Objectives This study investigated whether cytokine enhancement of a biodegradable patch could restore cardiac function after surgical ventricular restoration (SVR) even when seeded with cells from ...old donors. Background SVR can partially restore heart size and improve function late after an extensive anterior myocardial infarction. However, 2 limitations include the stiff synthetic patch used and the limited healing of the infarct scar in aged patients. Methods We covalently immobilized 2 proangiogenic cytokines (vascular endothelial growth factor and basic fibroblast growth factor) onto porous collagen scaffolds. We seeded human mesenchymal stromal cells from young (50.0 ± 8.0 years, N = 4) or old (74.5 ± 7.4 years, N = 4) donors into the scaffolds, with or without growth factors. The patches were characterized and used for SVR in a rat model of myocardial infarction. Cardiac function was assessed. Results In vitro results showed that cells from old donors grew slower in the scaffolds. However, the presence of cytokines modulated the aging-related p16 gene and enhanced cell proliferation, converting the old cell phenotype to a young phenotype. In vivo studies showed that 28 days after SVR, patches seeded with cells from old donors did not induce functional recovery as well as patches seeded with young cells. However, cytokine-enhanced patches seeded with old cells exhibited preserved patch area, prolonged cell survival, and augmented angiogenesis, and rats implanted with these patches had better cardiac function. The patch became an elastic tissue, and the old cells were rejuvenated. Conclusions This sustained-release, cytokine-conjugated system provides a promising platform for engineering myocardial tissue for aged patients with heart failure.
Bleeding is the most common adverse event in those with cardiovascular (CV) disease receiving antithrombotic therapy, and it most commonly occurs in the gastrointestinal (GI) tract. Clinicians often ...dismiss bleeding as an adverse event that is reversible with effective antithrombotic therapy, but bleeding is associated with substantial morbidity and mortality, most likely mediated through an increased risk of CV events. Reducing the burden of bleeding requires knowledge of the potentially modifiable risk factors for bleeding and the potentially modifiable risk factors for adverse outcomes after bleeding.
INTERBLEED is an international, multicentre, 2-component, observational study, with an incident case-control study examining the risk factors for GI bleeding, and a prospective cohort study of risk factors for CV events after GI bleeding. Cases either have CV disease and present to the hospital with GI bleeding or develop GI bleeding during hospitalization. Controls have CV disease, but no history of GI bleeding. We use a questionnaire to obtain detailed information on known and potential risk factors for GI bleeding and for CV events and outcomes after bleeding. We obtain CV and anthropometric measurements, perform functional and cognitive assessments, and follow participants at 3 months and 12 months.
As of April 1, 2022, the study is ongoing in 10 countries at 31 centres and has recruited 2407 cases and 1478 controls.
Knowledge of risk factors for bleeding, and risk factors for CV events and functional decline after bleeding, will help develop strategies to prevent bleeding and subsequent complications.
L’hémorragie est l’effet indésirable le plus fréquent chez les patients atteints de maladies cardiovasculaires (CV) qui reçoivent un traitement antithrombotique, et elle survient le plus souvent dans le tractus gastro-intestinal (GI). Les cliniciens considèrent souvent l’hémorragie comme une simple manifestation indésirable réversible par un traitement antithrombotique efficace, mais une morbidité et une mortalité considérables y sont associées, probablement en raison d’un risque accru d’événements CV. Une réduction du fardeau de l’hémorragie nécessite une connaissance des facteurs de risque potentiellement modifiables tant de l’hémorragie que des événements indésirables qui surviennent après l’hémorragie.
