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Generative artificial intelligence (AI) can exhibit biases, compromise data privacy, misinterpret prompts that are adversarial attacks, and produce hallucinations. Despite the potential of generative AI for many applications in digital health, practitioners must understand these tools and their limitations. This scoping review pays particular attention to the challenges with generative AI technologies in medical settings and surveys potential solutions. Using PubMed, we identified a total of 120 articles published by March 2024, which reference and evaluate generative AI in medicine, from which we synthesized themes and suggestions for future work. After first discussing general background on generative AI, we focus on collecting and presenting 6 challenges key for digital health practitioners and specific measures that can be taken to mitigate these challenges. Overall, bias, privacy, hallucination, and regulatory compliance were frequently considered, while other concerns around generative AI, such as overreliance on text models, adversarial misprompting, and jailbreaking, are not commonly evaluated in the current literature.

BackgroundBlack adolescents with type 1 diabetes (T1D) are at increased risk for suboptimal diabetes health outcomes; however, evidence-based interventions for this population are lacking. Depression affects a high percentage of youth with T1D and increases the likelihood of health problems associated with diabetes. ObjectiveOur aim was to test whether baseline levels of depression moderate the effects of a brief eHealth parenting intervention delivered to caregivers of young Black adolescents with T1D on youths’ glycemic control. MethodsWe conducted a multicenter randomized controlled trial at 7 pediatric diabetes clinics located in 2 large US cities. Participants (N=149) were allocated to either the intervention group or a standard medical care control group. Up to 3 intervention sessions were delivered on a tablet computer during diabetes clinic visits over a 12-month period. ResultsIn a linear mixed effects regression model, planned contrasts did not show significant reductions in hemoglobin A1c (HbA1c) for intervention adolescents compared to controls. However, adolescents with higher baseline levels of depressive symptoms who received the intervention had significantly greater improvements in HbA1c levels at 6-month follow-up (0.94%; P=.01) and 18-month follow-up (1.42%; P=.002) than those with lower levels of depression. Within the intervention group, adolescents had a statistically significant reduction in HbA1c levels from baseline at 6-month and 18-month follow-up. ConclusionsA brief, culturally tailored eHealth parenting intervention improved health outcomes among Black adolescents with T1D and depressive symptoms. Trial RegistrationClinicalTrials.gov NCT03168867; https://clinicaltrials.gov/study/NCT03168867

In the context of multimodal treatments for abdominal cancer, including procedures such as cytoreductive surgery and intraperitoneal chemotherapy, recurrence rates remain high, and long-term survival benefits are uncertain due to post-operative complications. Notably, treatment-limiting side effects often arise from an uncontrolled activation of the immune system, particularly peritoneally localized macrophages, leading to massive cytokine secretion and phenotype changes. Exploring alternatives, an increasing number of studies investigated the potential of plasma-activated liquids (PAL) for adjuvant peritoneal cancer treatment, aiming to mitigate side effects, preserve healthy tissue, and reduce cytotoxicity towards non-cancer cells. To assess the non-toxicity of PAL, we isolated primary human macrophages from the peritoneum and subjected them to PAL exposure. Employing an extensive methodological spectrum, including flow cytometry, Raman microspectroscopy, and DigiWest protein analysis, we observed a pronounced resistance of macrophages towards PAL. This resistance was characterized by an upregulation of proliferation and anti-oxidative pathways, countering PAL-derived oxidative stress-induced cell death. The observed cellular effects of PAL treatment on human tissue-resident peritoneal macrophages unveil a potential avenue for PAL-derived immunomodulatory effects within the human peritoneal cavity. Our findings contribute to understanding the intricate interplay between PAL and macrophages, shedding light on the promising prospects for PAL in the adjuvant treatment of peritoneal cancer.

