Current hyaluronic acid (HA) hydrogel systems often cause cytotoxicity to encapsulated cells and lack the adhesive property required for effective localization of transplanted cells in vivo. In ...addition, the injection of hydrogel into certain organs (e.g., liver, heart) induces tissue damage and hemorrhage. In this study, we describe a bioinspired, tissue‐adhesive hydrogel that overcomes the limitations of current HA hydrogels through its improved biocompatibility and potential for minimally invasive cell transplantation. HA functionalized with an adhesive catecholamine motif of mussel foot protein forms HA‐catechol (HA‐CA) hydrogel via oxidative crosslinking. HA‐CA hydrogel increases viability, reduces apoptosis, and enhances the function of two types of cells (human adipose‐derived stem cells and hepatocytes) compared with a typical HA hydrogel crosslinked by photopolymerization. Due to the strong tissue adhesiveness of the HA‐CA hydrogel, cells are easily and efficiently transplanted onto various tissues (e.g., liver and heart) without the need for injection. Stem cell therapy using the HA‐CA hydrogel increases angiogenesis in vivo, leading to improved treatment of ischemic diseases. HA‐CA hydrogel also improved hepatic functions of transplanted hepatocytes in vivo. Thus, this bioinspired, tissue‐adhesive HA hydrogel can enhance the efficacy of minimally invasive cell therapy.
Bioinspired, catechol‐modified hyaluronic acid (HA) hydrogel is highly biocompatible and exhibits improved tissue adhesiveness in comparison to HA hydrogel crosslinked via photopolymerization. Tissue adhesive catechol‐modified HA hydrogel can mediate highly effective, minimally invasive cell therapy in defected models such as liver resection and myocardial infarction.
In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation ...strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction.
In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055.
From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority<0·001; HR 0·55 95% CI 0·40–0·76, psuperiority=0·0001). There was no significant difference in composite of cardiovascular death, myocardial infarction, or stroke between de-escalation (2·1%) and the active control group (3·1%; HR 0·69; 95% CI 0·42–1·14, p=0·15). Composite of BARC 2, 3, or 5 bleeding occurred less frequently in the de-escalation group (3·0% vs 5·6%, HR 0·52; 95% CI 0·35–0·77, p=0·0012).
In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events.
ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.
Background and Aims
The effects of low‐level alcohol consumption on fatty liver disease and the potential for effect modification by obesity is uncertain. We investigated associations among low‐level ...alcohol consumption, obesity status, and the development of incident hepatic steatosis (HS), either with or without an increase in noninvasive liver fibrosis score category (from low to intermediate or high category).
Approach and Results
A total of 190,048 adults without HS and a low probability of fibrosis with alcohol consumption less than 30 g/day (men) and less than 20 g/day (women) were followed for up to 15.7 years. Alcohol categories of no, light, and moderate consumption were defined as 0, 1‐9.9, and 10‐29.9 g/day (10‐19.9 g/day for women), respectively. HS was diagnosed by ultrasonography, and the probability of fibrosis was estimated using the fibrosis‐4 index (FIB‐4). Parametric proportional hazards models were used to estimate multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 43,466 participants developed HS, 2,983 of whom developed HS with an increase in FIB‐4 index (to intermediate or high scores). Comparing light drinkers and moderate drinkers with nondrinkers, multivariable‐adjusted HRs (95% CI) for incident HS were 0.93 (0.90‐0.95) and 0.90 (0.87‐0.92), respectively. In contrast, comparing light drinkers and moderate drinkers with nondrinkers, multivariable‐adjusted HRs (95% CI) for developing HS plus intermediate/high FIB‐4 were 1.15 (1.04‐1.27) and 1.49 (1.33‐1.66), respectively. The association between alcohol consumption categories and incident HS plus intermediate/high FIB‐4 was observed in both nonobese and obese individuals, although the association was stronger in nonobese individuals (P for interaction by obesity = 0.017).
Conclusions
Light/moderate alcohol consumption has differential effects on the development of different stages of fatty liver disease, which is modified by the presence of obesity.
