Background: The efficacy of virtual reality (VR)-based intervention for improving cognition in patients with the chronic stage of stroke is controversial. The aims of this meta-analysis were to evaluate the effect of VR-based training combined with traditional rehabilitation on cognition, motor function, mood, and activities of daily living (ADL) after chronic stroke.Methods: The search was performed in the Cochrane Library (CENTRAL), EBSCO, EMBASE, Medline (OVID), Web of Science databases, PubMed, CINAHL Ovid, and Scopus from inception to May 31, 2021. All included studies were randomized controlled trials (RCTs) examining VR-based intervention combined with traditional rehabilitation for chronic stroke. The main outcomes of this study were cognition, including overall cognition , global cognition , and attention/execution. The additional outcomes were motor function, mood, and ADL. Subgroup analyses were conducted to verify the potential factors for heterogeneity.Results: Six RCTs including 209 participants were included for systematic review, and five studies of 177 participants were included in meta-analyses. Main outcome analyses showed large and significant effect size (ES) of VR-based training on overall cognition  and attention/execution . Non-significant result was found for VR-based intervention on global cognition . Additional outcome analyses showed no superiority of VR-based intervention over traditional rehabilitation on motor function and ADL. The ES of VR-based intervention on mood  was large and significant. In the subgroup analysis, large effects for higher daily intensity, higher weekly frequency, or greater dose of VR intervention were found.Conclusion: Our findings indicate that VR-based intervention combined with traditional rehabilitation showed better outcomes for overall cognition, attention/execution, and depressive mood in individuals with chronic stroke. However, VR-based training combined with traditional rehabilitation showed a non-significant effect for global cognition, motor function, and ADL in individuals with chronic stroke. Stroke is one of the global leading causes of death and may cause long-term disability for many stroke survivors . Up to tIn recent years, interventions for poststroke motor and cognitive impairment, depression, and reduced functional independence have become the focus of international stroke rehabilitation research, and novel clinical rehabilitation therapies  have shown great potential in future practice . VR-baseThe Lancet Neurology by Recently, many clinical studies favored VR-based intervention for motor function, balance, gait, and activities of daily living (ADL) in patients with stroke. Although multiple systematic reviews and meta-analyses have indicated that VR-based training was useful for upper limb motor function, lower limb motor function, balance, gait, and activities of daily living (ADL) in stroke , two recConventional paper-and-pencil exercises and computer-assisted cognitive training designed to improve specific domains of cognitive deficits are widely used for patients with stroke with cognitive impairment. However, traditional cognitive training is limited by its insufficient personalization and adaptation and suboptimal intensity . PrelimiTo date, however, few systematic reviews and meta-analyses have investigated VR-based training for cognitive function in contrast to cognitive exercise or motor exercise on the chronic stage of stroke. Therefore, this study aimed to explore the effect of VR-based training on cognition, motor function, mood, and ADL among individuals at the chronic phase of stroke.The current meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.Systematic search was performed using electronic databases such as Cochrane Library (CENTRAL), EBSCO, EMBASE, Medline (OVID), PubMed, CINAHL Ovid, Scopus, and Web of Science databases from inception to May 31, 2021. Boolean search terms included the following: “cerebrovascular accident (CVA),” “stroke,” “VR” with different combinations, and associated Medical Subject Headings. The specific search syntax  is available in We also hand-searched the reference lists from relevant reviews and articles to identify any potentially relevant studies.In this review, randomized controlled trials (RCTs) that examined the effects of VR on cognition, motor function, mood, or ADL in patients with chronic stroke were included. Eligibility criteria were formulated based on the PICOS framework : (1) ParTwo independent reviewers (YG and LM) screened the retrieved titles, abstracts, and full texts for eligibility according to their relevance. Full-text evaluations and data extraction were performed where abstracts did not provide sufficient information. The respective authors were contacted by mail if the information available was incomplete or any obscurities were present. Disagreements regarding study eligibility were resolved by consensus after a discussion.Data including general characteristics , patient characteristics , intervention characteristics  in each trial were extracted. The intervention design and the difference in the two groups and main outcome measures were also summarized and compared. Active interventions were defined for the control group receiving the same total training time as the experimental group, while passive interventions were defined as a blank control group.The Physiotherapy Evidence Database (PEDro) Scale  was usedg was used to quantify the efficacy of VR-based training. The effect size (ES) was categorized as follows: small (<0.3), medium (≥0.3 and <0.6), and large (≥0.6)  was used to perform the meta-analysis. Means and SD between groups from baseline to immediately after intervention were reported as provided by the authors, estimated from a graph or from the medians and IQR. Studies were excluded from meta-analysis if data estimated from a graph or from the medians and IQR were significantly skewed away from normality. The Hedges’ e (≥0.6) . ES outcogeneity . The pooThe flow diagram of identifying eligible trials is outlined in The study quality of the included RCTs is shown in g = 0.642; 95% CI = 0.134–1.149; P = 0.013; and I2 = 0%) and attention/execution . Non-significant result was found for VR-based intervention on global cognition   .g = 0.180; 95% CI = −0.233–0.594; P = 0.393; and I2 = 0%), motor-upper extremity , and ADL . However, the ES of VR-based training on mood  was significant and large  than dose lower than 20 h . Regarding VR-based intervention frequency, the ES of more than four times per week  was larger and significant than less than four times per week . The average ES for VR intervention daily intensity more than 60 min was larger and significant  than studies with daily intensity less than 60 min . In terms of the intervention sessions, cognitive task, and additional therapy, non-significant ES was observed for subgroups between VR and control groups with the random effects model.Results of subgroup analysis based on study characteristics are reported in In the present meta-analysis from five high-quality RCTs, the baseline global cognitive scores all reported mild cognitive impairment, and we showed the superiority of using VR-based intervention combined with rehabilitation on overall cognition, attention, and executive function in individuals with chronic stroke compared with control groups. However, VR-based training combined with rehabilitation showed non-significant improvement in global cognition in patients with chronic stroke. The positive result of VR-based training on attention/execution and overall cognition of patients with stroke in the current meta-analysis was in consistence with data from a previous systematic review of mild cognitive impairment or dementia . HoweverThe results of the limited current review provided evidence that VR could not contribute