietary ALA modulates inflammation and metabolism in T2DM via the gut-liver axis, specifically through the GPR120-NF-κB/NLRP3 pathway. This elucidates ALA's dual function in reshaping the gut microbiota and combating systemic inflammation, positioning it as a potentially efficacious dietary component for managing T2DM.
目的：为探索局部晚期宫颈癌（LACC）的新型治疗方法，我们评估了热疗（HT）和/或靶向治疗联合顺铂同步放化疗（CCRT）的疗效和安全性。 方法：这项回顾性研究分析了我院（2021年1月至2024年10月）治疗的119例LACC患者（肿瘤直径≥4 cm），分为：CCRT组（n = 48）、靶向治疗+CCRT组（T-CCRT，n = 44）和HT+靶向治疗+CCRT组（HT-T-CCRT，n = 27）。评估3/12个月时的完全/客观缓解率（CRR/ORR）。使用标准软件进行统计分析以比较疗效并评估不良事件（AE）。 结果：1. 疗效：3个月时，HT-T-CCRT组的CRR最高（85.19% vs. CCRT组58.33%，P < 0.05），ORR为96.30%。T-CCRT组的ORR显著更高（95.46% vs. CCRT组81.25%，P < 0.05）。12个月时，组间CRR（58.33%/61.36%/77.78%）或ORR（70.83%/75.00%/77.78%）无显著差异。2. 安全性：CCRT组的腹泻（52.08% vs. 81.82%）和呕吐（50.00% vs. 86.36%）发生率低于T-CCRT组（均P < 0.05）。与T-CCRT组相比，HT-T-CCRT组进一步降低了呕吐（55.56% vs. 86.36%）、腹泻（55.56% vs. 81.82%）和肝功能损害（22.22% vs. 47.73%）（均P < 0.05），安全性与CCRT组相当。 结论：疗效：靶向联合组在3/12个月时的ORR和CRR高于单纯放化疗组，3个月时的ORR差异显著。热疗-靶向组的CRR/ORR最高，3个月时的CRR显著优于单纯放化疗组，但不优于单纯靶向治疗组。 安全性：放化疗组的腹泻/呕吐发生率低于靶向治疗组；热疗-靶向组的腹泻/呕吐/肝损伤发生率低于单纯靶向治疗组，总体不良事件与放化疗组相当。
The RET receptor tyrosine kinase is essential for cell growth, differentiation, and survival. Its cysteine-rich domain (CRD) is crucial for ligand-induced dimerization, activation, and structural stability, significantly influenced by calcium ion coordination. Mutations in key cysteine residues can disrupt disulfide bonds, alter calcium binding, and destabilize the CRD, leading to oncogenic transformations. This study investigates the impact of cysteine mutations on calcium ion binding and the structural stability of the RET receptor's CRD. Using molecular dynamics simulations and free energy calculations, the research examines the structural effects of specific cysteine mutations (C565F, C581F, and C585S) in the CRD. The findings indicate that these mutations disrupt disulfide bonds, alter calcium binding, and destabilize the CRD. RMSD and RMSF analyses show that each mutant affects structural dynamics and flexibility differently. The C581F mutant exhibited the most significant effect, with average RMSD values of 0.21 nm compared to the wild-type (0.19 nm) and other mutants (C565F, 0.14 nm; C585S, 0.17 nm). Higher residue fluctuations were observed in C581F and C585S, particularly in the calcium-coordinating residues. Binding free energy analysis indicates reduced calcium-binding stability in the mutants, while weighted contact maps reveal altered residue interaction patterns and new contact formations. These results suggest that while global structural changes are minimal, cysteine mutations cause localized destabilization of calcium ion binding sites. The disruption of key disulfide bonds and reduced residue contacts likely contribute to decreased binding stability in the mutants, underscoring the importance of cysteine residues and calcium coordination in maintaining the integrity of the RET-CRD.
C-phycocyanin is a natural blue-colored pigment-protein complex existing as phycobiliprotein in cyanobacteria. C-phycocyanin is made up of two different subunits of α- and -β monomers. These subunits assemble to form a cylindrical structure known as phycocyanobilin chromophore. In the present study, C-phycocyanin was purified from the cyanobacterium Spirulina subsalsa HKAR-19 using ammonium sulfate precipitation followed by sucrose density gradient ultracentrifugation methods and characterized by various spectroscopic techniques. The purified C-phycocyanin showed an absorption peak at 615 nm. A characteristic fluorescence emission peak at 642 nm when excited over 615 nm, indicates the integrity and functionality of protein structure. The scavenging activity against free radicals of DPPH, ABTS, and superoxide (O·) was evaluated by using free radical scavenging assays. C-phycocyanin showed dose-dependent in vitro antioxidative properties towards free radicals. It possesses higher antioxidant activity toward ABTS and DPPH. Due to its high antioxidant activity, it can be used as a colorant and therapeutic agent against oxidative stress.
