Five days of inpatient scoliosis-specific exercises improve preoperative spinal flexibility and facilitate curve correction of patients with rigid idiopathic scoliosis.

Preoperative spine flexibility plays a key role in the intraoperative treatment course of severe scoliosis. In this cohort study, we examined the effects of 5 day inpatient scoliosis-specific exercise (SSE) on the spinal flexibility of patients with adolescent idiopathic scoliosis before surgery. A total of 65 patients were analyzed. These patients were divided into a prospective cohort (n = 43, age: 15 ± 1.6 years, 36 girls and 7 boys, Lenke class 1 and 2, Cobb angle: 64 ± 11°) who underwent spinal fusion in 2020, and a retrospective cohort (n = 22, age: 15 ± 1.5 years, 17 girls and 5 boys, Lenke class 1 or 2, Cobb angle: 63 ± 10°), who underwent surgery between 2018 and 2019 and did not receive preoperative SSE. Rigid scoliosis was defined as a reduction of less than 50% in Cobb angle between the preoperative fulcrum bending and initial standing curve magnitude. In the prospective cohort, 21 patients (Cobb angle: 65 ± 11°) presented with rigid thoracic scoliosis (pre-SSE fulcrum bending: 40 ± 9°, 39% reduction), and therefore received 5-day SSE to improve their preoperative spinal flexibility (SSE group), whereas 22 patients (Cobb angle: 63 ± 12°) presented with flexible thoracic scoliosis (pre-SSE fulcrum bending: 27 ± 8°, 58% reduction), and therefore underwent surgery without preoperative SSE (non-SSE group). For patients who received 5-day preoperative SSE for 4 h every day, the International Schroth Three-Dimensional Scoliosis Therapy technique was implemented with an inpatient model. After 5 days of SSE, improvements in Cobb angle with post-SSE fulcrum-bending radiography (23 ± 7°, 66% reduction) and pulmonary function (forced expiratory volume in 1 s/forced expiratory volume: 87% before SSE and 92% after SSE, p < 0.01) were observed. At the postoperative day 5, the degree of scoliosis had reduced from 44 ± 6.6° to 22 ± 6° in the SSE group, which is 1° less than the Cobb angle obtained on post-SSE fulcrum-bending radiography. In the non-SSE group, the degree of scoliosis decreased to 26 ± 5.7°. In the retrospective cohort, the degree of scoliosis decreased to 35 ± 5°, with the group also having higher postoperative pain (Visual Analog Scale score = 7, range = 5-10) and an extended hospitalization duration (11 ± 3 days). At 2-year follow-up, curve correction was found to be maintained without adding-on or proximal junctional kyphosis. Compared with the non-SSE group, the SSE group exhibited a greater curve correction (66%) with a shorter hospitalization duration (5 ± 1 days) and a lower degree of postoperative pain (Visual Analog Scale score = 4, range = 3-8). Taken together, our findings indicate that 5 day SSE improves preoperative spinal flexibility and facilitates curve correction.

Solid-state electron-mediated z-scheme heterostructured semiconductor nanomaterials induce dual programmed cell death for melanoma therapy.

