A B7-H3-targeted CD28 bispecific antibody enhances the activity of anti-PD1 and CD3 T-cell engager immunotherapies.

T-cell activation is a multistep process requiring T-cell receptor engagement by peptide-major histocompatibility complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell-mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells (PBMCs) and cancer cells, and in mice engrafted with human PBMCs and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated interleukin (IL)2 and interferon (IFN)γ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the anti-apoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell-mediated cytotoxicity in vitro. XmAb808 combined with a EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Further, XmAb808 combined with an anti-PD1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti-PD1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen-targeted anti-CD3 (Signal 1) T-cell engagers.

Amorphous Solid Dispersion Formation for Enhanced Release Performance of Racemic and Enantiopure Praziquantel.

Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound (RS-PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the S-enantiomer. While many approaches have been explored for improving PZQ's dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using RS-PZQ and R-PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for RS-PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of RS-PZQ and R-PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of RS-PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE R-PZQ ASDs with HPMCAS-MF released the drug as effectively as RS-PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the R-enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.

Conformations of membrane human immunodeficiency virus (HIV-1) envelope glycoproteins solubilized in Amphipol A18 lipid-nanodiscs.

Upon binding to the host cell receptor, CD4, the pretriggered (State-1) conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer undergoes transitions to downstream conformations important for virus entry. State 1 is targeted by most broadly neutralizing antibodies (bNAbs), whereas downstream conformations elicit immunodominant, poorly neutralizing antibody (pNAb) responses. Extraction of Env from the membranes of viruses or Env-expressing cells disrupts the metastable State-1 Env conformation, even when detergent-free approaches like styrene-maleic acid lipid nanoparticles (SMALPs) are used. Here, we combine three strategies to solubilize and purify mature membrane Envs that are antigenically native (i.e., recognized by bNAbs and not pNAbs): (1) solubilization of Env with a novel amphipathic copolymer, Amphipol A18; (2) use of stabilized pretriggered Env mutants; and (3) addition of the State-1-stabilizing entry inhibitor, BMS-806. Amphipol A18 was superior to the other amphipathic copolymers tested (SMA and AASTY 11-50) for preserving a native Env conformation. A native antigenic profile of A18 Env-lipid-nanodiscs was maintained for at least 7 days at 4°C and 2 days at 37°C in the presence of BMS-806 and was also maintained for at least 1 h at 37°C in a variety of adjuvants. The damaging effects of a single cycle of freeze-thawing on the antigenic profile of the A18 Env-lipid-nanodiscs could be prevented by the addition of 10% sucrose or 10% glycerol. These results underscore the importance of the membrane environment to the maintenance of a pretriggered (State-1) Env conformation and provide strategies for the preparation of lipid-nanodiscs containing native membrane Envs.IMPORTANCEThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Envs) mediate virus entry into the host cell and are targeted by neutralizing antibodies elicited by natural infection or vaccines. Detailed studies of membrane proteins like Env rely on purification procedures that maintain their natural conformation. In this study, we show that an amphipathic copolymer A18 can directly extract HIV-1 Env from a membrane without the use of detergents. A18 promotes the formation of nanodiscs that contain Env and membrane lipids. Env in A18-lipid nanodiscs largely preserves features recognized by broadly neutralizing antibodies (bNAbs) and conceals features potentially recognized by poorly neutralizing antibodies (pNAbs). Our results underscore the importance of the membrane environment to the native conformation of HIV-1 Env. Purification methods that bypass the need for detergents could be useful for future studies of HIV-1 Env structure, interaction with receptors and antibodies, and immunogenicity.

Atypical fractures at non-classical sites associated with anti-resorptive therapy: A Systematic Review.

BACKGROUND: Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described. AIMS: We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years. METHODS: A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 years) and receiving anti-resorptive medication for >3 years were included, with data extracted and analysed by two independent reviewers. RESULTS: Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%). CONCLUSIONS: Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.