INTERBLEED est une étude internationale, observationnelle et multicentrique à deux volets; le premier volet est une étude cas-témoins incidents visant à examiner les facteurs de risque d’hémorragie GI, alors que le second volet est une étude de cohorte prospective visant à examiner les facteurs de risque d’événements CV après une hémorragie GI. Les cas sont des patients atteints de maladies CV qui consultent les services hospitaliers pour une hémorragie GI ou qui présentent une hémorragie GI en cours d’hospitalisation. Les témoins sont des patients atteints de maladies CV, mais sans antécédents d’hémorragie GI. Un questionnaire est utilisé pour obtenir des renseignements détaillés au sujet de facteurs de risque connus et potentiels d’hémorragie GI et d’événements CV et d’autres résultats de santé après une hémorragie. Des mesures cardiovasculaires et anthropométriques ainsi que des évaluations fonctionnelles et cognitives sont réalisées, et les participants sont revus après trois mois et 12 mois.
En date du 1er avril 2022, l’étude est en cours dans 10 pays et 31 établissements de santé; 2 407 cas et 1 478 témoins ont été recrutés.
La connaissance des facteurs de risque d’hémorragie, ainsi que des facteurs de risque d’événements CV et de déclin fonctionnel à la suite d’une hémorragie, aidera à mettre en place des stratégies pour prévenir les hémorragies et les complications qui peuvent en découler.
Objective: Surgical outcomes of acute type A aortic dissection have been recognized to be associated with the surgical volume of individual hospitals and surgeons. In this study, we aimed to ...investigate the results and learning curves of acute type A aortic dissection operations performed by early-career cardiovascular surgeons. Methods: A total of 248 surgical repairs of acute type A aortic dissections were conducted at a tertiary medical center between 2010 and 2018. By using the cumulative sum test, cardiovascular surgeons in their early career were identified, and their performances were assessed. The outcomes of patients who were operated by early-career cardiovascular surgeons were compared with those by experienced or senior surgeons. Results: During the study period, 202 (81.5%) of the 248 acute type A aortic dissection operations were performed primarily by the 4 newly appointed attending cardiovascular surgeons. In cumulative sum curves, all surgeons exhibited a steady performance throughout the study period. On the basis of our institutional result of acute type A aortic dissection operation, early career was defined as performing fewer than 32 acute type A aortic dissection operations. The 30-day mortality rates of acute type A aortic dissection operations performed by early-career surgeons were equivalent to those performed by experienced/senior surgeons (10.9% vs 12.5%, P = .844). There was also no difference in mid-term overall survival and aortic event-free survival between the 2 groups (P = .638 and P = .574, respectively). Conclusions: In a center with a well-established program, cardiovascular surgeons could accomplish surgical repair of acute type A aortic dissection with adequate early- and mid-term results from the initiation of their careers.
Objective Studies on the partial thrombosis of a false lumen after repairing a type A acute aortic dissection (TAAAD) have reported conflicting results. We investigated the effects of a partially ...thrombosed false lumen on the segmental growth rates, distal aortic reoperations, and long-term survival. Methods The postoperative computed tomography scans of 67 patients were retrospectively reviewed. A false lumen was independently defined at 3 segments of the descending thoracic aorta (DTA) on the last follow-up computed tomography scan: the proximal segment near the aortic arch, the distal segment near the diaphragm, and the middle segment. Results The segmental aortic growth rate of completely thrombosed, completely patent, and partially thrombosed false lumens was −0.10 ± 0.31, 0.09 ± 0.22, and 0.35 ± 0.60 mm/mo at the proximal DTA ( P = .001), −0.04 ± 0.18, 0.12 ± 0.19, and 0.28 ± 0.28 mm/mo at the middle DTA ( P < .001), and −0.02 ± 0.13, 0.07 ± 0.07, and 0.16 ± 0.14 mm/mo at the distal DTA ( P < .001), respectively. The corresponding freedom from reoperation rates for the proximal DTA at 10 years were 100%, 88%, and 62% ( P = .013). The overall 10-year survival rate was 89% and was not significantly different among the study groups. Conclusions Partial thrombosis at each segment of a residual false lumen after TAAAD repair correlated with a faster regional aortic growth rate and predicted a greater reoperation rate but did not affect long-term overall survival.