The programmed cell death (PCD) pathway removes functionally insignificant, infection-prone, or potentially tumorigenic cells, underscoring its important role in maintaining the stability of the internal environment and warding off cancer and a host of other diseases. PCD includes various forms, such as apoptosis, copper death, iron death, and cellular pyroptosis. However, emerging solid-state electron-mediated Z-scheme heterostructured semiconductor nanomaterials with high electron-hole (e-h+) separation as a new method for inducing PCD have not been well studied. We synthesize the Bi2S3-Bi2O3-Au-PEG nanorods (BB-A-P NRs) Z-scheme heterostructured semiconductor has a higher redox capacity and biocompatibility. Firstly, the BB-A-P NRs are excited by near-infrared (NIR) light, which mimics the action of catalase by supplying oxygen (O2) and converting it to a single-linear state of oxygen (1O2) via e-h+ transfer. Secondly, they react with hydrogen peroxide (H2O2) and water (H2O) in tumor to produce hydroxyl radicals (•OH), inducing apoptosis. Intriguingly, the Caspase-1/Gasdermin D (GSDMD)-dependent conventional pyroptosis pathway induced cellular pyroptosis activated by apoptosis and reactive oxygen species (ROS) which causes the intense release of damage associated molecular patterns (DAMPs), leading to the inflammatory death of tumor cells. This, in turn, activates the immunological environment to achieve immunogenic cell death (ICD). BB-A-P enables computed tomography imaging, which allows for visualization of the treatment. BB-A-P activated dual PCD can be viewed as an effective mode of cell death that coordinates the intracellular environment, and the various pathways are interrelated and mutually reinforcing which shows promising therapeutic effects and provides a new strategy for eliminating anoxic tumors.

Towards higher load capacity: innovative design of a robotic hand with soft jointed structure.

In this paper, the innovative design of a robotic hand with soft jointed structure is carried out and a tendon-driven mechanism, a master-slave motor coordinated drive mechanism, a thumb coupling transmission mechanism and a thumb steering mechanism are proposed. These innovative designs allow for more effective actuation in each finger, enhancing the load capacity of the robotic hand while maintaining key performance indicators such as dexterity and adaptability. A mechanical model of the robotic finger was made to determine the application limitations and load capacity. The robotic hand was then prototyped for a set of experiments. The experimental results showed that the proposed theoretical model were reliable. Also, the fingertip force of the robotic finger could reach up to 10.3 N, and the load force could reach up to 72.8 N. When grasping target objects of different sizes and shapes, the robotic hand was able to perform the various power grasping and precision grasping in the Cutkosky taxonomy. Moreover, the robotic hand had good flexibility and adaptability by means of adjusting the envelope state autonomously.

[Effect and mechanism of obstructive sleep apnea on maxillofacial development in children].

In recent years, a large number of studies have demonstrated that obstructive sleep apnea （OSA） can lead to the abnormal development of maxillofacial region in pediatric patients, which may result in a 'vicious circle' aggravating OSA, therefore adversely affecting quality of life. Understanding the effect and mechanism of OSA on children's maxillofacial development is helpful to better prevent and treat OSA and maxillofacial dysplasia in children.

Utility of plasma nucleocapsid protein in predicting severity and prognosis in severe COVID-19 patients with comorbidities.

OBJECTIVES: The COVID-19 pandemic poses ongoing challenges to global public health systems, emphasizing the critical necessity for efficient diagnostic and prognostic markers. This study evaluates the MAGLUMI® SARS-CoV-2 Ag N protein chemiluminescent immunoassay (MAG-CLIA) for its analytical performance and its role in predicting disease severity and prognosis among severe COVID-19 patients with comorbidities. METHODS: Analytical validation of plasma MAG-CLIA SARS-CoV-2 Ag N protein encompassed precision, interference, LoQ and linearity. Plasma N protein concentrations and other biomarkers were measured within 48 h of admission, tracked until discharge or death. The Mann-Whitney U test explored the association between plasma N protein and COVID-19 severity or prognosis. Longitudinal monitoring of plasma N protein dynamics was conducted in representative patients. RESULTS: MAG-CLIA demonstrated precise quantification of plasma N protein with a CV below 10 % and minimal interference. The LoQ was 0.88 ng/L, with a broad linear range. Plasma N protein showed high diagnostic accuracy for COVID-19, achieving 95.42 % specificity and 78.32 % sensitivity at 2.388 ng/L. Plasma N protein emerged as a valuable prognostic indicator, correlating with mechanical ventilation need and patient survival. Plasma N protein concentrations ≥ 424.3 ng/L (AUC 0.8102, sensitivity 78.38 %, specificity 85.48 %) were associated with poor prognosis in severe COVID-19 patients with comorbidities. CONCLUSIONS: MAG-CLIA's SARS-CoV-2 N protein detection in plasma demonstrates both analytical reliability and clinical relevance in our inaugural evaluation. As a promising prognostic biomarker for severe COVID-19 patients, it offers crucial insights into disease severity and progression, emphasizing the significance of early monitoring and intervention, especially for patients with comorbidities.