Chronic low back pain is often caused by intervertebral disc (IVD) degeneration. Preceding this degenerative process, the main cellular phenotype in the nucleus pulposus shifts from notochordal cells (NCs) to nucleus pulposus cells (NPCs). In previous studies, porcine NC-derived matrix (NCM), containing NC-secreted factors, induced matrix anabolic effects and inhibited pro-inflammatory mediators in NPCs in vitro and in degenerated canine IVDs in vivo. As the underlying mechanisms remained elusive, this study aimed to explore this with targeted gene expression and proteomic (DigiWest technology) analysis focused on inflammatory signaling pathways. After 6 hours, NCM (10 mg/mL) treatment initially stimulated pro-inflammatory mediators in canine and human NPCs in vitro and increased signaling in a chondrosarcoma derived Nuclear factor-κB reporter cell line. At protein level, NCM mainly induced changes in the Mitogen-activated protein kinase (MAPK) pathway after 72 hours. Expression of inhibitory Dual-specificity phosphatase (DUSP) proteins was increased in NCM-treated NPCs, whereas the expression of the three main pillars of the MAPK pathway (extracellular signal-regulated kinase (ERK)/cJun N-terminal kinase (JNK)/protein kinase C (PKC)) was inhibited. In follow-up validation, in vivo degenerated canine IVDs treated with an intradiscal NCM injection demonstrated increased DUSP5 and healthy nucleus pulposus marker (cytokeratin 19, Paired box 1 (PAX1), Forkhead Box F1 (FOXF1)) immunopositivity after 6 months of treatment. Altogether, NCM initially stimulated pro-inflammatory mediators in vitro, but thereafter exerts its prolonged effects by inhibiting the MAPK pathway. These findings provide insights in the underlying mechanisms involved in the instructive capacity of this naturally-derived biomaterial with the potential to serve as a cell-free NC-based therapy to treat intervertebral disc degeneration.

The Modeling Self-Efficacy Scale was developed to measure students' confidence in understanding and solving modeling tasks. The scale was administered to 225 eighth- and ninth-grade students. Participants read modeling tasks adapted from Programme for International Student Assessment's 2003 problem-solving assessment and rated their confidence on a 100-point self-efficacy scale. Confirmatory factor analysis indicated that modeling self-efficacy is a unidimensional construct, best elicited by a repeated-measures-style survey design in which participants responded to the same self-efficacy items across multiple modeling problems. The omega reliability coefficient for the scale was 0.88. The findings suggest that the Modeling Self-Efficacy Scale is a reliable and valid instrument for middle and high school mathematics students.

Abstract Despite tremendous progress in deciphering breast cancer at the genomic level, the pronounced intra- and intertumoral heterogeneity remains a major obstacle to the advancement of novel and more effective treatment approaches. Frequent treatment failure and the development of treatment resistance highlight the need for patient-derived tumor models that reflect the individual tumors of breast cancer patients and allow a comprehensive analyses and parallel functional validation of individualized and therapeutically targetable vulnerabilities in protein signal transduction pathways. Here, we introduce the generation and application of breast cancer patient-derived 3D microtumors (BC-PDMs). Residual fresh tumor tissue specimens were collected from n = 102 patients diagnosed with breast cancer and subjected to BC-PDM isolation. BC-PDMs retained histopathological characteristics, and extracellular matrix (ECM) components together with key protein signaling pathway signatures of the corresponding primary tumor tissue. Accordingly, BC-PDMs reflect the inter- and intratumoral heterogeneity of breast cancer and its key signal transduction properties. DigiWest®-based protein expression profiling of identified treatment responder and non-responder BC-PDMs enabled the identification of potential resistance and sensitivity markers of individual drug treatments, including markers previously associated with treatment response and yet undescribed proteins. The combination of individualized drug testing with comprehensive protein profiling analyses of BC-PDMs may provide a valuable complement for personalized treatment stratification and response prediction for breast cancer.

Abstract High-fat diet (HFD) is associated with Alzheimer’s disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer’s microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.

This paper demonstrates the process of invariance testing in diagnostic classification models in the presence of attribute hierarchies via an extension of the log-linear cognitive diagnosis model (LCDM). This extension allows researchers to test for measurement (item) invariance as well as attribute (structural) invariance simultaneously in a single analysis. The structural model of the LCDM was parameterized as a Bayesian network, which allows attribute hierarchies to be modeled and tested for attribute invariance via a series of latent regression models. We illustrate the steps for carrying out the invariance analyses through an in-depth case study with an empirical dataset and provide JAGS code for carrying out the analysis within the Bayesian framework. The analysis revealed that a subset of the items exhibit partial invariance, and evidence of full invariance was found at the structural level.

