Recent Advances in Immunomodulatory Therapy in Sepsis: A Comprehensive Review.

Sepsis remains a critical healthcare challenge, characterized by dysregulated immune responses to infection, leading to organ dysfunction and high mortality rates. Traditional treatment strategies often fail to address the underlying immune dysregulation, necessitating exploring novel therapeutic approaches. Immunomodulatory therapy holds promise in sepsis management by restoring immune balance and mitigating excessive inflammation. This comprehensive review examines the pathophysiology of sepsis, current challenges in treatment, and recent advancements in immunomodulatory agents, including biologics, immunotherapy, and cellular therapies. Clinical trial outcomes, safety profiles, and future research and clinical practice implications are discussed. While immunomodulatory therapies show considerable potential in improving sepsis outcomes, their successful implementation requires further research, collaboration, and integration into standard clinical protocols.

Echocardiography as a Vital Tool in Assessing Shock: A Comprehensive Review.

Shock is a critical condition characterized by inadequate tissue perfusion, leading to cellular hypoxia and organ dysfunction. Early and accurate assessment is crucial for timely intervention and improved patient outcomes. Echocardiography has emerged as a vital tool in the assessment of shock, offering real-time visualization of cardiac anatomy, function, and hemodynamics. This comprehensive review aims to elucidate the role of echocardiography in shock assessment by providing an overview of its principles, techniques, and clinical applications. We discuss the importance of early diagnosis, identification of underlying pathology, monitoring response to therapy, and prognostic value offered by echocardiography in managing shock. Furthermore, we explore its utility in different types of shock, including hypovolemic, cardiogenic, distributive, and obstructive shock. Challenges and limitations of echocardiography, as well as future directions and innovations, are also discussed. Through a synthesis of current evidence and clinical insights, this review underscores the significance of echocardiography in optimizing shock management and highlights areas for further research and development.

AngioMT: A MATLAB based 2D image-to-physics tool to predict oxygen transport in vascularized microphysiological systems.

Microphysiological models (MPS) are increasingly getting recognized as in vitro preclinical systems of pathophysiology and drug discovery. However, there is also a growing need to adapt and advance MPS to include the physiological contributions of the capillary vascular dynamics, because they undergo angiogenesis or vasculogenesis to deliver soluble oxygen and nutrients to its organs. Currently, the process of formation of microvessels in MPS is measured arbitrarily, and vascularized MPS do not include oxygen measurements in their analysis. Sensing and measuring tissue oxygen delivery is extremely difficult because it requires access to opaque and deep tissue, and/or requires extensive integration of biosensors that makes such systems impractical to use in the real world. Here, a finite element method-based oxygen transport program, called AngioMT, is built in MATLAB. AngioMT processes the routinely acquired 2D confocal images of microvascular networks in vitro and solves physical equations of diffusion-reaction dominated oxygen transport phenomena. This user-friendly image-to-physics transition in AngioMT is an enabling tool of MPS analysis because unlike the averaged morphological measures of vessels, it provides information of the spatial transport of oxygen both within the microvessels and the surrounding tissue regions. Further, it solves the more complex higher order reaction mechanisms which also improve the physiological relevance of this tool when compared directly against in vivo measurements. Finally, the program is applied in a multicellular vascularized MPS by including the ability to define additional organ/tissue subtypes in complex co-cultured systems. Therefore, AngioMT serves as an analytical tool to enhance the predictive power and performance of MPS that incorporate microcirculation.

Granular Biphasic Colloidal Hydrogels for 3D Bioprinting.

Granular hydrogels composed of hydrogel microparticles are promising candidates for 3D bioprinting due to their ability to protect encapsulated cells. However, to achieve high print fidelity, hydrogel microparticles need to jam to exhibit shear-thinning characteristics, which is crucial for 3D printing. Unfortunately, this overpacking can significantly impact cell viability, thereby negating the primary advantage of using hydrogel microparticles to shield cells from shear forces. To overcome this challenge, we introduce a novel solution: a biphasic, granular colloidal bioink designed to optimize cell viability and printing fidelity. The biphasic ink consists of cell-laden polyethylene glycol (PEG) hydrogel microparticles embedded in a continuous gelatin methacryloyl (GelMA)-nanosilicate colloidal network. Here, we demonstrate that this biphasic bioink offers outstanding rheological properties, print fidelity, and structural stability. Furthermore, we demonstrate its utility for engineering complex tissues with multiple cell types and heterogeneous microenvironments, which we demonstrate by incorporating ß-islet cells into the PEG microparticles and endothelial cells in the GelMA-nanosilicate colloidal network. Using this approach, it is possible to induce cell patterning, enhance vascularization, and direct cellular function. The proposed biphasic bioink holds significant potential for numerous emerging biomedical applications, including tissue engineering and disease modeling. This article is protected by copyright. All rights reserved.