Primary cilia are microtubule based extensions on the surface of most cells that play a crucial role in cellular signaling during development, tissue homeostasis, and organ function. Defective cilia result in a wide variety of clinical manifestations affecting multiple organ systems, collectively termed ciliopathies. Ciliopathies are rare, exhibit tremendous genetic diversity and an overlap of clinical features, making diagnosis and treatment challenging. Identifying and characterizing novel ciliary variants is critical to gain an improved understanding of ciliopathic pathologies. To address this need, we performed a forward genetic screen using N-ethyl-N-nitrosourea (ENU) mutagenesis and subsequent complementation analysis. We found a novel variant in Pibf1, a gene essential for ciliogenesis and previously linked to the ciliopathy, Joubert syndrome. Pibf1 embryos exhibited a collection of craniofacial anomalies associated with ciliopathies including midline defects, maxillary hyperplasia, micrognathia, and high arched palate. Interestingly, Pibf1 embryos also presented with semilobar holoprosencephaly, a phenotype not typically associated with ciliopathies. Molecular analysis revealed aberrant Shh expression and GLI3 processing concomitant with an expansion of Fgf8 and Lhx6 expression across structures in the face, brain, and oral cavity. In summary, these data suggest a role for PIBF1 and cilia in establishing proper SHH/FGF8 signaling axes across the embryo and suggest that holoprosencephaly is a part of the ciliopathic phenotypic spectrum associated with Joubert syndrome.
BACKGROUND: Medication review is a structured interview of the patient, performed by the pharmacist and aimed at optimizing drug treatments. In practice, medication review is a long and cognitively-demanding task that requires specific knowledge. Various tools and criteria have been proposed, but their application is tedious. METHODS: We designed ABiMed, a clinical decision support system for medication reviews. The design was supported by literature reviews and clinicians focus groups. ABiMed supports the pharmacist by implementing the STOPP/START v2 criteria and by presenting aggregated drug knowledge, such as dosage, interactions or adverse effects, visually using tables, graphs and flower glyphs. We evaluated ABiMed with 39 community pharmacists during a simulation trial, each pharmacist performing a medication review for two fictitious patients without ABiMed, and two others with ABiMed. We recorded the problems identified by the pharmacist, the interventions proposed, the response time, the perceived usability and the comments. Pharmacists' medication reviews were compared to an expert-designed gold standard. RESULTS: With ABiMed, pharmacists found 1.6 times more relevant drug-related problems during the medication review (p < 0.0001) and proposed better interventions (p < 0.0001), without needing more time (p = 0.56). The System Usability Scale score is 82.7, which is ranked "excellent". In their comments, pharmacists appreciated the visual aspect of ABiMed and its ability to compare the current treatment with the proposed one. A multifactor analysis showed no difference in the support offered by ABiMed according to the pharmacist's age or sex, in terms of percentage of problems identified or quality of the proposed interventions. CONCLUSIONS: The use of an intelligent and visual clinical decision support system can help pharmacists when they perform medication reviews. Our main perspective is the evaluation of the system with real patients, and its diffusion among pharmacists.
Alterations in skeletal muscle morphology after an anterior cruciate ligament (ACL) tear are a major contributing factor to protracted quadriceps muscle weakness limiting person's return to function. Microstructural changes in skeletal muscle are difficult to assess noninvasively, but understanding these changes is vital to provide clinicians with additional information to assess injury and guide recovery. The purpose of this study was to evaluate the potential of magnetic resonance diffusion tensor imaging to provide noninvasive metrics of quadriceps muscle morphology and strength. Following a primary ACL tear and prior to surgical reconstruction, 44 individuals underwent bilateral isometric knee extension testing, vastus lateralis muscle biopsies, and diffusion tensor magnetic resonance of the thighs. Significant between limb differences were identified for quadriceps strength, fractional anisotropy, mean diffusivity, radial diffusivity, pooled fiber cross-sectional area, and pooled fiber minimum feret diameter. Fractional anisotropy and radial diffusivity were significantly associated with isometric knee extension peak torque for both limbs, after adjusting for mass. Fractional anisotropy was also significantly associated pooled cross-sectional area in the ACL-deficient limb only, after adjusting for mass. Our findings suggest that fractional anisotropy, mean diffusivity, and radial diffusivity can differentiate between the vastus lateralis of an ACL-injured limb and the healthy limb. Additionally, fractional anisotropy exhibited relationships with both measures of vastus lateral muscle fiber size and quadriceps strength for the ACL-deficient limb. These finding suggest that measures of diffusivity may be used cross-sectionally to infer between limb differences after an ACL-injury and that FA may be used to infer knee extensor strength.