to motor rehabilitation. In this meta-analysis, 3 of the included 5 RCTs measured motor function (upper extremity motor function), while two included RCTs  used VR Improvement in ADLs was included in two of the studies. In one included study , the FIMThe controversial findings for VR-based training for cognitive and motor function may be related to the following aspects. First, insufficient VR programs designed for cognitive function training might be used. Second, this might be related to the wide range of training duration. Third, the different assessment tools for cognition after stroke were used. Finally, the time since onset of stroke before intervention largely varied from the acute phase to several years after stroke.) for VR interventions using immersive, semi-immersive, and non-immersive environments for patients with subacute and chronic stroke with a mean dose of 17.6 h for upper extremity and 13.2 h for motor function. While the VR-based intervention was argued not to be exclusively dependent on a higher dose, frequency, or daily intensity , the subPalma et al., 2017The multisensory stimulation of head-mounted display (HMD) device-induced immersive VR training is thought to have a better effect on behavioral outcomes in patients with stroke. However, a recent study conducted by To the best of our knowledge, this meta-analysis was the first to explore the effects of VR-based therapy for cognition, motor function, depressive mood, and ADL in the chronic phase of patients with stroke. Specific cognitive domains and subgroup analysis including intervention frequency, intervention daily intensity, dose of intervention, and intervention sessions were also performed based on study characteristics. However, this review had several limitations. First, due to the less number of participants, the impact of stroke type and stroke locality and severities of stroke on the effect of VR-based rehabilitation could not be controlled. Second, all included studies used semi-immersive VR therapy systems, and no study used immersive VR therapy systems. Third, the limited number of RCTs may affect the effect of VR-based therapy and might be subject to potential publication bias. Although VR techniques were widely used in neurological diseases in the recent 20 years, only 6 RCTs were included in the current systematic review. Finally, future multicenter clinical studies are needed to investigate the long-term effects of VR-based rehabilitation on changes in neuroimaging biomarkers and neuroelectrophysiological mechanism.Our pooled data from the literature suggests that VR-based therapy combined with traditional rehabilitation showed better outcomes compared with traditional rehabilitation on overall cognition, attention, executive function, and depressive mood in individuals with chronic stroke. However, VR-based training combined with traditional rehabilitation showed a non-significant effect over traditional rehabilitation therapy on global cognition, motor function, and ADL for individuals with chronic stroke. Subgroup analysis for VR-based training suggested a greater intervention dose (more than 20 h of intervention), higher intervention frequency (more than four times a week), and daily intensity (more than 60 min of daily intervention) may be more advantageous for patients with chronic stroke to enhance their overall function, activity, and participant. Larger multicenter randomized trials determining the efficacy and effectiveness of VR-based therapy on cognition after chronic stroke are needed. Well-designed RCTs will advance our understanding on the dosage, frequency, and intensity of VR-based therapy for cognition in chronic stroke.The original contributions presented in the study are included in the article/YG, LM, CL, and HF conceptualized and performed the analysis. TW and JG supervised the study. YG, LM, and LLY drafted the manuscript. SZ, CL, and XY analyzed the data. YG and TW participated in the whole process and made final decisions. All authors contributed to the writing of this manuscript and read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Auto-immune diseases involved at least 25% of the population in wealthy countries. Several factors including genetic, epigenetic, and environmental elements are implicated in development of Rheumatoid Arthritis as an autoimmune disease. Autoantibodies cause synovial inflammation and arthritis, if left untreated or being under continual external stimulation, could result in chronic inflammation, joint injury, and disability. T- and B-cells, signaling molecules, proinflammatory mediators, and synovium-specific targets are among the new therapeutic targets. Exosomes could be employed as therapeutic vectors in the treatment of autoimmune diseases. Herein, the role of cell organelle particularly exosomes in Rheumatoid Arthritis had discussed and some therapeutic applications of exosome highlighted. What is deemed to culminate in auto-immune diseases is the inability of immune system to distinguish self-cells from non-self-ones. Recognizing the self-cells as foreigner, the immune system attacks and impairs self-molecules. Auto-immunity has been estimated to encompass wealthy nations which accounted for well over 25%, following a swift increase incidence therefrom , 2. SuchIn Rheumatoid Arthritis (RA), aggressive synovial hyperplasia – which destroy articular joints – is a significant hallmark. Several genetic, epigenetic, and environmental factors are held culprits for the initiation and progression of RA . Immune Herein the role of cell organelle such as exosomes in rheumatoid pathogenesis and the therapeutic application of exosomes in RA will be discussed in detail.Several aspects have been deemed to exacerbate arthritis, namely genetic, epigenetic, and environmental factors. Environmental risk factors which are included chemicals, smoking, and microorganisms can cause per se local inflammatory responses and immune system induction followed by epigenetic and post translation modifications (PTMs) of proteins .Presentation of native or pseudo-native peptides (in breakdown of tolerance mechanisms) via dendritic cells culminate in T- and B-cells activation, thereafter it produces cytokines and autoantibodies. It was also pointed out that autoantibodies developed during the onset of clinical disease were able to recognize many neoepitopes on the process of epitope spreading .Autoimmune responses to post-translationally both modified and unmodified self-antigens embark upon the disease, prior to emerging subclinical synovitis and clinical symptoms. Furthermore, autoantibodies produced during this preclinical process can cause both bone degradation and pain. Auto-antibodies are attached to various epitopes and create immunological complexes, resulting in synovial inflammation and arthritis , 10.Many tissues are targeted in the RA cases and the main of which is the synovium. Inflammatory and joint-destructive substances are primarily stored in these cells. Auto-antibodies have an important role as mediator of joint inflammation and bone degradation to accelerate the inflammatory processes. Depending on the severity of the disease, auto-antibodies are found in 50–80% of RA patients , 12. TheIn this case, autoantibodies’ glycosylation is crucial. It has been reported that increased IgG-Fc sialylation has been associated to reduce inflammatory bone decay. However, decreased sialylation has been associated to RA and osteoclastogenesis. In short, the main causes of bone degradation are synovial inflammation, pro-inflammatory cytokines, autoantibodies, and receptor activator of nuclear factor B ligand (RANKL) . In the Mitochondrial malfunction has been shown in RA, neurological diseases, diabetes, cancer, and obesity. The linkage between Rheumatoid Arthritis and mitochondrial dysfunction has been shown by