Microbial determinants of dementia risk in subjects of Mexican descent with type 2 diabetes living in South Texas.

Type 2 diabetes (T2D) is a common forerunner of neurodegeneration and dementia, including Alzheimer's Disease (AD), yet the underlying mechanisms remain unresolved. Individuals of Mexican descent living in South Texas have increased prevalence of comorbid T2D and early onset AD, despite low incidence of the predisposing APOE-e4 variant and an absence of the phenotype among relatives residing in Mexico - suggesting a role for environmental factors in coincident T2D and AD susceptibility. Here, in a small clinical trial, we show dysbiosis of the human gut microbiome could contribute to neuroinflammation and risk for AD in this population. Divergent Gastrointestinal Symptom Rating Scale (GSRS) responses, despite no differences in expressed dietary preferences, provided the first evidence for altered gut microbial ecology among T2D subjects (sT2D) versus population-matched healthy controls (HC). Metataxonomic 16S rRNA sequencing of participant stool revealed a decrease in alpha diversity of sT2D versus HC gut communities and identified BMI as a driver of gut community structure. Linear discriminant analysis effect size (LEfSe) identified a significant decrease in the relative abundance of the short-chain fatty acid-producing taxa Lachnospiraceae, Faecalibacterium, and Alistipes and an increase in pathobionts Escherichia-Shigella, Enterobacter, and Clostridia innocuum among sT2D gut microbiota, as well as differentially abundant gene and metabolic pathways. These results suggest characterization of the gut microbiome of individuals with T2D could identify key actors among "disease state" microbiota which may increase risk for or accelerate the onset of neurodegeneration. Furthermore, they identify candidate microbiome-targeted approaches for prevention and treatment of neuroinflammation in AD.

The therapeutic potential of immunoengineering for systemic autoimmunity.

Disease-modifying drugs have transformed the treatment options for many systemic autoimmune diseases. However, an evolving understanding of disease mechanisms, which might vary between individuals, is paving the way for the development of novel agents that operate in a patient-tailored manner through immunophenotypic regulation of disease-relevant cells and the microenvironment of affected tissue domains. Immunoengineering is a field that is focused on the application of engineering principles to the modulation of the immune system, and it could enable future personalized and immunoregulatory therapies for rheumatic diseases. An important aspect of immunoengineering is the harnessing of material chemistries to design technologies that span immunologically relevant length scales, to enhance or suppress immune responses by re-balancing effector and regulatory mechanisms in innate or adaptive immunity and rescue abnormalities underlying pathogenic inflammation. These materials are endowed with physicochemical properties that enable features such as localization in immune cells and organs, sustained delivery of immunoregulatory agents, and mimicry of key functions of lymphoid tissue. Immunoengineering applications already exist for disease management, and there is potential for this new discipline to improve disease modification in rheumatology.

Exploring Novel Non-pharmacologic Approaches to Address Preoperative Anxiety and Postoperative Pain in Pediatric Patients Undergoing In-Patient Surgical Procedures: A Scoping Review.

The pediatric population is more prone to experiencing anxiety and fear before undergoing an inpatient surgical procedure than adults. Non-pharmaceutical interventions, such as music therapy and virtual reality programs, have shown significant promise in reducing the post-operative pain associated with pre-operative anxiety of patients and their caregivers. While there is evidence to support the use of non-pharmaceutical treatment in the mitigation of pre-operative anxiety, there are limited published reports of non-pharmacological interventions for pre-operative anxiety in children undergoing inpatient surgical procedures. The goal of this scoping review was to identify and classify specific non-pharmacological interventions utilized inpatient among children to improve pre-operative anxiety and post-operative complications inflicting pain. Comprehensive searches were conducted using Ovid Medline, Embase Emtree, CINAHL Complete, and COCHRANE Central databases. The articles had to be peer-reviewed, written in English, published between 2000-2022, and contain measurements of pre-operative anxiety and post-operative pain to be included in the scoping review. Articles that reported findings on patients younger than 18 undergoing elective and/or routine surgeries, excluding emergent surgical cases, were selected. After a systemized screening process, 9 articles were selected for the final review. The findings indicated that non-pharmacological interventions such as virtual reality, hypnosis, and clowns reduced pre-operative anxiety and post-operative pain in pediatric patients. This scoping review identified a wide range of non-pharmacological interventions to mitigate the post-operative effects of pre-operative anxiety among children, including but not limited to music, visual reality, and other holistic methods. More longitudinal studies are warranted to understand the specific interventions that may be the most efficacious.

