-
Frontiers in Bioscience (Landmark... Jun 2024Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach for a variety of diseases due to their immunomodulatory and tissue regeneration... (Review)
Review
Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach for a variety of diseases due to their immunomodulatory and tissue regeneration capabilities. Despite their potential, the clinical application of MSC therapies is hindered by limited cell retention and engraftment at the target sites. Electrospun scaffolds, with their high surface area-to-volume ratio and tunable physicochemical properties, can be used as platforms for MSC delivery. However, synthetic polymers often lack the bioactive cues necessary for optimal cell-scaffold interactions. Integrating electrospun scaffolds and biological polymers, such as polysaccharides, proteins, and composites, combines the mechanical integrity of synthetic materials with the bioactivity of natural polymers and represents a strategic approach to enhance cell-scaffold interactions. The molecular interactions between MSCs and blended or functionalized scaffolds have been examined in recent studies, and it has been shown that integration can enhance MSC adhesion, proliferation, and paracrine secretion through the activation of multiple signaling pathways, such as FAK/Src, MAPK, PI3K/Akt, Wnt/β-catenin, and YAP/TAZ. Preclinical studies on small animals also reveal that the integration of electrospun scaffolds and natural polymers represents a promising approach to enhancing the delivery and efficacy of MSCs in the context of regenerating bone, cartilage, muscle, cardiac, vascular, and nervous tissues. Future research should concentrate on identifying the distinct characteristics of the MSC niche, investigating the processes involved in MSC-scaffold interactions, and applying new technologies in stem cell treatment and biofabrication to enhance scaffold design. Research on large animal models and collaboration among materials scientists, engineers, and physicians are crucial to translating these advancements into clinical use.
Topics: Humans; Mesenchymal Stem Cells; Tissue Scaffolds; Mesenchymal Stem Cell Transplantation; Animals; Polymers; Tissue Engineering
PubMed: 38940050
DOI: 10.31083/j.fbl2906228 -
Frontiers in Bioscience (Landmark... Jun 2024Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of... (Comparative Study)
Comparative Study
BACKGROUND
Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of UCMSC transplantation, such as infusion routes and doses, need to be further optimized.
METHODS
In this study, we compared the therapeutic effects of UCMSCs transplanted via intravenous injection and intratracheal instillation on lipopolysaccharide-induced ALI using a rat model. Following transplantation, levels of inflammatory factors in serum; neutrophils, total white blood cells, and lymphocytes in bronchoalveolar lavage fluid (BALF); and lung damage levels were analyzed.
RESULTS
The results indicated that UCMSCs administered via both intravenous and intratracheal routes were effective in alleviating ALI, as determined by analyses of arterial blood gas, lung histopathology, BALF contents, and levels of inflammatory factors. Comparatively, the intratracheal instillation of UCMSCs was found to result in lower levels of lymphocytes and total proteins in BALF, whereas greater reductions in the serum levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were detected in rats receiving intravenously injected stem cells.
CONCLUSIONS
Our findings in this study provide convincing evidence to indicate the efficacy of UCMSC therapy in the treatment of ALI mediated via different delivery routes, thereby providing a reliable theoretical basis for further clinical studies. Moreover, these findings imply that the effects obtained using the two assessed delivery routes for UCMSC transplantation are mediated via different mechanisms, which could be attributable to different cellular or molecular targets.
Topics: Animals; Acute Lung Injury; Lipopolysaccharides; Mesenchymal Stem Cell Transplantation; Umbilical Cord; Rats, Sprague-Dawley; Rats; Male; Bronchoalveolar Lavage Fluid; Mesenchymal Stem Cells; Tumor Necrosis Factor-alpha; Injections, Intravenous
PubMed: 38940047
DOI: 10.31083/j.fbl2906217 -
Infectious Disorders Drug Targets Jun 2024The Bruton tyrosine kinase (BTK), an important element for the production of several inflammatory cytokines, may play a role in the pathogenesis of COVID-19. The aim of...
