A personalized osteoarthritic joint-on-a-chip as a screening platform for biological treatments.

Osteoarthritis (OA) is a highly disabling pathology, characterized by synovial inflammation and cartilage degeneration. Orthobiologics have shown promising results in OA treatment thanks to their ability to influence articular cells and modulate the inflammatory OA environment. Considering their complex mechanism of action, the development of reliable and relevant joint models appears as crucial to select the best orthobiologics for each patient. The aim of this study was to establish a microfluidic OA model to test therapies in a personalized human setting. The joint-on-a-chip model included cartilage and synovial compartments, containing hydrogel-embedded chondrocytes and synovial fibroblasts, separated by a channel for synovial fluid. For the cartilage compartment, a Hyaluronic Acid-based matrix was selected to preserve chondrocyte phenotype. Adding OA synovial fluid induced the production of inflammatory cytokines and degradative enzymes, generating an OA microenvironment. Personalized models were generated using patient-matched cells and synovial fluid to test the efficacy of mesenchymal stem cells on OA signatures. The patient-specific models allowed monitoring changes induced by cell injection, highlighting different individual responses to the treatment. Altogether, these results support the use of this joint-on-a-chip model as a prognostic tool to screen the patient-specific efficacy of orthobiologics.

Exploring the Performance of ChatGPT Versions 3.5, 4, and 4 With Vision in the Chilean Medical Licensing Examination: Observational Study.

Background: The deployment of OpenAI's ChatGPT-3.5 and its subsequent versions, ChatGPT-4 and ChatGPT-4 With Vision (4V; also known as "GPT-4 Turbo With Vision"), has notably influenced the medical field. Having demonstrated remarkable performance in medical examinations globally, these models show potential for educational applications. However, their effectiveness in non-English contexts, particularly in Chile's medical licensing examinations-a critical step for medical practitioners in Chile-is less explored. This gap highlights the need to evaluate ChatGPT's adaptability to diverse linguistic and cultural contexts. Objective: This study aims to evaluate the performance of ChatGPT versions 3.5, 4, and 4V in the EUNACOM (Examen Único Nacional de Conocimientos de Medicina), a major medical examination in Chile. Methods: Three official practice drills (540 questions) from the University of Chile, mirroring the EUNACOM's structure and difficulty, were used to test ChatGPT versions 3.5, 4, and 4V. The 3 ChatGPT versions were provided 3 attempts for each drill. Responses to questions during each attempt were systematically categorized and analyzed to assess their accuracy rate. Results: All versions of ChatGPT passed the EUNACOM drills. Specifically, versions 4 and 4V outperformed version 3.5, achieving average accuracy rates of 79.32% and 78.83%, respectively, compared to 57.53% for version 3.5 (P<.001). Version 4V, however, did not outperform version 4 (P=.73), despite the additional visual capabilities. We also evaluated ChatGPT's performance in different medical areas of the EUNACOM and found that versions 4 and 4V consistently outperformed version 3.5. Across the different medical areas, version 3.5 displayed the highest accuracy in psychiatry (69.84%), while versions 4 and 4V achieved the highest accuracy in surgery (90.00% and 86.11%, respectively). Versions 3.5 and 4 had the lowest performance in internal medicine (52.74% and 75.62%, respectively), while version 4V had the lowest performance in public health (74.07%). Conclusions: This study reveals ChatGPT's ability to pass the EUNACOM, with distinct proficiencies across versions 3.5, 4, and 4V. Notably, advancements in artificial intelligence (AI) have not significantly led to enhancements in performance on image-based questions. The variations in proficiency across medical fields suggest the need for more nuanced AI training. Additionally, the study underscores the importance of exploring innovative approaches to using AI to augment human cognition and enhance the learning process. Such advancements have the potential to significantly influence medical education, fostering not only knowledge acquisition but also the development of critical thinking and problem-solving skills among health care professionals.

Mixed Connective Tissue Disease (MCTD) in a Girl with Lower Extremities Edema: A Brief Report.

