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The preponderance of large-scale healthcare databases provide abundant opportunities for comparative effectiveness research. Evidence necessary to making informed treatment decisions often relies on comparing effectiveness of multiple treatment options on outcomes of interest observed in a small number of individuals. Causal inference with multiple treatments and rare outcomes is a subject that has been treated sparingly in the literature. This paper designs three sets of simulations, representative of the structure of our healthcare database study, and propose causal analysis strategies for such settings. We investigate and compare the operating characteristics of three types of methods and their variants: Bayesian Additive Regression Trees (BART), regression adjustment on multivariate spline of generalized propensity scores (RAMS) and inverse probability of treatment weighting (IPTW) with multinomial logistic regression or generalized boosted models. Our results suggest that BART and RAMS provide lower bias and mean squared error, and the widely used IPTW methods deliver unfavorable operating characteristics. We illustrate the methods using a case study evaluating the comparative effectiveness of robotic-assisted surgery, video-assisted thoracoscopic surgery and open thoracotomy for treating non-small cell lung cancer.

Acute spinal cord injury (SCI) is a serious traumatic event to the spinal cord with considerable morbidity and mortality. This injury leads to short- and long-term variations in the spinal cord, and can have a serious effect on the patient’s sensory, motor, or autonomic functions. Due to the complicated pathological process of SCI, there is currently no successful clinical treatment strategy. Exosomes, extracellular vesicles (EVs) with a double-layer membrane structure of 30–150 nm diameter, have recently been considered as critical mediators for communication between cells and tissues by transferring proteins, lipids, and nucleic acids. Further studies verified that exosomes participate in the pathophysiological process of several diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases, and could have a significant impact in their treatment. As natural carriers of biologically active cargos, exosomes have emerged as pathological mediators of SCI. In this review article, we critically discuss the functions of exosomes as intracellular mediators and potential treatments in SCI and provide an outlook on future research.

Background Retinal ischemia–reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells. Methods Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N -dimethyl-3β-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R). Results DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of − 6.6 kcal/mol, suggesting highly stable binding. Conclusion Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury.

Background Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear. Methods To this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing. Results We found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4 ) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD. Conclusions Our study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases.

Background Aging is a holistic change that has a major impact on the immune system, and immunosenescence contributes to the overall progression of aging. The bone marrow is the most important hematopoietic immune organ, while the spleen, as the most important extramedullary hematopoietic immune organ, maintains homeostasis of the human hematopoietic immune system (HIS) in cooperation with the bone marrow. However, the overall changes in the HIS during aging have not been described. Here, we describe a hematopoietic immune map of the spleen and bone marrow of young and old mice using single-cell sequencing and flow cytometry techniques. Results We observed extensive, complex changes in the HIS during aging. Compared with young mice, the immune cells of aged mice showed a marked tendency toward myeloid differentiation, with the neutrophil population accounting for a significant proportion of this response. In this change, hypoxia-inducible factor 1-alpha (Hif1α) was significantly overexpressed, and this enhanced the immune efficacy and inflammatory response of neutrophils. Our research revealed that during the aging process, hematopoietic stem cells undergo significant changes in function and composition, and their polymorphism and differentiation abilities are downregulated. Moreover, we found that the highly responsive CD62L + HSCs were obviously downregulated in aging, suggesting that they may play an important role in the aging process. Conclusions Overall, aging extensively alters the cellular composition and function of the HIS. These findings could potentially give high-dimensional insights and enable more accurate functional and developmental analyses as well as immune monitoring in HIS aging.

Stroke is associated with a high disability and fatality rate, and adversely affects the quality of life of patients and their families. Traditional Chinese Medicine (TCM) has been used effectively in the treatment of stroke for more than 2000 years in China and surrounding countries and regions, and over the years, this field has gleaned extensive clinical treatment experience. The Phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway is important for regulation of cell migration, proliferation, differentiation, and apoptosis, and plays a vital role in vascularization and oxidative stress in stroke. Current Western medicine treatment protocols for stroke include mainly pharmacologic or mechanical thrombectomy to restore blood flow. This review collates recent advances in the past 5 years in the TCM treatment of stroke involving the PI3K/AKT pathway. TCM treatment significantly reduces neuronal damage, inhibits cell apoptosis, and delays progression of stroke via various PI3K/AKT-mediated downstream pathways. In the future, TCM can provide new perspectives and directions for exploring the key factors, and effective activators or inhibitors that affect occurrence and progression of stroke, thereby facilitating treatment.