Tomato NADPH oxidase SlWfi1 interacts with the effector protein RipBJ of Ralstonia solanacearum to mediate host defence.

Reactive oxygen species (ROS) play a crucial role in regulating numerous functions in organisms. Among the key regulators of ROS production are NADPH oxidases, primarily referred to as respiratory burst oxidase homologues (RBOHs). However, our understanding of whether and how pathogens directly target RBOHs has been limited. In this study, we revealed that the effector protein RipBJ, originating from the phytopathogenic bacterium Ralstonia solanacearum, was present in low- to medium-virulence strains but absent in high-virulence strains. Functional genetic assays demonstrated that the expression of ripBJ led to a reduction in bacterial infection. In the plant, RipBJ expression triggered plant cell death and the accumulation of H2O2, while also enhancing host defence against R. solanacearum by modulating multiple defence signalling pathways. Through protein interaction and functional studies, we demonstrated that RipBJ was associated with the plant's plasma membrane and interacted with the tomato RBOH known as SlWfi1, which contributed positively to RipBJ's effects on plants. Importantly, SlWfi1 expression was induced during the early stages following R. solanacearum infection and played a key role in defence against this bacterium. This research uncovers the plant RBOH as an interacting target of a pathogen's effector, providing valuable insights into the mechanisms of plant defence.

Phylodynamic and Epistatic Analysis of Coxsackievirus A24 and Its Variant.

Coxsackievirus A24 (CV-A24) is a human enterovirus that causes acute flaccid paralysis. However, a Coxsackievirus A24 variant (CV-A24v) is the most common cause of eye infections. The causes of these variable pathogenicity and tissue tropism remain unclear. To elucidate the phylodynamics of CV-A24 and CV-A24v, we analyzed a dataset of 66 strains using Bayesian phylodynamic approach, along with detailed sequence variation and epistatic analyses. Six CV-A24 strains available in GenBank and 60 CV-A24v strains, including 11 Taiwanese strains, were included in this study. The results revealed striking differences between CV-A24 and CV-A24v exhibiting long terminal branches in the phylogenetic tree, respectively. CV-A24v presented distinct ladder-like clustering, indicating immune escape mechanisms. Notably, 10 genetic recombination events in the 3D regions were identified. Furthermore, 11 missense mutation signatures were detected to differentiate CV-A24 and CV-A24v; among these mutations, the F810Y substitution may significantly affect the secondary structure of the GH loop of VP1 and subsequently affect the epitopes of the capsid proteins. In conclusion, this study provides critical insights into the evolutionary dynamics and epidemiological characteristics of CV-A24 and CV-A24v, and highlights the differences in viral evolution and tissue tropism.

Controlling 229Th isomeric state population in a VUV transparent crystal.

The radioisotope thorium-229 (229Th) is renowned for its extraordinarily low-energy, long-lived nuclear first-excited state. This isomeric state can be excited by vacuum ultraviolet (VUV) lasers and 229Th has been proposed as a reference transition for ultra-precise nuclear clocks. To assess the feasibility and performance of the nuclear clock concept, time-controlled excitation and depopulation of the 229Th isomer are imperative. Here we report the population of the 229Th isomeric state through resonant X-ray pumping and detection of the radiative decay in a VUV transparent 229Th-doped CaF2 crystal. The decay half-life is measured to 447(25) s, with a transition wavelength of 148.18(42) nm and a radiative decay fraction consistent with unity. Furthermore, we report a new "X-ray quenching" effect which allows to de-populate the isomer on demand and effectively reduce the half-life. Such controlled quenching can be used to significantly speed up the interrogation cycle in future nuclear clock schemes.