OBJECTIVES
The Bruton tyrosine kinase (BTK), an important element for the production of several inflammatory cytokines, may play a role in the pathogenesis of COVID-19. The aim of this study was to investigate the level of BTK gene expression in COVID-19 cases based on the severity and the outcome of the disease.
METHODS
In this study, 33 hospitalized patients with COVID-19 were recruited and were divided into two groups based on the severity of the disease: "mild to moderate" and "severe to critical". A blood sample was taken from each patient, peripheral blood mononuclear cells (PBMCs) were extracted, and BTK gene expression was measured. The level of BTK gene expression was compared based on the demographic data, laboratory results, and the severity and outcome of the disease.
RESULTS
Among 33 patients, 22 (66.7%) were male. Nearly half of the cases had at least one underlying disease. According to the severity of the disease, 12 patients were in the "mild to moderate" group, and 21 were in the "severe to critical" group; eight (24.2%) eventually died. Age, weight, and BMI had no significant relationship with BTK expression. BTK expression was significantly lower in "severe to critical" and ICU-admitted cases and in subjects with low O2 saturation. There was no significant difference in BTK expression between cured and dead patients (p=0.117).
CONCLUSION
BTK gene expression in PBMCs had an inverse relationship with the severity of the disease of COVID-19. However, no correlation between BTK expression and disease outcome was observed.
PubMed: 38939988
DOI: 10.2174/0118715265301312240529044923 -
Admission Total Leukocyte Count as a Predictor of Mortality in Cardiac Intensive Care Unit Patients.JACC. Advances Jan 2024Inflammation is a sequela of cardiovascular critical illness and a risk factor for mortality.
BACKGROUND
Inflammation is a sequela of cardiovascular critical illness and a risk factor for mortality.
OBJECTIVES
This study aimed to evaluate the association between white blood cell count (WBC) and mortality in a broad population of patients admitted to the cardiac intensive care unit (CICU).
METHODS
This retrospective cohort study included patients admitted to the Mayo Clinic CICU between 2007 and 2018. We analyzed WBC as a continuous variable and then categorized WBC as low (<4.0 × 10/mL), normal (≥4.0 to <11.0 × 10/mL), high (≥11.0 to <22.0 × 10/mL), or very high (≥22.0 × 10/mL). The association between WBC and in-hospital mortality was evaluated using multivariable logistic regression and random forest models.
RESULTS
We included 11,699 patients with a median age of 69.3 years (37.6% females). Median WBC was 9.6 (IQR: 7.4-12.7). Mortality was higher in the low (10.5%), high (12.0%), and very high (33.3%) WBC groups relative to the normal WBC group (5.3%). A rising WBC was incrementally associated with higher in-hospital mortality after adjustment (AICc adjusted OR: 1.03 [95% CI: 1.02-1.04] per 1 × 10 increase in WBC). After adjustment, only the high (AICc adjusted OR: 1.37 [95% CI: 1.15-1.64]) and very high (AICc adjusted OR: 1.99 [1.47-2.71]) WBC groups remained associated with increased risk of in-hospital mortality.
CONCLUSIONS
Leukocytosis is associated with an increased mortality risk in a diverse cohort of CICU patients. This readily available marker of systemic inflammation may be useful for risk stratification within the increasingly complex CICU patient population.
PubMed: 38939813
DOI: 10.1016/j.jacadv.2023.100757 -
JACC. Advances Apr 2024Cost-effectiveness of testing for coronary artery calcium (CAC) relative to other treatment strategies is not established in Canada.
BACKGROUND
Cost-effectiveness of testing for coronary artery calcium (CAC) relative to other treatment strategies is not established in Canada.
OBJECTIVES
The purpose of this study was to evaluate the cost-effectiveness of using CAC score-guided statin treatment compared with universal statin therapy among intermediate-risk, primary prevention patients eligible for statins.
