A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale.

Poor aqueous solubility of preexisting and emerging drug molecules is a common issue faced in the field of pharmaceutics. To address this, particle size reduction techniques, including drug micro- and nanonisation have been widely employed. Nanocrystals (NCs), drug particles with particle sizes below 1 µm, offer high drug content, improved dissolution, and long-acting capabilities. Media milling is the most used method to prepare NCs using of-the-shelf machinery, both at the laboratory and industrial scales. However, early NCs development, especially when limited amounts of the active are available, require the use of milligram-scale media milling. This study introduces a novel mini-scale milling device (Mini-mill) that incorporates temperature control through a water-cooled jacket. The device was used to produce NCs of three model hydrophobic drugs, itraconazole, ivermectin and curcumin, with lowest particle sizes of 162.5 ± 0.4 nm, 178 ± 2 nm, and 116.7 ± 0.7 nm, respectively. Precise control of milling temperature was achieved at 15, 45, and 75°C, with drug dependent particle size reduction trends, with no adverse effects on the milling materials or polymorphic changes in the NCs, as confirmed by calorimetric analysis. Finally, a scale-up feasibility study was carried out in a lab-scale NanoDisp®, confirming that the novel Mini-mills are a material-efficient tool for early formulation development, with potential for scale-up to commercial mills.

Multiscale Equation-Oriented Optimization Decreases the Carbon Intensity of Shale Gas to Liquid Fuel Processes.

Shale gas is revolutionizing the U.S. energy and chemical commodity landscape and can ease the transition to a sustainable decarbonized economy. This work develops an equation-oriented (EO) multiscale modeling framework using the open-source IDAES-PSE platform that tractably incorporates microkinetic detail in process design via reduced-order kinetic (ROK) models. Using multiobjective optimization with embedded heat integration and life-cycle analysis, we simultaneously minimize the minimum selling price of liquid hydrocarbons (e.g., liquid fuels/additives from shale gas) and process emissions (via a CO2 tax). Optimization reduces greenhouse gas emissions per MJ of fuel produced by over 35% compared to the literature and achieves a carbon efficiency of 87%. The optimizer changes the recycling rate, temperatures, and pressures to mitigate the effect of ROK model-form uncertainty on product portfolio predictions. Moreover, we show that the optimal process design is insensitive to changing CO2 tax rates. Finally, the EO framework enables a fast sensitivity analysis of shale gas composition variability across 12 regions of the Eagle Ford basin. These results highlight the benefits of the open-source EO framework: fast, scalable, customized, and reproducible system analysis and optimization for sustainable energy technologies beyond shale utilization.

Propofol-sparing and hemodynamic effects of guaifenesin in sheep.

OBJECTIVE: To evaluate the propofol-sparing and hemodynamic effects of guaifenesin administered for co-induction of anesthesia in sheep. STUDY DESIGN: Prospective, blinded, two-way crossover experimental study. ANIMALS: Thirteen healthy adult female sheep. METHODS: Anesthesia was induced without premedication with intravenous (IV) guaifenesin 5% at 100 mg kg-1 (GGE) or an equivalent volume of physiologic saline (SAL), followed by IV propofol at a controlled rate (1 mg kg-1 min-1). Heart rate (HR), respiratory rate and oscillometric noninvasive arterial blood pressure (NIBP) were recorded at baseline after co-induction administration, following endotracheal intubation and every 2 minutes thereafter for 10 minutes. Propofol doses required to achieve intubation after each co-induction treatment were compared by independent Student's t-test. Values of p < 0.05 were considered statistically significant. RESULTS: The propofol dose required (mean ± standard deviation) to achieve intubation was significantly lower (p = 0.001) in the GGE treatment (3.40 ± 0.74 mg kg-1) than in the SAL treatment (5.94 ± 1.09 mg kg-1). HR was increased after anesthetic induction compared with baseline in both treatments. HR was generally lower in the GGE treatment than in the SAL treatment. NIBP did not vary between GGE and SAL treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Guaifenesin, when administered as a co-induction agent with propofol in sheep, reduces propofol dose requirements and maintains hemodynamic variables within a clinically acceptable range.