Bronze disease is a severe type of degradation in ancient copper-based artifacts and poses challenges to their preservation. This "disease" is an active cyclic corrosion process primarily caused by chlorine, oxygen and moisture. Products formed during this process, such as cuprous chloride (CuCl), continue to spread across the artifact's surface until all available oxygen is consumed, resulting in irreversible destruction. Bronze disease is difficult to distinguish from other corrosion processes, leading to inaccurate assessments of the degradation mechanisms affecting the artifact. Combined scanning electron microscopy (SEM) and energy-dispersive x-ray spectroscopy (EDS) is a viable method for analyzing bronze disease in ancient artifacts and for differentiating it from other forms of degradation. This study investigated suspected bronze disease on a Chinese cast bronze vessel dating from the 11th - 10th century BCE, part of the collection at the Royal Ontario Museum in Toronto, Canada. Corrosion product sampled from the vessel using two different methods, was chemically and topographically analyzed using SEM-EDS. The first method involved the removal of corrosion product using a scalpel, resulting in the collection of mixed particles. The second method, involving the creation of replicas, utilized an adhesive to directly remove the corrosion product, capturing the particles in their original locations. The sampled material contained copper and chlorine, consistent with the presence of bronze disease, though further work is required for confirmation. Although both techniques can investigate bronze disease, the replica technique offers a more promising approach, as it enables more precise, site-specific analysis of the corrosion product.
O'Donnell-Luria-Rodan syndrome (ODLURO) is a very rare disorder caused by heterozygous pathogenic variants in KMT2E. While intellectual disability is associated with this syndrome based on retrospective chart review, the neurocognitive phenotype remains unexplored. This case series provides insight into the cognitive profile of ODLURO and discusses these trends in the context of other better-characterized disorders in the KMT2 families. This study involved a retrospective chart review of psychological or neuropsychological assessment reports from 10 patients with a likely pathogenic or pathogenic variant in KMT2E. The majority of participants scored within normal limits in verbal abstract reasoning and expressive vocabulary. In contrast, most participants performed below average to very low ranges in non-verbal abstract reasoning, working memory, sight word reading, and math computation skills. Wilcoxon paired tests showed verbal reasoning was stronger than non-verbal reasoning skills (p = 0.04). Over half of respondents rated their children in the at-risk to clinically significant range for attention problems and hyperactivity. Our cohort of patients with ODLURO presented with greater difficulties in non-verbal reasoning, attention, working memory, sight word reasoning, and math computation skills, juxtaposed with relative strengths in verbal skills. Our resulting trends show some similarities to cognitive profiles of Wiedemann-Steiner syndrome and Kabuki syndrome type 1, disorders caused by variants in KMT2A and KMT2D, respectively. Emergent findings suggest possible endophenotypes related to haploinsufficiency of the histone methyltransferases in the KMT2 group.
BACKGROUND AND OBJECTIVE: Electronic Health Records (EHRs) depicting patient-related information have been accumulated in a distributed manner and significantly contributed to clinical prediction. Although federated learning can collaborate with multiple medical centers without data sharing, the heterogeneity within multi-center EHRs poses a difficulty to achieve satisfactory predictive performance among different individuals. The objective is to train a personalized model for each client that performs well on local data while simultaneously benefiting from federated training. METHODS: In this paper a Personalized Federated Learning (PFL) method named FedRew is proposed. FedRew adopts the problem setup of model agnostic meta learning and conducts hierarchical reweighting both for local adaptation and global aggregation during federated training. For each independent participant, an alternative minimization scheme is tailored to realize sample reweighting and high-performance personalized clinical prediction models are generated. For the central server, a continuously updated weighting mechanism is adopted for aggregation, to ensure local models capable of mitigating data heterogeneity can exert a higher impact. RESULTS: Extensive experiments were conducted on the collected eICU-CRD dataset containing EHRs from 10 medical centers. The results validated FedRew achieved superior average performance and mean rank, compared to 2 baseline methods and 6 state-of-the-arts PFL methods. For in-hospital mortality prediction, FedRew achieved an average AUROC of 0.894 and a mean rank of 3.2. For remaining length of stay, FedRew achieved an average RMSE of 1.464 and a mean rank of 2.6. CONCLUSION: Our FedRew shows competitive performance across clients for two ICU clinical prediction tasks, demonstrating the potential of FedRew in handling data heterogeneity within multi-center EHRs.