ABCD of IA: A multi-scale agent-based model of T cell activation in inflammatory arthritis.

Biomaterial-based agents have been demonstrated to regulate the function of immune cells in models of autoimmunity. However, the complexity of the kinetics of immune cell activation can present a challenge in optimizing the dose and frequency of administration. Here, we report a model of autoreactive T cell activation, which are key drivers in autoimmune inflammatory joint disease. The model is termed a multi-scale Agent-Based, Cell-Driven model of Inflammatory Arthritis (ABCD of IA). Using kinetic rate equations and statistical theory, ABCD of IA simulated the activation and presentation of autoantigens by dendritic cells, interactions with cognate T cells and subsequent T cell proliferation in the lymph node and IA-affected joints. The results, validated with in vivo data from the T cell driven SKG mouse model, showed that T cell proliferation strongly correlated with the T cell receptor (TCR) affinity distribution (TCR-ad), with a clear transition state from homeostasis to an inflammatory state. T cell proliferation was strongly dependent on the amount of antigen in antigenic stimulus event (ASE) at low concentrations. On the other hand, inflammation driven by Th17-inducing cytokine mediated T cell phenotype commitment was influenced by the initial level of Th17-inducing cytokines independent of the amount of arthritogenic antigen. The introduction of inhibitory artificial antigen presenting cells (iaAPCs), which locally suppress T cell activation, reduced T cell proliferation in a dose-dependent manner. The findings in this work set up a framework based on theory and modeling to simulate personalized therapeutic strategies in IA.

Feasibility of cross-vendor linkage of ophthalmic images with electronic health record data: an analysis from the IRIS Registry®.

Purpose: To link compliant, universal Digital Imaging and Communications in Medicine (DICOM) ophthalmic imaging data at the individual patient level with the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight). Design: A retrospective study using de-identified EHR registry data. Subjects Participants Controls: IRIS Registry records. Materials and Methods: DICOM files of several imaging modalities were acquired from two large retina ophthalmology practices. Metadata tags were extracted and harmonized to facilitate linkage to the IRIS Registry using a proprietary, heuristic patient-matching algorithm, adhering to HITRUST guidelines. Linked patients and images were assessed by image type and clinical diagnosis. Reasons for failed linkage were assessed by examining patients' records. Main Outcome Measures: Success rate of linking clinicoimaging and EHR data at the patient level. Results: A total of 2 287 839 DICOM files from 54 896 unique patients were available. Of these, 1 937 864 images from 46 196 unique patients were successfully linked to existing patients in the registry. After removing records with abnormal patient names and invalid birthdates, the success linkage rate was 93.3% for images. 88.2% of all patients at the participating practices were linked to at least one image. Conclusions and Relevance: Using identifiers from DICOM metadata, we created an automated pipeline to connect longitudinal real-world clinical data comprehensively and accurately to various imaging modalities from multiple manufacturers at the patient and visit levels. The process has produced an enriched and multimodal IRIS Registry, bridging the gap between basic research and clinical care by enabling future applications in artificial intelligence algorithmic development requiring large linked clinicoimaging datasets.

Immunomodulatory Nanoparticles for Modulating Arthritis Flares.

Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan70-84 and type 2 bovine collagen256-270. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). CLNP had a ∼200 nm hydrodynamic diameter with a low polydispersity index. In vitro, CLNP induced phenotypic changes in bone marrow derived dendritic cells (DC), reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4+ T cells but without generalized suppression of T cell-dependent immune response. The results support the potential of CLNP as modulators of disease flares in autoimmune arthropathies.

Advanced Metrics and Early Predictors of Cardiogenic Shock.

