Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

There is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and mundulone acetate (MA) as inhibitors of in vitro intracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic potential of these compounds using human myometrial samples and a mouse model of preterm birth. In a phenotypic assay, mundulone displayed greater efficacy, while MA showed greater potency and uterine-selectivity in the inhibition of intracellular-Ca2+ mobilization. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted inhibition of myometrial contractions and that neither compounds affected vasoreactivity of ductus arteriosus. A high-throughput combination screen identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these combinations, mundulone+atosiban demonstrated a significant improvement in the in vitro therapeutic index compared to mundulone alone. The ex vivo and in vivo synergism of mundulone+atosiban was substantiated, yielding greater tocolytic efficacy and potency on myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone after mifepristone administration dose-dependently delayed the timing of delivery. Importantly, mundulone+atosiban permitted long-term management of PL, allowing 71% dams to deliver viable pups at term (>day 19, 4-5 days post-mifepristone exposure) without visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the development of mundulone as a single or combination tocolytic for management of PL.

Light scattering in a three-phase photosensitive system via Monte Carlo approach.

Digital light processing (DLP)-based additive manufacturing has emerged as a powerful technique for fabricating structures from filled resin systems, in which the light scattering behavior is critical to the dimensional fidelity of the cured part. Recently created low density filled resins that incorporate hollow microspheres introduce a third optically active phase, producing yet more complex scattering and cure behaviours that existing empirical relationships cannot predict. This study simulates light scattering in these systems via Mie theory and a novel Monte Carlo model, providing insight into the relationship between filler volume fraction and cured dimensions, and proposes an inversion parameter for predicting film dimensions. Cured resin geometry dimensions such as cured depth (CD) and cured width (CW) are predicted using the developed model for 10, 30, and 50 vol% hollow glass microsphere filled resin systems. In contrast to standard two-phase models, our three-phase model predicts a positive relationship between cured depths and half-widths and the filler volume fraction, consistent with experimental data. By elucidating the intricacies of light scattering in three-phase systems, this work provides valuable insights for advancing DLP-based additive manufacturing and designing filled resin formulations to achieve the desired cured dimensions.

Perceptually Discriminating the Highest Priority Alarms Reduces Response Time: A Retrospective Pre-Post Study at Four Hospitals.

OBJECTIVE: Reduce nurse response time for emergency and high-priority alarms by increasing discriminability between emergency and all other alarms and suppressing redundant and likely false high-priority alarms in a secondary alarm notification system (SANS). BACKGROUND: Emergency alarms are the most urgent, requiring immediate action to address a dangerous situation. They are clinician-triggered and have higher positive predictive value (PPV). High-priority alarms are automatically triggered and have lower PPV. METHOD: We performed a retrospective pre-post study, analyzing data 15 months before and 25 months after a SANS redesign was implemented in four hospitals. For emergency alarms, we incorporated digitized human speech to distinguish them from automatically triggered alarms, leaving their onset and escalation pathways unchanged. For automatically triggered alarms, we suppressed some by delaying initial onset and escalation by 20 s. We used linear mixed models to assess the change in response time, Fisher's exact test for the proportion of response times longer than 120 s, and control charts for process stability. RESULTS: Response time for emergency alarms decreased at all hospitals (main, from 26.91 s to 22.32 s, p < .001; cardiac, from 127.10 s to 52.43 s, p < .001; cancer, from 18.03 s to 15.39 s, p < .001). Improvements were sustained. Automatically triggered alarms decreased 25.0%. Response time for the three automatically triggered cardiac alarms increased at the four hospitals. CONCLUSION: Auditory sound disambiguation was associated with a sustained reduced nurse response time for emergency alarms, but suppressing some high-priority automatically triggered alarms was not. APPLICATION: Distinguishing and escalating urgent, actionable alarms with higher PPV improves response time.

Development of Fused Deposition Modeling of Multiple Materials (FD3M) Through Dynamic Coaxial Extrusion.

