From theory to practice: Harmonizing taxonomies of trustworthy AI.

The increasing capabilities of AI pose new risks and vulnerabilities for organizations and decision makers. Several trustworthy AI frameworks have been created by U.S.

The impact of the COVID-19 pandemic on students' views of a career in general practice: a focus group study.

Background: General practice is an essential part of healthcare systems in the UK and internationally but continues to struggle with recruitment. Despite this, few studies have explored factors that influence medical students' career choices around primary care.

Aim: We aimed to revisit factors that had previously been proposed following new ways of working adopted since the COVID-19 pandemic, including the impact of these changes on learning experiences in primary care.

Structural characterization of antibody-responses from Zolgensma treatment provides the blueprint for the engineering of an AAV capsid suitable for redosing.

Monoclonal antibodies (mAbs) are useful tools to dissect the neutralizing antibody response against the adeno-associated virus (AAV) capsids used as gene therapy delivery vectors. This study structurally characterizes the interactions of 21 human-derived antibodies from patients treated with the AAV9 vector, Zolgensma , utilizing high-resolution cryo-electron microscopy. The majority of the bound antibodies do not conform to the icosahedral symmetry of the capsid, thus requiring localized reconstructions.

Epidemiology and Risk Factors for Invasive Fungal Infections in Pancreas Transplant in the Absence of Postoperative Antifungal Prophylaxis.

Background: Invasive fungal infections (IFIs) remain a rare yet dreaded complication following pancreas transplantation. Current guidelines recommend antifungal prophylaxis in patients with 1 or more risk factors. At our center, single-dose antifungal prophylaxis is administered in the operating room but none subsequently, regardless of risk factors.

Engineering highly thermostable Cas12b via de novo structural analyses for one-pot detection of nucleic acids.

CRISPR-Cas-based diagnostics have the potential to elevate nucleic acid detection. CRISPR-Cas systems can be combined with a pre-amplification step in a one-pot reaction to simplify the workflow and reduce carryover contamination. Here, we report an engineered Cas12b with improved thermostability that falls within the optimal temperature range (60°C-65°C) of reverse transcription-loop-mediated isothermal amplification (RT-LAMP).

The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical regulator of IFNβ-mediated Lyme arthritis.

Type I interferon (IFN) has been identified in patients with Lyme disease, and its abundant expression in joint tissues of C3H mice precedes development of Lyme arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. burgdorferi-induced IFNβ expression and Lyme arthritis severity.

Impacts of variants of uncertain significance on parental perceptions of children after prenatal chromosome microarray testing.

Objective: There are concerns regarding the potential harms in receipt of prenatal chromosome microarray (CMA) results, particularly variants of uncertain significance (VUS). We examined the influence that the return of genomic results had on parental well-being and perceptions of children's development.

Methods: Parents (n = 138) of 83 children who underwent prenatal chromosomal microarray testing completed questionnaires assessing perception of children's development, parent-child attachment, parental mood, parenting competence, martial satisfaction, satisfaction with the decision to undergo testing, and attitudes about genetics at age 12 and/or 36 months.

IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis.

T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4 and CD8 T cells leads to arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non- epitopes confirmed that bystander T cell activation was responsible for disease development.

Genetic Control of Lyme Arthritis by Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin.

Previously, using a forward genetic approach, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus underlying arthritis-associated locus 1 (). In this study, we show that mAb blockade revealed a unique role for IFN-β in Lyme arthritis development in B6.C3- mice.

Antagonistic Interplay between MicroRNA-155 and IL-10 during Lyme Carditis and Arthritis.

MicroRNA-155 has been shown to play a role in immune activation and inflammation, and is suppressed by IL-10, an important anti-inflammatory cytokine. The established involvement of IL-10 in the murine model of Borrelia burgdorferi-induced Lyme arthritis and carditis allowed us to assess the interplay between IL-10 and miR-155 in vivo. As reported previously, Mir155 was highly upregulated in joints from infected severely arthritic B6 Il10-/- mice, but not in mildly arthritic B6 mice.

Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring.

Background: The prevalence of some autoimmune diseases is greater in females compared with males, although disease severity is often greater in males. The reason for this sexual dimorphism is unknown, but it may reflect negative selection of Y chromosome-bearing sperm during spermatogenesis or male fetuses early in the course of conception/pregnancy. Previously, we showed that the sexual dimorphism in experimental autoimmune encephalomyelitis (EAE) is associated with copy number variation (CNV) in Y chromosome multicopy genes.