Bisphosphonates and denosumab, anti-resorptive medications, have been effective treatments for osteoporosis for more than 30 years. Rare but serious side effects of these therapies include medication-related osteonecrosis of the jaw and atypical femur (thigh bone) fractures. Increasingly however, atypical fractures at non-classical sites have been described. To address this, we systemically reviewed published cases of atypical fractures at sites other than the femur. We identified 151 cases of atypical fractures in 114 individuals. The most frequent site was the ulna, followed by the tibia. All patients were taking anti-resorptive medication prior to or at the time of fracture, most frequently alendronate (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Although rare, clinicians should be alert to the presence of atypical fractures at sites additional to the femur. If confirmed to be an atypical fracture in the setting of anti-resorptive therapy, we recommend considering cessation of anti-resorptive treatment, limit weight-bearing, consider surgical management and manage their underlying osteoporosis.

Recent advances in portable devices for environmental monitoring applications.

Environmental pollution remains a major societal problem, leading to serious impacts on living organisms including humans. Human activities such as civilization, urbanization, and industrialization are major causes of pollution. Imposing stricter rules helps control environmental pollutant levels, creating a need for reliable pollutant monitoring in air, water, and soil. The application of traditional analytical techniques is limited in low-resource areas because they are sophisticated, expensive, and bulky. With the development of biosensors and microfluidics technology, environmental monitoring has significantly improved the analysis time, low cost, portability, and ease of use. This review discusses the fundamentals of portable devices, including microfluidics and biosensors, for environmental control. Recently, publications reviewing microfluidics and biosensor device applications have increased more than tenfold, showing the potential of emerging novel approaches for environmental monitoring. Strategies for enzyme-, immunoassay-, and molecular-based analyte sensing are discussed based on their mechanisms and applications. Microfluidic and biosensor platforms for detecting major pollutants, including metal ions, pathogens, pesticides, and antibiotic residues, are reviewed based on their working principles, advantages, and disadvantages. Challenges and future trends for the device design and fabrication process to improve performance are discussed. Miniaturization, low cost, selectivity, sensitivity, high automation, and savings in samples and reagents make the devices ideal alternatives for in-field detection, especially in low-resource areas. However, their operation with complicated environmental samples requires further research to improve the specificity and sensitivity. Although there is a wide range of devices available for environmental applications, their implementation in real-world situations is limited. This study provides insights into existing issues that can be used as references and a comparative analysis for future studies and applications.

Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures.

Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.

We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone. These fractures are related to the use of bisphosphonates (BP), which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used BP, using a genetic technique called whole exome sequencing. Our results suggested three genes­XRN2, SORD, and PLOD2­might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF.

Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial.

Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.

The prevalence and prognostic value of systemic inflammation in good performance status patients with advanced, inoperable non-small cell lung cancer receiving palliative radiotherapy: Comparison of composite ratios and cumulative scores.