Cardiogenic shock (CS) can be defined as a range of illnesses that describes a state where cardiac output, which is the blood volume ejected from the left ventricle every minute that leads to tissue perfusion of nutrients, is insufficient in providing adequate oxygenation to the systemic circulation. The incidence of CS on admission has increased in recent years, with the six- and 12-month mortality rates remaining unchanged. The purpose of this literature review is to bring forth several parameters that have been utilized in the past 10 years to predict CS mortality. Further studies to implement these parameters in management algorithms, along with early screenings and advanced treatment options such as mechanical cardiac assist devices, can improve the mortality associated with CS. This literature-based review was conducted by evaluating current research focusing on the clinical presentation of CS and predictors of CS. PubMed served as the primary database for article retrieval due to access. Two searches were conducted: One for clinical presentations and advanced metrics for CS and another for early predictors for CS. Thirteen articles regarding clinical presentation and seven articles regarding early predictors were selected. Three tools/scores and five laboratory tests were identified that allowed clinicians to prognosticate outcomes in patients suffering from CS based on clinical and laboratory presentations. Examining these predictors will allow earlier intervention in the development of CS and potentially help lower the mortality rate of CS. The eventual creation of a scoring system that incorporates multiple metrics discussed in this review can provide the most accurate prognosis of CS, which can lead to more targeted interventions.

Biodegradable scaffolds for enhancing vaccine delivery.

Sustained release of vaccine components is a potential method to boost efficacy compared with traditional bolus injection. Here, we show that a biodegradable hyaluronic acid (HA)-scaffold, termed HA cryogel, mediates sustained antigen and adjuvant release in vivo leading to a durable immune response. Delivery from subcutaneously injected HA cryogels was assessed and a formulation which enhanced the immune response while minimizing the inflammation associated with the foreign body response was identified, termed CpG-OVA-HAC2. Dose escalation studies with CpG-OVA-HAC2 demonstrated that both the antibody and T cell responses were dose-dependent and influenced by the competency of neutrophils to perform oxidative burst. In immunodeficient post-hematopoietic stem cell transplanted mice, immunization with CpG-OVA-HAC2 elicited a strong antibody response, three orders of magnitude higher than dose-matched bolus injection. In a melanoma model, CpG-OVA-HAC2 induced dose-responsive prophylactic protection, slowing the tumor growth rate and enhancing overall survival. Upon rechallenge, none of the mice developed new tumors suggesting the development of robust immunological memory and long-lasting protection against repeat infections. CpG-OVA-HAC2 also enhanced survival in mice with established tumors. The results from this work support the potential for CpG-OVA-HAC2 to enhance vaccine delivery.

Is It Safe to Perform Revision Hip Arthroplasty Without Suction Drains?

Background There is a number of studies showing no significant benefit of using drains after primary hip arthroplasty. However, there is no consensus in the literature about the usage of drains in revision hip replacement. This study aims to assess the effect of drains in revision hip arthroplasty. Methods A retrospective analysis was performed of all consecutive revision hip replacement surgeries performed at our unit over a five-month period (November 2018 to March 2019). Case notes, laboratory investigations, and operative records were reviewed. The effects of drains on postoperative hemoglobin (Hb), transfusion rate, and complications were analyzed. Results Overall, 92 patients were analyzed who underwent revision hip replacement during the study period. There were 46 male and 46 female patients with a mean age of 72 years. Aseptic loosening was the most common indication for the revision (41 patients) followed by instability (21 patients), infection (11 patients), and periprosthetic fractures (eight patients). Seventy-two patients had no drains while suction drains were used in 20 patients. Both groups were similar regarding age, sex, and indications for revision surgery. There was a significantly higher drop in postoperative Hb in patients with drains than those without drains (33 g/L: 27 g/L, p=0.03). There were significantly more blood transfusions in patients with drains as compared to those without drains (15%: 8%, relative risk 1.8, and odds ratio 1.94). There was no difference in both groups with regard to returning to the theater. Discussion Use of suctions drains in revision hip surgery was associated with increased postoperative blood loss and increased requirement for postoperative blood transfusion. Revision hip surgery without routine usage of suction drains did not increase wound complications. Conclusion Revision surgery without routine usage of drains is safe and may decrease postoperative blood loss and the rate of transfusion.

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis.

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (Treg ) and suppression of Treg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory Treg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of Treg . PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.

Immune-responsive biodegradable scaffolds for enhancing neutrophil regeneration.

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.