Borrelia burgdorferi arthritis-associated locus Bbaa1 regulates Lyme arthritis and K/B×N serum transfer arthritis through intrinsic control of type I IFN production.

Localized upregulation of type I IFN was previously implicated in development of Borrelia burgdorferi-induced arthritis in C3H mice, and was remarkable due to its absence in the mildly arthritic C57BL/6 (B6) mice. Independently, forward genetics analysis identified a quantitative trait locus on Chr4, termed B. burgdorferi-associated locus 1 (Bbaa1), that regulates Lyme arthritis severity and includes the 15 type I IFN genes.

MicroRNA-146a provides feedback regulation of lyme arthritis but not carditis during infection with Borrelia burgdorferi.

MicroRNAs have been shown to be important regulators of inflammatory and immune responses and are implicated in several immune disorders including systemic lupus erythematosus and rheumatoid arthritis, but their role in Lyme borreliosis remains unknown. We performed a microarray screen for expression of miRNAs in joint tissue from three mouse strains infected with Borrelia burgdorferi. This screen identified upregulation of miR-146a, a key negative regulator of NF-κB signaling, in all three strains, suggesting it plays an important role in the in vivo response to B.

Association of copy number variants with specific ultrasonographically detected fetal anomalies.

Objective: To evaluate the association of other-than-common benign copy number variants with specific fetal abnormalities detected by ultrasonogram.

Methods: Fetuses with structural anomalies were compared with fetuses without detected abnormalities for the frequency of other-than-common benign copy number variants. This is a secondary analysis from the previously published National Institute of Child Health and Human Development microarray trial.

Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity.

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity.

The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.

Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J (B6) background, we show that susceptibility to two diverse animal models of autoimmune disease, experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. On the B6 background, ChrY possesses gene regulatory properties that impact genome-wide gene expression in pathogenic CD4(+) T cells.

Chromosomal microarray versus karyotyping for prenatal diagnosis.

Background: Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis.

Methods: Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory.

Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials.

Background: Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.

Localized production of IL-10 suppresses early inflammatory cell infiltration and subsequent development of IFN-γ-mediated Lyme arthritis.

IL-10 is a nonredundant inflammatory modulator that suppresses arthritis development in Borrelia burgdorferi-infected mice. Infected C57BL/6 (B6) IL-10(-/-) mice were previously found to have a prolonged IFN-inducible response in joint tissue. Infection of B6 IL-10 reporter mice identified macrophages and CD4(+) T cells as the primary sources of IL-10 in the infected joint tissue, suggesting that early local production of IL-10 dampened the proarthritic IFN response.

Histamine H4 receptor optimizes T regulatory cell frequency and facilitates anti-inflammatory responses within the central nervous system.

Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. The pleiotropic effects of histamine are mediated by four G protein-coupled receptors, as follows: Hrh1/H(1)R, Hrh2/H(2)R, Hrh3/H(3)R, and Hrh4/H(4)R. H(4)R expression is primarily restricted to hematopoietic cells, and its role in autoimmune inflammatory demyelinating disease of the CNS has not been studied.

Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis.

Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B.

A cloned pig model for examining atherosclerosis induced by high fat, high cholesterol diets.

The pig is a recognized model for the onset of coronary heart disease and heart attacks. Previous studies have shown that serum cholesterol levels in the pig can be elevated using a high fat, high cholesterol (HFHC) diet. What has been lacking is a genetically defined model corresponding to human ApoE4 susceptibility that can be linked to diets capable of inducing atherosclerosis.

The postnatal maternal environment affects autoimmune disease susceptibility in A/J mice.

The postnatal maternal environment is known to increase susceptibility to a number of autoimmune diseases. Here we asked whether the postnatal maternal environment could influence autoimmune disease development to day 3 thymectomy (d3tx)-induced autoimmune ovarian disease (AOD) and experimental allergic encephalomyelitis (EAE) in cross-fostered A/J and B6 mice. A/J pups foster-nursed by B6 mothers exhibit an increase in autoimmune disease development while cross-fostering B6 pups on A/J mothers did not alter their susceptibility.

Interval-specific congenic lines reveal quantitative trait Loci with penetrant lyme arthritis phenotypes on chromosomes 5, 11, and 12.

The observation that Borrelia burgdorferi-induced arthritis is severe in C3H mice and milder in C57BL/6 (B6) mice has allowed a forward genetics approach for the identification of genetic elements that regulate the arthritis response. Quantitative trait loci (QTL) on five chromosomes (Chr) were identified previously in segregating crosses between C3H and B6 mice and collectively designated B. burgdorferi arthritis-associated (Bbaa) QTL.