Experimental and theoretical model of microvascular network remodeling and blood flow redistribution following minimally invasive microvessel laser ablation.

Overly dense microvascular networks are treated by selective reduction of vascular elements. Inappropriate manipulation of microvessels could result in loss of host tissue function or a worsening of the clinical problem. Here, experimental, and computational models were developed to induce blood flow changes via selective artery and vein laser ablation and study the compensatory collateral flow redistribution and vessel diameter remodeling. The microvasculature was imaged non-invasively by bright-field and multi-photon laser microscopy, and optical coherence tomography pre-ablation and up to 30 days post-ablation. A theoretical model of network remodeling was developed to compute blood flow and intravascular pressure and identify vessels most susceptible to changes in flow direction. The skin microvascular remodeling patterns were consistent among the five specimens studied. Significant remodeling occurred at various time points, beginning as early as days 1-3 and continuing beyond day 20. The remodeling patterns included collateral development, venous and arterial reopening, and both outward and inward remodeling, with variations in the time frames for each mouse. In a representative specimen, immediately post-ablation, the average artery and vein diameters increased by 14% and 23%, respectively. At day 20 post-ablation, the maximum increases in arterial and venous diameters were 2.5× and 3.3×, respectively. By day 30, the average artery diameter remained 11% increased whereas the vein diameters returned to near pre-ablation values. Some arteries regenerated across the ablation sites via endothelial cell migration, while veins either reconnected or rerouted flow around the ablation site, likely depending on local pressure driving forces. In the intact network, the theoretical model predicts that the vessels that act as collaterals after flow disruption are those most sensitive to distant changes in pressure. The model results correlate with the post-ablation microvascular remodeling patterns.

Impact of Ticagrelor Versus Clopidogrel on Bleeding Outcomes of Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Increased bleeding risks have been documented in patients exposed to P2Y12 inhibitors within 5 days of coronary artery bypass surgery (CABG). This study aimed to determine the relative CABG bleeding risks of clopidogrel versus ticagrelor exposure and the proper time course of ticagrelor discontinuation prior to surgery. METHODS: Clinical outcomes were assessed in 2075 isolated CABG patients, including 375 who had received P2Y12 inhibitors within 5 days of surgery (155 clopidogrel, 213 ticagrelor, 7 prasugrel). BARC-4 CABG bleeding complications and perioperative blood product usage were assessed in propensity-matched P2Y12-inhibited and non-P2Y12-inhibited cohorts. RESULTS: P2Y12-inhibited patients (n = 375) in comparison to matched non-P2Y12-inhibited patients (n = 1138) had higher rates of re-operation for bleeding (3.8 % vs 1.3 %, p = 0.003), postoperative red blood cell transfusion ≥5 units (5.7 % vs 2.7 %, p = 0.007), and intraoperative and postoperative blood product utilization (42.3 % vs 27.1 %, p < 0.001; 41.8 % vs 32.2 %, p < 0.001, respectively). Univariate predictors of BARC-4 bleeding included clopidogrel (OR: 2.145, 95 % CI: 1.131-4.067, p = 0.019) and ticagrelor discontinued within 3 days of surgery (OR: 2.153, 95 % CI: 1.003-4.169, p = 0.049). Multivariate logistic regression demonstrated that only clopidogrel exposure was an independent BARC-4 bleeding predictor (OR: 1.850, 95 % CI: 1.007-3.398, p = 0.048). Unadjusted ticagrelor patients with drug discontinuation 4-5 days prior to CABG only demonstrated higher rates of perioperative platelet transfusion, without additional signs of excessive bleeding. CONCLUSIONS: Clopidogrel exposure within 5 days of CABG is an independent predictor of BARC-4 bleeding, whereas major ticagrelor bleeding effects are confined to drug exposure within 3 days of surgery.

Modulating Drug Release from Short Poly(ethylene glycol) Block Initiated Poly(L-lactide) Di-block Copolymers.

This paper investigates drug release from a novel series of mPEG-functionalised PLLA polymers whose individual components (PEG and PLLA) have regulatory FDA approval. Two processing methods were explored to understand their effect on the morphology and drug release profiles of the polymers, with and without mPEG functionalisation. In the first method the polymer and Propranolol.HCl drug powders were mixed together before injection moulding. In the second method, supercritical CO2 was used to mix the polymer and drug before injection moulding. When non-functionalised PLLA was processed through injection moulding alone, there were no signs of polymer-drug interaction, and the drug was confined to crystals on the surface. This resulted in up to 85 wt% burst release of propranolol.HCl after one day of incubation. By contrast, injection moulding of mPEG-functionalised polymers resulted in the partial dissolution of drug in the polymer matrix and a smaller burst (50 wt% drug) followed by sustained release. This initial burst release was completely eliminated from the profile of mPEG-functionalised polymers processed via supercritical CO2. The addition of mPEG facilitated the distribution of the drug into the bulk matrix of the polymer. Paired with supercritical CO2 processing, the drug release profile showed a slow, sustained release throughout the 4 months of the study.