INTRODUCTION: The present study sought to examine the relationships between systemic inflammatory composite ratios/cumulative scores, magnitude of systemic inflammatory response (SIR) and survival in good performance status patients (ECOG-PS 0/1) with advanced NSCLC receiving palliative radiotherapy. METHODS: Systemic inflammatory composite ratios/cumulative scores included the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), C-reactive protein, (CRP)-albumin ratio (CAR), neutrophil- lymphocyte score (NLS), platelet-lymphocyte score (PLS), lymphocyte-monocyte score (LMS), neutrophil-platelet score (NPS), modified Glasgow prognostic score (mGPS). The magnitude of SIR was determined by serum CRP concentration, with a median CRP concentration of >10 m mg/L considered to be systemically inflamed. Relationships between systemic inflammatory composite ratios/ cumulative scores and clinicopathological characteristics were examined using chi-square analysis. Relationships between overall survival (OS) and systemic inflammatory composite ratios/ cumulative scores were examined using cox regression analysis. RESULTS: 479 patients were included. 48% (n = 231) of patients were male and 70% (n = 338) were ≥65 years of age. 29% (n = 140) patients were ECOG-PS 0 and 71% (n = 339) were ECOG-PS 1. 98% (n = 469) of patients died during follow-up. The median survival was 5 months (2-11). A similar prevalence of systemic inflammation was noted across the various ratios/scores (NLR >3 68%; LMR <2.4 65%; PLR >150 70%; CAR >0.20 83%; NLS ≥1 66%; LMS ≥1 71%; NPS≥1 50%; PLS≥1 60% and mGPS≥1 75%). Despite not considered to be systemically inflamed, an NLR <3, LMR ≥2.4, PLR ≤150, NLS 0, LMS 0, NPS 0 and PLS 0 all had a median CRP concentration of >10 mg/L. When adjusted for ECOG-PS, CAR>0.40 (p < 0.001) and mGPS 2 (p < 0.05) remained significantly associated with OS. CONCLUSION: Liver-based measures of systemic inflammation (CAR and mGPS) appear more reliable for the quantification of the magnitude of SIR and have prognostic value in patients with advanced NSCLC.

mRNA Profiling and Transcriptomics Analysis of Chickens Received Newcastle Disease Virus Genotype II and Genotype VII Vaccines.

Newcastle Disease Virus (NDV) genotype VII (GVII) is becoming the predominant strain of NDV in the poultry industry. It causes high mortality even in vaccinated chickens with a common NDV genotype II vaccine (GII-vacc). To overcome this, the killed GVII vaccine has been used to prevent NDV outbreaks. However, the debate about vaccine differences remains ongoing. Hence, this study investigated the difference in chickens' responses to the two vaccines at the molecular level. The spleen transcriptomes from vaccinated chickens reveal that GVII-vacc affected the immune response by downregulating neuroinflammation. It also enhanced a synaptogenesis pathway that operates typically in the nervous system, suggesting a mechanism for the neurotrophic effect of this strain. We speculated that the down-regulated immune system regulation correlated with protecting the nervous system from excess leukocytes and cytokine activity. In contrast, GII-vacc inhibited apoptosis by downregulating PERK/ATF4/CHOP as part of the unfolded protein response pathway but did not affect the expression of the same synaptogenesis pathway. Thus, the application of GVII-vacc needs to be considered in countries where GVII is the leading cause of NDV outbreaks. The predicted molecular signatures may also be used in developing new vaccines that trigger specific genes in the immune system in combating NDV outbreaks.

The adaptation of 3T3 cells to simulated microgravity by retrieving the major cell cycle-related protein expression during long-term in vitro proliferation.

The present study aimed to assess the effects of simulated microgravity (SMG) on 3T3 cell proliferation and the expression of cell cycle regulators. 3T3 cells were induced to SMG by Gravite® for 8 days, while the control group was treated with 1G condition. The result showed that the SMG condition causes a decrease in proliferative activity in 3T3 cells. In the SMG group, the expression of cell cycle-related proteins was lower than the control on day 3. However, these proteins were upregulated in 3T3 cells of the SMG group on day 5, suggesting that these cells were rescued from the arrest and retrieved a higher proliferation. A down-regulation of cell cycle-related proteins was observed in 3T3 cells of both SMG and control groups on day 7. In conclusion, SMG results in the attenuation of cell proliferation during the initial exposure to SMG, but the cells will adapt to this condition and retrieve normal proliferation by increasing the expression of cell cycle regulators.

15N metabolic labeling-TMT multiplexing approach to facilitate the quantitation of glycopeptides derived from cell lines.

