Decoded cardiopoietic cell secretome linkage to heart repair biosignature.

Cardiopoiesis-primed human stem cells exert sustained benefit in treating heart failure despite limited retention following myocardial delivery. To assess potential paracrine contribution, the secretome of cardiopoiesis conditioned versus naïve human mesenchymal stromal cells was decoded by directed proteomics augmented with machine learning and systems interrogation. Cardiopoiesis doubled cellular protein output generating a distinct secretome that segregated the conditioned state. Altering the expression of 1035 secreted proteins, cardiopoiesis reshaped the secretome across functional classes. The resolved differential cardiopoietic secretome was enriched in mesoderm development and cardiac progenitor signaling processes, yielding a cardiovasculogenic profile bolstered by upregulated cardiogenic proteins. In tandem, cardiopoiesis enhanced the secretion of immunomodulatory proteins associated with cytokine signaling, leukocyte migration, and chemotaxis. Network analysis integrated the differential secretome within an interactome of 1745 molecules featuring prioritized regenerative processes. Secretome contribution to the repair signature of cardiopoietic cell-treated infarcted hearts was assessed in a murine coronary ligation model. Intramyocardial delivery of cardiopoietic cells improved the performance of failing hearts, with undirected proteomics revealing 50 myocardial proteins responsive to cell therapy. Pathway analysis linked the secretome to cardiac proteome remodeling, pinpointing 17 cardiopoiesis-upregulated secretome proteins directly upstream of 44% of the cell therapy-responsive cardiac proteome. Knockout, in silico, of this 22-protein secretome-dependent myocardial ensemble eliminated indices of the repair signature. Accordingly, in vivo, cell therapy rendered the secretome-dependent myocardial proteome of an infarcted heart indiscernible from healthy counterparts. Thus, the secretagogue effect of cardiopoiesis transforms the human stem cell secretome, endows regenerative competency, and upregulates candidate paracrine effectors of cell therapy-mediated molecular restitution.

Biventricular catheterization combined with pressure-volume loop monitoring provides insight into the dynamic effects of left ventricular assist devices ramp on right ventricular function.

Ramp studies are utilized for speed optimization of continuous flow left ventricular assist devices (CF-LVADs). We here report the utility of combined left and right heart catheterization during a ramp study to ensure a comprehensive understanding of the hemodynamic implications on both ventricles. Pressure-volume loop (PV loop) monitoring uncovered compromised systolic and mildly compromised right ventricular function with increasing LVAD speeds, despite improvement in left ventricular unloading. These findings informed patient management and highlight the potential utility of PV loop monitoring as an adjunct to left and right heart catheterization during ramp studies of next-generation LVADs.

Predicting 60-4 visual field tests using 3D facial reconstruction.

BACKGROUND: Despite, the potential clinical utility of 60-4 visual fields, they are not frequently used in clinical practice partly, due to the purported impact of facial contour on field defects. The purpose of this study was to design and test an artificial intelligence-driven platform to predict facial structure-dependent visual field defects on 60-4 visual field tests. METHODS: Subjects with no ocular pathology were included. Participants were subject to optical coherence tomography, 60-4 Swedish interactive thresholding algorithm visual field tests and photography. The predicted visual field was compared with observed 60-4 visual field results in subjects. Average and point-specific sensitivity, specificity, precision, negative predictive value, accuracy, and F1-scores were primary outcome measures. RESULTS: 30 healthy were enrolled. Three-dimensional facial reconstruction using a convolution neural network (CNN) was able to predict facial contour-dependent 60-4 visual field defects in 30 subjects without ocular pathology. Overall model accuracy was 97%±3% and 96%±3% and the F1-score, dependent on precision and sensitivity, was 58%±19% and 55%±15% for the right eye and left eye, respectively. Spatial-dependent model performance was observed with increased sensitivity and precision within the far inferior nasal field reflected by an average F1-score of 76%±20% and 70%±29% for the right eye and left eye, respectively. CONCLUSIONS: This pilot study reports the development of a CNN-enhanced platform capable of predicting 60-4 visual field defects in healthy controls based on facial contour. Further study with this platform may enhance understanding of the influence of facial contour on 60-4 visual field testing.