ABSTRACT Wolbachia are a genus of insect endosymbiotic bacteria which includes strains wMel and wAlbB that are being utilized as a biocontrol tool to reduce the incidence of Aedes aegypti-transmitted viral diseases like dengue. However, the precise mechanisms underpinning the antiviral activity of these Wolbachia strains are not well defined. Here, we generated a panel of Ae. aegypti-derived cell lines infected with antiviral strains wMel and wAlbB or the non-antiviral Wolbachia strain wPip to understand host cell morphological changes specifically induced by antiviral strains. Antiviral strains were frequently found to be entirely wrapped by the host endoplasmic reticulum (ER) membrane, while wPip bacteria clustered separately in the host cell cytoplasm. ER-derived lipid droplets (LDs) increased in volume in wMel- and wAlbB-infected cell lines and mosquito tissues compared to cells infected with wPip or Wolbachia-free controls. Inhibition of fatty acid synthase (required for triacylglycerol biosynthesis) reduced LD formation and significantly restored ER-associated dengue virus replication in cells occupied by wMel. Together, this suggests that antiviral Wolbachia strains may specifically alter the lipid composition of the ER to preclude the establishment of dengue virus (DENV) replication complexes. Defining Wolbachia’s antiviral mechanisms will support the application and longevity of this effective biocontrol tool that is already being used at scale.IMPORTANCEAedes aegypti transmits a range of important human pathogenic viruses like dengue. However, infection of Ae. aegypti with the insect endosymbiotic bacterium, Wolbachia, reduces the risk of mosquito to human viral transmission. Wolbachia is being utilized at field sites across more than 13 countries to reduce the incidence of viruses like dengue, but it is not well understood how Wolbachia induces its antiviral effects. To examine this at the subcellular level, we compared how different strains of Wolbachia with varying antiviral strengths associate with and modify host cell structures. Strongly antiviral strains were found to specifically associate with the host endoplasmic reticulum and induce striking impacts on host cell lipid droplets. Inhibiting Wolbachia-induced lipid redistribution partially restored dengue virus replication demonstrating this is a contributing role for Wolbachia's antiviral activity. These findings provide new insights into how antiviral Wolbachia strains associate with and modify Ae. aegypti host cells.

Summary: Understanding the emergence of human notochordal cells (NC) is essential for the development of regenerative approaches. We present a comprehensive investigation into the specification and generation of bona fide NC using a straightforward pluripotent stem cell (PSC)-based system benchmarked with human fetal notochord. By integrating in vitro and in vivo transcriptomic data at single-cell resolution, we establish an extended molecular signature and overcome the limitations associated with studying human notochordal lineage at early developmental stages. We show that TGF-β inhibition enhances the yield and homogeneity of notochordal lineage commitment in vitro. Furthermore, this study characterizes regulators of cell-fate decision and matrisome enriched in the notochordal niche. Importantly, we identify specific cell-surface markers opening avenues for differentiation refinement, NC purification, and functional studies. Altogether, this study provides a human notochord transcriptomic reference that will serve as a resource for notochord identification in human systems, diseased-tissues modeling, and facilitating future biomedical research.

Objective: Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated brain pathology and β-cell cytotoxicity. Here, we evaluated the role of RIPK3 in amyloid-induced β-cell loss using a humanized mouse model of T2D that expresses hIAPP and is prone to islet amyloid formation. Methods: We quantified amyloid deposition, cell death and caspase 3/7 activity in islets isolated from WT, Ripk3−/−, hIAPP and hIAPP; Ripk3−/− mice in real time, and evaluated hIAPP-stimulated inflammation in WT and Ripk3−/− bone marrow derived macrophages (BMDMs) in vitro. We also characterized the role of RIPK3 in glucose stimulated insulin secretion (GSIS) in vitro and in vivo. Finally, we examined the role of RIPK3 in high fat diet (HFD)-induced islet amyloid deposition, β-cell loss and glucose homeostasis in vivo. Results: We found that amyloid-prone hIAPP mouse islets exhibited increased cell death and caspase 3/7 activity compared to amyloid-free WT islets in vitro, and this was associated with increased RIPK3 expression. hIAPP; Ripk3−/− islets were protected from amyloid-induced cell death compared to hIAPP islets in vitro, although amyloid deposition and caspase 3/7 activity were not different between genotypes. We observed that macrophages are a source of Ripk3 expression in isolated islets, and that Ripk3−/− BMDMs were protected from hIAPP-stimulated inflammatory gene expression (Tnf, Il1b, Nos2). Following 52 weeks of HFD feeding, islet amyloid-prone hIAPP mice exhibited impaired glucose tolerance and decreased β-cell area compared to WT mice in vivo, whereas hIAPP; Ripk3−/− mice were protected from these impairments. Conclusions: In conclusion, loss of RIPK3 protects from amyloid-induced inflammation and islet cell death in vitro and amyloid-induced β-cell loss and glucose intolerance in vivo. We propose that therapies targeting RIPK3 may reduce islet inflammation and β-cell loss and improve glucose homeostasis in the pathogenesis of T2D.

