Older patients (aged 60 years or more) awaiting heart transplant often have comorbidities that may limit overall survival independent of cardiac status. We hypothesized that these comorbidities have ...a more-limiting impact on survival than age of donor heart and that older allografts might be utilized in these patients without compromising outcomes.
We identified all transplant recipients aged more than 60 years in the United Network for Organ Sharing database. Local regression analysis detected the point above which increasing donor age incurred increasing risk of mortality, above and below which two cohorts were defined. Kaplan-Meier analysis compared cumulative 5-year survival between groups. Cox proportional hazard modeling was then used to determine the hazards of death in the two groups.
An inflection point in posttransplant survival was detected near donor age 50 years. Of 14,113 older recipients studied, 86% received younger donor hearts (less than 50 years of age), and 14% received advanced age allografts (50 years of age or more). Baseline characteristics were comparable between groups except more recipients had left ventricular assist devices at time of transplant in the younger donor group (15% versus 9%, p < 0.001). Five-year survival was significantly lower among recipients receiving advanced age hearts compared with those receiving younger hearts (67% versus 73%, log rank p < 0.001). Adjusting for relevant recipient baseline characteristics, patients receiving advanced age hearts were 30% more likely to die by 5 years compared with patients receiving younger hearts.
Transplant recipients aged 60 years and more who receive advanced age donor hearts (50 years or more) have a significantly increased risk of mortality. With careful allograft selection, use of donor hearts to age 50 may be acceptable among older transplant recipients.
IMPORTANCE: Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac ...recovery. OBJECTIVE: To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018. INTERVENTIONS: Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival. RESULTS: Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio RR, 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio HR, 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, −7.89; 95% CI, −39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-days; difference, −0.07; 95% CI, −0.41 to 0.27; P = .68). CONCLUSIONS AND RELEVANCE: Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02362646
The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal ...peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.
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•A family of gene clusters in gut bacteria encodes dipeptide aldehydes•Present in 88% of humans and transcribed under conditions of host colonization•One compound, Phe-Phe-H, targets cathepsins in an unbiased cell-based assay•Uncovers a possible role for lysosomal proteases in microbiota-host interactions
Guo et al. report the discovery of a new family of microbial metabolites that are widely produced by the microbes of the human gut and that chemically modify host cellular proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The thiazolylpeptides are a family of > 50 bactericidal antibiotics that block the initial steps of bacterial protein synthesis. Here, we report a biosynthetic gene cluster for thiocillin and ...establish that it, and by extension the whole class, is ribosomally synthesized. Remarkably, the C-terminal 14 residues of a 52-residue peptide precursor undergo 13 posttranslational modifications to give rise to thiocillin, making this antibiotic the most heavily posttranslationally-modified peptide known to date.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background The CorCap cardiac support device (Acorn Cardiovascular, Inc, St Paul, Minn) is the first device that specifically addresses ventricular remodeling in heart failure by reducing wall ...stress. We previously reported outcomes from the Acorn randomized trial to a common closing date (22.9 months of follow-up). This report summarizes results of extended followup to 5 years. Methods A total of 107 patients were enrolled in the no–mitral valve repair/replacement stratum including 57 in the CorCap treatment group and 50 in the control (optimal medical therapy alone) group. Patients were assessed every year, until completing 5 years of follow-up, for survival, adverse events, major cardiac procedures, New York Heart Association (NYHA) functional status, and echocardiograms, which were read at a core laboratory. Results Overall survivals were similar between the treatment and control groups, demonstrating no late adverse effect on mortality. The treatment group had significant reductions in left ventricular end-diastolic volume ( P = .029) as well as a small increase in sphericity index. More patients in the treatment group improved by at least 1 NYHA functional class ( P = .0005). There was no difference in rates of adverse events. In a subgroup of patients with an intermediate left ventricular end-diastolic dimension, there was a significant reduction in the Kaplan-Meier estimate of the freedom from the composite end point of death and major cardiac procedures ( P = .04). Conclusions These cumulative data demonstrate the sustained reverse remodeling of the left ventricle and the long-term safety and efficacy of the CorCap cardiac support device as an adjunctive therapy for patients with heart failure who remain symptomatic despite optimal medical therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The relationship between low oxygen delivery (DO2) on cardiopulmonary bypass and morbidity and mortality following cardiac surgery remains unexamined.