Propensity-matched comparison of right mini-thoracotomy versus median sternotomy for isolated mitral valve repair.

BACKGROUND: A right mini-thoracotomy (RT) versus median sternotomy (MS) approach for isolated mitral valve (MV) repair has been associated with less postoperative morbidity, shorter hospital stay, and faster functional recovery, but with consistently longer cross-clamp time and higher operative costs. METHODS: We assessed the impact of a modified operative technique on outcomes in 158 RT versus 129 MS patients treated with myxomatous MV repair from 2016 through 2021. Propensity matching based upon the Society of Thoracic Surgeons Risk Score was used to compare 108 patients in each cohort. RESULTS: Propensity-matched RT patients had reductions in total ventilation time (P=0.025), postoperative atrial fibrillation (P=0.019), and hospital length of stay (P<0.001). RT and MS patients had similar cross-clamp times (66.4±13.7 vs 64.8±16.0 minutes, P=0.414), with less overall leaflet resection (32.4% vs 57.4%, P<0.001) and fewer Gore-Tex NeoChords implanted per patient (1.7±0.7 vs 2.1±1.0, P=0.028) in the RT group. The two cohorts did not differ with respect to 30-day major surgical complications. No patient died and there was no difference between the two groups with respect to freedom from re-operation (98.2% vs 98.2%, P=0.800) at a mean follow-up of 21.4±18.5 months. Direct total hospital costs were lower for the RT group (P=0.018), with reductions in postoperative charges offsetting increased operating room costs. CONCLUSIONS: In this single-center study, the RT compared to the MS approach for myxomatous MV repair resulted in less postoperative morbidity and shorter hospital length of stay, with similar cross-clamp time, reduced total hospital costs, and comparable intermediate outcomes.

Capecitabine-Associated Coronary Vasospasm and Cardiac Arrest.

Capecitabine is a prodrug of fluorouracil that specifically targets cancer cells, commonly used as monotherapy for metastatic breast and colorectal cancer. Its side effects include nausea, diarrhea, vomiting, abdominal pain, anorexia, palmar-plantar erythrodysesthesia, anemia, and hyperbilirubinemia. Rarely, this chemotherapy agent has been associated with cardiotoxicity, including cardiac arrest, likely secondary to coronary vasospasm. This case report serves to highlight the unfortunate case of a 32-year-old female who suffered a ventricular fibrillation cardiac arrest three days after initiating capecitabine therapy.

Hemiplegic migraine episode triggered by regadenoson.

SPECT and PET myocardial perfusion imaging (MPI) are widely used to evaluate patients for coronary artery disease. Regadenoson (a selective A2A adenosine receptor agonist) is a commonly used vasodilator agent for stress MPI because of its safety profile and ease of use. Common adverse reactions such as headache, shortness of breath, flushing, and chest and abdominal discomfort are typically mild and can be effectively reversed using methylxanthines such as aminophylline and caffeine. Neurological adverse reactions such as seizure and stroke have rarely been reported with the use of regadenoson. The hemodynamic changes associated with regadenoson administration, such as an exaggerated hypotensive or hypertensive response, may be the cause for the reported cerebrovascular accidents. Activation of central nervous system A2A adenosine receptors is thought to be responsible for seizure episodes in patients with or without known histories of seizure. A2A adenosine receptors activation is also believed to play a role in headaches and migraine. This patient reported who has a history of hemiplegic migraine developed left side weakness and headache following the administration of regadenoson during a PET MPI study. Imaging work-up to rule out cerebrovascular accident was normal. After 1 hour from the onset of his symptoms, his weakness and headache significantly improved with complete resolution within 24 hours. We concluded that regadenoson triggered a hemiplegic migraine episode in this patient, which has not been previously reported in the literature. It may be prudent to avoid regadenoson and adenosine use in patients with a history of hemiplegic migraine.

Assessment of Cardiovascular Risk by the Combination of Clinical Risk Scores Plus Platelet Expression of FcγRIIa.

