Microwave NDT of Smart Composite Structures with Embedded Antennas.

The integration of antennas in composite structures is gaining popularity with advances in wireless communications and the ever-increasing demands for efficient smart structures. Efforts are ongoing to ensure that antenna-embedded composite structures are robust and resilient to inevitable impacts, loading and other external factors that threaten the structural integrity of these structures. Undoubtedly, the in situ inspection of such structures to identify anomalies and predict failures is required. In this paper, the microwave non-destructive testing (NDT) of antenna-embedded composite structures is introduced for the first time. The objective is accomplished using a planar resonator probe operating in the UHF frequency range (~525 MHz). High-resolution images of a C-band patch antenna fabricated on an aramid paper-based honeycomb substrate and covered with a glass fiber reinforced polymer (GFRP) sheet are presented. The imaging prowess of microwave NDT and its distinct advantages in inspecting such structures are highlighted. The qualitative as well as the quantitative evaluation of the images produced by the planar resonator probe and a conventional K-band rectangular aperture probe are included. Overall, the potential utility of microwave NDT for the inspection of smart structures is demonstrated.

Geometrical Scaling Effects in the Mechanical Properties of 3D-Printed Body-Centered Cubic (BCC) Lattice Structures.

This paper investigates size effects on the mechanical response of additively manufactured lattice structures based on a commercially available polylactic acid (PLA) polymer. Initial attention is focused on investigating geometrical effects in the mechanical properties of simple beams and cubes. Following this, a number of geometrically scaled lattice structures based on the body-centered cubic design were manufactured and tested in order to highlight size effects in their compression properties and failure modes. A finite element analysis was also conducted in order to compare the predicted modes of failure with those observed experimentally. Scaling effects were observed in the compression response of the PLA cubes, with the compression strength increasing by approximately 19% over the range of scale sizes investigated. Similar size-related effects were observed in the flexural samples, where a brittle mode of failure was observed at all scale sizes. Here, the flexural strength increased by approximately 18% when passing from the quarter size sample to its full-scale counterpart. Significant size effects were observed following the compression tests on the scaled lattice structures. Here, the compression strength increased by approximately 60% over the four sample sizes, in spite of the fact that similar failure modes were observed in all samples. Finally, reasonably good agreement was observed between the predicted failure modes and those observed experimentally. However, the FE models tended to over-estimate the mechanical properties of the lattice structures, probably as a result of the fact that the models were assumed to be defect free.

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling.

Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach-duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation.

Investigation of drug partition property in artificial sebum.

Targeted delivery of a therapeutic agent into the hair and sebaceous follicles greatly depends on the extent of drug partitioning/diffusion in the sebum. The objective of the present research was to develop a method to determine the sebum partition coefficient in order to facilitate the selection of sebum-targeted drug candidates. Partition coefficients of model drugs with different chemical structures and 4-hydroxybenzoate series compounds were measured in artificial sebum/water (K(sebum)) and human stratum corneum/water (K(sc)) at 37 degrees C. The relationship was evaluated between logK(sebum), logK(sc) and clogP. The results of the partition coefficient studies indicate that the K(sebum) of some drugs was significantly higher than the K(sc), whereas some drugs showed lower or similar K(sebum) when compared with K(sc). Overall, a relatively poor correlation was observed between logK(sebum), logK(sc) and clog P. However, a linear relationship exists between logK(sebum) and clog P in the 4-hydroxybenzoate series compounds, indicating that K(sebum) depends on the lipophilicity and chemical structure of the compounds. The results of the present study demonstrate that K(sebum) is different from K(sc) and calculated P and is likely to be a critical parameter reflecting drug delivery into hair and sebaceous follicles.

Solubility measurement of polymorphic compounds via the pH-metric titration technique.

In drug development, the thermodynamically most stable form of a compound is preferred because metastable forms are prone to transform to the stable form during processing, formulation, or storage [Guillory, J.K., 1999. Generation of polymorphs, hydrates, solvates, and amorphous solids. In: Brittain, H.G. (Ed.), Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, pp. 183-226]. It is therefore important to discover and characterize the stable form as early as possible. One of the most important properties to determine is thermodynamic solubility. However, due to compound and time constraints this solubility value is usually not determined until late in discovery. This report explores the ability of the pH-metric titration method to measure intrinsic solubility of the stable form of compounds that exist in one or more polymorphic forms. One metastable form and the stable form of eight compounds were examined. Intrinsic solubility was measured via pH-metric titration. The technique was performed on a larger scale in order to monitor polymorphic form changes by powder X-ray diffraction. Shake-flask solubility and corresponding X-ray diffraction data of each form was also determined. The results of this study indicate that, in general, when starting with a metastable polymorph, the pH-metric titration method is able to achieve the solubility of the stable form by the third titration, while the traditional shake-flask solubility method is unable to consistently determine the stable form solubility.

Solubility: it's not just for physical chemists.