Usefulness of a murine model of hepatic cystic echinococcosis for preclinical drug trials: Efficacy of albendazole vs albendazole nanocrystals.

Cystic echinococcosis is a zoonotic infection caused by the larval stage of Echinococcus granulosus sensu lato. The disease is characterized by the long-term growth of cysts, most commonly in the liver and lungs. Although an ideal model of cystic echinococcosis should induce the development of cysts in the liver and imitate the natural infection route, the murine model of intraperitoneal is still widely used in the field of experimental theraphy. The aim of the present work was to evaluate the usefulness of the murine model of hepatic CE for preclinical drug trials. The effectiveness of albendazole could also be assessed by measuring the diameter of the hepatic cyst. The albendazole significantly reduced the size of the cysts. The ultrastructural alterations of the germinal layer of hepatic cysts provoked by albendazole coincided with those observed in the intraperitoneal model. Similar results were obtained with both albendazole doses. Therefore, the efficacy of albendazole nanocrystals in the murine model of hepatic cystic echinococcosis was carried out at albendazole doses of 25 mg/kg. The abdominal ultrasound allows us to assess the response of cysts to drugs only in a qualitative manner. Although the size of cysts in the albendazole nanocrystal group was not significantly lower than that observed with albendazole, at the ultrastructural level, a greater extent of damage was observed. The murine model of hepatic cystic echinococcosis can be effectively used for assessing the effect of novel formulations or compounds. The main advantage of this model is that cysts are located in the orthotopic organ, which resembles the location most commonly found in human cases. In future studies, the usefulness of the model for pharmacokinetics studies in hepatic cysts will be evaluated.

Improved biodistribution and enhanced immune response of subunit vaccine using a nanostructure formed by self-assembly of ascorbyl palmitate.

New adjuvant strategies are needed to improve protein-based subunit vaccine immunogenicity. We examined the potential to use nanostructure of 6-O-ascorbyl palmitate to formulate ovalbumin (OVA) protein and an oligodeoxynucleotide (CpG-ODN) (OCC). In mice immunized with a single dose, OCC elicited an OVA-specific immune response superior to OVA/CpG-ODN solution (OC). Rheological studies demonstrated OCC's self-assembling viscoelastic properties. Biodistribution studies indicated that OCC prolonged OVA and CpG-ODN retention at injection site and lymph nodes, reducing systemic spread. Flow-cytometry assays demonstrated that OCC promoted OVA and CpG-ODN co-uptake by Ly6ChiCD11bhiCD11c+ monocytes. OCC and OC induced early IFN-γ in lymph nodes, but OCC led to higher concentration. Conversely, mice immunized with OC showed higher serum IFN-γ concentration compared to those immunized with OCC. In mice immunized with OCC, NK1.1+ cells were the IFN-γ major producers, and IFN-γ was essential for OVA-specific IgG2c switching. These findings illustrate how this nanostructure improves vaccine's response.

Design of a pilot plant-type pharmaceutical reactor to address the problem of interchangeability of generic semisolid formulations.

OBJECTIVE AND SIGNIFICANCE: This research aims to design and develop a pilot plant-type pharmaceutical reactor with a strong focus on its volumetric capacity and heat transfer capabilities. The primary goal is to replicate design and control strategies at the laboratory or pilot scale to analyze and produce generic semisolid formulations. METHODS: Computational fluid dynamics and heat transfer modeling, utilizing the finite volume method, were employed to determine the reactor's performance and particle trajectory during the mixing and stirring. This allowed for the establishment of optimal operational parameters and variables. Furthermore, prototypes were constructed at 1:2.5 and 1:15 scales to examine the reactor's morphology, ensure volumetric versatility, and conduct mixing, homogenization, and coloration tests using varying volumes. RESULTS AND CONCLUSIONS: The outcomes of this study yielded a versatile reactor suitable for processing pharmaceutical semisolids at both laboratory and pilot-scale volumes. Notably, the reactor demonstrated exceptional volumetric capacity within a single vessel while effectively facilitating heat transfer to its interior.

