Randomized Clinical Comparison of the Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Combo Stent With the Sirolimus-Eluting Orsiro Stent in Patients Treated With Percutaneous Coronary Intervention: The SORT OUT X Trial.

BACKGROUND: Target lesion failure remains an issue with contemporary drug-eluting stents. Thus, the dual-therapy sirolimus-eluting and CD34+ antibody-coated Combo stent (DTS) was designed to further improve early healing. This study aimed to investigate whether the DTS is noninferior to the sirolimus-eluting Orsiro stent (SES) in an all-comers patient population. METHODS: The SORT OUT X (Combo Stent Versus Orsiro Stent) trial, was a large-scale, randomized, multicenter, single-blind, 2-arm, noninferiority trial with registry-based follow-up. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, analyzed using intention-to-treat. The trial was powered for assessing target lesion failure noninferiority of the DTS compared with the SES with a predetermined noninferiority margin of 0.021. RESULTS: A total of 3146 patients were randomized to treatment with the DTS (1578 patients; 2008 lesions) or SES (1568 patients; 1982 lesions). At 12 months, intention-to-treat analysis showed that 100 patients (6.3%) assigned the DTS and 58 patients (3.7%) assigned the SES met the primary end point (absolute risk difference, 2.6% [upper limit of 1-sided 95% CI, 4.1%]; P (noninferiority)=0.76). The SES was superior to the DTS (incidence rate ratios for target lesion failure, 1.74 [95% CI, 1.26-2.41]; P=0.00086). The difference was explained mainly by a higher incidence of target lesion revascularization in the DTS group compared with the SES group (53 [3.4%] vs. 24 [1.5%]; incidence rate ratio, 2.22 [95% CI, 1.37-3.61]; P=0.0012). CONCLUSIONS: The DTS did not confirm noninferiority to the SES for target lesion failure at 12 months in an all-comer population. The SES was superior to the DTS mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the 2 stent groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03216733.

Dual-therapy CD34 antibody-covered sirolimus-eluting COMBO stents versus sirolimus-eluting Orsiro stents in patients treated with percutaneous coronary intervention: the three-year outcomes of the SORT OUT X randomised clinical trial.

BACKGROUND: Target lesion failure (TLF) remains an issue with contemporary drug-eluting stents. The dual-therapy sirolimus-eluting and CD34 antibody-coated COMBO stent (DTS) was designed to improve early healing. AIMS: We aimed to compare the 3-year outcomes of the DTS and the sirolimus-eluting Orsiro stent (SES) in all-comer patients treated with percutaneous coronary intervention. METHODS: The SORT OUT X trial is a prospective multicentre randomised clinical trial with a registry-based follow-up comparing DTS and SES. The primary endpoint, TLF, is a composite of cardiac death, myocardial infarction or target lesion revascularisation (TLR). RESULTS: A total of 3,146 patients were randomised to treatment with the DTS (1,578 patients) or the SES (1,568 patients). At 3 years, an intention-to-treat analysis showed that 155 patients (9.8%) who were assigned the DTS and 118 patients (7.5%) who were assigned the SES met the primary endpoint (incidence rate ratio for TLF=1.33, 95% confidence interval: 1.04-1.70; p=0.02). This difference was caused by a significantly higher TLF rate in the DTS group compared to the SES group within the first year, which was mainly explained by a higher incidence of TLR in the DTS group compared to the SES group. Of note, the TLF rates were almost identical from 1 year to 3 years in both stent groups. CONCLUSIONS: At 3 years, the SES was superior to the DTS, mainly because the DTS was associated with an increased risk of TLF within the first year but not from 1 to 3 years. CLINICALTRIALS: gov: NCT03216733.

Hypoxia and adipose-derived stem cell-based tissue regeneration and engineering.

INTRODUCTION: Realization that oxygen is one of the key regulators of development and differentiation has a profound significance on how current cell-based and tissue engineering applications using adipose-derived stem cells (ASCs) can be further improved. AREAS COVERED: The article provides an overview of mechanisms of hypoxic responses during physiological adaptations and development. Furthermore, a synopsis of the hypoxic responses of ASCs is provided, and this information is presented in context of their utility as a major source of stem cells across the regenerative applications explored to date. EXPERT OPINION: The reader will obtain insight into a highly specific area of stem cell research focusing on ASCs and hypoxia. In order to enhance the level of comprehension, a broader context with other stem cell and experimental systems is provided. It is emphasized that the pericellular oxygen tension is a critical regulatory factor that should be taken into account when devising novel stem cell-based therapeutic applications along with other parameters, such as biochemical soluble factors and the growth substrates.

Adipose-derived stem cells from the brown bear (Ursus arctos) spontaneously undergo chondrogenic and osteogenic differentiation in vitro.

In the den, hibernating brown bears do not develop tissue atrophy or organ damage, despite almost no physical activity. Mesenchymal stem cells could play an important role in tissue repair and regeneration in brown bears. Our objective was to determine if adipose tissue-derived stem cells (ASCs) can be recovered from wild Scandinavian brown bears and characterize their differentiation potential. Following immobilization of wild brown bears 7-10 days after leaving the den in mid-April, adipose tissue biopsies were obtained. ASCs were recovered from 6 bears, and shown to be able to undergo adipogenesis and osteogenesis in monolayer cultures and chondrogenesis in pellet cultures. Remarkably, when grown in standard cell culture medium in monolayer cultures, ASCs from yearlings spontaneously formed bone-like nodules surrounded by cartilaginous deposits, suggesting differentiation into osteogenic and chondrogenic lineages. This ability appears to be lost gradually with age. This is the first study to demonstrate stem cell recovery and growth from brown bears, and it is the first report of ASCs spontaneously forming extracellular matrix characteristic of bone and cartilage in the absence of specific inducers. These findings could have implications for the use of hibernating brown bears as a model to study disuse osteoporosis.

Comparative analysis of highly defined proteases for the isolation of adipose tissue-derived stem cells.

BACKGROUND: Before the potential of adipose tissue-derived stem cells can fully be exploited for a broad scope of tissue-engineering and cell-based therapeutical applications, an effective and reproducible method for isolation is needed. AIM: To comparatively analyze five highly defined protease formulations, Blendzyme 1-4, liberase H1 and a crude collagenase mixture in the course of digestion that consisted of three 1-h intervals. METHODS: The resulting digests of human adipose tissue aspirates were evaluated for the yield of nucleated cells, viability and frequency of specific lineages, in particular CD90, CD34 and CD45, by flow cytometry. The functionality of the cells was assessed as to the colony-forming capacity in limiting dilution assays. RESULTS: Based on all evaluation criteria, Blendzymes 1 and 2 and liberase H1 demonstrated a superior performance and highest consistency. Blendzyme 3 clearly underperformed compared with all other enzymes, and the performance of the rest of enzymes appeared erratic. As for the length of digestion, a 2-h interval appeared optimal when weighing both the yield and functionality of the cells in the stromal vascular fractions obtained from different adipose tissue samples. CONCLUSION: Our results demonstrate that the highly purified proteases provide a valuable alternative to crude collagenase preparations, especially in scenarios where a high definition and reproducibility of the digestion process is of importance.

Ventricular tachycardia after administration of sildenafil citrate: a case report.

BACKGROUND: It has not previously been reported that sildenafil citrate causes malignant arrhythmias in humans. CASE PRESENTATION: A 41-year-old man developed sustained ventricular tachycardia following sildenafil citrate administration. CONCLUSION: It cannot be dismissed that this patient experienced ventricular tachycardia as an adverse effect of sildenafil citrate administration.