BACKGROUND: Mixed Connective Tissue Disease (MCTD) is a rare condition in children, characterized by a high titer of anti-ribonucleoprotein-U1 (anti-U1 RNP) antibodies, often presenting with overlapping features of two or more rheumatologic disorders, including juvenile idiopathic arthritis (JIA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), and juvenile dermatomyositis/polymyositis (JDM/PM). CASE PRESENTATION: We report the case of an 8-year-old girl with a history of fever, hair loss, lower extremities edema, weakness, oral aphthous ulcers, and a high titer of anti-U1 RNP antibodies, which is consistent with the diagnosis of MCTD. The patient received immunomodulator drugs, and her disease went into remission. CONCLUSION: Diagnosing MCTD in pediatric patients can be challenging. It should be considered especially in cases with recurrent muscular weakness or pain, lupus-like manifestations, and edema. Moreover, serum anti-U1 RNP testing can be a helpful diagnostic tool.

Association between polymorphism at codon 469 of the ICAM-1 gene and Henoch-Schönlein purpura in an Iranian cohort.

Henoch-Schönlein purpura (HSP) is a common form of IgA1-mediated blood vessel inflammation affecting mainly children. Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms have been shown to be associated with HSP in different populations; in this study, we investigated its potential association and influence on the development of severe complications in Iranian HSP patients. Twenty-three patients diagnosed with IgAV/HSP according to the criteria of the American College of Rheumatology (ACR) with 53 age- and sex-matched control subjects were referred to us. Cases and controls were genotyped using Sanger sequencing. Based on our research data, we found an association between codon 469 K/E of the ICAM1 gene and risk of HSP. Our results revealed that KK genotype and allele K are more common in control than in the HSP group, therefore the subjects with KK genotype are protected against HSP. Our data also suggested that the genotype EE is associated with higher risk of HSP progression compared to KK genotype.

Global perspectives of the impact of the COVID-19 pandemic on learning science in higher education.

The COVID-19 pandemic required higher education institutions to rapidly transition to Emergency Remote Instruction (ERI) with little preparation. Discussions are now underway globally to learn the lessons of COVID-19 and to use this knowledge to shape the future of learning science in higher education. In this study, we examined the experiences of instructors and students to ERI in three universities across three continents-America, Europe, and Australia. We measured the instructional strategies used by instructors including assessment types, and interaction opportunities during and outside class schedules. We also measured the learning challenges experienced by students including planning, distractions, technology, learning resources, their views on educational quality and what characterized quality interactions during ERI. Our findings suggest that most instructional strategies used by instructors changed little during ERI, although the nature of instructor and student interactions during class relied more heavily on technology. Students reported significant learning challenges which included distractions from their physical and social media environments and access to technology. Both instructors and students reported that interactions with each other and their peers were concerningly low, albeit similar to pre COVID-19 pandemic levels. There were differences in the perceptions of instructors and students on whether instructor-student interactions were better or worse online. Common among all universities, there was a large proportion of students reporting mental health and work-related stress. Lessons to be learned from the COVID-19 pandemic include ensuring more support for instructors to implement effective and equitable pedagogies and an increased recognition of the importance of practicals, and the social, interactive and hands-on aspects of learning science in higher education. We predict that the incorporation of active learning pedagogies and strategies which increase student engagement and foster a sense of belonging will be ongoing global challenges for learning science in a post COVID-19 campus.

Association of autoimmune pancreatitis with Raghib syndrome.

Key Clinical Message: Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis scarcely found in children. Raghib syndrome is a rare congenital heart defect known as persistent left superior vena cava (LSVC) draining into the left atrium. Total signs of Raghib syndrome in AIP case accompanied by an IgG4-related disease were described. Abstract: Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis scarcely found in children. Raghib syndrome is a rare congenital heart defect known as persistent left superior vena cava (LSVC) draining into the left atrium. Here, we describe Raghib syndrome in AIP case accompanied by an IgG4-related disease (AIP/IgG4RD). A 13-year-old boy presented with a 3-month history of fever and abdominal pain. The laboratory findings showed SGOT and SGPT, ALP was increased, while amylase and γ-GT were normal. Immunoglobulins were normal, except for IgG. Endosonography, spiral CT of the abdomen, and cholangiopancreatography showed an enlargement of the pancreas. Contrast echocardiography discovered opacification of the coronary sinus and left atrium. Transesophageal echocardiography for LSVC revealed a dilatation in the coronary sinus, indicating persistent LSVC. Following the injection of agitated saline into the left antecubital vein, bubbles entered both left and right atria in LSVC. It is reasonable to exclude some of these rare disorders as Raghib syndrome, in cases that will be started on medications like corticosteroids, which increases the susceptibility to thromboembolic events.