Serum Hyaluronan as a Predictor of Severity in COVID-19: A Retrospective Study.

OBJECTIVE: We conducted this study to determine the impact of serum glycosaminoglycan hyaluronan (HA) on the prognosis of coronavirus disease 2019 (COVID-19). METHODS: A total of 497 hospitalized patients with COVID-19 were included. Patients were divided into two subgroups based on the severity of infection: mild (n=344) and severe (n=153). The levels of HA, lymphocyte count, C-reactive protein (CRP), ferritin, interleukin 6 (IL-6), and D-dimer were measured and the correlation of these parameters with the prognosis of COVID-19 was assessed. RESULTS: The mean HA level of the severe group was significantly higher than that of the mild group (204.4 ng/mL versus 850.6 ng/mL, P<0.01). In receiver operating characteristic curve analysis, an HA level ≥607.8 ng/mL predicted severe COVID-19 with a sensitivity of 62.3% and specificity of 88.6%. Multivariate regression analysis demonstrated that serum HA level was a significant predictor of disease severity (odds ratio=60.56, P<0.01). CONCLUSION: Our findings show that higher serum HA concentrations are associated with severe COVID-19 disease. Early analysis of HA level in patients with COVID-19 might effectively predict disease severity.

Anatomical-Marker-Driven 3D Markerless Human Motion Capture.

Marker-based motion capture (mocap) is a conventional method used in biomechanics research to precisely analyze human movement. However, the time-consuming marker placement process and extensive post-processing limit its wider adoption. Therefore, markerless mocap systems that use deep learning to estimate 2D keypoint from images have emerged as a promising alternative, but annotation errors in training datasets used by deep learning models can affect estimation accuracy. To improve the precision of 2D keypoint annotation, we present a method that uses anatomical landmarks based on marker-based mocap. Specifically, we use multiple RGB cameras synchronized and calibrated with a marker-based mocap system to create a high-quality dataset (RRIS40) of images annotated with surface anatomical landmarks. A deep neural network is then trained to estimate these 2D anatomical landmarks and a ray-distance-based triangulation is used to calculate the 3D marker positions. We conducted extensive evaluations on our RRIS40 test set, which consists of 10 subjects performing various movements. Compared against a marker-based system, our method achieves a mean Euclidean error of 13.23 mm in 3D marker position, which is comparable to the precision of marker placement itself. By learning directly to predict anatomical keypoints from images, our method outperforms OpenCap's augmentation of 3D anatomical landmarks from triangulated wild keypoints. This highlights the potential of facilitating wider integration of markerless mocap into biomechanics research. The RRIS40 test set is made publicly available for research purposes at koonyook.github.io/rris40.

Logistic regression modeling of cytokines for cerebrospinal fluid evaluation in primary central nervous system lymphoma.

BACKGROUND: The diagnostic utility of cerebrospinal fluid (CSF) cytology encounters impediments stemming from variability in cell collection techniques and pathologists' morphological acumen, resulting in wide-ranging CSF positivity rates for primary central nervous system lymphomas (PCNSL). Such disparity impacts patient evaluation, treatment stratagem, and prognostication. Thus, this study endeavors to explore liquid biomarkers complementary to CSF cytology or immunophenotype analysis in the diagnosis of CSF involvement. METHODS: 398 newly diagnosed PCNSL patients were categorized into CSF involvement and non-involvement groups based on CSF cytology and immunophenotype analysis. Binary logistic regression analysis was performed on 338 patients to investigate factors predicting CSF involvement and to develop a joint prediction model. An additional cohort of 60 PCNSL patients was recruited for model validation. Statistical analyses included the Mann-Whitney U test for comparing various CSF parameters between two groups. ROC curve analyses were performed for each biomarker to identify PCNSL CSF involvement. RESULTS: The cytokine IL-10 level in CSF has emerged as the most promising biomarker for CSF evaluation, boasting an ROC AUC of 0.922. C-TNFα and soluble C-IL2R demonstrate efficacy in quantifying tumor burden within the CSF. Logistic regression identified C-IL10lg (OR = 30.103, P < 0.001), C-TNC (OR = 1.126, P < 0.001), C-IL2Rlg (OR = 3.743, P = 0.029) as independent predictors for CSF involvement, contributing to a joint predictive model with an AUC of 0.935, sensitivity of 74.1 %, and specificity of 93.0 %. Validation of the model in an independent cohort confirmed its effectiveness, achieving an AUC of 0.9713. CONCLUSIONS: The identification of these feasible biomarkers and the development of an accurate prediction model may facilitate the precise evaluation of CSF status in PCNSL, offering significant advancements in patient management.