METHODS
A state transition, microsimulation model used data from Canadian sources and the Multi-Ethnic Study of Atherosclerosis to simulate clinical and economic consequences of cardiovascular disease from a Canadian publicly funded health care system perspective. In the CAC score-guided treatment arm, statins were started when CAC ≥1. Outcome of interest was the incremental cost-effectiveness ratio at 5 and 10 years; an incremental cost-effectiveness ratio <$50,000 per quality-adjusted life year (QALY) gained was considered cost-effective. Sensitivity analyses examined uncertainty in model parameters.
RESULTS
Compared with universal statin treatment at 5 and 10 years, CAC score-guided statin treatment was projected to increase mean costs by $326 (95% CI: $325-$326) and $172 (95% CI: $169-$175), increase mean QALYs by 0.01 (95% CI: 0.01-0.01) and 0.02 (95% CI: 0.02-0.02), and cost $54,492 (95% CI: $52,342-$56,816) and $8,118 (95% CI: $7,968-$8,279) per QALY gained, respectively. The model was most sensitive to statin cost, CAC testing cost, adherence to statin monitoring, and disutility associated with daily statin use. At 5 years, CAC score-guided statin treatment was cost-effective when CAC test costs ranged from $80 to $160 in different scenarios.
CONCLUSIONS
CAC score-guided statin initiation in comparison to universal statin treatment was borderline cost-neutral at 5 years and cost-effective at 10 years in statin-eligible Canadian patients at intermediate cardiovascular disease risk.
PubMed: 38939688
DOI: 10.1016/j.jacadv.2024.100886 -
JACC. Advances Apr 2024
PubMed: 38939684
DOI: 10.1016/j.jacadv.2024.100856 -
JACC. Advances Apr 2024Pediatric pulmonary embolism (PE) is rare and potentially life-threatening. Though thrombolysis and thrombectomy are increasingly used in adult PE, trends in pediatric...
BACKGROUND
Pediatric pulmonary embolism (PE) is rare and potentially life-threatening. Though thrombolysis and thrombectomy are increasingly used in adult PE, trends in pediatric treatment and outcomes remain incompletely described.
OBJECTIVES
The purpose of this study was to describe the incidence of PE, proportion of cases treated with anticoagulation alone, systemic thrombolysis, and directed therapy (local thrombolysis and thrombectomy), clinical outcomes, and total costs.
METHODS
A multicenter observational study was performed using administrative data from the Pediatric Health Information System database to study PE treated at U.S. pediatric hospitals from 2015 to 2021. Outcomes by treatment were evaluated using multivariable generalized linear mixed effects models.
RESULTS
Of 3,136 subjects, 70% were at least 12 years of age, and 46% were male. Sixty-two percent had at least 1 comorbidity, and congenital heart disease of any kind was the most prevalent (20%). Eighty-eight percent of subjects received anticoagulation alone, 7% received systemic thrombolysis, and 5% received directed therapy. Overall in-hospital mortality was 7.5%. Treatment approach did not change over time ( = 0.98). After adjusting for patient characteristics, directed therapy was associated with a lower risk of mortality (adjusted percentage -3%, [95% CI: -5% to 0%]) than anticoagulation alone. Systemic thrombolysis was associated with a greater total cost of hospitalization ($113,043 greater [95% CI: $62,866, $163,219]). Length of hospital stay did not differ by treatment.
CONCLUSIONS
Pediatric patients with PE have a high incidence of underlying chronic disease. Anticoagulation alone remains the mainstay of treatment, with thrombolysis and thrombectomy rarely being used. Given the relative rarity of pediatric PE, additional research requiring innovative study designs is paramount.
PubMed: 38939674
DOI: 10.1016/j.jacadv.2024.100895 -
JACC. Advances Apr 2024Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models...
BACKGROUND
Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction.
OBJECTIVES
The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes.
METHODS
Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications.
RESULTS
The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%).
CONCLUSIONS
ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.