The study of glycoproteomics presents a set of unique challenges, primarily due to the low abundance of glycopeptides and their intricate heterogeneity, which is specific to each site. Glycoproteins play a crucial role in numerous biological functions, including cell signaling, adhesion, and intercellular communication, and are increasingly recognized as vital markers in the diagnosis and study of various diseases. Consequently, a quantitative approach to glycopeptide research is essential. One effective strategy to address this need is the use of multiplex glycopeptide labeling. By harnessing the synergies of 15N metabolic labeling via the isotopic detection of amino sugars with glutamine (IDAWG) technique for glycan parts and tandem mass tag (TMT)pro labeling for peptide backbones, we have developed a method that allows for the accurate quantification and comparison of multiple samples simultaneously. The adoption of the liquid chromatography-synchronous precursor selection (LC-SPS-MS3) technique minimizes fragmentation interference, enhancing data reliability, as shown by a 97% TMT labeling efficiency. This method allows for detailed, high-throughput analysis of 32 diverse samples from 231BR cell lines, using both 14N and 15N glycopeptides at a 1:1 ratio. A key component of our methodology was the precise correction for isotope and TMTpro distortions, significantly improving quantification accuracy to less than 5% distortion. This breakthrough enhances the efficiency and accuracy of glycoproteomic studies, increasing our understanding of glycoproteins in health and disease. Its applicability to various cancer cell types sets a new standard in quantitative glycoproteomics, enabling deeper investigation into glycopeptide profiles.

Investor attention and corporate social responsibility of family businesses in Vietnam: The moderating role of CEO overpower.

This study examines the influence of investor attention and Chief Executive Officers (CEOs) power on Corporate Social Responsibility (CSR) within Vietnamese family businesses. Unlike most of the past literature, this study further investigates the potential moderating effects of CEOs' power on the relationship between investor attention and CSR. Utilizing the dynamic system Generalized Method of Moments (GMM), this study analyzes a dataset comprising 116 Vietnamese family businesses from 2005 to 2020. The findings reveal an inverted U-shape between CEO power and CSR within family businesses; meanwhile, investor attention demonstrates a negative impact on CSR. Moreover, the results report that CEO power is a moderating factor in the relationship between investor attention and CSR. These results are consistent with various theoretical frameworks, including agency theory, overinvestment, career concern, career horizon, and conflict-resolution hypotheses. Finally, our study offers management implications to foster the sustainable development of CSR within family businesses, particularly within emerging markets.

Membrane HIV-1 envelope glycoproteins stabilized more strongly in a pretriggered conformation than natural virus Envs.

The pretriggered conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120/gp41)3) is targeted by virus entry inhibitors and broadly neutralizing antibodies (bNAbs). The lability of pretriggered Env has hindered its characterization. Here, we produce membrane Env variants progressively stabilized in pretriggered conformations, in some cases to a degree beyond that found in natural HIV-1 strains. Pretriggered Env stability correlated with stronger trimer subunit association, increased virus sensitivity to bNAb neutralization, and decreased capacity to mediate cell-cell fusion and virus entry. For some highly stabilized Env mutants, after virus-host cell engagement, the normally inaccessible gp120 V3 region on an Env intermediate became targetable by otherwise poorly neutralizing antibodies. Thus, evolutionary pressure on HIV-1 Env to maintain trimer integrity, responsiveness to the CD4 receptor, and resistance to antibodies modulates pretriggered Env stability. The strongly stabilized pretriggered membrane Envs reported here will facilitate further characterization of this functionally important conformation.

Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology.

Studies have shown that disrupting the formation of the ligand-RET-GFRα complex could be an effective way of treating pain and itch. Compared to traditional high-throughput screens, DNA encoded libraries (DELs) have distinguished themselves as a powerful technology for hit identification in recent years. The present work demonstrates the use of DEL technology identifying compound 16 as the first GFRa2/GFRa3 small molecule inhibitor (0.1/0.2 µM respectively) selective over RET. This molecule represents an opportunity to advance the development of small-molecule inhibitors targeting the GFRα-RET interface for the treatment of pain and itch.

AFFnet - a deep convolutional neural network for the detection of atypical femur fractures from anteriorposterior radiographs.