Leishmania donovani is an intracellular protozoan parasite that has successfully evolved to manipulate host macrophages. The exact mechanism by which Leishmania spp evades macrophage function is not fully understood. Recently, several studies have shown that pathogens target host-microRNA to alter cellular pathways for their persistence. Here, we explored the alterations in host sphingolipid biosynthetic pathway regulatory microRNAs during Leishmania donovani infection. Here, the sphingolipid biosynthetic pathway genes serine palmitoyltransferase long chain base subunit 1 (SPTLC1), 3-ketodihydrosphingosine reductase (KDSR), ceramide synthase 1(CERS1) and dihydroceramide desaturase 1 (DEGS1) were found to be upregulated while N-Acylsphingosine Amidohydrolase 1 (ASAH1) was downregulated but no significant changes were observed in sphingomyelin synthase 1 (SGMS1) and sphingosine kinase 1 (SPHK1) in Leishmania donovani infected THP-1 derived macrophages (TDM) at 24 h. Bioinformatic analysis using miRWalk 2.0 predicted SPTLC1 to be a target of hsa-miR-15a-5p and hsa-miR-330-5p, CERS1 to be targeted by hsa-miR-10396a-3p, and ASAH1 by hsa-miR-513a-5p; all of these miRNAs have been previously reported to be dysregulated during infection. Since hsa-miR-15a-5p was found common to target SPTLC1 in all three databases, namely Targetscan, miRDB, and miRTarBase therefore the expression of hsa-miR-15a-5p was selected for further studies. We found a downregulated expression of hsa-miR-15a-5p during Leishmania donovani infection. In silico target prediction followed by in vitro target validation of hsa-miR-15a-5p showed SPTLC1 as one of the targets. Additionally, mimics of hsa-miR-15a-5p reduced the expression of SPTLC1, upregulated mainly the proinflammatory cytokines, and reduced the parasites in TDM as well as Peripheral Blood Mononuclear Cell (PBMC) derived human macrophages.