Short-chain fatty acids (SCFAs) are major metabolic products of indigestible polysaccharides in the gut and mediate the function of immune cells to facilitate homeostasis. The immunomodulatory effect of SCFAs has been attributed, at least in part, to the epigenetic modulation of immune cells through the inhibition the nucleus-resident enzyme histone deacetylase (HDAC). Among the downstream effects, SCFAs enhance regulatory T cells (Treg) over inflammatory T helper (Th) cells, including Th17 cells, which can be pathogenic. Here, we characterize the potential of two common SCFAs-butyrate and pentanoate-in modulating differentiation of T cells in vitro. We show that butyrate but not pentanoate exerts a concentration-dependent effect on Treg and Th17 differentiation. Increasing the concentration of butyrate suppresses the Th17-associated RORγtt and IL-17 and increases the expression of Treg-associated FoxP3. To effectively deliver butyrate, encapsulation of butyrate in a liposomal carrier, termed BLIPs, reduced cytotoxicity while maintaining the immunomodulatory effect on T cells. Consistent with these results, butyrate and BLIPs inhibit HDAC and promote a unique chromatin landscape in T cells under conditions that otherwise promote conversion into a pro-inflammatory phenotype. Motif enrichment analysis revealed that butyrate and BLIP-mediated suppression of Th17-associated chromatin accessibility corresponded with a marked decrease in bZIP family transcription factor binding sites. These results support the utility and further evaluation of BLIPs as an immunomodulatory agent for autoimmune disorders that are characterized by chronic inflammation and pathogenic inflammatory T cells.

The pathologic double contour sign and the trochlea shape patterns can diagnose trochlea dysplasia.

OBJECTIVES: The goal of this study is to describe the distinct morphologic patterns of the normal and dysplastic trochleae, the trochlear shape patterns (TSP) seen on the axial views of MRI scans. METHOD: Two cohorts of patients were used for comparison. Cohort 1: MRI scans of 100 patients with no history of patella instability. Cohort 2: MRI scans of 66 patients diagnosed with severe trochlea dysplasia and patella instability. The presence of the pathologic double contour (PDC) sign and the type of TSP were identified in the axial views at the level of three specific anatomical references: Trochlear Specific Zone 0 (TSZ 0), posterior femoral condyle line (PFCL) and transverse distal femoral physis line (tv-DFPL). The pathologic double contour sign is an area of flat or convex lateral trochlea which is elevated over the contour of the medial femoral condyle. Three basic morphologic patterns of trochlear shape were identified. TSP type 1 (normal trochlea): There is no PDC. There is a clearly defined sulcus delineating the lateral and medial trochlear facets (sulcus angle <165°). TSP type 2 (normal but shallow trochlea): There is no PDC. The trochlear groove is shallow (sulcus angle >165°), but the lateral and medial facets are present. TSP type 3: This pattern is characterised by the presence of a PDC. The chi-square test was used to determine whether the distribution of the TSP was the same between the two cohorts at the anatomical reference lines. RESULTS: The differences observed in distribution of the TSP between the two cohorts were statistically significant. There was a strong positive correlation between the morphology of the trochlea (TSP) and patella instability. All patients in the patella instability cohort showed a PDC. CONCLUSION: Normal trochleae show TSP type 1 and 2 proximal to the tv-DFPL. The presence of the pathologic double contour sign and trochlea shape pattern type 3 (TSP 3) proximal to the tv-DFPL (PFCL or TSZ 0) are diagnostic of trochlea dysplasia.

3D-Bioprinted Phantom with Human Skin Phototypes for Biomedical Optics.

3D-bioprinted skin-mimicking phantoms with skin colors ranging across the Fitzpatrick scale are reported. These tools can help understand the impact of skin phototypes on biomedical optics. Synthetic melanin nanoparticles of different sizes (70-500 nm) and clusters are fabricated to mimic the optical behavior of melanosome. The absorption coefficient and reduced scattering coefficient of the phantoms are comparable to real human skin. Further the melanin content and distribution in the phantoms versus real human skins are validated via photoacoustic (PA) imaging. The PA signal of the phantom can be improved by: 1) increasing melanin size (3-450-fold), 2) increasing clustering (2-10.5-fold), and 3) increasing concentration (1.3-8-fold). Then, multiple biomedical optics tools (e.g., PA, fluorescence imaging, and photothermal therapy) are used to understand the impact of skin tone on these modalities. These well-defined 3D-bioprinted phantoms may have value in translating biomedical optics and reducing racial bias.

Using immersive externship experiences within medical education to bridge the physician-administrator divide.