Naringin: Nanotechnological Strategies for Potential Pharmaceutical Applications.

Polyphenols comprise a number of natural substances, such as flavonoids, that show interesting biological effects. Among these substances is naringin, a naturally occurring flavanone glycoside found in citrus fruits and Chinese medicinal herbs. Several studies have shown that naringin has numerous biological properties, including cardioprotective, cholesterol-lowering, anti-Alzheimer's, nephroprotective, antiageing, antihyperglycemic, antiosteoporotic and gastroprotective, anti-inflammatory, antioxidant, antiapoptotic, anticancer and antiulcer effects. Despite its multiple benefits, the clinical application of naringin is severely restricted due to its susceptibility to oxidation, poor water solubility, and dissolution rate. In addition, naringin shows instability at acidic pH, is enzymatically metabolized by ß-glycosidase in the stomach and is degraded in the bloodstream when administered intravenously. These limitations, however, have been overcome thanks to the development of naringin nanoformulations. This review summarizes recent research carried out on strategies designed to improve naringin's bioactivity for potential therapeutic applications.

Cell Membrane Oscillations under Radiofrequency Electromagnetic Modulation.

Cell responses to external radiofrequencies (RF) are a fundamental problem of much scientific research, clinical applications, and even daily lives surrounded by wireless communication hardware. In this work, we report an unexpected observation that the cell membrane can oscillate at the nanometer scale in phase with the external RF radiation from kHz to GHz. By analyzing the oscillation modes, we reveal the mechanism behind the membrane oscillation resonance, membrane blebbing, the resulting cell death, and the selectivity of plasma-based cancer treatment based on the difference in the membrane's natural frequencies among cell lines. Therefore, a selectivity of treatment can be achieved by aiming at the natural frequency of the target cell line to focus the membrane damage on the cancer cells and avoid normal tissues nearby. This gives a promising cancer therapy that is especially effective in the mixing lesion of the cancer cells and normal cells such as glioblastoma where surgical removal is not applicable. Along with these new phenomena, this work provides a general understanding of the cell coupling with RF radiation from the externally stimulated membrane behavior to the cell apoptosis and necrosis.

Plantar osteochondral fragments in young Standardbreds are associated with minimal joint inflammation at the time of surgical removal.

BACKGROUND: Plantar osteochondral fragments (POF) are common but their effect on joint health of young Standardbreds in race training is largely unknown. OBJECTIVES: Evaluate the inflammatory effects of POF in metatarsophalangeal joints of young Standardbreds as a step towards developing evidence-based recommendations for surgical removal. STUDY DESIGN: Cohort study. METHODS: Forty-nine Standardbred horses (age 11-33 months) presented for surgical removal of POF from 56 metatarsophalangeal joints. Synovial tissue collected at arthroscopy was subjected to histopathology. IL-1ß, TNF-α, and PGE-2 were measured in synovial fluid using ELISA. Digital arthroscopy images were scored for inflammation. Racing performance data were retrieved from a public database. RESULTS: Median time in race training prior to surgery was 8 weeks (IQR 4-12; range 0-40). There was minimal evidence of synovial inflammation as assessed by histopathology (median total score 2/20, IQR 0-2, range 0-5) or arthroscopy (median average total score 2.67/15, IQR 1.79-4, range 0-8.83). IL-1ß was not detected in any sample. TNF-α (median 0 pg/mL, IQR 0-0) and PGE-2 (median 56.6 pg/mL, IRQ 40.5-99.8) were measured at low levels. Weeks in training prior to surgery was associated with the number of starts in the season after surgery (incidence rate ratio 1.02, 95% CI 1.00, 1.04, P = .03). MAIN LIMITATIONS: Small sample size from a single breed with a relatively short training time prior to surgery. CONCLUSIONS: There was minimal evidence of synovial inflammation in the metatarsophalangeal joints in this population of young Standardbred horses with POF. It is possible that POF may result in a different inflammatory response than other fragments because they are generally well-embedded in situ. These findings suggest that, in Standardbreds, race training can commence several weeks prior to surgical removal of POF with minimal detrimental effects on joint health, although further investigation of long-term effects of POF on joint health is warranted.