Immune dysregulation and pathogenic pathways mediated by common infections in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the world's most prevalent inflammatory autoimmune diseases, affecting between 0.4 and 1.3% of the population. The susceptibility to RA appears to be influenced by a complex interaction between a favorable genetic background and the existence of a specific immune reaction against a wide range of environmental variables. Among the known environmental variables, infections are believed to have a significant role in promoting the formation of autoimmune disorders, which are frequently caused by specific microorganisms. Infections have been linked to RA in recent medical studies. In this study, we selected the most prevalent infections associated with RA from the literature and described the data confirming their pathogenic role in RA. Our investigation included Mycobacterium, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Proteus mirabilis, Epstein-Barr virus, parvovirus, and Prevotella copri.

A systematic review of the 60 year literature: Effects of outreach programs in supporting historically marginalized and first-generation, low-income students in healthcare education.

We have reviewed over 60 years of studies on healthcare education outreach programs that are aimed to support first-generation, low-income, as well as underrepresented racial and ethnic minority groups (historically marginalized students) to pursue pre-health professions. As a systematic literature review, we present the challenges studies on healthcare education outreach programs had as three main categories: 1) Design, 2) Evaluation, and 3) Analysis. 1) Designs of studies on healthcare education outreach programs often lacked theoretical foundations whereby a) the interventions did not present theories underlying a causal mechanism of inequity in health professions; and/or 1b) the defined outcome measures were not clearly aligned with the problem the intervention tried to address. 2) Evaluations of studies on healthcare education outreach programs were not always conducted effectively whereby: 2a) controlled groups were commonly absent for comparison with the intervention group; and/or 2b) post measures were solely used without pre-measures. 3) Analyses of studies on healthcare education outreach programs were not adequate whereby: 3a) the response rates and effect size were commonly low; and/or 3b) qualitative results commonly did not supplement quantitative results. Overall, our findings reveal studies on healthcare education outreach programs have common challenges that hinder the reliability of their effects supporting historically marginalized students in pursuing pre-health professions. To address such challenges with studies on healthcare education outreach programs aimed at supporting historically marginalized students, we created a decision flow chart for researchers to ask themselves: 1) how is the design guided by theoretical goals; 2) how are measurements used to evaluate success; and 3) how does the analysis lead to reliable results?

Exploring the pre-instruction gender gap in physics.

There is a substantial body of work in physics education looking at gender disparities in physics. Recent work has linked gender disparities in college physics course performance to disparities in high school physics preparation, but to our knowledge, the origin of the disparity in high school physics preparation is still underexplored. In a select sample, we found that women on average had lower force and motion conceptual evaluation (FMCE) pre-scores (the FMCE is a short conceptual assessment of Newton's laws), and FMCE pre-score entirely mediated the effects of high school preparation and social-psychological factors on exam performance. The gender gap in FMCE pre-scores could not be explained by differences in the number of physics courses taken in high school. Instead, we find that the gender gap in the FMCE is partially explained by female students' higher levels of general test anxiety. We hypothesize that the format of the FMCE, a timed assessment, triggers stereotype threat in female students despite being a low-stakes assessment. Therefore, instructors and researchers should take care in interpreting the results of such concept inventory scores and should re-think the way they assess understanding of physics concepts. Results of this work aligned with previous findings on gender disparity in timed exams call upon investigating gender equitable assessment formats for evaluating physics knowledge to replace timed assessments, either high or low stakes.

Development of anti DLL4 Nanobody fused to truncated form of Pseudomonas exotoxin: As a novel immunotoxin to inhibit of cell proliferation and neovascularization.