分次照射会导致肿瘤细胞过早衰老。迄今为止，衰老、免疫系统和生存信号之间的相互作用仍知之甚少。由于丝裂原活化蛋白激酶（MAP激酶）与免疫抵抗有关，本研究在头颈部鳞状细胞癌（HNSCC）的二维和三维模型中，探讨了放射后程序性死亡配体1（PD-L1）的衰老相关调节以及MAP激酶ERK1/2表达的检测。使用已建立的HNSCC细胞系（UM-SCC-11B、UM-SCC-14C和UM-SCC-22B），在给予4×2 Gy照射后，通过免疫组织化学研究p21、组蛋白H2AX（γH2AX）、PD-L1和磷酸化（p）ERK1/2的表达水平。此外，使用衰老相关β-半乳糖苷酶（SA-β-Gal）染色评估放射后衰老的诱导情况。结果在具有活性外植体的三维HNSCC模型中得到验证。在电离辐射（IR）后，在所有细胞系中均观察到衰老样亚群，其PD-L1、pERK1/2以及已确定的衰老标志物p21和γH2AX均上调。在所有细胞系中均发现了SA-β-Gal阳性细胞。这些结果在三维肿瘤模型中得到了支持。分次IR可产生一群HNSCC细胞亚群，其特征为具有衰老典型的细胞变化以及PD-L1和pERK1/2的显著表达。二维和三维癌症模型中的放射后衰老可能与生存信号和免疫检查点调节有关，这是肿瘤发生和进展的关键因素。
记忆是人类行为的基石，成瘾为记忆的持久性和可塑性提供了一个引人注目的模型。记忆痕迹研究的范围迅速扩大，已涵盖与成瘾相关的现象。与成瘾相关的记忆，如同强烈的厌恶记忆一样，往往对消退具有高度抗性，并且在药物使用停止很久之后仍能继续驱动复吸。这些持久的行为效应表明，药物记忆痕迹，即稀疏分布的编码与药物相关经历的神经集合，通过强大的突触和分子可塑性得以稳定。与此同时，它们的可塑性或许是开发新治疗方法的关键所在。这篇小型综述综合了关于药物记忆痕迹的最新研究发现，突出了与成瘾相关记忆痕迹相关的特定神经回路、分子机制及行为后果。我们着重探讨记忆痕迹标记和再激活技术如何揭示了多个脑区中特定于成瘾的神经集合以及促进或减弱觅药行为的重要通路。我们还讨论了直接操控药物记忆痕迹如何有望减弱与药物相关线索及其他复吸触发因素的影响，同时增强保护性神经回路以降低复吸风险。然而，一些基本问题仍然存在，比如在从娱乐性使用过渡到成瘾的过程中药物记忆痕迹是如何演变的？解决这些问题对于开发以维持成瘾的记忆系统为靶点的、基于神经回路的持久干预措施至关重要。
我们报告了一例患有严重低镁血症的患者，在谵妄状态下出现阵发性下跳性眼球震颤、共济失调和构音障碍。全面检查未发现其他解释。在开始补充镁后的48小时内，她的发作症状消退，但患者仍处于意识模糊和共济失调状态，6周后逐渐完全康复。低镁血症很可能是长期服用质子泵抑制剂（PPI）所致。阵发性下跳性眼球震颤很少见，迄今为止仅在各种原因引起的低镁血症中得到一致描述。
自然史研究有助于告知临床医生和护理人员预期情况，形成管理指南的基础，并为治疗干预提供对照。在罕见病中，由于前瞻性纵向数据的收集不及时且不切实际，来自不同年龄多个个体的准自然史数据提供了一种替代方法。我们对64例具有致病性或可能致病性ASXL3变异的个体进行了详细的基因型-表型分析，包括定性和定量数据。大部分数据是通过与个体和/或护理人员直接门诊咨询收集的。我们报告了显著的表型变异性，但随着时间推移，喂养、肌张力减退、语言表达和运动技能有改善趋势。研究结果包括：产前和新生儿结构异常的患病率增加，一种新出现的肾脏表型，出生后生长发育不良的倾向（有儿童后期肥胖的新报告），以及癫痫发作的患病率低于预期（与现有文献相比）。我们还首次对不同年龄的几名轻度受影响的先证者进行了定性描述。我们的建议包括：诊断后进行基线肾脏影像学检查，以及对所有人进行牙科和眼科随访。我们描述了迄今为止最大的与ASXL3相关疾病个体队列，包括24种新变异、新的临床发现、准自然史趋势、管理见解和建议。