Multimaterial additive manufacturing is expanding the design space realizable with 3D printing, yet is largely constrained to sequential deposition of each individual material. The ability to coextrude two materials and change the ratio of materials while printing would enable custom-tailored polymer composites. Here, the evolution of a dynamic material coextrusion process for additive manufacturing capable of printing any ratio between and including two neat input materials is described across 3 hot-end generations and 14 implemented design iterations. The designs evolved with increased understanding of manufacturing constraints associated with the additive manufacturing of metal components with internal flow bore diameters on the order of 2 mm and typical bore length around 50 mm. The second generation overcame this issue by partitioning the design into two pieces to locate the flow channel geometry at the interface between the components so that the details could be easily printed on the components' external surfaces. The third concept generation then focused on minimizing flow channel volume to reduce the average length when transitioning between materials by 92%. The third-generation design was also used to investigate the improvements in dimensional stability during annealing of acrylonitrile butadiene styrene (ABS) made possible by coextruding ABS with a polycarbonate (PC) core. The standard deviation of part shrinkage after annealing was 7.08% for the neat ABS but reduced to 0.24% for the coextruded ABS/PC components.

Results of an interlaboratory study on the working curve in vat photopolymerization.

The working curve informs resin properties and print parameters for stereolithography, digital light processing, and other photopolymer additive manufacturing (PAM) technologies. First demonstrated in 1992, the working curve measurement of cure depth vs radiant exposure of light is now a foundational measurement in the field of PAM. Despite its widespread use in industry and academia, there is no formal method or procedure for performing the working curve measurement, raising questions about the utility of reported working curve parameters. Here, an interlaboratory study (ILS) is described in which 24 individual laboratories performed a working curve measurement on an aliquot from a single batch of PAM resin. The ILS reveals that there is enormous scatter in the working curve data and the key fit parameters derived from it. The measured depth of light penetration Dp varied by as much as 7x between participants, while the critical radiant exposure for gelation Ec varied by as much as 70x. This significant scatter is attributed to a lack of common procedure, variation in light engines, epistemic uncertainties from the Jacobs equation, and the use of measurement tools with insufficient precision. The ILS findings highlight an urgent need for procedural standardization and better hardware characterization in this rapidly growing field.

Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

Currently, there is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and its analog mundulone acetate (MA) as inhibitors of in vitro intracellular Ca 2+ -regulated myometrial contractility. In this study, we probed the tocolytic and therapeutic potential of these small molecules using myometrial cells and tissues obtained from patients receiving cesarean deliveries, as well as a mouse model of PL resulting in preterm birth. In a phenotypic assay, mundulone displayed greater efficacy in the inhibition of intracellular-Ca 2+ from myometrial cells; however, MA showed greater potency and uterine-selectivity, based IC 50 and E max values between myometrial cells compared to aorta vascular smooth muscle cells, a major maternal off-target site of current tocolytics. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted concentration-dependent inhibition of ex vivo myometrial contractions and that neither mundulone or MA affected vasoreactivity of ductus arteriosus, a major fetal off-target of current tocolytics. A high-throughput combination screen of in vitro intracellular Ca 2+ -mobilization identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these synergistic combinations, mundulone + atosiban demonstrated a favorable in vitro therapeutic index (TI)=10, a substantial improvement compared to TI=0.8 for mundulone alone. The ex vivo and in vivo synergism of mundulone and atosiban was substantiated, yielding greater tocolytic efficacy and potency on isolated mouse and human myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone 5hrs after mifepristone administration (and PL induction) dose-dependently delayed the timing of delivery. Importantly, mundulone in combination with atosiban (FR 3.7:1, 6.5mg/kg + 1.75mg/kg) permitted long-term management of PL after induction with 30 µg mifepristone, allowing 71% dams to deliver viable pups at term (> day 19, 4-5 days post-mifepristone exposure) without any visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the future development of mundulone as a stand-alone single- and/or combination-tocolytic therapy for management of PL.

Effects of Solvents, Emulsions, Cosolvents, and Complexions on Ex Vivo Mouse Myometrial Contractility.

A great need exists to develop tocolytic and uterotonic drugs that combat poor, labor-related maternal and fetal outcomes. A widely utilized method to assess novel compounds for their tocolytic and uterotonic efficacy is the isometric organ bath contractility assay. Unfortunately, water-insoluble compounds can be difficult to test using the physiological, buffer-based, organ bath assay. Common methods for overcoming solubility issues include solvent variation, cosolvency, surfactant or complexion use, and emulsification. However, these options for drug delivery or formulation can impact tissue function. Therefore, the goal of this study was to evaluate the ability of common solvents, surfactants, cosolvents, and emulsions to adequately solubilize compounds in the organ bath assay without affecting mouse myometrial contractility. We found that acetone, acetonitrile, and ethanol had the least effect, while dimethylacetamide, ethyl acetate, and isopropanol displayed the greatest inhibition of myometrial contractility based on area under the contractile curve analyses. The minimum concentration of surfactants, cosolvents, and human serum albumin required to solubilize nifedipine, a current tocolytic drug, resulted in extensive bubbling in the organ bath assay, precluding their use. Finally, we report that an oil-in-water base emulsion containing no drug has no statistical effect beyond the control (water), while the drug emulsion yielded the same potency and efficacy as the freely solubilized drug.