Biomembrane camouflaged nanoparticles: A paradigm shifts in targeted drug delivery system.

Targeted drug delivery has emerged as a pivotal approach within precision medicine, aiming to optimize therapeutic efficacy while minimizing systemic side effects. Advanced biomimetic membrane-coated formulations have garnered significant interest from researchers as a promising strategy for targeted drug delivery, site-specific accumulation and heightened therapeutic outcomes. Biomimetic nanotechnology is able to retain the biological properties of the parent cell thus are able to exhibit superior targeting compared to conventional formulations. In this review, we have described different types of cell membrane camouflaged NPs. Mechanism of isolation and coating of the membranes along with the applications of each type of membrane and their mechanism to reach the desired site. Furthermore, a fusion of different membranes in order to prepare hybrid membrane biomimetic NPs which could possess better efficacy is discussed in detail in the review. Later, applications of the hybrid membrane-cloaked NPs along with current development were discussed in detail along with the challenges associated with it. Although membrane-cloaked NPs are currently in the preliminary stage of development, there is a huge potential to explore this biodegradable and biocompatible delivery system.

Autonomic neuronal modulations in cardiac arrhythmias: Current concepts and emerging therapies.

The pathophysiology of atrial fibrillation and ventricular tachycardia that result in cardiac arrhythmias is related to the sustained complicated mechanisms of the autonomic nervous system. Atrial fibrillation is when the heart beats irregularly, and ventricular arrhythmias are rapid and inconsistent heart rhythms, which involves many factors including the autonomic nervous system. It's a complex topic that requires careful exploration. Cultivation of speculative knowledge on atrial fibrillation; the irregular rhythm of the heart and ventricular arrhythmias; rapid oscillating waves resulting from mistakenly inconsistent P waves, and the inclusion of an autonomic nervous system is an inconceivable approach toward clinical intricacies. Autonomic modulation, therefore, acquires new expansions and conceptions of appealing therapeutic intelligence to prevent cardiac arrhythmia. Notably, autonomic modulation uses the neural tissue's flexibility to cause remodeling and, hence, provide therapeutic effects. In addition, autonomic modulation techniques included stimulation of the vagus nerve and tragus, renal denervation, cardiac sympathetic denervation, and baroreceptor activation treatment. Strong preclinical evidence and early human studies support the annihilation of cardiac arrhythmias by sympathetic and parasympathetic systems to transmigrate the cardiac myocytes and myocardium as efficient determinants at the cellular and physiological levels. However, the goal of this study is to draw attention to these promising early pre-clinical and clinical arrhythmia treatment options that use autonomic modulation as a therapeutic modality to conquer the troublesome process of irregular heart movements. Additionally, we provide a summary of the numerous techniques for measuring autonomic tone such as heart rate oscillations and its association with cutaneous sympathetic nerve activity appear to be substitute indicators and predictors of the outcome of treatment.

Angiogenesis-Enabled Human Ovarian Tumor Microenvironment-Chip Evaluates Pathophysiology of Platelets in Microcirculation.