We compared the efficacy and safety of third‐standard‐dose triple and third‐standard‐dose dual antihypertensive combination therapies in patients with mild to moderate hypertension. This was a phase ...II multicenter, randomized, double‐blind, parallel‐group trial. After a 4‐week placebo run‐in period, 245 participants were randomized to the third‐dose triple combination (ALC group; amlodipine 1.67 mg + losartan potassium 16.67 mg + chlorthalidone 4.17 mg) or third‐dose dual combination (AL group; amlodipine 1.67 mg + losartan potassium 16.67 mg, LC group; losartan potassium 16.67 mg + chlorthalidone 4.17 mg, AC group; amlodipine 1.67 mg + chlorthalidone 4.17 mg) therapy groups and followed up for 8 weeks. The mean systolic blood pressure (BP) reduction was ‐18.3 ± 13.2, ‐13.0 ± 13.3, ‐16.3 ± 12.4, and ‐13.8 ± 13.2 mmHg in the ALC, AL, LC, and AC groups, respectively. The ALC group showed significant systolic BP reduction compared to the AL and AC groups at weeks 4 (P = .010 and P = .018, respectively) and 8 (P = .017 and P = .036, respectively). At week 4, the proportion of systolic BP responders was significantly higher in the ALC group (42.6%) than in the AL (22.0%), LC (23.3%), and AC (27.1%) groups (P = .013, P = .021, and P = .045, respectively). At week 8, the proportion of systolic and diastolic BP responders was significantly higher in the ALC group (59.7%) than in the AL (39.3%) and AC (42.4%) groups (P = .022 and P = .049, respectively) at week 8. Third‐standard‐dose triple antihypertensive combination therapy demonstrated early effective BP control compared to third‐standard‐dose dual combination therapies, without increasing adverse drug reactions in patients with mild‐to‐moderate hypertension.
The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, ...intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of ‘vascular sinus folding’ (VSF) and mural cell drop‐out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy — just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF‐A secreted from the progesterone receptor (PR)‐expressing decidual stromal cells which are largely distributed in the anti‐mesometrial region (AMR). In comparison, P4‐PR‐regulated VEGF‐A‐VEGFR2 signalling, ligand‐independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand‐independent manner, with marked reduction of VEGF‐A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors — VEGFR2 and Tie2 — strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner.
VEGFR2 and Tie2 differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri, questioning the use of treatments affecting these pathways during pregnancy and postpartum.
The aim of this clinical trial was to assess the efficacy and safety of low‐dose triple combinations of amlodipine, telmisartan, and chlorthalidone in patients with essential hypertension. After a ...2‐week placebo run‐in period, 176 patients were randomized to seven treatment groups (placebo, quarter‐dose combination, third‐dose combination, half‐dose combination, amlodipine 5 mg, amlodipine 10 mg, and telmisartan 80 mg) and administered the assigned study drug orally for 8 weeks. The primary efficacy endpoint was the change in the mean sitting systolic blood pressure (BP) (MSSBP) at Week 8. The MSSBP and mean sitting diastolic BP in the quarter‐dose and half‐dose groups were significantly lower compared to the placebo and amlodipine 5 mg groups, with similar BP‐lowering effects observed compared to the amlodipine 10 mg and telmisartan 80 mg groups. However, the third‐dose group showed significant BP improvement only compared to the placebo group. A similar pattern was observed for the control rate of hypertension and response rates. Additional analysis was conducted after correcting for gender and age effects, and, as a result, the third‐dose group showed similar results with regard to the BP‐lowering effect as the quarter‐dose and half‐dose groups. In terms of safety, no special adverse events and clinically significant results were noted, and all dose groups of the triple combination are considered safe for use in essential hypertension patients. The current findings indicated that low‐dose triple combination of amlodipine, telmisartan, and chlorthalidone over 8 weeks effectively improved the BP‐lowering effect in patients with essential hypertension without any safety concerns.
The association of physical activity with the development and progression of coronary artery calcium (CAC) scores has not been studied. This study aimed to evaluate the prospective association ...between physical activity and CAC scores in apparently healthy adults.