Despite well-defined criteria for radiographic diagnosis of atypical femur fractures (AFFs), missed and delayed diagnosis is common. An AFF diagnostic software could provide timely AFF detection to prevent progression of incomplete or development of contralateral AFFs. In this study, we investigated the ability for an artificial intelligence (AI)-based application, using deep learning models (DLMs), particularly convolutional neural networks (CNNs), to detect AFFs from femoral radiographs. A labelled Australian dataset of pre-operative complete AFF (cAFF), incomplete AFF (iAFF), typical femoral shaft fracture (TFF), and non-fractured femoral (NFF) X-ray images in anterior-posterior view were used for training (N = 213, 49, 394, 1359, respectively). An AFFnet model was developed using a pretrained (ImageNet dataset) ResNet-50 backbone, and a novel Box Attention Guide (BAG) module to guide the model's scanning patterns to enhance its learning. All images were used to train and internally test the model using a 5-fold cross validation approach, and further validated by an external dataset. External validation of the model's performance was conducted on a Sweden dataset comprising 733 TFF and 290 AFF images. Precision, sensitivity, specificity, F1-score and AUC were measured and compared between AFFnet and a global approach with ResNet-50. Excellent diagnostic performance was recorded in both models (all AUC >0.97), however AFFnet recorded lower number of prediction errors, and improved sensitivity, F1-score and precision compared to ResNet-50 in both internal and external testing. Sensitivity in the detection of iAFF was higher for AFFnet than ResNet-50 (82 % vs 56 %). In conclusion, AFFnet achieved excellent diagnostic performance on internal and external validation, which was superior to a pre-existing model. Accurate AI-based AFF diagnostic software has the potential to improve AFF diagnosis, reduce radiologist error, and allow urgent intervention, thus improving patient outcomes.

COVID-19 vaccine related anxiety partially mediates the association between COVID-19 related anxiety and student adjustment to college during the pandemic.

The COVID-19 pandemic caused severe disruptions in living and learning to millions of college students. Here we investigated using mediation analysis two dimensions of anxiety that were specific to the pandemic - COVID-19 related anxiety and COVID-19 vaccine anxiety - to evaluate their relationship to college adjustment during the pandemic. Using cross-sectional survey data across three semester waves (Spring 2021, Fall 2021, and Spring 2022) we probed whether anxiety functioned as a challenge or hindrance stressor on adjustment. We found that although anxiety decreased in both COVID-19 dimensions across semesters, student adjustment to college remained consistently low. Our mediation analysis revealed that both COVID-19 related anxiety and COVID-19 vaccine-related anxiety functioned as challenge stressors, elevating academic, social, personal-emotional, and institutional adjustment during the pandemic. We discuss the role of positive COVID impacts on college adjustment, including enhanced social support.

Recent advances in biosensors for screening plant pathogens.

Worldwide, plant pathogens have been a considerably important cause of economic loss in agriculture especially in the decades of agricultural intensification. The increasing losses in agriculture due to biotic plant diseases have drawn attention towards the development of plant disease analyzing methods. In this context, biosensors have emerged as significantly important tools which help farmers in on-field diagnosis of plant diseases. Compared to traditional methods, biosensors have outstanding features such as being highly sensitive and selective, cost-effective, portable, fast and user-friendly operation, and so on. There are three common types of biosensors including electrochemical, fluorescent, and colorimetric biosensors. In this review, some common biotic plant diseases caused by fungi, bacteria, and viruses are first summarized. Then, current advances in developing biosensors are discussed.

Compensatory Modulation of Seed Storage Protein Synthesis and Alteration of Starch Accumulation by Selective Editing of 13 kDa Prolamin Genes by CRISPR-Cas9 in Rice.