numerous studies. Nuclear DNA (nDNA) encodes some proteins that translocated to mitochondria. In the recent times, it has been reported that such proteins have a pivotal role to play in mitochondrial dysfunction, in particularly, in the cases of oxidative stress-related processes, apoptosis, and RA.The provocation of internal nucleic acid sensors as well as the Toll-like receptor (TLR) 9 are induced by unmethylated CpG patterns in mitochondrial DNA (mtDNA). The immune response of mtDNA is increased by containing 8-oxo-guanine residues. These residues, albeit being far more common in mtDNA than in nDNA, are as a consequence of oxidative events which were caused by reactive oxygen species (ROS) . ROS mayIn addition to aforementioned, the 1158 nDNA-encoded proteins can be translocated to mitochondria as well as involving in ROS production pathways . In termIt is worth noticing that the apoptosis is important for synovial hyperplasia in RA to be controlled, as it can be triggered by both extrinsic and intrinsic processes. The intrinsic occurs in mitochondria caused by oxidative stress, whereas the extrinsic routs are inactive in the fibroblast-like synoviocytes (FLS) of RA patients. Notably, both mechanisms can lead to the activation of a protease cascade, known as caspases .To recognize importance molecules in cytokine signaling in RA, protein-protein interaction (PPI) networks has been created by some researchers at the cellular level . ImportaThe existence of the electron transport system in mitochondrial has a key role in the modifications of mtDNA. In addition, the absence of histones in mtDNA makes them more vulnerable to ROS induced damages. There are two biochemical variables that influence into immunological capacity. Protein synthesis process in mitochondria is like that of bacteria which begins with a formylated amino acid. Formylated peptides can also stimulate neutrophil receptors, inducing activation and chemotaxis. The other mitochondrial protein – mitochondrial transcription factor A (TFAM) – is immunologically active. TFAM having similar structure to high-mobility group box 1 (HMGB1) can function as an alarmin and promotes inflammation like nucleus counterpart thereof .Some chemicals may leave the mitochondria as permeability breaks down because of cell stress. Cytochrome c will elude the mitochondria’s sinking ship and interact with other molecules, causing apoptosis. In the case that of mtDNA is outside the mitochondria, it can activate the inflammasome by interacting with internal sensors. Owing to sever cell malfunction, all these mitochondrial products leave the cell, and also along with individual components which leak or release, entire mitochondria might depart from the cell with the payload of hazardous molecules. Following the stimulation of eosinophils, the mitochondrial catapult as an intelligent mechanism allows the entire mitochondria to be exteriorized .Platelet activation is the epitome of presenting entire mitochondria in an extracellular position . MicropaTerminology is affected by changing personality of mitochondria and the desire for becoming outright hazardous. Relying on the origin of functions, mitochondrial products differ from one another. For instance, products can be DAMPs (disease-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns) if the activity are triggered by cell death and the same molecular structures, respectively .To refrain conflict and prolonged disputes, it is better to use a neutral and non-committal word; to wit: MAMP  refers to a form of mitochondrial molecular pattern. The discovery of immunological potential of the mitochondrion promotes the increasing picture of molecules which are repurposed to enhance innate immunity .The endoplasmic reticulum (ER) biosynthesizes both secretory and membrane proteins. The ER lumen provides a desired situation which is required for proper folding of membrane and secretory proteins. The homeostasis in the ER is preserved by the unfolded protein response (UPR), ER-associated degradation (ERAD), and a structured adaptive program. A variety of factors, such as altered cellular metabolism, mutations in substrate and route chaperones, and infection, are involved in predisposing proteins to misfolding , 28.The initiation of a UPR signaling cascade throughout ER stress – not to mention it is caused by the aggregation of unfolded proteins – is done by the glucose regulated protein 78 kDa (GRP78) which has been known as BiP (binding immunoglobulin protein) . IncidenIt is worth mentioning that the cell might lose the ability to rectify the protein folding deficiency and restore ER balance under long-term ER stress, thus the activation of cell death programs such as apoptosis and autophagy by the UPR. It has been shown that many diseases such as cancer, ischemia/reperfusion injury, neurological disorders hypoxia, cardiac disease, inflammatory bowel disease, infection, obstructive airway disease, and diabetes are associated with the ER stress response. The impaired ER stress, in turn, can lead to chronic autoimmune inflammatory disorders. The implication of a microarray study, moreover, revealed that the ER response can be escalated in skeletal muscle damage in the situation in which autoimmune myositis as the GRP78 expression is exerted in the muscle tissue of these patients .The impact on RA of ER stress has remained a subject of intense debate. According to recent studies, a linkage between ER stress response and chronic autoimmune inflammation has been reported, whereby ER stress may induce or affect inflammatory disorders’ phenotype. Likewise, a study carried out to realize the impact of GRP78 on RA pathogenesis reached meaningful consequences. In the inflamed RA joints, some conditions are capable of increasing ER stress in both innate and adaptive immune cells; to wit: hypoxia, ROS, glucose deprivation, and pro-inflammatory cytokines. Inasmuch as the expression of GRP78 in RA-FLS is particularly upregulated in response to ER stress, such event enhances FLS survival and proliferation, hence synovial proliferation. The level of ER stress-mediated GRP78 in the ER lumen increased then can re-localize to cell surface from the ER, which in turn can be considered a target for Anti-citrullinated protein antibodies (ACPAs) and act as an auto-antigen for T- and B-cells . FurtherIn addition, having bound to ACPA , citrullAccording to several studies carried out to ascertain other functions of GRP78, they pointed out that both cytoplasm and cell membrane are encompassed of GRP78, and also it plays a remarkable role in cell survival, metastasis, tumor angiogenesis, and resistance to chemotherapy. The discovery that GRP78 exists on FLS surface can pave the way to novel therapeutic means targeting the pathologic hallmarks of RA, synoviocyte proliferation, and endothelial cells .The conjunction of toxin or apoptosis-inducing with the synthetic peptides having the potential to be blended with GRP78 such as WIFPWIQL peptide, may suppress synovial angiogenesis, proliferation, and pannus development . It is iAlthough RA-FLS studies, focusing mainly on changing occurred in cellular viability and possible repercussions for synovial hyperplasia thereof, it was myeloid-specific manipulation of UPR pathways that was shown to culminate in a remarkable decline in cytokine expression and in reducing K/BxN serum-induced arthritis. It was also pointed out that ER stress condition affect the RA-FLS to resist apoptosis, owing to increasing the rate of autophagy and the activation of proteasoms. Even so, our knowledge is limited of how ER stress has impact on FLS ability to influence synovial inflammation.In recent times, a linkage between XBP1 splicing and TLR-mediated activation of RA-FLS has been reported . NoteworThe actin cytoskeleton fulfills many functions such as cellular