INTRODUCTION/CONTEXTE: Les fragments plantaires ostéochondraux (POF) sont communs mais leur effet au niveau sur la santé articulaire chez les jeunes Standardbreds en entraînement de course demeure inconnu. OBJECTIFS: Évaluer les effets inflammatoires des POF des articulations métatarsophalangiennes chez les jeunes Standardbreds dans le but d'ajouter à l'évidence disponible concernant les recommandations pour leur retrait chirurgical. TYPE D'ÉTUDE: Étude de cohorte descriptive clinique. MÉTHODES: Quarante-neuf chevaux Standardbreds (âgés 11-33 mois) ont été présentés pour retrait chirurgical de POF en provenance de 56 articulations métatarsophalangiennes. Un échantillon de membrane synoviale recueilli au moment de l'arthroscopie a été soumis en histopathologie. IL-1ß, TNF-α, and PGE-2 ont été mesurés dans le liquide synovial par ELISA. Les images digitales d'arthroscopie ont été évaluées pour la présence d'inflammation. Les données de performance en course ont été retrouvées via une base de données publique. RÉSULTATS: Le temps médian de retour à l'entraînement suivant la procédure chirurgicale était de 8 semaines (IQR 4-12; étendu 0-40). Peu d'inflammation synoviale a été détectée en histopathologie (score médian total 2/20, IQR 0-2, étendu 0-5) ou arthroscopie (score médian total 2.67/15, IQR 1.79-4, étendu 0-8.83). IL-1ß a été détectée dans aucun échantillon. TNF-α (médiane 0 pg/mL, IQR 0-0) et PGE-2 (médiane 56.6 pg/mL, IQR 40.5-99.8) ont été détectés en faible quantité. Le nombre de semaines à l'entraînement avant la procédure chirurgicale était associé au nombre de départs pour la saison suivant la chirurgie (IRR 1.02, P = 0.03). LIMITES PRINCIPALES: Petite taille d'échantillon provenant d'une seule race de chevaux ayant une période d'entraînement relativement courte avant la procédure chirurgicale. CONCLUSIONS: Il y a peu d'évidence d'inflammation synoviale dans les articulations métatarsophalangiennes chez cette population de jeunes chevaux Standardbreds ayant des POF. Il est possible que les POF entraînent une réponse inflammatoire différente des autres fragments puisqu'ils sont généralement bien attachés dans l'articulation. Ces résultats suggèrent que chez les Standardbreds, l'entraînement de course puisse commencer plusieurs semaines avant le retrait chirurgical des POF en ayant des effets délétères minimaux pour la santé articulaire. Ceci dit, davantage de recherche est nécessaire pour établir les effets à long-terme de ces POF sur la santé articulaire.

Optimizing the accuracy of viscoelastic characterization with AFM force-distance experiments in the time and frequency domains.

Atomic Force Microscopy (AFM) force-distance (FD) experiments have emerged as an attractive alternative to traditional micro-rheology measurement techniques owing to their versatility of use in materials of a wide range of mechanical properties. Here, we show that the range of time dependent behaviour which can reliably be resolved from the typical method of FD inversion (fitting constitutive FD relations to FD data) is inherently restricted by the experimental parameters: sampling frequency, experiment length, and strain rate. Specifically, we demonstrate that violating these restrictions can result in errors in the values of the parameters of the complex modulus. In the case of complex materials, such as cells, whose behaviour is not specifically understood a priori, the physical sensibility of these parameters cannot be assessed and may lead to falsely attributing a physical phenomenon to an artifact of the violation of these restrictions. We use arguments from information theory to understand the nature of these inconsistencies as well as devise limits on the range of mechanical parameters which can be reliably obtained from FD experiments. The results further demonstrate that the nature of these restrictions depends on the domain (time or frequency) used in the inversion process, with the time domain being far more restrictive than the frequency domain. Finally, we demonstrate how to use these restrictions to better design FD experiments to target specific timescales of a material's behaviour through our analysis of a polydimethylsiloxane (PDMS) polymer sample.