Prospective cohort study of men and women free of overt cardiovascular disease who underwent comprehensive health screening examinations between 1 March 2011 and 31 December 2017. Baseline physical activity was measured using the International Physical Activity Questionnaire Short Form (IPAQ-SF) and categorised into three groups (inactive, moderately active and health-enhancing physically active (HEPA)). The primary outcome was the difference in the 5-year change in CAC scores by physical activity category at baseline.
We analysed 25 485 participants with at least two CAC score measurements. The proportions of participants who were inactive, moderately active and HEPA were 46.8%, 38.0% and 15.2%, respectively. The estimated adjusted average baseline CAC scores (95% confidence intervals) in participants who were inactive, moderately active and HEPA were 9.45 (8.76, 10.14), 10.20 (9.40, 11.00) and 12.04 (10.81, 13.26). Compared with participants who were inactive, the estimated adjusted 5-year average increases in CAC in moderately active and HEPA participants were 3.20 (0.72, 5.69) and 8.16 (4.80, 11.53). Higher physical activity was association with faster progression of CAC scores both in participants with CAC=0 at baseline and in those with prevalent CAC.
We found a positive, graded association between physical activity and the prevalence and the progression of CAC, regardless of baseline CAC scores.
Aim
To perform a systematic review and meta-analysis of the effectiveness and complications of BRTO for gastric varices.
Materials and Methods
A systematic review was performed to identify relevant ...articles. Inclusion criteria were applied to select studies with at least ten patients with acute bleeding or at-risk gastric varices treated with BRTO. Meta-analysis with random effects model was performed to calculate data for immediate technical success, clinical success, and complications.
Results
A total of 1,016 Patients from 24 studies met inclusion criteria. Technical success rate for BRTO was 96.4 % (95 % CI 93.7, 98.3 %;
Q
= 3,269.26,
p
< 0.01,
I
2
= 99.39 %). Clinical success (defined as no recurrence or rebleed of gastric varices, or complete obliteration of varices on subsequent imaging) rate was 97.3 % (95 % CI 95.2, 98.8 %;
Q
= 3,105.91,
p
< 0.01,
I
2
= 99.29 %). Major complication rate was 2.6 % (95 % CI 1.1, 4.6 %;
Q
= 3,348.98,
p
< 0.01,
I
2
= 99.34 %). Esophageal variceal recurrence rate was 33.3 % (95 % CI 24.6, 42.6 %;
Q
= 7,291.75,
p
< 0.01,
I
2
= 99.74 %).
Conclusion
BRTO is safe and efficacious for gastric varices, and current best evidence suggests that BRTO could be considered as therapy for patients with gastric varices.
This study evaluated an oscillometric device (OD), Microlife WatchBP Office AFIB, and a hybrid manual auscultatory device (AD), Greenlight 300TM, to determine a suitable blood pressure (BP) ...measurement device for the Korea National Health and Nutrition Examination Survey in a mercury‐free context. Adhering to the 2018 Universal Standard's suggested consensus, the study involved 800 subjects (mean age 51.2 ± 17.5 years; 44.3% male), who underwent triplicate BP measurements following 5 min of rest in a randomized order (OD‐first: 398 participants; AD‐first: 402 participants). BP difference was calculated as OD value minus AD value, with results stratified by measurement sequence. The overall BP difference and tolerable error probability were ‐1.1 ± 6.5/‐2.6 ± 4.9 mmHg and 89.2%/92.5% for systolic/diastolic BP (SBP/DBP), respectively. Lin's concordance correlation coefficient was 0.907/0.844 for SBP/DBP (OD‐first/AD‐first: 0.925/0.892 for SBP, 0.842/0.845 for DBP). The overall agreement for hypertension (BP ≥ 140 and/or 90 mmHg) was 0.71 (p < 0.0001), and the OD underestimated the overall hypertension prevalence by 5.1%. Analysis of the AD‐first data revealed a lower level of agreement compared to the OD‐first data; however, the observed blood pressure difference adhered to Criterion 1 of the 2018 Universal Standard. Microlife met the Criterion 1 of 2018 Universal Standard but underestimated the prevalence of hypertension. The BP discrepancy increased with higher BP levels, male sex, and smaller AC. With increasing age, the discrepancy decreased for SBP and increased for DBP.
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