We reviewed patients undergoing Society of ...Thoracic Surgeons index procedures from March 2019 to July 2020, coincident with implementation of a new electronic perfusion record that provides for continuous recording of DO2 and flow parameters. Continuous perfusion variables were analyzed using area-over-the-curve (AOC) calculations below predefined thresholds (DO2 <280 mL O2/min/m2, cardiac index <2.2 L/min, hemoglobin < baseline, and mean arterial pressure <65 mm Hg) to quantify depth and duration of potentially harmful exposures. Multivariable logistic regression adjusted by Society of Thoracic Surgeons predicted-risk scores were used to assess for relationship of perfusion variables with the primary composite outcome of any Society of Thoracic Surgeons index procedure, as well as individual Society of Thoracic Surgeons secondary outcomes (eg, mortality, renal failure, prolonged ventilation >24 hours, stroke, sternal wound infection, and reoperation).
Eight hundred thirty-four patients were included; 42.7% (356) underwent isolated coronary artery bypass grafting (CABG), whereas 57.3% underwent nonisolated CABG (eg, valvular or combined CABG/valvular operations). DO2 <280-AOC trended toward association with the primary outcome across all cases (P = .07), and was significantly associated for all nonisolated CABG cases (P = .02)—more strongly than for cardiac index <2.2-AOC (P = .04), hemoglobin <7-AOC (P = .51), or mean arterial pressure <65-AOC (P = .11). Considering all procedures, DO2 <280-AOC was independently associated prolonged ventilation >24 hours (P = .04), an effect again most pronounced in nonisolated-CABG cases (P = .002), as well as acute kidney injury <72 hours (P = .04). Patients with glomerular filtration rate <65 mL/min and baseline hemoglobin <12.5 g/dL appeared especially vulnerable.
Low DO2 on bypass may be associated with morbidity/mortality following cardiac surgery, particularly in patients undergoing nonisolated CABG. These results underscore the importance of goal-directed perfusion strategies.
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Background The aim of this study was to evaluate institutional volume-outcome relationships in extracorporeal membrane oxygenation (ECMO) with subanalyses of ECMO in patients with a primary diagnosis ...of respiratory failure. Methods All institutions with adult ECMO discharges in the Nationwide Inpatient Sample from 2002 to 2011 were evaluated. International Classification of Diseases (ninth revision) codes were used to identify ECMO-treated patients, indications, and concurrent procedures. Patients who were treated with ECMO after cardiotomy were excluded. Annual institutional and national volume of ECMO hospitalizations varied widely, hence the number of ECMO cases performed at an institution was calculated for each year independently. Institutions were grouped into high-, medium-, and low-volume terciles by year. Statistical analysis included hierarchical, multivariable logistic regression. Results The in-hospital mortality rates for ECMO admissions at low-, medium-, and high-volume ECMO centers were 48% (n = 467), 60% (n = 285), and 57% (n = 445), respectively ( p = 0.001). In post hoc pairwise comparisons, patients in low-volume hospitals were more likely to survive to discharge compared with patients in medium-volume ( p = 0.001) and high-volume ( p = 0.005) hospitals. There was no significant difference in survival between medium-volume and high-volume hospitals ( p = 0.81). In a subanalysis of patients with respiratory failure, low-volume ECMO centers maintained the lowest rates of in-hospital mortality (47%), versus 61% in medium-volume institutions ( p = 0.045) and 56% in high-volume institutions ( p = 0.15). Multivariable logistical regression produced similar results in the entire study sample and in patients with respiratory failure. Conclusions ECMO outcomes in the Nationwide Inpatient Sample do not follow a traditional volume-outcome relationship, and these results suggest that, in properly selected patients, ECMO can be performed with acceptable results in U.S. centers that do not perform a high volume of ECMO.
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