Objective Cell therapy has received much attention for its potential to regenerate ischemic organs, but initial clinical trials in aged patients did not replicate the dramatic benefits recorded in ...preclinical studies with young animals. This study was designed to improve our understanding of age-related changes in the response to ischemic injury and the regenerative capacity of implanted cells in the context of cell therapy for older recipients. Methods and Results Restoration of regional perfusion after hind limb femoral artery ligation was impaired ( P < .05) in old (vs young) rats, reflecting approximately 50% reductions in circulating endothelial progenitor cells and the release of vascular endothelial growth factor/basic fibroblast growth factor. Bone marrow stromal cells from young or old donors implanted into the ischemic hind limbs of young or old rats restored regional perfusion. Specifically, we documented significantly greater ( P < .05) angiogenic potential in young (vs old) donor cells when recipient age was controlled and greater ( P < .05) regenerative responses in young (vs old) recipients when donor cell age was controlled. Contributing to these differences were significantly greater survival in young (vs old) donor cells (in vitro and after implantation) and about 2-fold more production of vascular endothelial growth factor/basic fibroblast growth factor and mobilization of endogenous endothelial progenitor cells in young (vs old) rats in response to ischemia. Conclusions The outcome of cell therapy in older recipients is determined by a combination of age effects on the donor cells and on the recipients' endogenous responses. Donor cell age and recipient age are equally important contributors to the outcome of cell therapy; thus, novel biointerventions will need to target both components of the process.
Objectives This study evaluated the capacity of ultrasound-targeted microbubble destruction (UTMD) to deliver angiogenic genes, improve perfusion, and recruit progenitor cells after a myocardial ...infarction (MI) in mice. Background Angiogenic gene therapy after an MI may become a clinically relevant approach to improve the engraftment of implanted cells if targeted delivery can be accomplished noninvasively. The UTMD technique uses myocardial contrast echocardiography to target plasmid gene delivery to the myocardium and features low toxicity, limited immunogenicity, and the potential for repeated application. Methods Empty plasmids (control group) or those containing genes for vascular endothelial growth factor (VEGF), stem cell factor (SCF), or green fluorescent protein (to visualize gene delivery) were incubated with perflutren lipid microbubbles. The microbubble-deoxyribonucleic acid mixture was injected intravenously into C57BL/6 mice at 7 days after coronary artery ligation (MI). The UTMD technique facilitated transgene release into the myocardium. Twenty-one days after MI, myocardial perfusion and function were assessed by contrast echocardiography. Protein expression was quantified by Western blot and enzyme-linked immunosorbent assay. Flow cytometry quantified progenitor cell recruitment to the heart. Blood vessel density was evaluated immunohistochemically. Results Green fluorescent protein expression in the infarcted myocardium demonstrated gene delivery. Myocardial VEGF and SCF levels increased significantly in the respective groups (p < 0.05). The physiologic impact of VEGF and SCF gene delivery was confirmed by increased myocardial recruitment of VEGF receptor 2– and SCF receptor (c-kit)–expressing cells, respectively (p < 0.05). Consequently, capillary and arteriolar density (Factor VIII and alpha-smooth muscle actin staining), myocardial perfusion, and cardiac function were all enhanced (p < 0.01 relative to control group) in recipients of VEGF or SCF. Conclusions Noninvasive UTMD successfully delivered VEGF and SCF genes into the infarcted heart, increased vascular density, and improved myocardial perfusion and ventricular function. The UTMD technique may be an ideal method for noninvasive, repeated gene delivery after an MI.