KATP channel dependent heart multiome atlas.

Plasmalemmal ATP sensitive potassium (KATP) channels are recognized metabolic sensors, yet their cellular reach is less well understood. Here, transgenic Kir6.2 null hearts devoid of the KATP channel pore underwent multiomics surveillance and systems interrogation versus wildtype counterparts. Despite maintained organ performance, the knockout proteome deviated beyond a discrete loss of constitutive KATP channel subunits. Multidimensional nano-flow liquid chromatography tandem mass spectrometry resolved 111 differentially expressed proteins and their expanded network neighborhood, dominated by metabolic process engagement. Independent multimodal chemometric gas and liquid chromatography mass spectrometry unveiled differential expression of over one quarter of measured metabolites discriminating the Kir6.2 deficient heart metabolome. Supervised class analogy ranking and unsupervised enrichment analysis prioritized nicotinamide adenine dinucleotide (NAD+), affirmed by extensive overrepresentation of NAD+ associated circuitry. The remodeled metabolome and proteome revealed functional convergence and an integrated signature of disease susceptibility. Deciphered cardiac patterns were traceable in the corresponding plasma metabolome, with tissue concordant plasma changes offering surrogate metabolite markers of myocardial latent vulnerability. Thus, Kir6.2 deficit precipitates multiome reorganization, mapping a comprehensive atlas of the KATP channel dependent landscape.

Longevity leap: mind the healthspan gap.

Life expectancy has increased by three decades since the mid-twentieth century. Parallel healthspan expansion has however not followed, largely impeded by the pandemic of chronic diseases afflicting a growing older population. The lag in quality of life is a recognized challenge that calls for prioritization of disease-free longevity. Contemporary communal, clinical and research trends aspiring to extend the health horizon are here outlined in the context of an evolving epidemiology. A shared action integrating public and societal endeavors with emerging interventions that target age-related multimorbidity and frailty is needed. A multidimensional buildout of a curative perspective, boosted by modern anti-senescent and regenerative technology with augmented decision making, would require dedicated resources and cost-effective validation to responsibly bridge the healthspan-lifespan gap for a future of equitable global wellbeing.

Screening for regenerative therapy responders in heart failure.

Risk of outcome variability challenges therapeutic innovation. Selection of the most suitable candidates is predicated on reliable response indicators. Especially for emergent regenerative biotherapies, determinants separating success from failure in achieving disease rescue remain largely unknown. Accordingly, (pre)clinical development programs have placed increased emphasis on the multi-dimensional decoding of repair capacity and disease resolution, attributes defining responsiveness. To attain regenerative goals for each individual, phenotype-based patient selection is poised for an upgrade guided by new insights into disease biology, translated into refined surveillance of response regulators and deep learning-amplified clinical decision support.

Secretome signature of cardiopoietic cells echoed in rescued infarcted heart proteome.

Stem cell paracrine activity is implicated in cardiac repair. Linkage between secretome functionality and therapeutic outcome was here interrogated by systems analytics of biobanked human cardiopoietic cells, a regenerative biologic in advanced clinical trials. Protein chip array identified 155 proteins differentially secreted by cardiopoietic cells with clinical benefit, expanded into a 520 node network, collectively revealing inherent vasculogenic properties along with cardiac and smooth muscle differentiation and development. Next generation RNA sequencing, refined by pathway analysis, pinpointed miR-146 dependent regulation upstream of the decoded secretome. Intracellular and extracellular integration unmasked commonality across cardio-vasculogenic processes. Mirroring the secretome pattern, infarcted hearts benefiting from cardiopoietic cell therapy restored the disease proteome engaging cardiovascular system functions. The cardiopoietic cell secretome thus confers a therapeutic molecular imprint on recipient hearts, with response informed by predictive systems profiling.

Need for Additional Glaucoma Surgery and Complications Following Glaucoma Drainage Device Surgery.