The tumor microenvironment (TME) promotes angiogenesis for its growth through the recruitment of multiple cells and signaling mechanisms. For example, TME actively recruits and activates platelets from the microcirculation to facilitate metastasis, but platelets may simultaneously also support tumor angiogenesis. Here, to model this complex pathophysiology within the TME that involves a signaling triad of cancer cells, sprouting endothelial cells, and platelets, an angiogenesis-enabled tumor microenvironment chip (aTME-Chip) is presented. This platform recapitulates the convergence of physiology of angiogenesis and platelet function within the ovarian TME and describes the contribution of platelets in promoting angiogenesis within an ovarian TME. By including three distinct human ovarian cancer cell-types, the aTME-Chip quantitatively reveals the following outcomes-first, introduction of platelets significantly increases angiogenesis; second, the temporal dynamics of angiogenic signaling is dependent on cancer cell type; and finally, tumor-educated platelets either activated exogenously by cancer cells or derived clinically from a cancer patient accelerate tumor angiogenesis. Further, analysis of effluents available from aTME-Chip validate functional outcomes by revealing changes in cytokine expression and several angiogenic and metastatic signaling pathways due to platelets. Collectively, this tumor microphysiological system may be deployed to derive antiangiogenic targets combined with antiplatelet treatments to arrest cancer metastasis.

Experimental Analysis for the Performance Assessment and Characteristics of Enhanced Magnesium Composites Reinforced with Nano-Sized Silicon Carbide Developed Using Powder Metallurgy.

Magnesium, which is lightweight and abundant by nature, was widely used in the 19th century to make parts for automobiles and airplanes. Due to their superior strength-to-weight ratios, magnesium alloys were favored for engineering applications over unadulterated magnesium. These alloys result from the combination of magnesium with various metals, including aluminum (Al), titanium (Ti), zinc (Zn), manganese (Mn), calcium (Ca), lithium (Li), and zirconium (Zr). In this study, an alloy of magnesium was created using the powder metallurgy (PM) technique, and its optimal performance was determined through the Taguchi-Gray (TG) analysis method. To enhance the alloy's mechanical properties, diverse weight fractions of silicon carbide (SiC) were introduced. The study primarily focused on the Mg-Zn-Cu-Mn alloy, achieving the optimal composition of Mg-3Zn-1Cu-0.7Mn (ZC-31). Subsequently, composites of ZC-31/SiC were produced via PM and the hot extrusion (HE) process, followed by the assessment of the mechanical properties under various strain rates. The use of silicon carbide (SiC) resulted in enhanced composite densities as a consequence of the increased density exhibited by SiC particles. In addition, the high-energy postsintering approach resulted in a decrease in porosity levels. By integrating silicon carbide (SiC) to boost the microhardness, as well as the ultimate compressive and tensile strength of the composite material, we can observe significant improvements in these mechanical properties. The experimental findings also demonstrated that an augmentation in the weight fraction of SiC and the strain rate led to enhanced ductility and a shift toward a more transcrystalline fracture behavior inside the composite material.

Engineering Lymphangiogenesis-On-Chip: The Independent and Cooperative Regulation by Biochemical Factors, Gradients, and Interstitial Fluid Flow.

Despite the crucial role of lymphangiogenesis during development and in several diseases with implications for tissue regeneration, immunity, and cancer, there are significantly fewer tools to understand this process relative to angiogenesis. While there has been a major surge in modeling angiogenesis with microphysiological systems, they have not been rigorously optimized or standardized to enable the recreation of the dynamics of lymphangiogenesis. Here, a Lymphangiogenesis-Chip (L-Chip) is engineered, within which new sprouts form and mature depending upon the imposition of interstitial flow, growth factor gradients, and pre-conditioning of endothelial cells with growth factors. The L-Chip reveals the independent and combinatorial effects of these mechanical and biochemical determinants of lymphangiogenesis, thus ultimately resulting in sprouts emerging from a parent vessel and maturing into tubular structures up to 1 mm in length within 4 days, exceeding prior art. Further, when the constitution of the pre-conditioning cocktail and the growth factor cocktail used to initiate and promote lymphangiogenesis are dissected, it is found that endocan (ESM-1) results in more dominant lymphangiogenesis relative to angiogenesis. Therefore, The L-Chip provides a foundation for standardizing the microfluidics assays specific to lymphangiogenesis and for accelerating its basic and translational science at par with angiogenesis.

Neuroethics and neurolaw in forensic neuropsychiatry: A guide for clinicians.