尽管上颌窦在面部结构中起着核心作用，但其形状从未得到过全面分析，部分原因是其形态不规则且缺乏可重复的标志点。虽然先前的研究已经探讨了鼻窦体积和二维测量值与性别、年龄和环境影响等因素之间的相关性，但对于与这些变量相关的更精细的结构变化，如小梁形成和表面复杂性，了解较少。本研究旨在探讨上颌窦的大小和形状如何与年龄、性别、烟草使用和药物使用等因素相关。从109名成年人的CT扫描中分割出左右上颌窦。采用球谐分析的新应用来量化上颌窦的形状。使用包括主成分分析、t检验和曼-惠特尼U检验在内的统计分析方法来评估由于性别、年龄、烟草使用和药物使用导致的鼻窦形状差异。结果显示，由于性别、烟草使用和药物使用，鼻窦形状存在显著差异。各组之间差异最大的区域位于最外侧的顶点以及上下角的前壁。男性的鼻窦较大，但在测试的各组中未发现鼻窦大小或不对称性的其他显著差异。先前确定的各年龄组上颌窦体积模式未得到证实。本研究阐明了与每个变量相关的差异最大的区域，对未来旨在了解不同群体鼻窦结构和引流情况的研究具有重要意义。
背景：中东国家重症监护病房（ICU）的临终关怀（EoLC）受到文化和法律限制的影响，给临床医生带来了独特的伦理困境和挑战。关于维持患者生命的治疗的 withholding 和 withdrawing 的可接受性存在伦理争议。 目的：整理和综合关于中东国家 ICU 临床医生临终关怀经历、态度和观点的现有证据。 研究设计：进行了系统的综合评价。在 AMED、CINAHL、EMBASE、Medline、PubMed 和谷歌学术上搜索了 2012 年至 2024 年发表的研究。定量结果被转化为文本数据，并与定性结果一起使用主题综合方法进行分析。 结果：27 项研究符合纳入标准：16 项定量研究、10 项定性研究和 1 项混合方法研究。确定了五个主题：（1）ICU 临终关怀决策中的挑战；（2）影响临终关怀提供的文化和伦理问题；（3）对全面临终关怀指南的需求；（4）ICU 临床医生的临终关怀教育和培训；（5）ICU 临床医生的整体支持系统。 结论：中东 ICU 提供临终关怀的挑战涉及沟通、与家属的问题互动和决策。还发现文化和伦理问题会影响临终关怀的提供，这表明全面和明确的指南很重要。未来的研究可以从中东国家更广泛的利益相关者的角度探索临终关怀，并确定如何将国际最佳实践调整到中东 ICU 以加强临终关怀的提供。 与临床实践的相关性：为了加强中东 ICU 的临终关怀，临床医生需要接受沟通技巧、文化敏感性和家庭参与策略的培训。需要组织支持来更好地指导与家属的沟通和姑息治疗决策。
角化病-鱼鳞病-耳聋（KID）综合征是一种罕见的常染色体显性外胚层疾病，由GJB2基因突变引起，该基因编码位于13号染色体q12.11上的缝隙连接蛋白连接蛋白26（Cx26）。本研究首次呈现了与KID综合征相关的死亡率分析，重点是一位拉丁美洲患者的病例报告。我们的目标是建立广泛的基因型-表型相关性，特别是与死亡原因相关的相关性。分子研究使我们能够确认该疾病的病因，并确定某些致病变异的死亡原因。这些信息为医疗保健专业人员提供了宝贵的管理指南，并有助于制定适当的治疗策略。
存在一个遍布全身的间质间隙网络，它包括三个组成部分：一个由充满液体的间隙构成的大规模筋膜网络，这些间隙含有胶原蛋白和其他细胞外基质成分，如透明质酸（HA）；血管周围/毛细血管间质；以及细胞间间质间隙。对结肠、皮肤和肝脏中的HA进行染色，已证明筋膜间质在组织层之间以及器官之间具有空间连续性，而神经束膜和器官边界外的外膜鞘之间HA染色的连续性证实它们也参与了这个遍布全身的网络。我们询问肺间质是否构成一个连续的全器官网络，并且也通过沿着神经和脉管系统的路径与遍布全身的间质相连。我们研究了来自6名女性和3名男性（平均年龄53±16.5岁）的包含所有肺解剖单位的正常组织的存档肺叶切除标本。为了进行比较，我们还研究了正常小鼠肺。使用多重免疫组织化学鸡尾酒来识别：（1）HA、CD34和波形蛋白——突出间质；（2）HA、CD34和足板蛋白（D2 - 40）——突出间质、脉管系统和淋巴管之间的关系。测量细胞外APP的大小。研究了9名患者（6名女性，3名男性，平均年龄53±16.5岁）的组织。HA染色在肺的五个主要解剖区域中是连续的：肺泡壁、胸膜下结缔组织、小叶中心支气管血管周围区域、小叶间隔区域以及肺门的轴向支气管血管周围区域，在小鼠肺组织中也有类似发现。证实了与神经束膜和外膜的间质间隙的连续性。APP的分布与已知的浅部和深部淋巴引流途径相对应。神经束膜和血管周围外膜内的APP进一步证明了肺内和肺外间质之间的连续性。总之，肺间质的所有部分都是相连的，并且沿着神经和血管树与一个遍布全身的通讯网络相连。这些发现对于理解肺生理学和病理生物学具有重要意义，提示了炎性细胞和介质、恶性细胞以及传染因子的通行途径。间质间隙在肺内外的微生物群信号传导中可能很重要，并且可能是肺 - 脑轴的一个组成部分。