Acute chest pain and dyspnea often raise coronary disease suspicion. When echocardiography and cardiac computed tomography findings appear normal, alternative diagnoses should be explored. We present a case initially suggestive of myocarditis but later revealed as coronary dissection by cardiac magnetic resonance. This case emphasizes the role of advanced imaging in atypical cardiac presentations.

Introduction: Non-combat musculoskeletal injuries (MSKIs) during military training significantly impede the US military’s functionality, with an annual cost exceeding $3.7 billion. This study aimed to investigate the effectiveness of a markerless motion capture system and full-body biomechanical movement pattern assessments to predict MSKI risk among military trainees.Methods: A total of 156 male United States Air Force (USAF) airmen were screened using a validated markerless biomechanics system. Trainees performed multiple functional movements, and the resultant data underwent Principal Component Analysis and Uniform Manifold And Projection to reduce the dimensionality of the time-dependent data. Two approaches, semi-supervised and supervised, were then used to identify at-risk trainees.Results: The semi-supervised analysis highlighted two major clusters with trainees in the high-risk cluster having a nearly five times greater risk of MSKI compared to those in the low-risk cluster. In the supervised approach, an AUC of 0.74 was produced when predicting MSKI in a leave-one-out analysis.Discussion: The application of markerless motion capture systems to measure an individual’s kinematic profile shows potential in identifying MSKI risk. This approach offers a novel way to proactively address one of the largest non-combat burdens on the US military. Further refinement and wider-scale implementation of these techniques could bring about substantial reductions in MSKI occurrence and the associated economic costs.

Abstract Wildlife translocations are increasingly used to combat declining biodiversity worldwide. Successful translocation often hinges on coexistence between humans and wildlife, yet not all translocation efforts explicitly include human dimensions (e.g., economic incentives, education programs, and conflict reduction assistance). To evaluate the prevalence and associated outcomes of including human dimensions as objectives when planning translocations, we analyze 305 case studies from the IUCN’s Global Re-Introduction Perspectives Series. We find that fewer than half of all projects included human dimension objectives (42%), but that projects including human dimension objectives were associated with improved wildlife population outcomes (i.e., higher probability of survival, reproduction, or population growth). Translocation efforts were more likely to include human dimension objectives if they involved mammals, species with a history of local human conflict, and local stakeholders. Our findings underscore the importance of incorporating objectives related to human dimensions in translocation planning efforts to improve conservation success.

In response to the global pressure that has led to an increased emphasis on international comparisons of student achievement since the 1980s, multiple federal reforms aimed at producing greater consistency in curricula have been initiated in the United States. The purpose of this study was to examine the feasibility of a national curriculum and whether it has the potential to improve the quality of physical education. Twenty-eight national leaders in physical education teacher education participated in formal and informal interviews. The themes that emerged indicated a uniform curriculum would not be readily realized or successfully implemented in the US due to the polyphonic governance structure and anti-federal sentiment, and widespread convictions among the educational community about an idiosyncratic curriculum approach.

Poor oral health is an important concern for athletes, as it can affect both general health and athletic performance. The aim of this study is to investigate the effects of activity in chlorinated water on oral health in elite swimmers compared to non-swimming athletes. This cross-sectional study included 101 swimmers and 100 other athletes aged 13–26 years with a minimum training intensity of five hours per week (for at least the preceding two years). Oral health was assessed using the approximal plaque index (API) and the decayed/missing/filled teeth (DMFT) index. A DIAGNOcam was used to detect caries. Results show that swimmers were younger (15 years vs. 18 years), were more likely to be female (54% vs. 17%), and had a lower body mass index (20.1 kg/m2 vs. 21.9 kg/m2) and a lower juice consumption (9% vs. 24%). Non-swimmers had significantly more decayed, missing, or filled teeth due to caries and plaque. In conclusion, by comparing elite swimmers and athletes competing in different sports, we have shown that competitive swimmers have a lower incidence of dental caries and plaque. Further research is needed to test our findings and to understand this relationship in greater detail.