As neuroscience technologies develop, ethical and legal questions arise regarding their use and societal impact. Neuroethics and neurolaw are growing interdisciplinary fields that address these questions. This review article presents the research agenda of both areas, examines the use and admissibility of neuroscience in expert testimony and legal settings, and discusses ethical issues related to forensic neuropsychiatrists claiming expertise in neuroscience, formulating medical opinions based on neuroscience, and considering its relevance to criminal responsibility. Forensic neuropsychiatrists should be aware of emerging neuroscientific evidence, its utility and limits in rendering diagnoses and explaining behavior, and, before seeking such evidence for legal purposes, its availability and admissibility. When testifying in matters involving neuroscientific evidence, ensuring truthfulness and balance, having sufficient and validated knowledge (including openness with confirming and disconfirming evidence), understanding standards of practice, and drawing relevant and appropriate conclusions remain important.

Machine learning chained neural network analysis of oxygen transport amplifies the physiological relevance of vascularized microphysiological systems.

Since every biological system requires capillaries to support its oxygenation, design of engineered preclinical models of such systems, for example, vascularized microphysiological systems (vMPS) have gained attention enhancing the physiological relevance of human biology and therapies. But the physiology and function of formed vessels in the vMPS is currently assessed by non-standardized, user-dependent, and simple morphological metrics that poorly relate to the fundamental function of oxygenation of organs. Here, a chained neural network is engineered and trained using morphological metrics derived from a diverse set of vMPS representing random combinations of factors that influence the vascular network architecture of a tissue. This machine-learned algorithm outputs a singular measure, termed as vascular network quality index (VNQI). Cross-correlation of morphological metrics and VNQI against measured oxygen levels within vMPS revealed that VNQI correlated the most with oxygen measurements. VNQI is sensitive to the determinants of vascular networks and it consistently correlates better to the measured oxygen than morphological metrics alone. Finally, the VNQI is positively associated with the functional outcomes of cell transplantation therapies, shown in the vascularized islet-chip challenged with hypoxia. Therefore, adoption of this tool will amplify the predictions and enable standardization of organ-chips, transplant models, and other cell biosystems.

Multi-omic analysis reveals metabolic pathways that characterize right-sided colon cancer liver metastasis.

There are well demonstrated differences in tumor cell metabolism between right sided (RCC) and left sided (LCC) colon cancer, which could underlie the robust differences observed in their clinical behavior, particularly in metastatic disease. As such, we utilized liquid chromatography-mass spectrometry to perform an untargeted metabolomics analysis comparing frozen liver metastasis (LM) biobank samples derived from patients with RCC (N = 32) and LCC (N = 58) to further elucidate the unique biology of each. We also performed an untargeted RNA-seq and subsequent network analysis on samples derived from an overlapping subset of patients (RCC: N = 10; LCC: N = 18). Our biobank redemonstrates the inferior survival of patients with RCC-derived LM (P = 0.04), a well-established finding. Our metabolomic results demonstrate increased reactive oxygen species associated metabolites and bile acids in RCC. Conversely, carnitines, indicators of fatty acid oxidation, are relatively increased in LCC. The transcriptomic analysis implicates increased MEK-ERK, PI3K-AKT and Transcription Growth Factor Beta signaling in RCC LM. Our multi-omic analysis reveals several key differences in cellular physiology which taken together may be relevant to clinical differences in tumor behavior between RCC and LCC liver metastasis.

Urinary Paraben Concentrations and Associations with the Periconceptional Urinary Metabolome: Untargeted and Targeted Metabolomics Analyses of Participants from the Early Pregnancy Study.