Frequency-dependent nanomechanical profiling for medical diagnosis.

Atomic force microscopy (AFM), developed in the early 1980s, has become a powerful characterization tool in micro- and nanoscale science. In the early 1990s, its relevance within biology and medicine research became evident, although its incorporation into healthcare applications remains relatively limited. Here, we briefly explore the reasons for this low level of technological adoption. We also propose a path forward for the incorporation of frequency-dependent nanomechanical measurements into integrated healthcare strategies that link routine AFM measurements with computer analysis, real-time communication with healthcare providers, and medical databases. This approach would be appropriate for diseases such as cancer, lupus, arteriosclerosis and arthritis, among others, which bring about significant mechanical changes in the affected tissues.

Technological avenues and market mechanisms to accelerate methane and nitrous oxide emissions reductions.

Strategies targeting methane (CH4) and nitrous oxide (N2O) emissions are critical to meeting global climate targets. Existing literature estimates the emissions of these gases from specific sectors, but this knowledge must be synthesized to prioritize and incentivize CH4 and N2O mitigation. Accordingly, we review emissions sources and mitigation strategies in all key sectors (fuel extraction and combustion, landfilling, agriculture, wastewater treatment, and chemical industry) and the role of carbon markets in reducing emissions. The most accessible reduction opportunities are in the hydrocarbon extraction and waste sectors, where half (>3 Gt-CO2e/year) of the emissions in these sectors could be mitigated at no net cost. In total, 60% of CH4 emissions can be mitigated at less than $50/t-CO2. Expanding the scope of carbon markets to include these emissions could provide cost-effective decarbonization through 2050. We provide recommendations for carbon markets to improve emissions reductions and set prices to appropriately incentivize mitigation.

Design and production of 3D printed oral capsular devices for the modified release of urea in ruminants.

The use of 3D printing for the production of systems intended for oral delivery of diet supplements in the veterinary pharmacy constitutes an attractive technology that has remained unexplored. In this sense, this work studies the design and 3D printing of capsular devices that allow the modified release of urea, which is frequently used as a source of non-protein nitrogen in ruminants, but highly toxic if fast ingested. The devices were printed with combinations of polylactic acid (PLA, water-insoluble) and polyvinyl alcohol (PVA, water-soluble) in order to modulate the urea release through the different parts. The optimization of the designs as well as printing parameters such as extrusion temperature, printing speed, retraction distance and nozzle speed resulted critical to obtain successful capsular devices. In addition, the dissolution studies confirmed that the developed designs showed a controlled release of urea, especially the ones that presented internal partitions. Finally, Logistic and Weibull equations were the kinetic models that best fitted the experimental data corresponding to functions that describe S-shaped dissolution profiles. Overall, this work constitutes a proof of concept and provides the first steps in the development of 3D printed simple devices for the controlled release of supplements and drugs in veterinary pharmacy.

Functionalized graphene quantum dots obtained from graphene foams used for highly selective detection of Hg2+ in real samples.

Here we report the use of graphene quantum dots (GQDs), obtained from 3D graphene foam, functionalized with 8-hydroxyquinoline (8-HQ) for the sensitive and selective detection of Hg2+ via front-face fluorescence. The great surface area and active groups within the GQDs permitted the functionalization with 8-HQ to increase their selectivity toward the analyte of interest. The fluorescence probe follows the Stern-Volmer model, yielding a direct relationship between the degree of quenching and the concentration of the analyte. Diverse parameters, including the pH and the use of masking agents, were optimized in order to improve the selectivity toward Hg2+ down to a limit of detection of 2.4 nmol L-1. It is hereby demonstrated that the functionalized GQDs work perfectly fine under adverse conditions such as acidic pH and in the presence of a large number of cationic and anionic interferences for the detection of Hg2+ in real samples. Parallel measurements using cold vapor atomic fluorescence spectrometry also demonstrated an excellent correlation with the front-face fluorescence method applied here for real samples including tap, river, underground, and dam waters.