homeostasis, modification of cell shape – migration, differentiation, and development thereof. It also has pivotal role in wound healing, polarity maintenance. To accomplish adequately such duties, it is imperative for every cell to coordinate its actin cytoskeleton with all external and intracellular. For instance, the number of both filamentous F-actin against monomeric G-actin and stress fibers are necessity to be controlled so as to movement. To this end, a complex intracellular protein network must be built, thereby allowing the cell to control actin polymerization, nucleation, depolymerisation, and actin organization relying on the cell’s needs .Modulation of actin organization as well as controlling actin polymerization is of great importance. As a result, variety of signaling and/or actin-binding proteins can alter the actin cytoskeleton structure, leading to focal adhesion, stress fibres, lamellipodia, or even filopodia formation based on the needs of specific cells at the given time –43. NotaNevertheless, it has been discovered that the activation of TNFα-induced NF-kB and cytokines secretion depends on the activation of RhoA in human cultured rheumatoid arthritis synovial fibroblasts (RASFs), which in turn this implies a crucial function of this GTPase in the arthritic inflammatory response. The implication of this issue is that the development of stress fibres can be exerted by Rho. Moreover, it has been pointed oud that the depletion of gelsolin – an actin binding protein involved in actin depolymerization by preventing F actin production – has exacerbated the illness in mice, resulting in the importance of gelsolin in regulating the actin cytoskeleton in RASFs of the RA cases , 47.According to a recent research on cadherin-11-deficient mice, the importance of tissue remodeling in RA was highlighted. The implication of that was to realize an important role of RASFs in reducing the migration, invasion, and adhesion capabilities. Whereas the resistance to the K/B6N serum-transfer arthritis (STA) was shown to be accomplished by RASFs , 49.In addition to aforementioned, the actin cytoskeleton has noticeable impact on cellular morphology and gene transcription, hence activating Mal – a modulator of gene expression. Following F-actin formation, Mal is separated from G actin, thenceforth it stimulates the serum response factor (SRF) as well as target genes which include genes controlling proliferation, cell growth, differentiation, and the actin cytoskeleton machinery. Interestingly, a dynamic relationship between actin cytoskeleton remodeling and SRF was found, as the ablation of the SRF can cause low F-actin levels and remarkable decline in migration and adhesion abilities in murine embryonic stem cells , 51. FurMore importantly, the actin cytoskeleton in numerous disease states, aside from RA, has the ability to maintain cell homeostasis and survival as well as playing significant role to keep going the function of many proteins being essential to fine-tune their organization. And also, a linkage was revealed between the failure in actin collection and polymerization in polymorph nuclear leucocytes with recessively inherited genetic condition known as neutrophil actin dysfunction. The actin polymerization is therefore important for neutrophil to move .What has been found to be increased among patients suffering from RA is the serum amyloid level; this elevation results in synovial hyperplasia and angiogenesis. Actin and/or actin-binding protein-associated diseases have been linked to affect cancer cells, as they can affect tumor cells to progress and to metastasize . IncidenAntikeratin antibodies have been found among nearly 68% of patients suffering from rheumatoid arthritis hand abnormalities, reaching a prevailing notion that there is an important linkage between Antikeratin antibodies and RA . Since AExosomes are nanoscale cell-derived extracellular vesicles (EVs) with 30–100 nm in diameters . They caExosomes fulfills various function as well as having noticeable roles in sundry processes irrespective of type of cells. The most important of such functions has been noticed is to transmit bioactive molecules among cells. Along whit transmitting, some conditions such as transmissible spongiform encephalopathies, Alzheimer, Parkinson, and amyotrophic lateral sclerosis can be affected by exosomes –64. ExosDepending on conditions and correlations, exosomes can deliver different substances. As an example, exosomes contained the TCR/CD3/zeta complex and major histocompatibility complex class II (MHC II)-peptide can be shown in the situation in which T-cells correlate with antigen presenting cells (APCs) . AdditioDependent and independent fusions have been considered as two different methods accomplished by exosomes to influence into nearby cells. Fusions per se are divided into two categories: 1) direct fusion pertaining to plasma membrane of the recipient cell – which relies on receptor-ligand interactions, 2) Back fusion relating to the vesicles are undergone endocytosis by recipient cell and hence the inclusion of the vesicles into the endosome’s membrane. However, the inverse function is shown in the fusions encompassed independent method, as the interaction between vesicles and recipient cells is incident. Function of delivering MHC-peptide having link to the T-cell receptor (TCR) on T-cells fulfilled by exosomes is the quintessential of such fusion , 70. To Long noncoding RNAs (lncRNAs) has been become a demand subject to investigate since it has impact on embryonic differentiation, pluripotency, and development. It was also reported to play key roles in variety of illnesses . Serum eExosomes are thought to be vehicles delivering immunosuppressive substances generated from their parents’ dendritic cells (DCs), even though the precise functional mechanism of immunosuppressive DC-derived exosomes has remained thus far unknown .To exert suppressive molecules their duties, the presence of certain substances on both exosomes and recipient animals is necessity; MHC II and B7–1/2 molecules are the epitome of such substances.According to trafficking analysis, exosomes cross-trafficking to the contrariwise lymph node is limited. Immunosuppressive DC exosomes therefore can change the function of endogenous immune cells, such as APCs, culminating in a systemic suppressive/anti-inflammatory impact , 76. IntFriedenstein et al. elicited MSCs from guinea-pig bone marrow and spleen. MSCs are deemed as self-renewable, multipotent, and spindle shape cells . Both peNitric oxide (NO), TGF-β, soluble HLA-G, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 (PGE2) can be produced by MSCs as a result of responding to high concentrations of TNF α, IFN γ, and TLR3 agonists. This reaction, even though activating CD4 + CD25 hiFoxP3+ regulatory T-cells (Tregs), can suppress natural killer (Nk) and T-cell responses , 82. ExoIn addition to what has been cited, cytokines affected by MSCs are the other molecules having impact on immune system. IFN – which is affected by MSC-derived cytokines/growth factors – as well as other cytokines such as TNF α, IL-1ß, IL-1, and IL-17 have been considered as immune modulator . In addiInterestingly, it has been recommended that MSCs be a unique alternative therapeutic for autoimmune illnesses because MSCs were shown to have a significant immune-regulatory impact against autoimmune illnesses. Further to this issue, MSCs were shown to be able to reduce the proliferation and activity of NK cells, as well as T/B-cells proliferation and DCs maturation. MSCs have also sparked a lot of interest for usage in autoimmune illnesses due to these therapeutically relevant characteristics . As to rHowever, the percentage of culture-expanded MSCs may be survived and be integrated with host tissues is negligible, accounting for less than 1 %, thereby