The composition of early trainee medical education is highly influential as it shapes the future of medicine and healthcare. Despite being frequently neglected, education about and exposure to hospital administration should be important aspects of medical student learning. Understanding how health systems coordinate and optimize functions of different departments to enhance patient care is a critical component of being a physician. In this Personal View, we share the tangible impact that a short immersive experience with hospital administration can bring to not only enrich medical student education but also influence their future perspectives and interactions within healthcare systems. Early integration of these learning opportunities has the potential to improve the physician-administrator relationship within hospitals and encourage innovative collaboration to provide more patient-centered and financially sustainable healthcare.

Lipid-based regulators of immunity.

Lipids constitute a diverse class of molecular regulators with ubiquitous physiological roles in sustaining life. These carbon-rich compounds are primarily sourced from exogenous sources and may be used directly as structural cellular building blocks or as a substrate for generating signaling mediators to regulate cell behavior. In both of these roles, lipids play a key role in both immune activation and suppression, leading to inflammation and resolution, respectively. The simple yet elegant structural properties of lipids encompassing size, hydrophobicity, and molecular weight enable unique biodistribution profiles that facilitate preferential accumulation in target tissues to modulate relevant immune cell subsets. Thus, the structural and functional properties of lipids can be leveraged to generate new materials as pharmacological agents for potently modulating the immune system. Here, we discuss the properties of three classes of lipids: polyunsaturated fatty acids, short-chain fatty acids, and lipid adjuvants. We describe their immunoregulatory functions in modulating disease pathogenesis in preclinical models and in human clinical trials. We conclude with an outlook on harnessing the diverse and potent immune modulating properties of lipids for immunoregulation.

A Photoacoustic-Fluorescent Imaging Probe for Proteolytic Gingipains Expressed by Porphyromonas gingivalis.

Porphyromonas gingivalis is a keystone pathogen in periodontal disease. We herein report a dual-modal fluorescent and photoacoustic imaging probe for the detection of gingipain proteases secreted by P. gingivalis. Upon proteolytic cleavage by Arg-specific gingipain (RgpB), five-fold photoacoustic enhancement and >100-fold fluorescence activation was measured with detection limits of 1.1 nM RgpB and 5.0E4 CFU mL-1 bacteria in vitro. RgpB activity was imaged in porcine jaws with low-nanomolar sensitivity. Diagnostic efficacy was evaluated in gingival crevicular fluid samples from subjects with and without periodontal disease, wherein activation was correlated to qPCR-based detection of P. gingivalis (Pearson's r=0.71). Finally, photoacoustic imaging of RgpB-cleaved probe was achieved in murine brains ex vivo, with relevance and potential utility for disease models of general infection by P. gingivalis, motivated by the recent biological link between gingipain and Alzheimer's disease.

ADAM Challenge: Detecting Age-Related Macular Degeneration From Fundus Images.

Age-related macular degeneration (AMD) is the leading cause of visual impairment among elderly in the world. Early detection of AMD is of great importance, as the vision loss caused by this disease is irreversible and permanent. Color fundus photography is the most cost-effective imaging modality to screen for retinal disorders. Cutting edge deep learning based algorithms have been recently developed for automatically detecting AMD from fundus images. However, there are still lack of a comprehensive annotated dataset and standard evaluation benchmarks. To deal with this issue, we set up the Automatic Detection challenge on Age-related Macular degeneration (ADAM), which was held as a satellite event of the ISBI 2020 conference. The ADAM challenge consisted of four tasks which cover the main aspects of detecting and characterizing AMD from fundus images, including detection of AMD, detection and segmentation of optic disc, localization of fovea, and detection and segmentation of lesions. As part of the ADAM challenge, we have released a comprehensive dataset of 1200 fundus images with AMD diagnostic labels, pixel-wise segmentation masks for both optic disc and AMD-related lesions (drusen, exudates, hemorrhages and scars, among others), as well as the coordinates corresponding to the location of the macular fovea. A uniform evaluation framework has been built to make a fair comparison of different models using this dataset. During the ADAM challenge, 610 results were submitted for online evaluation, with 11 teams finally participating in the onsite challenge. This paper introduces the challenge, the dataset and the evaluation methods, as well as summarizes the participating methods and analyzes their results for each task. In particular, we observed that the ensembling strategy and the incorporation of clinical domain knowledge were the key to improve the performance of the deep learning models.