Abstract Background Surgical site infection (SSI) after total knee arthroplasty (TKA) is a catastrophic complication. Administration of prophylactic antibiotics within 60 minutes before surgery is a ...well-established strategy to prevent SSI. The study is aimed to identify the risk factors for SSI regarding primary TKA in patients with timely administration of systemic prophylactic antibiotics. Methods A retrospective review of patients with primary TKA between 2009 and 2013 was conducted. Patients who had prophylactic antibiotics administered after skin incision or >60 minutes before skin incision were excluded. Results Of the 3152 patients enrolled, the incidence of SSI and deep-implant SSI was 1.52% and 0.79%, respectively. Charlson Comorbidity Index ≥3 was an independent risk factor for both SSI (odds ratio OR, 2.34; 95% confidence interval CI, 1.24-4.44, P = .01) and deep-implant SSI (OR, 3.46; 95% CI, 1.52-7.91, P < .01). Optimal dose of systemic antibiotics adjusted by patients’ body weight for prophylaxis (OR, 0.29; 95% CI, 0.17-0.62, P < .01) and using antibiotic-laden bone cement (OR, 0.33; 95% CI, 0.17-0.64, P < .01) were significant protective factors for SSI. Meanwhile, using antibiotic-laden bone cement (OR, 0.31; 95% CI, 0.13-0.76, P = .01) also significantly decreased the risk of deep-implant SSI. Conclusion Our findings highlight the importance of appropriate dosage of prophylactic antibiotics and use of antibiotic-laden cement in preventing SSI after primary TKA. For prevention of deep-implant SSI, using antibiotic-laden bone cement seems to be an advisable strategy.
Summary Background The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine ...produced by ten Chinese manufacturers. Methods In this multicentre, double-blind, randomised trial, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7·5 μg, 15 μg, or 30 μg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 μg or 10 μg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre GMT of haemagglutination inhibition antibody), and seroprotection (GMT ≥1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov , numbers NCT00956111 and NCT00975572 . The other eight studies were registered with the State Food and Drug Administration of China. Findings 12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69·5% (95% CI 65·9–72·8) for the 7·5 μg adjuvant split-virion formulation to 92·8% (91·9–93·6) for the 30 μg non-adjuvant split-virion formulation. The seroprotection rate was 86·5% (796 of 920; 84·1–88·7) in recipients of one dose of the 7·5 μg non-adjuvant split-virion vaccine compared with 9·8% (140 of 1432; 8·3–11·4) in recipients of placebo (p<0·0001). One dose of the 7·5 μg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76·7%, 70·7–82·0), 211 of 218 adolescents (12 years to <18 years; 96·8%, 93·5–98·7), 289 of 323 adults (18–60 years; 89·5%, 85·6–92·6), and 118 of 147 adults older than 60 years (80·3%, 72·9–86·4), meeting the European Union's licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7·5 μg formulation increased the seroprotection rate to 97·7% (215 of 220, 94·8–99·3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0·6%, 0·5–0·8) recipients of vaccine compared with one recipient (0·1%, 0–0·2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0·22%; 0·14–0·33) recipients of vaccine after the first dose and four (0·04%; 0·01–0·09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose. Interpretation One dose of non-adjuvant split-virion vaccine containing 7·5 μg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7·5 μg doses might be needed. Funding Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.
Summary Background Seroprevalence data suggest that a third of the world's population has been infected with the hepatitis E virus. Our aim was to assess efficacy and safety of a recombinant ...hepatitis E vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial. Methods Healthy adults aged 16–65 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of HEV 239 (30 μg of purified recombinant hepatitis E antigen adsorbed to 0·8 mg aluminium hydroxide suspended in 0·5 mL buffered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months. Randomisation was done by computer-generated permuted blocks and stratified by age and sex. Participants were followed up for 19 months. The primary endpoint was prevention of hepatitis E during 12 months from the 31st day after the third dose. Analysis was based on participants who received all three doses per protocol. Study participants, care givers, and investigators were all masked to group and vaccine assignments. This trial is registered with ClinicalTrials.gov , number NCT01014845. Findings 11 165 of the trial participants were tested for hepatitis E virus IgG, of which 5285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n=56 302) or placebo (n=56 302). 48 693 (86%) participants in the vaccine group and 48 663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100·0% (95% CI 72·1–100·0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted. Interpretation HEV 239 is well tolerated and effective in the prevention of hepatitis E in the general population in China, including both men and women age 16–65 years. Funding Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&D Programme, Chinese National Science Fund for Distinguished Young Scholars, Fujian Provincial Department of Sciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund for Distinguished Young Scholars.
PDF