BACKGROUND: Parabens, found in everyday items from personal care products to foods, are chemicals with endocrine-disrupting activity, which has been shown to influence reproductive function. OBJECTIVES: This study investigated whether urinary concentrations of methylparaben, propylparaben, or butylparaben were associated with the urinary metabolome during the periconceptional period, a critical window for female reproductive function. Changes to the periconceptional urinary metabolome could provide insights into the mechanisms by which parabens could impact fertility. METHODS: Urinary paraben concentrations were measured in paired pre- and postconception urine samples from 42 participants in the Early Pregnancy Study, a prospective cohort of 221 women attempting to conceive. We performed untargeted and targeted metabolomics analyses using ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry. We used principal component analysis, orthogonal partial least-squares discriminant analysis, and permutation testing, coupled with univariate statistical analyses, to find metabolites associated with paraben concentration at the two time points. Potential confounders were identified with a directed acyclic graph and used to adjust results with multivariable linear regression. Metabolites were identified using fragmentation data. RESULTS: Seven metabolites were associated with paraben concentration (variable importance to projection score >1, false discovery rate-corrected q-value<0.1). We identified four diet-related metabolites to the Metabolomics Standards Initiative (MSI) certainty of identification level 2, including metabolites from smoke flavoring, grapes, and olive oil. One metabolite was identified to the class level only (MSI level 3). Two metabolites were unidentified (MSI level 4). After adjustment, three metabolites remained associated with methylparaben and propylparaben, two of which were diet-related. No metabolomic markers of endocrine disruption were associated with paraben concentrations. DISCUSSION: This study identified novel relationships between urinary paraben concentrations and diet-related metabolites but not with metabolites on endocrine-disrupting pathways, as hypothesized. It demonstrates the feasibility of integrating untargeted metabolomics data with environmental exposure information and epidemiological adjustment for confounders. The findings underscore a potentially important connection between diet and paraben exposure, with applications to nutritional epidemiology and dietary exposure assessment. https://doi.org/10.1289/EHP12125.

Supracarinal lymph node positivity in esophageal squamous cell carcinoma (ESCC) and factors predicting metastasis in supracarinal compartment nodes: Should a total mediastinal node dissection be the standard of care?

Background: Adequate lymphadenectomy in middle- and lower-third esophagus cancer is still a matter of debate. This study aims to find out the extent of histopathological supracarinal lymph nodes positivity rate to establish an adequate lymph node dissection in esophageal squamous cell carcinoma cases operated up-front or after neoadjuvant chemotherapy (CT) + radiotherapy (RT) and its short-term oncological outcome. Materials and Methods: After approval from institutional board review, a retrospective study was conducted from April 2017 to September 2019. A total of 76 patients having mid- or lower-third carcinoma esophagus were operated at our institute for partial/total esophagectomy with extended two-field lymph node dissection were followed. Intraoperative nodal stations were harvested separately and lebeled individually according to the Japanese Esophageal Classification and sent for histopathological examination. Results: The patients had an average age of 52 years. Histologically all were squamous cell carcinoma (SCC). Forty-four patients received preoperative concurrent RT plus drug therapy, whereas 18 cases were operated up-front. Fourteen patients were operated after palliative treatment (CT/RT). The average total lymph node yield was 22 nodes (range 3-69). In 26 patients (34.2%), lymph nodes were positive (N+ disease). Supracarinal nodes were positive in 20 cases (26.31%). The average supracarinal lymph node yield was 10.33 nodes (range 2-32). Five patients (6.5%) had only supracarinal lymph nodes positive on histopathological examination. Seventeen patients had a complete pathological response rate (pCR). Conclusion: In cases of mid-third esophageal carcinoma, extended two fields with supracarinal lymphadenectomy is strongly recommended even after the patient has received neoadjuvant treatment, although the same for lower-third/gastroesophageal (GE) junction tumors should be considered.

The prospects of microphysiological systems in modeling platelet pathophysiology in cancer.

The contribution of platelets is well recognized in thrombosis and hemostasis. However, platelets also promote tumor progression and metastasis through their crosstalk with various cells of the tumor microenvironment (TME). For example, several cancer models continue to show that platelet functions are readily altered by cancer cells upon activation leading to the formation of platelet-tumor aggregates, triggering release of soluble factors from platelet granules and altering platelet turnover. Further, activated platelets protect tumor cells from shear forces in circulation and assault of cytotoxic natural killer (NK) cells. Platelet-secreted factors promote proliferation of malignant cells, metastasis, and chemoresistance. Much of our knowledge of platelet biology in cancer has been achieved with animal models, particularly murine. However, this preclinical understanding of the complex pathophysiology is yet to be fully realized and translated to clinical trials in terms of new approaches to treat cancer via controlling the platelet function. In this review, we summarize the current state of knowledge of platelet physiology obtained through existing in vivo and in vitro cancer models, the complex interactions of platelets with cancer cells in TME and the pathways by which platelets may confer chemoresistance. Since the FDA Modernization Act recently passed by the US government has made animal models optional in drug approvals, we critically examine the existing and futuristic value of employing bioengineered microphysiological systems and organ-chips to understand the mechanistic role of platelets in cancer metastasis and exploring novel therapeutic targets for cancer prevention and treatment.