Solubility data are used to make crucial decisions from the earliest stages of drug discovery throughout the development process, but often the decision-maker is far removed, in terms of both organization and scientific background, from the scientist who generates the data. Here we provide a reference point for consumers of solubility who are presented with increasingly sophisticated strategies to measure sooner, faster or more accurately. We discuss the fundamental forces that govern solubility, the role of physical-chemical parameters such as pH and pK(a), and the principles involved in different solubility measurements. Our ultimate goal is to enable a decision-maker, when presented with solubility data, to have in hand the tools to evaluate not just the magnitude but also the context and appropriateness of those measurements to the drug in question.

Evaluation of the chemiluminescent nitrogen detector for solubility determinations to support drug discovery.

Solubility measurements using chemiluminescent nitrogen detection (CLND) has advantages of reduced compound requirement and increased throughput compared to UV-spectrophotometric and HPLC-based measurements. CLND with direct flow injection was evaluated for the measurement of thermodynamic solubility to support drug discovery. The limit of quantitation (LOQ), accuracy, and day-to-day reproducibility of the detector were measured. Measurements made on CLND were compared to those obtained from UV spectrophotometry and HPLC. Based on the results obtained, it was concluded that the CLND performs satisfactorily for discovery stage thermodynamic solubility measurements.

Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose.

Micronization is a commonly used enabling technology to improve the bioavailability of compounds where absorption is dissolution rate limited. However, decreasing particle size often results in increased Van der Waals' interactions and electrostatic attraction between particles. This causes agglomeration of particles, thereby compromising the increase in surface area gained by micronization. Comicronization with excipients has been reported to offer significant advantages over neat micronization. The present work describes the comicronization of a model compound CI-1040 at a high drug load that shows an increase in the dissolution rate and bioavailability in male Wistar rats. Physicochemical characterization of the comicronized and neat micronized material is presented to help explain the in-vitro and in-vivo data.

Dissolution behavior of a poorly water soluble compound in the presence of Tween 80.

PURPOSE: To investigate the mechanism by which Tween 80 impedes the dissolution of CI-1041, a poorly water-soluble compound in its free form. METHODS: Bulk powder and intrinsic dissolution (ID) of CI-1041 in 0.1 N HCl with various concentrations of Tween 80 were conducted. The residual solids of the dissolution experiments were characterized. The surface tension and the critical micellar concentration (CMC) of Tween 80 in 0.1 N HCl were determined. RESULTS: CI-1041 underwent solvent mediated conversion to its chloride salt (CS) in 0.1 N HCl. The coating of the CS on the surface of the CI-1041 pellet decreased the ID rate 20 to 30 fold. When the Tween 80 concentration in 0.1 N HCl was below 0.5 mg/ml, the CS formation rate increased with increasing Tween 80 concentration. Above 0.5 mg/ml of Tween 80 in 0.1 N HCl, opposite trend was observed. The change in trend at 0.5 mg/ml Tween 80 coincided approximately with the CMC of Tween 80 in 0.1 N HCl. CONCLUSIONS: The authors propose the following mechanism mediated by Tween 80. Below CMC, reduced surface tension caused by addition of Tween 80 increases the rate of nucleation of insoluble CS, causing the formation of CS on the surface of the CI-1041 free form. This, in turn, decreases the dissolution rate by decreasing the release of compound into solution. Above CMC, the effect of reduced surface tension on the CS nucleation and therefore its formation may be negated by other factors, such as an increase in viscosity or adsorption of surfactant on the crystal surface.

Dissolution testing of a poorly soluble compound using the flow-through cell dissolution apparatus.

Dissolution of Pfizer Compound PD198306, a poorly soluble compound, was studied in 25 mM pH 9 sodium phosphate solution with 0.5% SLS using the flow-through cell dissolution apparatus. Unmicronized and micronized drug powders were tested. Several methods of loading the drug powder into the flow-through dissolution cells and their impact on dissolution were investigated. The influence of flow rate of the dissolution medium on the rate and extent of dissolution were studied. PD198306 has poor wettability even in the presence of 0.5% SLS. It was found that loading the drug powder into the dissolution cell in the form of a suspension provided the best dissolution profile in terms of the rate and extent of dissolution. The flow rate of 4 ml/min resulted in good particle size discrimination.

Collagen injections for urinary stress incontinence in a small urban urology practice: time to failure analysis of 99 cases.

PURPOSE: We examined the durability of collagen injection response for female incontinence using Kaplan-Meier survival statistics and the log rank test. MATERIALS AND METHODS: A total of 99 women 26 to 84 years old (mean age 60) underwent collagen injections for urethral incompetence. In this retrospective chart audit treatment failures were analyzed using survival statistics. In addition, we conducted a sensitivity analysis of the data using a worst and best case model to account for variability of the data due to the high amount of censored observations. RESULTS: Mean incidence of success was 56% with a mean followup of 9.5 months (95% confidence interval 0.17 to 24.6). Median duration of success was 4.7 months (95% confidence interval 3.4 to 5.9). Of the 10 time to failure function comparisons only cystometric incontinence classification had a statistically significant predictive value for treatment failures (p = 0.003). The survival analysis curve provided a 13% success probability at 18 months and was close to the worst case time to failure function. CONCLUSIONS: Collagen injection has minimal morbidity and a low median success rate. Bladder instability, as determined by cystometrogram, is an important determinant of success. Survival statistics methods should be used more widely to describe urological outcomes because they provide dynamic and, thus, more meaningful information to urologists and patients than summary statistics.