A double boronic acid affinity "sandwich" SERS biosensor based on magnetic boronic acid controllable-oriented imprinting for high-affinity biomimetic specific recognition and rapid detection of target glycoproteins.

Transferrin (TRF), recognized as a glycoprotein clinical biomarker and therapeutic target, has its concentration applicable for disease diagnosis and treatment monitoring. Consequently, this study developed boronic acid affinity magnetic surface molecularly imprinted polymers (B-MMIPs) with pH-responsitivity as the "capture probe" for TRF, which have high affinity similar to antibodies, with a dissociation constant of (3.82 ± 0.24) × 10-8 M, showing 7 times of reusability. The self-copolymerized imprinted layer synthesized with dopamine (DA) and 3-Aminophenylboronic acid (APBA) as double monomers avoided nonspecific binding sites and produced excellent adsorption properties. Taking the gold nanostar (AuNS) with a branch tip "hot spot" structure as the core, the silver-coated AuNS functionalized with the biorecognition element 4-mercaptophenylboronic acid (MPBA) was employed as a surface-enhanced Raman scattering (SERS) nanotag (AuNS@Ag-MPBA) to label TRF, thereby constructing a double boronic acid affinity "sandwich" SERS biosensor (B-MMIPs-TRF-SERS nanotag) for the highly sensitive detection of TRF. The SERS biosensor exhibited a detection limit for TRF of 0.004 ng/mL, and its application to spiked serum samples confirmed its reliability and feasibility, demonstrating significant potential for clinical TRF detection. Moreover, the SERS biosensor designed in this study offers advantages in stability, detection speed (40 min), and cost efficiency. The portable Raman instrument for SERS detection fulfills the requirements for point-of-care testing.

Analysis of Coding Gain Due to In-Loop Reshaping.

Reshaping, a point operation that alters the characteristics of signals, has been shown capable of improving the compression ratio in video coding practices. Out-of-loop reshaping that directly modifies the input video signal was first adopted as the supplemental enhancement information (SEI) for the HEVC/H.265 without the need to alter the core design of the video codec. VVC/H.266 further improves the coding efficiency by adopting in-loop reshaping that modifies the residual signal being processed in the hybrid coding loop. In this paper, we theoretically analyze the rate-distortion performance of the in-loop reshaping and use experiments to verify the theoretical result. We prove that the in-loop reshaping can improve coding efficiency when the entropy coder adopted in the coding pipeline is suboptimal, which is in line with the practical scenarios that video codecs operate in. We derive the PSNR gain in a closed form and show that the theoretically predicted gain is consistent with that measured from experiments using standard testing video sequences.

Diagnostic potential of vitreoretinal lymphoma by detection of gene mutations with NGS in 25 Chinese patients.