Mechanical characterization of 3D printed mimic of human artery affected by atherosclerotic plaque through numerical and experimental methods.

This paper proposes a novel experimental investigation based on 3D printing to validate numerical models for biomechanics simulations. Soft elastomeric materials have been used in Polyjet multi-material 3D printer to mimicking arteries affected by atherosclerotic plaque. The nonlinear mechanical properties of five digital materials are characterized and used as an input for finite element (FE) modeling. Pressurized air is applied to the internal cavity of the printed model to reproduce the internal blood pressure in the artery. Digital Imaging Correlation is adopted to measure the displacement and deformation. A 1D linear higher-order FE model based on the Carrera Unified Formulation is compared to 3D nonlinear FE solutions.

Effect of surface wettability on the interfacial adhesion of a thermosetting elastomer on glass.

Interfacial adhesion dictates properties and performance of both composites and adhesively bonded structures. Weak adhesion at the interfaces of polymer composites leads to void formation and debonding, which adversely affect composite structural integrity and mechanical performance. This work investigated the relationship between surface wettability and interfacial fracture energy with the goal of tailoring interfacial adhesion within polymer composites. A series of model functionalized surfaces was created using silane coupling agents with different organo-functionalities to alter surface wettability. Based on the analysis of interfacial fracture energy between a thermosetting elastomeric polymer network and model surfaces, interfacial adhesion was found to be positively correlated to resin wettability. The results provide a fast and simple approach to screen different material combinations for the development of novel polymeric composites and adhesively bonded structures with tailorable adhesion.

Antimicrobial activity of Substance P and Neuropeptide Y against laboratory strains of bacteria and oral microorganisms.

Infection and inflammation of mucosal tissue may induce the production of neuropeptides, specifically Substance P and Neuropeptide Y. Since these neuropeptides are similar to antimicrobial peptides in their amino acid composition, amphipathic design, cationic charge, and size, we wanted to determine if they had antimicrobial activity against a panel of common bacteria and oral microorganisms using the radial diffusion assay. Neuropeptide Y and Substance P had antimicrobial activity against E. coli (MIC 20.6+/-5.5 microg/ml SEM and 71.5+/-15 SEM microg/ml, respectively), but did not have activity against laboratory strains of Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Serratia marcescens (MIC>500 microg/ml) nor oral strains of Streptococcus mutans, Candida albicans, and Actinobacillus actinomycetemcomitans (MIC>500 microg/ml). While Substance P and Neuropeptide Y did not have direct antimicrobial activity against the microorganisms tested, they still may stimulate local epithelial cells to produce other innate immune factors like defensins and cathelicidins. However, this remains to be determined.

Results from the Endologix PowerLink multicenter trial.

The Endologix PowerLink system is a one-piece, bifurcated, fully supported endoluminal graft for the treatment of abdominal aortic aneurysms (AAA). In a recently completed multicenter trial, the device has proven to be effective with a high technical success rate, low morbidity and mortality rates, and a mean decrease in AAA size over time. A 16-month mean follow-up has found low endoleak and migration rates. There have been no ruptures to date. The Endologix PowerLink device compares favorably with previously published results of other endoluminal grafts.

High-throughput printing via microvascular multinozzle arrays.

Microvascular multinozzle arrays are designed and fabricated for high-throughput printing of functional materials. Ink-flow uniformity within these multigeneration, bifurcating microchannel arrays is characterized by computer modeling and microscopic particle image velocimetry (micro-PIV) measurements. Both single and dual multinozzle printheads are produced to enable rapid printing of multilayered periodic structures over large areas (≈1 m(2)).

Human beta-defensin 3 binds to hemagglutinin B (rHagB), a non-fimbrial adhesin from Porphyromonas gingivalis, and attenuates a pro-inflammatory cytokine response.