Background Neural stem cell-derived extracellular vesicles (NSC-EVs) mediated endogenous neurogenesis determines a crucial impact on spontaneous recovery after stroke. Here, we checked the influence of Lycium barbarum polysaccharide (LBP) on the biogenesis of NSC-EVs and then focused on studying mechanisms of LBP in ameliorating ischemic stroke outcome. Methods LBP was prepared to precondition NSCs and isolate EVs. MCAO models and primary NSCs were administrated to evaluate the therapeutic effect. RT-PCR, western blot, flow cytometry, and immunofluorescence techniques were performed to explore the mechanism. Results LBP pretreatment increased the production of NSC-EVs and improved the neuroprotective and recovery effects of NSC-EV in ischemic stroke mice. LBP-pretreated NSC-EV in a dose-dependent manner substantially reduced neuronal death compared with NSC-EV. Screening of the signaling cascade involved in the interaction between NSC-EV and neurons revealed that AMPK/mTOR signaling pathway inhibited autophagic activity in neurons receiving either treatment paradigm. NSC-EVs but not EVs collected from NSCs pretreated with the anti-miR-133a-3p oligonucleotide reduced cell death, whereas the anti-oligonucleotide promoted autophagy activity and cell death by modulating AMPK/mTOR signaling in OGD-induced primary neurons. Conclusion LBP activated AMPK/mTOR signaling pathway by increasing the enrichment and transfer of miR-133a-3p in NSC-EVs to inhibit stroke-induced autophagy activity.

A summary schematic of application of 3D scaffold-based stem cell/exosome therapy. Recently, biomaterial scaffolds have been widely applied in the field of tissue engineering and regenerative medicine. Due to different production methods, unique types of three-dimensional (3D) scaffolds can be fabricated to meet the structural characteristics of tissues and organs, and provide suitable 3D microenvironments. The therapeutic effects of stem cell (SC) therapy in tissues and organs are considerable and have attracted the attention of academic researchers worldwide. However, due to the limitations and challenges of SC therapy, exosome therapy can be used for basic research and clinical translation. The review briefly introduces the materials (nature or polymer), shapes (hydrogels, particles and porous solids) and fabrication methods (crosslinking or bioprinting) of 3D scaffolds, and describes the recent progress in SC/exosome therapy with 3D scaffolds over the past 5 years (2016–2020). Normal SC/exosome therapy can improve the structure and function of diseased and damaged tissues and organs. In addition, 3D scaffold-based SC/exosome therapy can significantly improve the structure and function cardiac and neural tissues for the treatment of various refractory diseases. Besides, exosome therapy has the same therapeutic effects as SC therapy but without the disadvantages. Hence, 3D scaffold therapy provides an alternative strategy for treatment of refractory and incurable diseases and has entered a transformation period from basic research into clinical translation as a viable therapeutic option in the future.

As a large and heterogeneous group of disorders, neurodegenerative diseases are characterized by the progressive loss of structure or function in neurons, finally leading to neuronal death. Neurodegenerative diseases cause serious threat to a patient’s quality of life and the most common are Alzheimer’s disease and Parkinson’s disease. Currently, little is known of the detailed etiology of these disorders; as such, there are no effective treatments available. Furthermore, the lack of targeted, effective, and resolvable therapy for neurodegenerative diseases, represents an expanding research field for the discovery of new therapeutic strategies. Investigations of the potential pathogenesis of neurodegenerative diseases will become the basis of preventing the occurrence and development of neurodegenerative diseases and finding effective therapies. Existing theories and mechanisms, such as genetic and environmental factors, abnormal protein accumulation, and oxidative stress, are intricately associated with each other. However, there is no molecular theory that can entirely explain the pathological processes underlying neurodegenerative diseases. Due to the development of experimental technology and the support of multidisciplinary integration, it has been possible to perform more in-depth research on potential targets for neurodegenerative diseases and there have been many exciting discoveries in terms of original theories and underlying mechanisms. With this review, we intend to review the existing literature and provide new insights into the molecular mechanisms underlying neurodegenerative diseases.