Platelet expression of FcγRIIa was quantified after myocardial infarction (MI) and we found that patients with high platelet FcγRIIa expression (>11,000/platelet) had a fourfold greater risk of subsequent MI, stroke, and death. This analysis of the original cohort of 197 patients was designed to determine whether platelet expression of FcγRIIa could be used in combination with clinical risk scores (GRACE [Global Registry of Acute Coronary Events] and DAPT [Dual Antiplatelet Therapy]) to refine cardiovascular risk assessment. Platelet expression of FcγRIIa quantified with the use of flow cytometry was broadly distributed in patients stratified into high and low risk groups based on clinical risk scores. In patients identified as high risk by the GRACE score, 62% had high platelet FcγRIIa expression. Similarly, in patients identified as high risk by DAPT, 55% had high platelet FcγRIIa expression. High platelet FcγRIIa expression discriminated high and low risk cohorts in patients with high cardiovascular risk defined by either the GRACE score (high platelet FcγRIIa 18.9% vs low platelet FcγRIIa 0%; odds ratio = 15.7, p = 0.06) or the DAPT score (high platelet FcγRIIa 15.4% vs low platelet FcγRIIa 3.7%; odds ratio = 5.6, p = 0.03) assessment. Platelet expression of FcγRIIa merits additional study to determine whether low platelet FcγRIIa expression can be used to guide early transition to aspirin monotherapy and high platelet FcγRIIa expression can be used to guide continuation of DAPT.

Earth's earliest and deepest purported fossils may be iron-mineralized chemical gardens.

Recognizing fossil microorganisms is essential to the study of life's origin and evolution and to the ongoing search for life on Mars. Purported fossil microbes in ancient rocks include common assemblages of iron-mineral filaments and tubes. Recently, such assemblages have been interpreted to represent Earth's oldest body fossils, Earth's oldest fossil fungi, and Earth's best analogues for fossils that might form in the basaltic Martian subsurface. Many of these putative fossils exhibit hollow circular cross-sections, lifelike (non-crystallographic, constant-thickness, and bifurcate) branching, anastomosis, nestedness within 'sheaths', and other features interpreted as strong evidence for a biological origin, since no abiotic process consistent with the composition of the filaments has been shown to produce these specific lifelike features either in nature or in the laboratory. Here, I show experimentally that abiotic chemical gardening can mimic such purported fossils in both morphology and composition. In particular, chemical gardens meet morphological criteria previously proposed to establish biogenicity, while also producing the precursors to the iron minerals most commonly constitutive of filaments in the rock record. Chemical gardening is likely to occur in nature. Such microstructures should therefore not be assumed to represent fossil microbes without independent corroborating evidence.

Comparative Outcomes of Balloon-Expandable S3 Versus Self-Expanding Evolut Bioprostheses for Transcatheter Aortic Valve Implantation.

To date, comparisons between the balloon-expandable Edwards Sapien S3 (S3) versus the self-expanding Evolut R or PRO (Evolut) valves have been limited with respect to procedural outcomes. We aim to compare the safety, efficacy, and procedural efficiency of the S3 versus the Medtronic Evolut bioprostheses in patients who underwent transcatheter aortic valve implantation for severe aortic stenosis. Retrospective analysis was performed of all consecutive transcatheter aortic valve implantation procedures performed through the transfemoral approach with either S3 or Evolut at our hospital between September 2015 and January 2019. A total of 581 patients were included. There were no significant differences between S3 (n = 452) and Evolut (n = 129) concerning in-hospital or 30-day safety outcomes. S3 was associated with significantly shorter fluoroscopy times, lower fluoroscopy Air Kerma, and higher contrast use. S3 had lower postprocedure aortic valve area (1.71 ± 0.45 vs 1.84 ± 0.50 cm2, p = 0.004), larger peak gradient at 30 days (10.7 ± 3.8 vs 7.0 ± 3.2 mm Hg, p <0.001), and lower aortic regurgitation (AR) rates postprocedure (47% vs 33%, p = 0.024) and at 30 days (50% vs 33%, p = 0.008), driven by mild AR. Device type was an independent predictor of AR postprocedure and at 30 days. Patients with ≥mild AR were more likely to have had Evolut valves (odds ratio = 2.94, p <0.001), especially in larger valves (>26 mm). Severe prosthesis-patient mismatch was higher in S3 (14.8% vs 7.9%, p <0.001). In conclusion, S3 is associated with less radiation exposure, higher contrast use, and lower incidence of AR at 30 days. Alternately, S3 has a higher transaortic gradient at 30 days, and higher levels of severe prosthesis-patient mismatch.

The role of cardiac rehabilitation in patients with heart disease.

Cardiac rehabilitation is a valuable treatment for patients with a broad spectrum of cardiac disease. Current guidelines support its use in patients after acute coronary syndrome, coronary artery bypass grafting, coronary stent placement, valve surgery, and stable chronic systolic heart failure. Its use in these conditions is supported by a robust body of research demonstrating improved clinical outcomes. Despite this evidence, cardiac rehabilitation referral and attendance remains low and interventions to increase its use need to be developed.

Poly(ethylene glycol)-Based Hyperbranched Polymer from RAFT and Its Application as a Silver-Sulfadiazine-Loaded Antibacterial Hydrogel in Wound Care.