PRCIS: In this longitudinal study of patients with open-angle (OAG), pseudoexfoliative (PXE), or neovascular glaucoma (NVG) receiving glaucoma drainage devices (GDD), posttube cumulative rates of reoperation, corneal graft, and visually threatening complications (VT-complications) increased beyond 5 years and were not significantly affected by glaucoma type. PURPOSE: To study the need for additional glaucoma surgery and development of complications after first GDD surgery in eyes with primary OAG, PXE, or NVG glaucoma. PATIENTS AND METHODS: There were 306 eyes with OAG (n=185), PXE (n=60), or NVG (n=61) glaucoma who received a first GDD between 1996 and 2017. Outcomes including glaucoma reoperation, corneal graft procedure, and VT-complications after GDD were measured. Kaplan-Meier analysis was used to compare cumulative rate of reaching outcomes over time after GDD placement among the 3 glaucoma groups. RESULTS: When comparing the OAG, PXE, and NVG groups, there were no significant differences in post-GDD cumulative rates of reoperation (P=0.33), corneal graft (P=0.26), or VT-complications (P=0.65) over time. For all eyes, the overall cumulative rates for each outcome measure increased beyond 5 years, and specific Kaplan-Meier rates (5-y, 10-y) included: reoperation (16%, 25%), corneal graft (6%, 12%), VT-complications (9%, 14%). When comparing specific GDDs, the Ahmed FP7 had a higher cumulative reoperation rate over time compared with the Baerveldt 350 (P=0.019). CONCLUSION: Glaucoma type did not significantly affect post-GDD cumulative rates of reoperation, corneal graft, and VT-complication among the OAG, PXE, and NVG groups. For all eyes, cumulative rates of reoperation, corneal graft, and VT-complications increased beyond 5 years. The Ahmed FP7 had a significantly higher cumulative reoperation rate compared with the Baerveldt 350 over time.

Rate of Corneal Grafting Post-Glaucoma Drainage Device Use in Pediatric and Adult Patients.

PRCIS: Kaplan-Meier analysis was used to compare the rate of corneal grafting after glaucoma drainage device (GDD) placement in pediatric and adult patients. Adults were at an increased risk of receiving a corneal graft after device placement. PURPOSE: The goal of this study was to compare the rate of corneal graft implantation after GDD placement in pediatric and adult patients. PATIENTS: Patients receiving a GDD between January 1, 1985 and December 31, 2017 were selected from the medical records. Patients receiving their first device while <18 years of age were considered children for the extent of the study. METHODS: We compared the rate of receiving a corneal graft after GDD implantation using Kaplan-Meier analysis. Baseline patient characteristics and surgical characteristics were compared using a generalized estimating equation. RESULTS: Corneal grafting occurred in 8.6% of adults and 4.7% of children from the original cohort. The rate of receiving a corneal graft at 5, 10, and 15 years was 9.4%, 16.8%, 39.4% and 1.6%, 1.6%, 12.5% for adults and children, respectively. However, certain characteristics were different between the 2 groups. CONCLUSION: Adult patients were more likely to receive a corneal graft after GDD placement. However, pediatric and adult patients differed in the prevalence of preexisting corneal disease, glaucoma type, GDD type used, and types of previous surgeries. Elucidation of the impact of these factors on corneal graft rate requires a larger cohort size.

Characterizing the effect of Poast on Chlorella vulgaris, a non-target organism.

Herbicides may cause unexpected damage to non-target organisms as it is challenging to predict undesirable biotic interactions. Poast is a widely used herbicide formulation that contains sethoxydim and targets the acetyl-CoA carboxylase of perennial grasses. In this study, Chlorella vulgaris, a unicellular green microalga, was exposed to a 0.08% working concentration of Poast and the physiological and biochemical changes that took place were monitored using biochemical assays, fluorometry, oximetry, and immunoblotting. Within 15 min, severe photosynthetic damage was observed through a reduction in oxygen production and a reduced rate of electron transfer beyond photosystem II. In addition to direct damage to the photosynthetic machinery, it was shown that cells experienced membrane fragmentation. Within 30 min, over 90% of the exposed cells were nonviable. However, sethoxydim, the active ingredient, did not cause detrimental effects when applied along with mineral spirits, the primary solvent of the formulation. A synergistic or additive effect between sethoxydim and the formulation components cannot be ruled out. This data suggests that Poast has the potential to cause severe harm to unicellular phototrophs in the case of herbicide over application or runoff.