not being found meaningful therapeutic impacts of MSCs by direct cell-to-cell interactions . Most imThe immunosuppressive properties of MSCs can be a result of TGF-β synthesis by these cells. TGF-β1 produced by MSCs controls the activity of mast cells, NK cells, macrophages, T-cells, and microglia . MSC-derSince the impact of MSCs on B cells has been considered a double-edge sword effect, this issue has been remained a subject of intense debate. To clarify by an example, they, on the one side, have the capability to decrease B-cell proliferation and antibody generation if they be exposed to IL40, cytosine–phosphate–guanosine (CpG), CD40L, anti-immunoglobulin, interleukin (IL)-2, and IL-4. But on the other side, MSCs were shown to not have effect on B cells in the situation of that they are provoked by allogeneic T-cell-depleted peripheral blood mononuclear cells (PBMCs) and CpG .When it comes to the impact on other immune cells of MSCs, they downregulate MHC II and co-stimulatory molecules expression, thus influencing into DC development. MSCs also affect the expression of IL-10 and IL-12 . Under tMSCs have been shown to prevent infection by delaying neutrophil death. MSC-derived exosomes, like their parental cells, are generally hypo-immunogenic, with the lack of MHC-II and low expression of MHC I. MSCs, furthermore, have been shown to produce more exosomes than human cell lines such as the human embryonic kidney (HEK) and human acute monocytes leukemia (THP-1), reaching to such deduction that MSCs can be deemed as the most useful source of immunoregulatory exosomes .Cosenza et al. compared the functions of cryopreserved MSC-derived exosomes to those of newly obtained exosomes and found that preservation destabilizes the membrane’s integrity, resulting in vesicle aggregation, content leakage, and a reduction in immunosuppressive capacity . MSC-derTo manage the symptoms of RA, a variety of biological disease-modifying anti-rheumatic drugs (bDMARDs) are available. For many years, inhibition of proinflammatory cytokines such as GM-CSF, TNF, and IL-6 using antibodies or soluble decoy receptors has been the mainstay of treatment for individuals suffering from RA . ImmunosOther roles of MSC-derived exosomes found are to suppress T-cell proliferation in a dose-dependent manner and to decline the amount of mature T- and B-cell subsets . NotablyAccording to a study carried out in 2018 by Chen et al., the impact of miRNAs on reducing recruitment and invasion of FLS was investigated. They found that miR-150 carried modified MSC-derived exosomes targets MMP-14, thus diminishing invasion of FLS . In addiOsteoprotegerin (OPG) is central for modulating bone repair and regeneration. The authors hypothesized that the underlying process could be linked to the regulation of the RANKL/OPG imbalance. They found that RANKL levels in the CIA rats’ serum and synovial tissues were reduced while the therapy increased OPG levels. In line with this study, hUCMSC derived exosomes injected can decline autoreactive function in filtering chemokine ligand CCL2 and CXCL12 in both blood and synovial fluid .Exosomes can be produced in large quantities by most of hematopoietic cells, including DCs. DCs are professional APCs which are generated from CD34+ stem cells with capability of regulating immunological reactivity. Although DCs were once thought to cause immunological responses such as organ graft rejection and autoimmune diseases, they have been associated with the progressing and maintaining tolerance to allo/auto antigens among tentative animals .Several factors influence DCs ability either to promote or to repress immune responses, the most important of which are their differentiation/maturation/activation stage and hematopoietic lineage affiliation. Noteworthy, antigen-specific T-cell responses can be reduced by immature DCs (iDCs), because of low levels of MHC and costimulatory molecules such as CD86, CD80, ICAM-1, CD40, and ICOSL. Incidentally, such “tolerogenic” DCs reduce amount of type 1 cytokines – IL-12 family member – and increase the level of immunosuppressive cytokines, namely TGF, IL-10, and VEGF. They also are found at the great quantities into the tryptophan catabolizing enzyme IDO, whereby they destroy free tryptophan and “starves” responder T-cells. This function, in turn, can lead to an increased T-cell death event .Induction of Treg, production of antigen-specific T-cell anergy or deletion, and polarizing T-cells are considered the other epitomes of processes regulated by tolerogenic DCs.DCs can be ameliorated by both genetic manipulation and exposure to cytokines or even to cytokine inhibitors, thereby stabilizing immunosuppressive/tolerogenic characteristics thereof . AdditioExosomes generated from pure DC are exceptionally stable vesicles that can represent a future treatment option for arthritis and other autoimmune diseases. Indeed, these vesicles can be employed as therapeutic vectors in the treatment of autoimmune illnesses. Exosomes derived from iDCs and being relevant to IL-4 and IL-10 immunomodulatory cytokines, are able to diminish the severity of established CIA in mice and to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH) . TherefoOther advantages of exosome-based therapy in comparison with gene and cell therapies are included the immunoregulatory or tolerogenic feature of exosomes as well as being situated in blood plasma and serum, providing a novel and safe treatment approach for arthritis , 113.Thus, although exosomes originated from immunosuppressive DCs have robust and long-lasting immunosuppressive effects, such exosomes can be better than their parent DCs since the high efficacy of therapeutic results therefrom has been shown to treat animal DTH and CIA, hence being potential for clinical application in RA .What has made the DC-derived exosomes remarkably safe in vivo delivery is the most important feature of which that they are more stable after isolation, compared to autologous cells. However, it ought to not be forgotten that DCs altered ex vivo have remained hitherto susceptible to maturation in an inflammatory environment. This issue is Because exosomes have a longer half-life than many other cell types following injection .Exosomes elicited directly from ACS seemed to mitigate the symptoms of patients afflicted by RA, making this idea that immunosuppressive exosomes be used in the clinic . On the Along with anti-inflammatory effects and reduced mice CIA detected in DCs treated with recombinant murine IL-10 (rm.IL-10) or adenoviral IL-10 gene (ad.IL-10), the released exosomes by DCs show immunosuppressive activities . In a miConsidering the therapeutic impact of exosome depends on the exosome membrane stability and integrity. For instance, repetitious freeze-thaw cycles disrupt the exosome structure, eliminating its curative effects. Exosomes lacking MHC II were shown to not be able to decrease DTH, indicating its critical role in cell-mediated immunity. Besides, B7–1/2 (CD80 and CD86) are necessary for the suppressive effects of IL-10-treated BMDC-derived exosomes. On the whole, the modified DC-derived exosomes can be more immunosuppressive in IL-10 based therapies .DCs undergone genetic modifiers which express IL-4 cytokine were shown to be a successful therapeutic candidate for murine CIA. As to a study, CIA mice were given immature bone marrow-derived dendritic cells (BMDCs) infected with an IL-4 expressing vector by an intravenous injection, thereby relatively full disease suppression over at least 4 weeks. According to another report, the therapeutic impact of IL-4 expressing DC (DC/IL-4) was much higher than rm.IL-4 or ad.IL-4 injection . For exaExosomes derived from DCs systemically and locally injected were observed to diminish intensity of CIA, and inhibit the DTH response, respectively. The immunosuppressive