BACKGROUND: Vitreoretinal lymphoma (VRL) is a rare malignant lymphoproliferative tumor. Our study aimed to investigate the mutational profile of VRL distinguishing from uveitis using next-generation sequencing (NGS) analysis on small amounts of vitreous fluid. METHODS: Vitreous samples from twenty-six eyes of twenty VRL patients and six eyes of five uveitis patients were enrolled. All vitreous samples underwent cytology, immunocytochemistry for B-cell markers, cytokines analysis of IL-10 and IL-6, and flow cytometry. NGS was performed in vitreous specimens from the 25 patients using 82 DLBCL-targeted mutation panels. Vitreous fluids from 8 cases were performed paired NGS-based mutation analysis on both cell-free DNA (cfDNA) and genomic DNA. RESULTS: The sensitivity and accuracy rates for vitreous cytology were 70 % and 76 %, and for cytokine analysis (IL-10/IL-6 > 1) were 65 % and 72 %, respectively. Overall, the common mutations in VRL were PIM1 (88.5 %), IGLL5 (88.5 %), KMT2C (73 %), MYD88 (77 %), CD79B (50 %) and TBL1XR1 (46.2 %). In addition, the genetic mutation in cfDNA was consistent with that in genomic DNA in eight VRL cases. CONCLUSIONS: The mutation analysis of 82 DLBCL-targeted spectrum mutation panels by NGS on the vitreous samples is a sensitive and specific tool for distinguishing VRL from uveitis. Utilizing cfDNA for NGS analysis may serve as a liquid biopsy to aid in the diagnosis of VRL, particularly when using small-volume aspirate.

EasyNAT Malaria: a simple, rapid method to detect Plasmodium species using cross-priming amplification technology.

Malaria infection remains a serious threat to human health worldwide. Rapid and accurate detection technology is crucial for preventing malaria transmission and minimizing damage. We aimed to establish and validate a new rapid molecular detection method for malaria, called EasyNAT Malaria Assay, targeting Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale, and Plasmodium malariae. The analytical performance of EasyNAT Malaria Assay was determined using positive materials. We identified 42 clinical samples as malaria positive and 95 negative samples. Each sample was examined by four methods: light microscopy, rapid diagnostic test, EasyNAT Malaria Assay, and digital PCR. Diagnostic accuracy and clinical performance were evaluated. The limit of detection (LOD)95% of EasyNAT Malaria was consistently 40 parasites/mL. It specifically amplified Plasmodium and performed with reliable repeatability and reproducibility. In 137 clinical samples, EasyNAT Malaria detected four more positive samples than microscopic examination and two more positive samples than rapid diagnostic test (RDT). One clinical sample was positive only under digital PCR. However, no significant differences statistically in sensitivity or specificity were observed. Compared with microscopy, the total, positive, and negative concordance rates of EasyNAT were 97.08%, 100%, and 95.79%, respectively. Enhanced diagnostic accuracy of EasyNAT Malaria in patients who had taken anti-malarial medication before their clinical appointment was observed. The EasyNAT Malaria Assay has good detection efficiency for clinical samples, presents a promising molecular detection tool in clinical practice, and is particularly suitable for rapid screening of high-risk populations in the emergency room. IMPORTANCE: This study established and validated EasyNAT Malaria Assay as a promising molecular detection tool for malaria screening of high-risk populations in clinical practice. This novel isothermal amplification method may effectively facilitate the rapid diagnosis of malaria and prevent its transmission.

Ternary heterostructure-driven photoinduced electron-hole separation enhanced oxidative stress for triple-negative breast cancer therapy.