Targeted tumor therapy is an attractive approach for cancer treatment. Delta-like ligand 4 (DLL4) is overexpressed in tumor vasculature and plays a pivotal role in tumor neovascular development and angiogenesis during tumor progression. Immunotoxins due to their superior cell-killing ability and the relative simplicity of their preparation, have great potential in the clinical treatment of cancer. The aim of this study was to develop a novel immunotoxin against DLL4 as a cell cytotoxic agent and angiogenesis maturation inhibitor. In present study, an immunotoxin, named DLL4Nb-PE, in which a Nanobody as targeting moiety fused to the Pseudomonas exotoxin A (PE) was constructed, expressed and assessed by SDS-PAGE, western blotting, ELISA and flowcytometry. The functional assessment was carried out via MTT, apoptosis and chicken chorioallantoic membrane (CAM) assays. It was demonstrated DLL4Nb-PE specifically binds to DLL4 and recognizes DLL4-expressing MKN cells. The cytotoxicity assays showed that this molecule could induce apoptosis and kill DLL4 positive MKN cells. In addition, it inhibited neovascularization in the chicken chorioallantoic membrane. Our findings indicate designed anti-DLL4 immunotoxin has valuable potential for application to the treatment of tumors with high DLL4 expression.

Pathogenic and therapeutic roles of cytokines in Kawasaki diseases.

Infancy and early childhood are the most common ages for acute pyretic Kawasaki disease (KD). Although the etiology remains a mystery, the current concept is that KD is caused by a contagious pathogen that infects the genetically vulnerable and induces an inflammatory mechanism aimed at cardiovascular organs. Resolving the inflammatory process and decreasing the incidence of coronary anomalies, namely coronary aneurysms, are two benefits of high-dose intravenous immunoglobulin (IVIG) administration. The etiology of KD has been linked to a large number of cytokines and treatment strategies to regulate these cytokines have been suggested. This review will focus on the critical role of cytokines in disease development and possible treatment approaches and potential clinical applications.

Differential Impact of the COVID-19 Pandemic on Female Graduate Students and Postdocs in the Chemical Sciences.

Over the past two and a half years, the COVID-19 pandemic severely disrupted almost all aspects of life as people throughout the world were instructed to work-from-home. Scientific researchers, whose work is reliant on access to laboratory equipment, have been acutely impacted by these global changes. In this study, we surveyed graduate students and postdocs in the chemical sciences at a selected number of academic institutions in the United States. We found that many survey participants, especially women, experienced severely diminished research progress and increased anxiety levels during the COVID-19 pandemic. Through factor analysis and multiple regression modeling, we found that during this challenging time participants who reported greater levels of professional support also reported greater research progress and lower levels of anxiety. We also found that, although advisors and departments provide some forms of professional support, there are other types of support that students and postdocs still desire. This phenomenon is magnified for female and underrepresented minority participants, as they need greater levels of professional support and place immense value on the quality of their work environments. Based on these results, we have identified some ways in which departments and advisors can provide the needed support for their graduate students and postdocs, thereby providing timeless advice that is applicable to improving academic work conditions not only during a global pandemic but also in a postpandemic world.

Detailed Methodology to Establish a Synovium/Cartilage-on-a-Chip Model to Investigate the Process of Monocyte Extravasation.

Microfluidics allows for recapitulating organotypic environments in miniaturized cell culture platforms. This ability paves the way to the investigation of complex biological processes in a relevant milieu. Here we describe the protocols to generate an organotypic model including a vascularized compartment mimicking the synovial membrane and designed for the study of monocyte extravasation during osteoarthritis.

Tumor Suppression by PD-1/PD-L1 Interaction Blockage in Mice Model.

Background: Overexpression of programmed cell death ligand 1 (PD-L1) in tumor cells and subsequent interaction with the programmed cell death protein 1 (PD-1) in tumor-infiltrating T cells cause an immune evasion of the tumor from cytotoxic T-cells. Therefore, inhibiting such interaction by a recombinant PD-1 can hinder tumor growth and extend the survival rate. Methods: The mouse extracellular domain of PD-1 (mPD-1) was expressed in E. coli BL21 (DE3) strain and purified using nickel affinity chromatography. The binding ability of the purified protein to human PD-L1 was studied using ELISA. Finally, the tumor-bearing mice were used to evaluate the potential antitumor effect. Results: The recombinant mPD-1 showed a significant binding capacity to human PD-L1 at the molecular level. The tumor size significantly decreased in the tumor-bearing mice after the intra-tumoral injections of mPD-1. Moreover, the survival rate increased significantly after eight weeks of monitoring. The histopathology revealed the necrosis in the tumor tissue of the control group compared to the mPD-1 received mice. Conclusions: Our outcomes propose that interaction blockade between PD-1 and PD-L1 is a promising approach for targeted tumor therapy.