Model-informed experimental design recommendations for distinguishing intrinsic and acquired targeted therapeutic resistance in head and neck cancer.

The promise of precision medicine has been limited by the pervasive resistance to many targeted therapies for cancer. Inferring the timing (i.e., pre-existing or acquired) and mechanism (i.e., drug-induced) of such resistance is crucial for designing effective new therapeutics. This paper studies cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) using tumor volume data obtained from patient-derived tumor xenografts. We ask if resistance mechanisms can be determined from this data alone, and if not, what data would be needed to deduce the underlying mode(s) of resistance. To answer these questions, we propose a family of mathematical models, with each member of the family assuming a different timing and mechanism of resistance. We present a method for fitting these models to individual volumetric data, and utilize model selection and parameter sensitivity analyses to ask: which member(s) of the family of models best describes HNSCC response to cetuximab, and what does that tell us about the timing and mechanisms driving resistance? We find that along with time-course volumetric data to a single dose of cetuximab, the initial resistance fraction and, in some instances, dose escalation volumetric data are required to distinguish among the family of models and thereby infer the mechanisms of resistance. These findings can inform future experimental design so that we can best leverage the synergy of wet laboratory experimentation and mathematical modeling in the study of novel targeted cancer therapeutics.

The effect of repeated freezing and thawing on the suture pull-out strength in equine arytenoid and cricoid cartilages.

OBJECTIVE: To assess the effect of repeated freezing and thawing on the suture pull-out strength in arytenoid and cricoid cartilages subjected to the laryngoplasty (LP) procedure. STUDY DESIGN: Ex vivo experimental study. SAMPLE POPULATION: Ten grossly normal equine cadaveric larynges. METHODS: Bilateral LP constructs were created using a standard LP technique. One hemilarynx was randomly allocated to the single freeze and thaw group and the other allocated to the repeated freeze and thaw (3 complete cycles) group. The suture ends of each LP construct were attached to a load frame and subjected to monotonic loading until construct failure. Mean load (N) and displacement (mm) at LP construct failure were compared between groups. RESULTS: All LP constructs failed by suture pull through the arytenoid cartilage. The mean load at failure was similar between groups (118.9 ± 25.5 N in the single freeze and thaw group and 113.4 ± 20.5 N in the repeated freeze and thaw group, P = .62). The mean displacement at failure was similar between groups (54.4 ± 15.1 mm in the single freeze and thaw group and 54.4 ± 15.4 mm in the repeated freeze and thaw group, P = .99). CONCLUSION: Repeated freezing and thawing did not affect the suture pullout strength of the arytenoid and cricoid cartilages. CLINICAL SIGNIFICANCE: Laryngeal specimens that have been subjected to repeated freezing and thawing can be utilized in the experimental evaluation of LP procedures because there is no alteration of the suture pull-out strength of the relevant cartilages.

Kinetic Analysis in Horses With Deep Digital Flexor Tendinopathy Within the Digit Diagnosed by Magnetic Resonance Imaging.