Zinc oxide nanoparticles (ZnO NPs) stand as among the most significant metal oxide nanoparticles in trigger the formation of reactive oxygen species (ROS) and induce apoptosis. Nevertheless, the utilization of ZnO NPs has been limited by the shallowness of short-wavelength light and the constrained production of ROS. To overcome these limitations, a strategy involves achieving a red shift towards the near-infrared (NIR) light spectrum, promoting the separation and restraining the recombination of electron-hole (e--h+) pairs. Herein, the hybrid plasmonic system Au@ZnO (AZ) with graphene quantum dots (GQDs) doping (AZG) nano heterostructures is rationally designed for optimal NIR-driven cancer treatment. Significantly, a multifold increase in ROS generation can be achieved through the following creative initiatives: (i) plasmonic Au nanorods expands the photocatalytic capabilities of AZG into the NIR domain, offering a foundation for NIR-induced ROS generation for clinical utilization; (ii) elaborate design of mesoporous core-shell AZ structures facilitates the redistribution of electron-hole pairs; (iii) the incorporation GQDs in mesoporous structure could efficiently restrain the recombination of the e--h+ pairs; (iv) Modification of hyaluronic acid (HA) can enhance CD44 receptor mediated targeted triple-negative breast cancer (TNBC). In addition, the introduced Au NRs present as catalysts for enhancing photothermal therapy (PTT), effectively inducing apoptosis in tumor cells. The resulting HA-modified AZG (AZGH) exhibits efficient hot electron injection and e--h+ separation, affording unparalleled convenience for ROS production and enabling NIR-induced PDT for the cancer treanment. As a result, our well-designed mesoporous core-shell AZGH hybrid as photosensitizers can exhibit excellent PDT efficacy.

Discovery of novel amide derivatives as potent quorum sensing inhibitors of Pseudomonas aeruginosa.

With the increasing reports of antibiotic resistance in this species, Pseudomonas aeruginosa is a common human pathogen with important implications for public health. Bacterial quorum sensing (QS) systems are potentially broad and versatile targets for developing new antimicrobial compounds. While previous reports have demonstrated that certain amide compounds can inhibit bacterial growth, there are few reports on the specific inhibitory effects of these compounds on bacterial quorum sensing systems. In this study, thirty-one amide derivatives were synthesized. The results of the biological activity assessment indicated that A9 and B6 could significantly inhibit the expression of lasB, rhlA, and pqsA, effectively reducing several virulence factors regulated by the QS systems of PAO1. Additionally, compound A9 attenuated the pathogenicity of PAO1 to Galleria mellonella larvae. Meanwhile, RT-qPCR, SPR, and molecular docking studies were conducted to explore the mechanism of these compounds, which suggests that compound A9 inhibited the QS systems by binding with LasR and PqsR, especially PqsR. In conclusion, amide derivatives A9 and B6 exhibit promising potential for further development as novel QS inhibitors in P. aeruginosa.

Population-based BRCA germline mutation screening in the Han Chinese identifies individuals at risk of BRCA mutation-related cancer: experience from a clinical diagnostic center from greater Shanghai area.

BACKGROUND: Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group. METHODS: We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers. RESULTS: Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months). CONCLUSION: The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.

Nonpathogenic E. coli engineered to surface display cytokines as a new platform for immunotherapy.

Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli (E. coli), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic.

"May I Speak?": Multi-modal Attention Guidance in Social VR Group Conversations.

In this paper, we present a novel multi-modal attention guidance method designed to address the challenges of turn-taking dynamics in meetings and enhance group conversations within virtual reality (VR) environments. Recognizing the difficulties posed by a confined field of view and the absence of detailed gesture tracking in VR, our proposed method aims to mitigate the challenges of noticing new speakers attempting to join the conversation. This approach tailors attention guidance, providing a nuanced experience for highly engaged participants while offering subtler cues for those less engaged, thereby enriching the overall meeting dynamics. Through group interview studies, we gathered insights to guide our design, resulting in a prototype that employs light as a diegetic guidance mechanism, complemented by spatial audio. The combination creates an intuitive and immersive meeting environment, effectively directing users' attention to new speakers. An evaluation study, comparing our method to state-of-the-art attention guidance approaches, demonstrated significantly faster response times (p < 0.001), heightened perceived conversation satisfaction (p < 0.001), and preference (p < 0.001) for our method. Our findings contribute to the understanding of design implications for VR social attention guidance, opening avenues for future research and development.