Mediation Analysis in Discipline-Based Education Research Using Structural Equation Modeling: Beyond "What Works" to Understand How It Works, and for Whom.

Advancing the field of discipline-based education research (DBER) requires developing theories based on outcomes that integrate across multiple methodologies. Here, we describe mediation analysis with structural equation modeling as one statistical tool that allows us to further examine mechanisms underlying well-documented trends in higher education. The use of mediation analysis in educational settings is particularly powerful, as learning outcomes result from complex relationships among many variables. We illustrate how mediation analysis can enhance education research, addressing questions that cannot be easily reached otherwise. We walk through critical steps to guide decision-making in mediation analysis and apply them to questions using real data to examine performance gaps in large introductory courses in biology. Through the use of mediation analysis with structural equation modeling, we add to a growing body of research that shows diverse quantitative approaches support evidence-based teaching in higher education.

Recapitulating monocyte extravasation to the synovium in an organotypic microfluidic model of the articular joint.

The synovium of osteoarthritis (OA) patients can be characterized by an abnormal accumulation of macrophages originating from extravasated monocytes. Since targeting monocyte extravasation may represent a promising therapeutic strategy, our aim was to develop an organotypic microfluidic model recapitulating this process. Synovium and cartilage were modeled by hydrogel-embedded OA synovial fibroblasts and articular chondrocytes separated by a synovial fluid channel. The synovium compartment included a perfusable endothelialized channel dedicated to monocyte injection. Monocyte extravasation in response to chemokines and OA synovial fluid was quantified. The efficacy of chemokine receptor antagonists, RS-504393 (CCR2 antagonist) and Cenicriviroc (CCR2/CCR5 antagonist) in inhibiting extravasation was tested pre-incubating monocytes with the antagonists before injection. After designing and fabricating the chip, culture conditions were optimized to achieve an organotypic model including synovial fibroblasts, articular chondrocytes, and a continuous endothelial monolayer expressing intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. A significantly higher number of monocytes extravasated in response to the chemokine mix (p< 0.01) and OA synovial fluid (p< 0.01), compared to a control condition. In both cases, endothelium pre-activation enhanced monocyte extravasation. The simultaneous blocking of CCR2 and CCR5 proved to be more effective (p< 0.001) in inhibiting monocyte extravasation in response to OA synovial fluid than blocking of CCR2 only (p< 0.01). The study of extravasation in the model provided direct evidence that OA synovial fluid induces monocytes to cross the endothelium and invade the synovial compartment. The model can be exploited either to test molecules antagonizing this process or to investigate the effect of extravasated monocytes on synovium and cartilage cells.

Mixed results from a multiple regression analysis of supplemental instruction courses in introductory physics.

Providing less prepared students with supplemental instruction (SI) in introductory STEM courses has long been used as a model in math, chemistry, and biology education to improve student performance, but this model has received little attention in physics education research. We analyzed the course performance of students enrolled in SI courses for introductory mechanics and electricity and magnetism (E&M) at Stanford University compared with those not enrolled in the SI courses over a two-year period. We calculated the benefit of the SI course using multiple linear regression to control for students' level of high school physics and math preparation. We found that the SI course had a significant positive effect on student performance in E&M, but that an SI course with a nearly identical format had no effect on student performance in mechanics. We explored several different potential explanations for why this might be the case and were unable to find any that could explain this difference. This suggests that there are complexities in the design of SI courses that are not fully understood or captured by existing theories as to how they work.

Determination of the Relationship Between Kobayashi, Sano, and Egami Criteria and Prevalence of Intravenous Immunoglobulin Resistance and Coronary Artery Aneurysm in Iranian Children with Kawasaki Disease.