本研究旨在描述猫胃肠道嗜酸性硬化性纤维增生症（FGESF）的计算机断层扫描（CT）和超声特征及其并发异常情况。对16只经组织病理学确诊为FGESF的猫进行了一项回顾性多中心研究。回顾性评估CT和超声特征，以评估病变的位置、形状、大小和分层模式。对包括衰减值在内的对比增强模式进行定性和定量分析。还评估了并发异常情况，如淋巴结病、胃肠道（GI）梗阻和穿孔。FGESF主要影响年轻至中年猫（中位年龄：3.5岁；范围：9个月至9岁），在纯种猫中，布偶猫是受影响最突出的品种。16例中有14例观察到胃肠道受累，最常见于十二指肠近端（33%）。病变生长模式与解剖位置显著相关；所有十二指肠近端和幽门病变均表现为内生性生长（p = 0.018）。常见的CT表现包括不均匀对比增强（86%）、黏膜层增强（86%）和溃疡形成（50%）。超声检查显示实质内高回声区（100%）、不均匀回声纹理（93%）和混合回声（93%）。93%的病例存在并发腹部淋巴结病，85%表现为明显肿大（>10 mm）。胃肠道梗阻（21%）和穿孔（14%）较少见；然而，穿孔病例预后较差，所有受影响的猫术后均未存活超过24小时。这些发现支持将FGESF纳入猫胃肠道肿块形成疾病的鉴别诊断中，并强调CT和超声检查在全面评估原发性病变和并发异常方面的实用性。
糖原贮积病是一组影响体内葡萄糖稳态的遗传性疾病。肌肉糖原储备对于在剧烈活动和持续肌肉工作期间释放葡萄糖以提供能量供应至关重要。肌肉糖原贮积病0型（GSD0B）与GYS1基因的双等位基因变异有关，导致肌肉糖原合成酶缺乏，此前已被确定为儿童期心脏骤停的一个原因。受影响在世亲属的肌肉活检显示糖原染色缺乏。我们描述了来自7个家庭的10名个体，以记录通过级联检测确定的个体中心脏疾病的演变情况。本研究扩展了对0型肌肉糖原贮积病临床表型的认识，将患有肌病的成年幸存者纳入其中，并进一步描述了心脏表现的自然史。
犁鼻系统在哺乳动物中接收信息素和异种信息素，其受体器官和主要整合中心分别为犁鼻器（VNO）和副嗅球（AOB）。由于鲸类、海牛类和港海豹不再拥有犁鼻系统，所以它对某些海洋哺乳动物可能并不重要。另一方面，海狗科的三个物种已证实有副嗅球，不过它们是否也有犁鼻器尚未得到研究。因此，我们详细研究了北海狮（Eumetopias jubatus）犁鼻器的形态和组织学特征。整个犁鼻器在切牙孔内垂直延伸，其管腔与切牙管形成一条短的共同管道，通向口腔。切牙管狭窄，穿过犁鼻器的外侧部分。犁鼻器广泛覆盖着感觉上皮，腹外侧为非感觉上皮。感觉上皮中基底细胞密集排列，这意味着支持细胞的快速更新可修复盐分引起的损伤。犁鼻器缺乏大的静脉窦，这表明北海狮在关闭一个鼻孔后，通过抽吸机制将物质吸入犁鼻器。感觉上皮和非感觉上皮下方的腺体分别含有丰富的粘液浆液细胞和粘液细胞。切牙管中的粘液腺对阿尔辛蓝（pH值1.0）染色呈阳性，表明这些腺体可防止海水侵害。北海狮犁鼻器的这些形态和组织学特性与其他陆生食肉动物的显著不同。副嗅球中抗G蛋白α亚基i2（Gαi2）和o（Gαo）的免疫组织化学结果显示，北海狮的犁鼻系统表达与Gαi2偶联的犁鼻器1型受体以检测挥发性物质，但不表达与Gαo偶联的2型受体来接收水溶性物质。这些发现表明犁鼻系统在海洋北海狮中很重要，尤其是在陆地上时。
我们报告了一例肾小管发育不全的病例，这是一种导致产前羊水过少和产后先天性肾衰竭的罕见病因，该病例为一名早产女婴，产前羊水过少且生长受限，并伴有此前未关联的先天性食管闭锁畸形。出生后，该患者出现无尿性肾衰竭、药物难治性低血压以及肺发育不全情况下的呼吸衰竭。采用三联体基因组测序进行基因检测发现，ACE基因存在双等位基因功能缺失变异，其中一个变异假定为新发突变，另一个为母系遗传。以下病例描述了产前和产后的诊断挑战，并对该病的现有知识及管理建议进行了综述。