A multifunctional branched copolymer was synthesized by Reversible Addition-Fragmentation Chain Transfer polymerization (RAFT) of poly(ethylene glycol) diacrylate (PEGDA Mn = 575) and poly(ethylene glycol) methyl methacrylate (PEGMEMA Mn = 500) at a feed molar ratio of 50:50. Proton nuclear magnetic resonance spectroscopy (1H NMR) confirmed a hyperbranched molecular structure and a high degree of vinyl functionality. An in situ cross-linkable hydrogel system was generated via a "click" thiol-ene-type Michael addition reaction of vinyl functional groups from this PEGDA/PEGMEMA copolymer system in combination with thiol-modified hyaluronic acid. Furthermore, encapsulation of antimicrobial silver sulfadiazine (SSD) into the copolymer system was conducted to create an advanced antimicrobial wound care dressing. This hydrogel demonstrated a sustained antibacterial activity against the bacterial strains Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in comparison to the direct topical application of SSD. In addition, in vitro toxicology evaluations demonstrated that this hydrogel-with low concentrations of encapsulated SSD-supported the survival of embedded human adipose derived stem cells (hADSCs) and inhibited growth of the aforementioned pathogens. Here we demonstrate that this hydrogel encapsulated with a low concentration (1.0% w/v) of SSD can be utilized as a carrier system for stem cells with the ability to inhibit growth of pathogens and without adverse effects on hADSCs.

Evidence for Seismogenic Hydrogen Gas, a Potential Microbial Energy Source on Earth and Mars.

UNLABELLED: The oxidation of molecular hydrogen (H2) is thought to be a major source of metabolic energy for life in the deep subsurface on Earth, and it could likewise support any extant biosphere on Mars, where stable habitable environments are probably limited to the subsurface. Faulting and fracturing may stimulate the supply of H2 from several sources. We report the H2 content of fluids present in terrestrial rocks formed by brittle fracturing on fault planes (pseudotachylites and cataclasites), along with protolith control samples. The fluids are dominated by water and include H2 at abundances sufficient to support hydrogenotrophic microorganisms, with strong H2 enrichments in the pseudotachylites compared to the controls. Weaker and less consistent H2 enrichments are observed in the cataclasites, which represent less intense seismic friction than the pseudotachylites. The enrichments agree quantitatively with previous experimental measurements of frictionally driven H2 formation during rock fracturing. We find that conservative estimates of current martian global seismicity predict episodic H2 generation by Marsquakes in quantities useful to hydrogenotrophs over a range of scales and recurrence times. On both Earth and Mars, secondary release of H2 may also accompany the breakdown of ancient fault rocks, which are particularly abundant in the pervasively fractured martian crust. This study strengthens the case for the astrobiological investigation of ancient martian fracture systems. KEY WORDS: Deep biosphere-Faults-Fault rocks-Seismic activity-Hydrogen-Mars. Astrobiology 16, 690-702.

The transition from linear to highly branched poly(ß-amino ester)s: Branching matters for gene delivery.

Nonviral gene therapy holds great promise but has not delivered treatments for clinical application to date. Lack of safe and efficient gene delivery vectors is the major hurdle. Among nonviral gene delivery vectors, poly(ß-amino ester)s are one of the most versatile candidates because of their wide monomer availability, high polymer flexibility, and superior gene transfection performance both in vitro and in vivo. However, to date, all research has been focused on vectors with a linear structure. A well-accepted view is that dendritic or branched polymers have greater potential as gene delivery vectors because of their three-dimensional structure and multiple terminal groups. Nevertheless, to date, the synthesis of dendritic or branched polymers has been proven to be a well-known challenge. We report the design and synthesis of highly branched poly(ß-amino ester)s (HPAEs) via a one-pot "A2 + B3 + C2"-type Michael addition approach and evaluate their potential as gene delivery vectors. We find that the branched structure can significantly enhance the transfection efficiency of poly(ß-amino ester)s: Up to an 8521-fold enhancement in transfection efficiency was observed across 12 cell types ranging from cell lines, primary cells, to stem cells, over their corresponding linear poly(ß-amino ester)s (LPAEs) and the commercial transfection reagents polyethyleneimine, SuperFect, and Lipofectamine 2000. Moreover, we further demonstrate that HPAEs can correct genetic defects in vivo using a recessive dystrophic epidermolysis bullosa graft mouse model. Our findings prove that the A2 + B3 + C2 approach is highly generalizable and flexible for the design and synthesis of HPAEs, which cannot be achieved by the conventional polymerization approach; HPAEs are more efficient vectors in gene transfection than the corresponding LPAEs. This provides valuable insight into the development and applications of nonviral gene delivery and demonstrates great prospect for their translation to a clinical environment.