The recent passage of the FDA Modernization Act by the US government has removed the requirement of the use of animal models in disease modeling and drug discovery process. This has resulted in a much-renewed excitement within engineers, scientists, and industry in applying in vitro cell biosystems as a platform technology that assists or replaces animals in reproducing human biology. The contribution of platelets is well recognized in thrombosis and hemostasis. However, platelets also promote tumor progression and metastasis through their crosstalk with various cells of the tumor microenvironment. In this review, we summarize the current state of knowledge of platelet physiology obtained through existing cancer models and also critically examine the existing and futuristic value of employing bioengineered organ-chips to improve the knowledge of the underlying biology.

Assessment of Lactobacillus rhamnosus mediated protection against arsenic-induced toxicity in zebrafish: a qPCR-based analysis of Firmicutes and Bacteroidetes groups and embryonic development.

Arsenic poses a significant health risk worldwide, impacting the gut microbiota, reproductive health, and development. To address this issue, a cost-effective method like probiotic supplementation could be beneficial. However, the interplay between arsenic toxicity, probiotics, gut microbiota, and maternal transcript modulation remains unexplored. This study investigates the impact of Lactobacillus rhamnosus (L. rhamnosus) DSM 20021 on the proportions of Firmicutes and Bacteroidetes, as well as its effects on embryonic development in zebrafish induced by arsenic trioxide (As2O3). Adult zebrafish were exposed to both high and environmentally relevant concentrations of As2O3 (10, 50, and 500 ppb) for 1, 6, and 12 weeks. qPCR analysis revealed increased proportions of Firmicutes and Bacteroidetes in all As2O3-exposed and As2O3 + L. rhamnosus-exposed groups, while no significant changes were observed in groups exposed only to L. rhamnosus DSM 20021. The larvae, exposed to 500 ppb of As2O3 for 12 weeks, exhibited low growth, decreased survival rates, and morphological deformities. However, these adverse effects were reversed upon exposure to only L. rhamnosus DSM 20021. Furthermore, the expression of DVR1 and ABCC5, which are involved in defense against xenobiotics and embryo development, decreased significantly in As2O3 (500 ppb) and As2O3 (500 ppb) + L. rhamnosus-exposed groups, whereas ameliorative effects were observed in only L. rhamnosus DSM 20021-exposed groups.

Electrically stimulated gene expression under exogenously applied electric fields.

Introduction: Electrical stimulation, the application of an electric field to cells and tissues grown in culture to accelerate growth and tight junction formation among endothelial cells, could be impactful in cardiovascular tissue engineering, allotransplantation, and wound healing. Methods: Using Electrical Cell Stimulation And Recording Apparatus (ECSARA), the exploration of the stimulatory influences of electric fields of different magnitude and frequencies on growth and proliferation, trans endothelial electrical resistance (TEER) and gene expression of human endothelia cells (HUVECs) were explored. Results: Within the range of endogenous electrical pulses studied, frequency was found to be more significant (p = 0.05) than voltage in influencing HUVEC gene expression. Localization of Yes Associated Protein (YAP) and expression of CD-144 are shown to be consistent with temporal manifestations of TEER. Discussion: This work introduces the field of electromics, the study of cellular gene expression profiles and their implications under the influence of exogenously applied electric fields. Homology of electrobiology and mechanobiology suggests use of such exogenous cues in tissue and regenerative engineering.

Safe Spaces: Mitigating Potential Aggression in Acute Care Psychiatry.

Awareness of potential aggression and violence is crucial when treating patients experiencing mental health crises in psychiatric emergency and inpatient settings. To provide a practical overview for health care workers in acute care psychiatry, the authors summarize relevant literature and clinical considerations on this important topic. Clinical contexts of violence in these settings, possible impact on patients and staff, and approaches to mitigating risk are reviewed. Considerations for early identification of at-risk patients and situations, and nonpharmacological and pharmacological interventions, are highlighted. The authors conclude with key points and future scholarly and practical directions that may further assist those entrusted with providing psychiatric care in these situations. Although working in these often high-paced, high-pressured settings can be challenging, effective violence-management strategies and tools can help staff optimize the focus on patient care while maintaining safety, their own well-being, and overall workplace satisfaction.