Regulatory mechanisms in mucosal secretions and tissues recognize antigens and attenuate pro-inflammatory cytokine responses. Here, we asked whether human beta-defensin 3 (HBD3) serves as an upstream suppressor of cytokine signaling that binds and attenuates pro-inflammatory cytokine responses to recombinant hemagglutinin B (rHagB), a non-fimbrial adhesin from Porphyromonas gingivalis strain 381. We found that HBD3 binds to immobilized rHagB and produces a significantly higher resonance unit signal in surface plasmon resonance spectroscopic analysis, than HBD2 and HBD1 that are used as control defensins. Furthermore, we found that HBD3 significantly attenuates (P<0.05) the interleukin (IL)-6, IL-10, granulocyte macrophage colony stimulating factor (GM-CSF) and tumor-necrosis factor-alpha (TNF-alpha) responses induced by rHagB in human myeloid dendritic cell culture supernatants and the extracellular signal-regulated kinases (ERK 1/2) response in human myeloid dendritic cell lysates. Thus, HBD3 binds rHagB and this interaction may be an important initial step to attenuate a pro-inflammatory cytokine response and an ERK 1/2 response.

Endovascular abdominal aortic aneurysm repair using the AneuRx stent graft: impact of excluding accessory renal arteries.

The aim of this study was to evaluate clinical sequelae of accessory renal artery exclusion during endo-AAA repair. Medical records and pre- and postoperative CT scans were reviewed from 114 AAA patients treated with the AneuRx stent graft between 1996-2001. Thirty-seven accessory renal arteries were identified in 32/114 patients (28%) with 19/32 patients having infrarenally located accessory renal arteries. In group I (11 patients), the stent graft excluded 11 accessory renal arteries. In group II (8 patients), eight accessory renal arteries were not excluded. Average infrarenal neck length was 24.9 mm in group I vs. 30.7 mm in group II (p = 0.07). The average length of device seal was similar in both groups (19.4 vs. 18.5 mm, p = 0.67). There were no perioperative deaths, significant postoperative hypertension, rise in serum creatinine, or postoperative renal infarctions in either group. Three of eight patients (38%) in the non-excluded group developed type I proximal endoleaks whereas none in the excluded patient group did (p = 0.06). Accessory renal arteries may be safely excluded during endovascular AAA repair and may result in a more secure proximal device fixation.

Complications of endovascular repair of high-risk and emergent descending thoracic aortic aneurysms and dissections.

PURPOSE: The advent of endovascular prostheses to treat descending thoracic aortic lesions offers an alternative approach in patients who are poor candidates for surgery. The development of this approach includes complications that are common to the endovascular treatment of abdominal aortic aneurysms and some that are unique to thoracic endografting. METHODS: We conducted a retrospective review of 60 emergent and high-risk patients with thoracic aortic aneurysms (TAAs) and dissections treated with endovascular prostheses over 4 years under existing investigational protocols or on an emergent compassionate use basis. RESULTS: Fifty-nine of the 60 patients received treatment, with one access failure. Thirty-five patients received treatment of TAAs. Four of these procedures were performed emergently because of active hemorrhage. Twenty-four patients with aortic dissections (16 acute, 8 chronic) also received treatment. Eight of the patients with acute dissection had active hemorrhage at the time of treatment. Three devices were used: AneuRx (Medtronic; n = 31), Talent (Medtronic; n = 27), and Excluder (Gore; n = 1). Nineteen secondary endovascular procedures were performed in 14 patients. Most were secondary to endoleak (14 of 19), most commonly caused by modular separation of overlapping devices (n = 8). Other endoleaks included 4 proximal or distal type I leaks and 2 undefined endoleaks. The remaining secondary procedures were performed to treat recurrent dissection (n = 1), pseudoaneurysm enlargement (n = 3), and endovascular abdominal aortic aneurysm repair (n = 1). One patient underwent surgical repair of a retrograde ascending aortic dissection after endograft placement. Procedure-related mortality was 17% in the TAA group and 13% in the dissection group, including 2 acute retrograde dissections that resulted in death from cardiac tamponade. Overall mortality was 28% at 2-year follow-up. CONCLUSION: Although significant morbidity and mortality remain, endovascular repair of descending TAAs and dissections in patients at high-risk patients can be accomplished with acceptable outcomes compared with traditional open repair. The major cause for repeat intervention in these patients was endoleak, most commonly caused by device separation. Improved understanding of these complications may result in a decrease in secondary procedures, morbidity, and mortality in these patients. The need for secondary interventions in a significant number of patients underscores the necessity for continued surveillance.