INTRODUCTION: Kawasaki disease (KD) is a systemic vasculitis that occurs mostly in children under five years old. Kawasaki affects the middle-size arteries, especially the coronary arteries. Therefore, without adequate treatment, it may cause coronary artery aneurysm in 25% of patients. The purpose of this study was to investigate the relationship between Kobayashi, Sano, and Egami criterions with coronary artery aneurysm in KD patients during the last ten years and to identify risk factors in patients with intravenous immunoglobulin (IVIG)-resistant and coronary artery aneurysms. METHODOLOGY: Medical records of 363 Kawasaki patients referred during 2008-2017 were reviewed. Patients' demographic data and Kobayashi, Sano, and Egami scores of each patient were calculated. Based on echocardiographic findings, cases of coronary artery aneurysm were determined. Sensitivity, specificity, positive and negative predictive value, and the accuracy of each criterion were determined to predicting IVIG resistance and detect coronary artery aneurysm. RESULTS: There was a slight relationship between IVIG-resistance in Kawasaki children and its prediction based on the Kobayashi risk score, but no relationship was found between the Egami and Sano criteria. Sixty-three patients (17.4%) had coronary artery lesions (CALs) on time of diagnosis. There were no statistically significant differences between gender and mean age of children with and without CALs. Also, there was no significant relationship between coronary artery aneurysm in Kawasaki children and its prediction based on the above three risk factors. The area under the ROC-curve of all three risk measures of Kobayashi, Egami, and Sano indicated that all three criteria were not useful in predicting CALs. CONCLUSION: Despite the low accuracy of the three above criteria to predictive of patients with IVIG resistance, it seems that the variables of age, duration of fever, and C-reactive protein (CRP) are more useful than other variables and may be utilized to evaluate patients by establishing a more appropriate cut-off point.

Expression analysis and genotyping of DGKZ: a GWAS-derived risk gene for schizophrenia.

Schizophrenia (SCZ) is a disabling and severe mental illness characterized by abnormal social behavior and disrupted emotions. Similar to other neuropsychological disorders, both genetics and environmental factors interplay so as to develop SCZ. It is acknowledged that genes such as DGKZ are involved in lipid signaling pathways that are the basis of neural activities, memory, and learning and are considered as candidate loci for SCZ. The aim of the present study was to evaluate the expression level and genotypes of DGKZ in patients with SCZ and controls. We used q-PCR to measure the relative expression of DGKZ in blood. To determine DGKZ-rs7951870 genotypes, tetra-ARMS PCR was used. Our results showed a significant difference in DGKZ mRNA ratio between SCZ patients and healthy controls (P = 2 × 10-4). Also, we showed that rs7951870-TT genotype was strongly associated with increased DGKZ expression level (P = 0.038). In conclusion, our findings revealed dysregulation of DGKZ in SCZ patients and a significant correction between the gene expression and DGKZ variant rs7951870.

The rs1986112 Variant is Associated with Increased RAB8B Gene Expression in Schizophrenic Patients.

BACKGROUND: Schizophrenia (SCZ) is a serious mental disorder that interferes with a person's cognitive processes and leads to social disability. A wide range of factors may play important roles in increased risk of SCZ development. Genetic contributors are among the most influential actors involved in different molecular mechanisms leading to the development of the nervous system, thus they play pivotal roles in psychotic disorders and SCZ de-velopment. RAB8B is characterized for its key roles in several cellular and molecular mechanisms which are linked with different psychotic disorders, such as SCZ. METHODS: In this study, we assessed the expression level of RAB8B gene in blood samples of schizophrenic patients and normal healthy controls by means of quantitative real time PCR. We also investigated the correlation between RAB8B-rs1986112 genotypes and RAB8B expression levels through SNP genotyping by means of the PCR-RFLP method. RESULTS: Our results indicated a significant difference of RAB8B mRNA ratio between SCZ patients and healthy controls. Moreover, we showed significant upregulation of RAB8B in patients with rs1986112 GG and AG genotype compared to AA genotype. CONCLUSIONS: Our findings suggest a role for RAB8B and its regulatory variation, rs1986112 in SCZ development.