PubMed: 38939660
DOI: 10.1016/j.jacadv.2024.100852 -
JACC. Advances Apr 2024There is controversy regarding sex differences in short-term mortality in acute type A aortic dissection (ATAAD).
BACKGROUND
There is controversy regarding sex differences in short-term mortality in acute type A aortic dissection (ATAAD).
OBJECTIVES
This study aimed to investigate the impact of sex differences on 30-day operative mortality after ATAAD surgery and to determine if other covariates modify the association.
METHODS
Consecutive patients (N = 5670) with surgically repaired ATAAD were identified from the multicenter China 5A study. The primary outcome was operative mortality. The age dependency was modeled using a cubic spline curve.
RESULTS
There were 1,503 females (26.5%) and 4,167 males (73.5%). Females were older and had a lower percentage of comorbidities compared with males. Females had higher mortality compared to males (10.2% vs 8.2%, = 0.019); however, there was no difference after propensity analyses (adjusted OR: 1.334 [95% CI: 0.918-1.938]). There was an interaction with sex and age ( = 0.035): older age was associated with higher odds of operative mortality among females (OR: 1.045 [95% CI: 1.029-1.061]) compared with males (OR: 1.025 [95% CI: 1.016-1.035]). The risk of mortality for males and females appears to diverge at 55 years of age ( = 0.019): females under 55 years of age had similar odds to males (OR: 0.852 [95% CI: 0.603-1.205]) but higher odds when over 55 years (OR: 1.420 [95% CI: 1.096-1.839]) compared to males.
CONCLUSIONS
Under the age of 55 years, females have similar odds of operative mortality compared with males; however, over the age of 55 years females have higher odds than males. Understanding differences in risk allows for individualized treatment strategies. (Additive Anti-inflammatory Action for Aortopathy & Arteriopathy; NCT04398992).
PubMed: 38939657
DOI: 10.1016/j.jacadv.2024.100909 -
JACC. Advances Apr 2024A treatment strategy for congenital heart defects with moderate to severe pulmonary arterial hypertension (PAH) has not been established.
BACKGROUND
A treatment strategy for congenital heart defects with moderate to severe pulmonary arterial hypertension (PAH) has not been established.
OBJECTIVES
The purpose of this study was to identify patients in whom a treat and repair strategy was considered and to examine pretreatment variables associated with successful defect repair.
METHODS
Patients with atrial or ventricular septal defect and PAH (pulmonary vascular resistance [PVR] ≥ 5 Wood units) eligible for the treat and repair strategy were included. Hemodynamics among pretreatment, pre-repair, and post-defect repair were compared. Clinical outcomes in patients with or without defect repair were also compared. Clinical outcomes included all-cause death, hospitalization for worsening pulmonary hypertension, and lung transplantation.
RESULTS
Among 25 eligible for the treat and repair strategy, 20 underwent successful repair (repaired group) and 5 did not have a repair (unrepaired group). In the repaired group, PVR significantly decreased from 9.6 ± 2.6 WU at pretreatment to 5.0 ± 3.4 pre-repair (ß coefficient -4.6 [95% CI: -5.9 to -3.3]). The pulmonary to systemic blood flow ratio (Qp/Qs) increased from 1.5 ± 0.6 at pretreatment to 2.4 ± 1.3 pre-repair (ß coefficient 0.9 [95% CI: 0.4-1.38]). In the unrepaired group, pretreatment PVR decreased with treatment; however, PVR remained elevated. Qp/Qs did not change between pretreatment and post-treatment. The repaired group had a better prognosis than the unrepaired group (HR 0.092 [95% CI: 0.009-0.905]). Pretreatment mean pulmonary artery pressure, PVR, Qp/Qs, and arterial oxygen saturations were associated with undergoing defect repair.
CONCLUSIONS
In this small cohort, a treat and repair strategy was successfully used in a significant proportion of the patients with congenital heart defects with moderate to severe PAH.
PubMed: 38939653
DOI: 10.1016/j.jacadv.2024.100887