In the literature there are numerous reports of developmental deformities in arthropods collected in their natural habitat. Since such teratogenically affected individuals are found purely by chance, the causes of their defects are unknown. Numerous potential physical, mechanical, chemical, and biological teratogens have been considered and tested in the laboratory. Thermal shocks, frequently used in teratological research on the spider Eratigena atrica, have led to deformities on both the prosoma and the opisthosoma. In the 2020/2021 breeding season, by applying alternating temperatures (14 °C and 32 °C, changed every 12 h) for the first 10 days of embryonic development, we obtained 212 postembryos (out of 3,007) with the following anomalies: oligomely, heterosymely, bicephaly, schistomely, symely, polymely, complex anomalies, and others. From these we selected six spiders with defects on the prosoma and two with short appendages on the pedicel for further consideration. The latter cases seem particularly interesting because appendages do not normally develop on this body part, viewed as the first segment of the opisthosoma, and appear to represent examples of atavism. In view of the ongoing development of molecular techniques and recent research on developmental mechanisms in spiders, we believe the observed phenotypes may result, at least in part, from the erroneous suppression or expression of segmentation or appendage patterning genes. We consider “knockdown” experiments described in the literature as a means for generating hypotheses about the sources of temperature-induced body abnormalities in E. atrica.

Aims/hypothesisAggregation of the beta cell secretory product human islet amyloid polypeptide (hIAPP) results in islet amyloid deposition, a pathological feature of type 2 diabetes. Amyloid formation is associated with increased levels of islet IL-1β as well as beta cell dysfunction and death, but the mechanisms that promote amyloid deposition in situ remain unclear. We hypothesised that physiologically relevant concentrations of IL-1β stimulate beta cell islet amyloid polypeptide (IAPP) release and promote amyloid formation.MethodsWe used a humanised mouse model of endogenous beta cell hIAPP expression to examine whether low (pg/ml) concentrations of IL-1β promote islet amyloid formation in vitro. Amyloid-forming islets were cultured for 48 h in the presence or absence of IL-1β with or without an IL-1β neutralising antibody. Islet morphology was assessed by immunohistochemistry and islet mRNA expression, hormone content and release were also quantified. Cell-free thioflavin T assays were used to monitor hIAPP aggregation kinetics in the presence and absence of IL-1β.ResultsTreatment with a low concentration of IL-1β (4 pg/ml) for 48 h increased islet amyloid prevalence (93.52 ± 3.89% vs 43.83 ± 9.67% amyloid-containing islets) and amyloid severity (4.45 ± 0.82% vs 2.16 ± 0.50% amyloid area/islet area) in hIAPP-expressing mouse islets in vitro. This effect of IL-1β was reduced when hIAPP-expressing islets were co-treated with an IL-1β neutralising antibody. Cell-free hIAPP aggregation assays showed no effect of IL-1β on hIAPP aggregation in vitro. Low concentration IL-1β did not increase markers of the unfolded protein response (Atf4, Ddit3) or alter proIAPP processing enzyme gene expression (Pcsk1, Pcsk2, Cpe) in hIAPP-expressing islets. However, release of IAPP and insulin were increased over 48 h in IL-1β-treated vs control islets (IAPP 0.409 ± 0.082 vs 0.165 ± 0.051 pmol/5 islets; insulin 87.5 ± 8.81 vs 48.3 ± 17.3 pmol/5 islets), and this effect was blocked by co-treatment with IL-1β neutralising antibody.Conclusions/interpretationUnder amyloidogenic conditions, physiologically relevant levels of IL-1β promote islet amyloid formation by increasing beta cell release of IAPP. Neutralisation of this effect of IL-1β may decrease the deleterious effects of islet amyloid formation on beta cell function and survival.

In the European Union, aquarium pets are organisms intended for closed places (e.g., pet shops, garden ponds, home aquariums). Until April 2021, regulations did not require veterinary inspection of these animals within the EU, although there is a potential risk of such organisms being released into the environment along with their symbiotes or parasites. Currently, a “disease-free” declaration is required, but no aquarium snail pathogen that needs attention in international trade has been included in the list of potential hazards. Here, we intended to check whether molluscs from the pet trade could be a source of parasites. We answered this question by using Anentome helena, a popular commodity in the ornamental pet industry, as a research model. Snail specimens were randomly collected from aquarium pet stocks imported from Bangkok (Thailand) to Warsaw (Poland) in March 2020. In total, three specimens were subjected to histological examination and 27 specimens were autopsied. Histological analysis revealed that one snail was infected with rediae (and the cercariae inside them). Our study is the first to show the presence of digenean larvae in A. helena originating from the ornamental pet industry. The spread of such “hitchhikers” in non-native areas will likely be associated with threats to environmental and public health. Therefore, it is necessary to constantly draw public attention to the possible consequences of releasing ornamental pets into the non-native environment.