effects of DC/IL-4 are the quintessential of this finding. To suppress the DTH response, merely syngeneic DC exosomes – not allogeneic ones – were effective. And also, it was syngeneic DC exosomes that was able to move to the spleen and liver, interacting with CD11c + DCs and F4/80+ macrophages . In the To alter strategy of downregulation of antigen-specific T-cell responses, APCs expressing death ligands e.g., Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) undergone genetic engineered mechanisms can be considered a useful alternative. It is because of their function pertaining to selectively inducing apoptosis of antigen-specific T-cells . The othDepending on systemic and local injection, the results of them differ from one another. For instance, systemic injection exosomes, FasL-expressing DCs decrease the collagen-reactive T lymphocytes, and the course of murine CIA , whereasIt is demonstrated that the inhibitory impact was dependent on MHC II – not MHC I making use of DC and not exosomes derived DC from various knockout mice models. Further to a comparison of synovial fluid acquired from patients suffering RA with traumatic arthritis patients, a remarkable linkage between bioactive APO2 ligand (APO2L)/TRAIL – deemed a TNF family member being able to cause cell apoptosis – with exosomes was found. APO2L/TRAIL can also make invading T-cells within the synovial fluid of patients suffering RA by far sensitive to apoptosis .Furthermore, in a rabbit model of RA, bioactive APO2L/TRAIL attached to the membrane of liposomes, was shown to significantly reduce inflammation following intra-articular injection, outperforming soluble, and unconjugated APO2L/TRAIL. Increasing cross-linking receptors as a consequence of higher local protein concentrated upon liposome distribution can elucidate the increased bioactivity .Decreasing T-cell activation and responses to auto- and allo-antigens can be induced by IDO during tryptophan depletion and/or producing toxic metabolites, as immunoregulatory DCs express the tryptophan catabolic enzyme , 122. InUnder situation in which DCs be pre-treated by either the IDO inhibitor – 1-MT – or high L-tryptophan, the suppressive impact of DC/CTLA4-Ig exosomes is shown to be diminished. The implication of such event is that the potential function of DC/CTLA4-Ig mainly relies on the activation of IDO in DCs and on deprivation of IDO-mediated tryptophan. The other molecules having significant role in provoking DC/IDO exosomes to play as an immunosuppressive substance is B7–1/2 molecules. Exosomes obtained from DC/IL-10, for instance, play an impaired anti-inflammatory role if they be transduced by IDO .Autoimmunity are distinct for each rheumatic disorder of that is described by the existence of disease-specific or disease-associated antibody profiles. RA is a multifactorial disorder, as the initiation and progression of which are affected by several factors, namely environmental and serological. Genomic technologies and computational techniques have paved the way for understanding mitochondrial dysfunction in disorders including RA, obesity, cardiovascular disorders, Leigh syndrome. Furthermore, metabolic profiling and whole-exome sequencing have firmly been associated with both mitochondrial metabolic abnormalities and bi-allelic mutations – which cause mito-ribosomal subunit instability.The present therapies are being used in the case of RA – biological therapies including proteins and antibodies associated with inflammatory factors – are mainly focused on relieving the symptoms of the disease rather than on reversing disease. Although novel therapy methods pertaining to genes have been deemed to promise to treat such disorders, the standpoint of that whether such approaches are safe enough has remained a subject of controversy. With regard to several studies, it has been explicit that in the case of animal models inflammation as well as autoimmune diseases such as RA, exosomes derived from immunosuppressive DCs and blood plasma and serum can act beneficial functions to enhance treatment processes.In addition to aforementioned, MSC-derived exosomes can affect cartilage and synoviocyte in rheumatic diseases. These effects are included inhibiting cartilage to be degraded, rather promoting regeneration thereof via anti-fibrotic, anti-apoptotic, and immune-modulatory impacts. They suppress synoviocyte proliferation, too.It also is pivotal to be noted that even though DC-derived exosomes can act as immune-modulator, thereby reducing RA pathogenesis via their anti-inflammatory features, other immune-modulatory exosomes – TNF-bound ones – were shown to act as a provocative for pro-inflammatory results, thus exacerbating RA pathogenesis. On the whole, making use of exosomes can be deemed to be effective, unique, and safe therapeutic method so as to the treatment of arthritis. A schematic representation of exosome therapy for RA joints showed in Fig.


In contrast to conventional digital images, high-dynamic-range (HDR) images have a broader range of intensity between the darkest and brightest regions to capture more details in a scene. Such images are produced by fusing images with different exposure values (EVs) for the same scene. Most existing multi-scale exposure fusion (MEF) algorithms assume that the input images are multi-exposed with small EV intervals. However, thanks to emerging spatially multiplexed exposure technology that can capture an image pair of short and long exposure simultaneously, it is essential to deal with two-exposure image fusion. To bring out more well-exposed contents, we generate a more helpful intermediate virtual image for fusion using the proposed Optimized Adaptive Gamma Correction (OAGC) to have better contrast, saturation, and well-exposedness. Fusing the input images with the enhanced virtual image works well even though both inputs are underexposed or overexposed, which other state-of-the-art fusion methods could not handle. The experimental results show that our method performs favorably against other state-of-the-art image fusion methods in generating high-quality fusion results. Image fusion has been a crucial low-level image processing task for various applications, such as multi-spectrum image fusion ,2, multiSeveral research works have been performed for Multi-scale Exposure Fusion (MEF) ,7,8. In The abovementioned methods produce good results using a sequence of images exposed in a small interval of different exposure values (EV). Thanks to advanced sensor technology, a camera with Binned Multiplexed Exposure High-Dynamic-Range (BME-HDR) or Spatially Multiplexed Exposure High-Dynamic-Range (SME-HDR) technology can simultaneously capture an image pair with short- and long-exposure image sensors. The captured pair has only a negligible difference, possibly caused by local motion blur between them. The existing MEF methods may not work well with two exposure images, since none of the inputs may have well-exposed contents. In addition, weighted-sum fusion based on well-exposedness may not be able to deal with highlighted regions of a short-exposure image that are darker than dark parts in a long-exposure image, resulting in the method ignoring contents in the short-exposure image. Yang et al.  proposedIn recent years, deep convolutional neural networks (CNNs) have gained tremendous success in low-level image processing works. In MEF, CNN-based methods ,11 can bOur image fusion framework adopting the proposed OAGC can produce better fusion results for two input images with various exposure ratios, even when both of the input images lack well-exposed regions.The proposed framework with OAGC can also adapt to single-image enhancement.We conduct an extensive experiment using a public multi-exposure dataset  to demonThis paper presents a two-exposure fusion framework that generates a