背景 前庭功能减退患者（PwVH）常表现出异常步态且跌倒风险增加。目前缺乏对PwVH维持行走平衡所采用策略的分析。 目的 本研究旨在探讨PwVH如何使用恢复策略并在受到干扰后保持稳定性。 方法 在行走过程中，通过左右地面移动对PwVH和健康对照者进行干扰，并记录运动学反应。 结果 总体而言，PwVH组（n = 9，单侧功能丧失）在足部位置、踝关节内翻、踝关节蹬离和躯干摆动变化方面的反应与健康参与者组（n = 15）相似。然而，PwVH的反应取决于前庭病变侧以及通过功能性步态评估（FGA）评估的功能代偿情况。当干扰导致身体向病变侧移动时，PwVH的稳定性变化更大；当干扰导致身体向远离病变侧移动时，PwVH的躯干反应更有效。此外，在FGA中表现较差的PwVH在内侧干扰后表现出更差的稳定性以及过度活跃的踝关节和躯干反应。 结论 这些发现表明PwVH在平衡恢复方面存在运动学差异，并提示PwVH在向病变侧跌倒时更容易出现不稳定。
背景：尽管已确定了许多谵妄的危险因素，但临床恶化动态模式的作用仍未得到充分探索。 目的：基于临床参数变化探讨谵妄风险。 研究设计：进行了一项基于电子健康记录（EHR）的回顾性研究。分析了2017年1月至2020年2月期间入住内科和外科重症监护病房（ICU）的3600例患者的电子健康记录，其中包括827例谵妄患者和2773例非谵妄患者。将入院至谵妄发作前一天记录的临床参数变化数据分为“恶化至或持续恶化”或“恢复至或持续正常”。进行逻辑回归以确定谵妄发生的显著危险因素。 结果：该模型的C统计量（在此情况下等同于ROC曲线下面积[AUC]）为0.88，表明其对谵妄患者的鉴别能力极佳。在14个变量中，8个与患者病情变化相关：舒张压（<60 mmHg，OR：2.01 [1.68 - 2.48]）、心率（>100次/分钟，OR：1.55 [1.23 - 1.95]）、呼吸频率（>25次/分钟，OR：1.26 [0.92 - 1.72]）、二氧化碳分压（PaCO>48 mmHg，OR：1.45 [1.02 - 2.06]）和碳酸氢盐（HCO水平>28 mEq/L，OR：0.77 [0.57 - 1.04]）、白蛋白（<3 g/dL，OR：2.27 [1.60 - 3.20]）、血尿素氮（>20 mg/dL，OR：1.45 [1.18 - 1.78]）和钠水平（>146 mmol/L，OR：2.06 [1.41 - 3.02]）。 结论：持续或恶化的生理紊乱与重症患者谵妄发作显著相关。 与临床实践的相关性：识别并同时处理血流动力学不稳定、酸碱失衡和电解质紊乱等恶化的临床趋势，可为高危ICU患者预防谵妄提供更早、更有针对性的干预措施。
文献中大多数关于骨质增生的记录来自浅水中发现的高度活跃的热带物种，而关于骨质增生的深海鱼类的信息却很少。本研究描述了在从巴西东南部里约热内卢两个不同地区获得的两个长体油胡瓜鱼（Evoxymetopon taeniatus Gill，1863）标本中出现的骨质增生（一种骨骼异常）情况。通过放射影像分析，在两个不同的骨骼区域观察到了骨质增生的存在：背鳍鳍担骨（DPT）和臀鳍鳍担骨（APT），受影响的骨骼数量很多：对于收集到的最大和最小个体，分别为87个DPT中的83个（95.40%）和85个中的40个（40.06%），以及55个APT中的55个（100%）和54个中的23个（42.59%）。对受该病症影响的DPT和APT进行的组织学分析显示，骨组织中的孔隙率很高，在骨质增生过程中通常会出现大量血管通道。这是关于长体油胡瓜鱼骨质增生的首次报告，长体油胡瓜鱼是一种中上层鱼类，很少被目击到，其特点是垂直洄游。
奈梅亨断裂综合征（NBS，MIM #251260）是一种罕见的DNA修复障碍疾病，其特征为小头畸形、生长发育迟缓、畸形特征、高促性腺激素性性腺功能减退、免疫缺陷以及易患癌症。NBS由双等位基因致病性变异引起，主要是NBN基因截短，该基因在同源重组途径中起作用。文献中报道了DNA修复障碍中的一些变异/非典型临床表现，它们与低表达变异有关。迄今为止，文献中仅报道了7例轻度NBS患者。在此，我们描述了一名患有前列腺癌的老年新患者，其NBN基因携带纯合的NM_002485.5:c.2140C>T（p.Arg714Ter）变异，无明显的奈梅亨断裂综合征症状。据我们所知，我们的患者是有致病性双等位基因NBN变异记录的最年长者。该患者在生育能力、染色体分析、个人癌症病史和皮肤病变方面与其他轻度NBS患者不同。考虑到文献中先前报道的其他轻度NBS患者，除了与NBN相关的不育表型外，可以推测可能存在一种NBN相关NBS的弱化形式，可能是由于低表达变异所致。本报告旨在拓宽我们对这种罕见表型和该综合征临床谱的理解。