Objectives: To determine the stance duration and ground reaction forces (GRF) of horses with deep digital flexor (DDF) tendinopathy at the level of the foot and compare the stance duration and GRF to those of clinically sound horses. Design: Prospective clinical study. Animals: Sixteen horses (seven horses with bilateral forelimb lameness, four horses with unilateral forelimb lameness, and five horses with no lameness). Procedures: Analyses of kinetic variables were performed on both forelimbs from sound horses and horses diagnosed with chronic DDF tendinopathy. Stance duration and longitudinal and vertical components of the GRF were determined for the limbs of clinically sound horses and limbs of horses with DDF tendinopathy. Separate Spearman correlation analyses were used to assess potential association within groups (combined left and right forelimbs of clinically sound horses, lamest limbs of horses with DDF tendinopathy, and contralateral limbs of horses with DDF tendinopathy) and with the set of kinetic variables. Analysis of variance on mean ranks of tied values was used to determine differences in kinetic variables between groups (PROC GLIMMIX) using the kinetic values of the clinically sound horses as the reference group. Results: There were a total of 11 lame horses. Seven horses had bilateral forelimb lameness and four had unilateral lameness. Of the 11 horses, there were 15 DDF tendinopathies. There were eight dorsal border DDF tendinopathies, five core DDF tendinopathies, and two sagittal/parasagittal splits DDF tendinopathies. The most lame limbs of horses with DDF tendinopathy had significantly smaller values for peak vertical force and time of peak braking force than did forelimbs of clinically sound horses. Also, the most lame limbs of horses with DDF tendinopathy had significantly larger values for the time of peak vertical force than did forelimbs of clinically sound horses. Conclusions and Clinical Relevance: Horses with chronic DDF tendinopathies develop certain alterations of GRF parameters. This information can be used in future studies to determine if particular kinetic variable changes in horses with DDF tendinopathies differ from those of horses with other pathologies within the foot and therefore could be diagnostic.

Performance of predictive models of survival in horses undergoing emergency exploratory laparotomy for colic.

OBJECTIVE: To evaluate previously published predictive survival models in a population of horses undergoing colic surgery in the midwestern United States. STUDY DESIGN: Retrospective cohort study; single referral hospital. ANIMALS: A total of 260 horses met the inclusion criteria. METHODS: Medical records of horses undergoing surgical treatment for colic were reviewed. Previously published models were applied to cohort data to predict outcome. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for prediction of short-term survival were calculated. RESULTS: Single-variable and multivariable models performed similarly for prediction of survival, with a mean 79% sensitivity (range: 44%-94%), 48% specificity (range: 22%-83%), 63% PPV (range: 56%-72%), 73% NPV (range: 60%-83%), and 64% accuracy (range: 59%-72%). Blood lactate ≤6 mmol/l and the colic severity score (CSS) were highly sensitive for prediction of survival; however, both had poor specificity. CONCLUSION: Single-variable and multivariable predictive models did not perform as well for prediction of survival in the study cohort compared to original reports, suggesting that population-specific factors contribute to patient survival. CLINICAL SIGNIFICANCE: Predictive models of survival developed in one population may be less reliable when used to predict outcome in horses undergoing colic surgery from an independent population. Additional model testing and refinement using data from multiple surgical centers could be considered to improve prediction of outcome for horses undergoing laparotomy for treatment of colic.

Modular Framework for Simulation-Based Multi-objective Optimization of a Cryogenic Air Separation Unit.

A framework to obtain optimal operating conditions is proposed for a cryogenic air separation unit case study. The optimization problem is formulated considering three objective functions, 11 decision variables, and two constraint setups. Different optimization algorithms simultaneously evaluate the conflicting objective functions: the annualized cash flow, the efficiency at the compression stage, and capital expenditures. The framework follows a modular approach, in which the process simulator PRO/II and a Python environment are combined. The results permit us to assess the applicability of the tested algorithms and to determine optimal operational windows based on the resultant 3-D Pareto fronts.

Nanocrystals as a master key to deliver hydrophobic drugs via multiple administration routes.

The poor aqueous solubility of many approved drugs and most new chemical entities poses a challenge to drug delivery scientists working in academic and industrial labs. Despite the high pharmacological activity these drugs may have, their limited water solubility leads to poor absorption and consequently to sub-therapeutic drug concentrations in target tissues. The formulation of drug nanocrystals (NCs) has emerged as one the most promising approaches for increasing the biopharmaceutical performance of hydrophobic drugs. Initially aimed at increasing the absorption of drugs administered orally, NCs have been increasingly utilised to allow drug delivery via multiple routes, namely, parenteral injections, transdermal, ocular, intranasal, and pulmonary. This review aims to describe the recent progress in the field and demonstrate how the NCs technology enabled the delivery of hydrophobic drugs through multiple administration routes.