Rice prolamins are categorized into three groups by molecular size (10, 13, or 16 kDa), while the 13 kDa prolamins are assigned to four subgroups (Pro13a-I, Pro13a-II, Pro13b-I, and Pro13b-II) based on cysteine residue content. Since lowering prolamin content in rice is essential to minimize indigestion and allergy risks, we generated four knockout lines using CRISPR-Cas9, which selectively reduced the expression of a specific subgroup of the 13 kDa prolamins. These four mutant rice lines also showed the compensatory expression of glutelins and non-targeted prolamins and were accompanied by low grain weight, altered starch content, and atypically-shaped starch granules and protein bodies. Transcriptome analysis identified 746 differentially expressed genes associated with 13 kDa prolamins during development. Correlation analysis revealed negative associations between genes in Pro13a-I and those in Pro13a-II and Pro13b-I/II subgroups. Furthermore, alterations in the transcription levels of 9 ER stress and 17 transcription factor genes were also observed in mutant rice lines with suppressed expression of 13 kDa prolamin. Our results provide profound insight into the functional role of 13 kDa rice prolamins in the regulatory mechanisms underlying rice seed development, suggesting their promising potential application to improve nutritional and immunological value.

Machine Learning Informed Diagnosis for Congenital Heart Disease in Large Claims Data Source.

Background: With an increasing interest in using large claims databases in medical practice and research, it is a meaningful and essential step to efficiently identify patients with the disease of interest. Objectives: This study aims to establish a machine learning (ML) approach to identify patients with congenital heart disease (CHD) in large claims databases. Methods: We harnessed data from the Quebec claims and hospitalization databases from 1983 to 2000. The study included 19,187 patients. Of them, 3,784 were labeled as true CHD patients using a clinician developed algorithm with manual audits considered as the gold standards. To establish an accurate ML-empowered automated CHD classification system, we evaluated ML methods including Gradient Boosting Decision Tree, Support Vector Machine, Decision tree, and compared them to regularized logistic regression. The Area Under the Precision Recall Curve was used as the evaluation metric. External validation was conducted with an updated data set to 2010 with different subjects. Results: Among the ML methods we evaluated, Gradient Boosting Decision Tree led the performance in identifying true CHD patients with 99.3% Area Under the Precision Recall Curve, 98.0% for sensitivity, and 99.7% for specificity. External validation returned similar statistics on model performance. Conclusions: This study shows that a tedious and time-consuming clinical inspection for CHD patient identification can be replaced by an extremely efficient ML algorithm in large claims database. Our findings demonstrate that ML methods can be used to automate complicated algorithms to identify patients with complex diseases.

Factors affecting loneliness among left-behind children.

BACKGROUND: In Vietnam, research on the impact of parental migration on left-behind children (LBC) has discussed various dimensions of the subject such as subjective well-being, emotional states, social skills, self-esteem and nutrition of LBC. However, there are still gaps in studies on loneliness among LBC in Vietnam. The study aims to explore the status of loneliness in LBC, including associated protective and risk factors, to make suggestions on preventive measures against LBC's loneliness. PARTICIPANTS AND PROCEDURE: The conveniently selected sample includes 439 LBC in 4 Vietnamese provinces: Thai Nguyen, Bac Ninh, Thai Binh and Nghe An. The mean age is 12.73 (SD = 1.68). Female children account for 47.80%. The Children's Loneliness Scale was employed in the study. RESULTS: The total loneliness score of LBC is 28.62 (SD = 9.40), 95% CI: 27.75-29.48. Perceived social support from friends, caregivers and resilience factors of affect control (RAC), family support (RFS) and help-seeking (RHS) are protective factors for loneliness of LBC, with regression coefficient of -.27, -.18, -.11, -.11 and -.09 respectively. CONCLUSIONS: Perceived social support from friends, care-giving attachment and resilience factors of RAC, RFS, and RHS are protective factors for LBC against loneliness. Parents, teachers and guardians are encouraged to have a close connection with LBC, provide adequate care giving; and create a supportive environment for LBC in pursuing healthy peer relationships and train/improve children's skills to strengthen their resilience.