more helpful intermediate virtual image for fusion using the proposed Optimized Adaptive Gamma Correction (OAGC). The virtual image has better contrast, saturation, and well-exposedness, and it is not restricted to being an interpolated version of the two input images. Fusing the input images with their virtual image processed by OAGC works well even though both inputs have no well-exposed contents or regions. MEF-based methods produce fusion results using a weighted combination of the input images based on each pixel’s “well-exposedness”. In , fusion Mertens et al.  construcGeneral MEF algorithms ,8 that rc, where M and N are the image width and height. Let In the following paragraphs, we introduce the techniques adopted in the work of Yang et al., including the generation of the virtual image and fusion weights and the multi-scale image fusion. Before continuing, we define several notations that are used here. Let In HDR imaging, an image taken at a certain exposure may contain underexposed or overexposed regions, which are less informative and should be assigned fewer weights in multi-exposure fusion. The input’s contrast, saturation, and well-exposedness determine a pixel’s weight at m,n . The conLet E is a normal distribution centered at P images The well-exposedness of the pixel, The weight map of the image In the MEF algorithm , a fusioneration . In thisApplying edge-preserving filtering to preserve edges in the weight maps before averaging the Laplacian pyramids in Equation  can redufunction:ΛGIF=∑m,nIn GGIF, a  σYpl,Ψ2 . This loσYpl,Ψ2 [ΛGG=∑m,n∈The fused image Equation , to presz is a pixel intensity. The two modified images with the same exposure are In , Yang etBased on , the IMFopted in . The twoopted in  is obtailgorithm .As described previously, Yang’s method often fails to produce a satisfying fusion result when the medium exposure between inputs is still under- or overexposure. The proposed method addresses this issue by improving the contrast, saturation, and well-exposedness for the intermediate virtual image to generate better fusion results under different input conditions.The algorithm in  can workFor example, to fuse Iv c generatIv e. We proIv d so thatIv f.In OAGC, we derive an optimal set to 1 . Here, tTo derive the optimal gamma, we design an objective function as follows:The optimal gamma, Since there is no closed-form solution for Equation , we appllgorithm ,9 to theIn the experiment, we compared the proposed method against state-of-the-art image fusion methods, which included Kou’s method , DeepFusWe compared different fusion results under various input conditions. First, I is a grayscale image, L represents the largest pixel intensity value, and l.Objectively, we compare the performance of our presented framework against other image fusion methods using five benchmark metrics: the Naturalness Image Quality Evaluator (NIQE) , Blind/RAs stated previously, the proposed framework works well for two-exposure image fusion in cases where the difference between the two input images’ EVs varies. In recent years, fusion-based single image enhancement methods have attracted much attention . We can Convergence of Gradient Descent: To further analyze the process of attaining the target gamma value To further attest to the effectiveness of OAGC, Limitation of OAGC: Using OAGC, we can attain a gamma coefficient Equation , and we al image d presentThis paper presented a two-exposure image fusion framework that utilizes the proposed OAGC to bring out additional well-exposed contents from an intermediate virtual image derived from the two inputs. It can work better for the input images with various combinations of exposure ratios and can produce more well-exposed fusion results. In addition, the proposed framework with OAGC can easily adapt to single image enhancement. The experimental results have demonstrated that the proposed method performs favorably against the state-of-the-art image fusion methods.


More nurse visits (p = 0.02), fewer emergency-room visits (p = 0.01), and a shorter waiting time to access PHC (p = 0.02) were found in the community group. There was no difference in the duration of survival and hospitalization between groups. Most hospital-based patients (57%) died in hospice wards, while most community-based patients died at home (52%). Community-based PHC is comparable to hospital-based PHC in Taiwan. Although it has fewer staffing and training requirements, it is an alternative for terminal patients to meet the growing end-of-life care demand. Evidence shows that community-based palliative home care (PHC) provision enhances continuous care and improves patient outcomes. This study compared patient survival, place of death, and medical utilization in community- versus hospital-based PHC. A retrospective cohort study was conducted of patients aged over 18 referred to either community- or hospital-based PHC from May to December 2018 at a tertiary hospital and surrounding communities in Southern Taiwan. A descriptive analysis, Chi-square test,  The aging population is rapidly increasing globally. According to the United Nations World Population Aging report 2019, there were approximately 703 million people aged over 65 years worldwide in 2019, and this figure is projected to double to 1.5 billion in 2050 [In Taiwan, the aging rate has surpassed 14%, becoming an “aged society” in 2018, and is projected to become a “super-aged society” in 2025, with 4.7 million Taiwanese people aged 65 years old or over ,4 reportPopulation aging will put increased financial pressure on old-age support and the healthcare system ,3; henceIn Taiwan, palliative care is provided in hospitals or via hospital-based PHC . Hospital-based PHC staff are experienced palliative care professionals including physicians, home care nurses, social workers, and psychologists. To expand PHC services to accommodate the increasing care needs of the aging population, the Ministry of Health and Welfare in Taiwan devised community-based PHC services  in 2014 [This is relevant to Taiwan, as the aging population is increasing rapidly; however, there is little evidence regarding community-based PHC in the Taiwanese context. The Ministry of Health and Welfare in Taiwan funded hospitals to develop a community-based PHC model to meet the increasing PHC needs in 2018  and thisThis is a retrospective cohort study analyzing data from patients receiving hospital-based PHC and community-based PHC at a tertiary hospital in southern Taiwan from 1 May to 31 December 2018. From our clinical experience, most patients die within a year after receiving PHC; therefore, we followed up the study participants for one year and set the study endpoint as 31 December 2019. The clinical data of deceased patients from both groups were collected until the endpoint for comparison of the duration of their survival, place of death, and medical utilization at a tertiary hospital in southern Taiwan. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidance was adopted for reporting . Hospital-based PHC is provided by a multi-disciplinary team in a tertiary university hospital, comprising four physicians, twenty hospice and palliative care unit nurses, three hospice-combined care nurses, three hospice home care nurses, one chaplain, one social worker, one clinical psychologist, and one case manager. There are twenty inpatient beds in the hospice and palliative care unit that provide symptom control, emotional support, and distress relief, incorporating community and home care. Four physicians and three hospice home care nurses within the team primarily provide hospital-based PHC. Community-based PHC is provided by local community clinics run by four physicians and four community home care nurses. Patients aged ≧18 years old diagnosed with any disease receiving either hospital-based or community-based service were deemed as the target cohort for intended outcome comparison. Patients were excluded if they were younger than 18 years old, if their residential area was out of the 10 km radius of the community-based services, or if they were alive at the study endpoint. Palliative care inpatient patients were suggested by the hospice and palliative care case managers to receive either hospital-based or community-based services during patient discharge. Patients at outpatient clinics were referred by primary care teams  to hospital palliative care specialists  for eligibility assessment and were then referred to the hospice and palliative care case managers for suggestions on group allocation. Patients and their family members were provided with information regarding service content, health insurance model, and out-of-pocket payment  by hospital palliative care specialists. The patients and their family members’ preferences and the distance from patient homes to the hospital were considered to inform the recommendations of care received .The hospital’s electronic medical record system was used to retrieve data for the hospital-based group. Relevant information in the community was provided by the community team in the local clinics or facilities. Patients’ demographic characteristics , medical utilization , place of death, and duration of survival were recorded. ®  for data management and analysis. Descriptive analysis was used to report patient demographic characteristics by presenting frequency and percentage for categorical data and mean and standard deviation for continuous data. The Chi-square test was used to determine group differences for categorical data and an independent t-test was used for continuous data. Furthermore, the Log-rank test was used to assess the difference in survival days between groups. One-to-one propensity score matching (PSM) for control of selection bias and sample size justification was adopted to have the same proportions of the two groups. Variables included in the PSM model were age, gender, religion, Eastern Cooperative Oncology Group (ECOG) score, and terminal diagnosis. The statistical analyses were performed among groups before and after PSM.The data were entered into Excel sheets and imported into SPSS 20.0Ethical approval was granted by the Kaohsiung Medical University Hospital (KMUH) Institutional Review Board (IRB Number: KMUHIRB-E(I)-20190225) as this is a retrospective anonymous secondary data analysis. Consent forms were not required given the retrospective nature of the study design. p < 0.01).A total of 184 patients were eligible for this study, 138 hospital-based patients and 46 community-based patients. After the application of the inclusion criteria, there were 131 hospital-based patients and 43 community-based patients, with 42 paired patient datasets entered for final data analysis after PSM . The demp < 0.01) and had longer nurse visit intervals (p < 0.01), as well as a longer average length of hospital stay (p = 0.03). However, more nurse visits (p = 0.01), shorter waiting time to access PHC (p < 0.01), and fewer emergency-room visits (p = 0.04) were found in the community-based group. There is no statistical difference in physician visit interval, total caring days, number of hospitalizations, and total length of hospital stay (p = 0.18) (p = 0.07) and the average length of hospital stay (p = 0.08). However, a significant difference in patient place of death was found (p = 0.02), with most patients in the hospital-based group tending to die in an inpatient hospice (57%), whereas patients in the community-based group were more likely to die at home (52%)   between me (52%) .Unlike previous studies ,17,18,19It is noteworthy in the hospital-based group that the visit frequency of nurses and physicians was similar (nurse versus physicians: mean ± SD: 5.57 ± 6.95 versus 5.17 ± 6.56), whereas the community-based group received more nurse visits (nurses versus physicians: mean ± SD: 10.19 ± 9.99 versus 3.14 ± 2.40). This might be explained by the different staffing levels in the two care models. For example, the hospital team usually pair a physician and a nurse to visit patients, whereas, in the community-based model, physicians or nurses often visit the patients alone, sharing patient information afterwards for continuous care provision. Therefore, community-based services are considered more flexible and accessible, with timely care provision, which might correlate with the findings in terms of shorter waiting times to access PHC services, fewer emergency-room visits, and timely symptom management. Our findings are comparable with studies conducted in Italy ,21 and SNo significant difference in patient survival days was found between the two PHC models during the study period, indicating that the community-based PHC team provides comparable end-of-life care to hospital-based services, even though staff received fewer training hours. In Taiwan, community-based PHC teams may consult hospital-based palliative care teams for complex cases, which might explain the aforementioned findings. The collaboration between the hospital and community teams could increase access to palliative care for all, improve the quality of care transition, and enhance the continuous care provision during a patient’s disease trajectory from diagnosis to death ,27. Taken together, these findings demonstrate that community-based PHC has the potential to provide comparable quality end-of-life care for patients and their family members compared to hospital-based PHC. Since 2015, the Taipei City medical system of Taiwan has advocated and promoted community- and home-based palliative care. They constructed a friendly and supportive healthcare system for health-promoting palliative care and encouraged community medical teams to involve end-of-life care. This strategy echoes our findings and is hoped to facilitate community end-of-life care provision and improve death literacy . AdditioThis study has several strengths. First, it is one of the first to compare patient outcomes of different PHC models for terminal patients in Taiwan. The findings promote the importance of community PHC provision and inform the policy regarding medical resource reallocation for people with palliative care needs in the community. Second, the low attrition rate is highlighted, which is rare in palliative care research, given the fact that the participants are often very frail and vulnerable. This might be explained by the proactive approach of healthcare staff, as well as trustful clinician–patient relationships. Third, we performed PSM to minimize the selection bias. However, there are limitations to adopting the findings in practice. First, the small sample size after PSM might limit the generalizability of the findings. Second, the patients’ emergency-room visits and medical utilization might be underestimated as we were unable to determine if they sought healthcare services from other healthcare facilities during the study period. Third, we cannot conduct a cost-effectiveness analysis due to the limited data collated. For example, we only collected the frequency of clinician visits, not the cost and total length of time spent on palliative home care provision.This study demonstrates that community-based PHC can provide palliative care comparable to hospital-based services to improve outcomes, even though community-based PHC requires less staffing and fewer training hours. Therefore, for terminal patients with end-of-life care needs, community-based PHC is an alternative to hospital-based PHC and should be promoted to meet the growing care demands. However, more research on the feasibility and effectiveness of implementing community-based services and cost evaluation is needed before widely integrating such services into routine practice.