A randomized controlled trial to assess the incidence of new onset hypertension in patients after shock wave lithotripsy for asymptomatic renal calculi.

PURPOSE: To answer the question of whether extracorporeal shock wave lithotripsy (ESWL*) induces hypertension, a prospective, randomized controlled trial of normotensive patients with asymptomatic renal calculi was designed. MATERIALS AND METHODS: Patients were randomized to receive immediate ESWL versus observation, reserving ESWL for the onset of symptoms. The rates of new onset hypertension were evaluated for both groups. RESULTS: There was no observed difference in the incidence of hypertension between the treatment and observation groups. CONCLUSIONS: The risk of hypertension in patients undergoing ESWL therapy is similar to that of a control cohort of initially observed asymptomatic patients.

Management of postnephrolithotomy perforation of the renal vein by a double-catheter technique.

Significant venous bleeding after nephrolithotomy is a relatively frequent and well-described complication. The authors report a case of renal vein perforation and its management through combined flank and groin access to the site of bleeding.

Nephrogenic adenoma with bladder exstrophy and immunosuppression.

Nephrogenic adenoma, an unusual proliferative lesion, often occurs in association with chronic inflammation of the bladder and is rarely found in children. Two cases are reported, one occurring in a young child born with bladder exstrophy, and one in a young female, with both interstitial cystitis and chronic use of immunosuppressive therapy. We believe these are the first case reports of nephrogenic adenoma occurring in this specific clinical setting.

Early and late complications of retroperitoneal lymphadenectomy in testis cancer.

The complications arising from 100 consecutive retroperitoneal lymphadenectomies done for nonseminomatous germ-cell tumours of the testis were reviewed. Thirty procedures were performed with sparing of sympathetic nerve fibres. There were no operative deaths. Complications were not stage-related, and the sympathetic nerve-sparing procedure did not alter their frequency. Long-term follow-up in the same cancer centre allowed documentation of all early and delayed complications as a measure of burden of surgical therapy. Median follow-up for survivors was 44 months. Complications that resulted in delayed hospital discharge or further operative intervention at any time were defined as major; all others, resulting in minimal morbidity to the patient, were documented as minor. Injury to renal vessels occurred in four patients intraoperatively. Delayed complications included small-bowel obstruction requiring laparotomy (six patients), incisional hernia requiring repair (two patients) and urethral stricture requiring urethroplasty (one patient). There were 49 complications (14 major, 35 minor) in 35 patients. The authors conclude that the majority of complications after retroperitoneal lymphadenectomy are minor and cause little morbidity. This information is useful when comparing surgery to alternative therapy with similar outcomes. The overall burden of treatment becomes all-important in the selection of optimal therapy.

Acute ureteral obstruction from candidal cystitis requiring bilateral percutaneous nephrostomies.

A case of acute bilateral ureteral obstruction due to severe candidal cystitis is described. The obstruction was due to inflammation and fungal plaque formation in the bladder, rather than the usual intraureteral fungus balls. Percutaneous nephrostomies were required bilaterally for resolution of sepsis and renal failure. The case and its management are presented.

Perforated ulcers in critical illness.

Although gastroduodenal ulcers rarely perforate during critical illness, this occurrence causes specific and difficult problems of diagnosis and management. In our review of the records of 19 critically ill patients whose ulcers perforated, we found that classical symptoms were frequently absent. The perforations often were manifested by nonspecific clinical events, such as unexplained ileus or hypotension. Diagnosis was typically delayed and on occasion was first suspected after observing pneumoperitoneum on a routine x-ray. While the ulcers were characteristically very large (greater than 2 cm), minimal inflammation surrounded them. Mortality was 56% in the 16 patients whose perforations were diagnosed before death or discharge. Fifteen patients were treated with simple patching of the ulcer. Perforated ulcers in critically ill patients differ in several important ways from those occurring in otherwise healthy individuals.

Measurement of carcinoembryonic antigen in patients with bronchogenic carcinoma.

Estimation of CEA levels by the Z-gel method indicates that smokers, patients with limited lung cancer and patients with extensive lung cancer have higher values than nonsmoking controls. The CEA levels within each group are significantly different from one another. Use of CEA estimation for diagnostic purposes is limited because of the considerable overlap between normal controls and patients with cancer, the relatively low incidence of elevated values in patients with limited disease and the high incidence of false negatives (20%) even in patients with extensive disease. Elevated CEA values are associated with a poor prognosis and could be of clinical value as an addition to clinical staging to determine survival particularly for patients with extra-thoracic disease. Persistently high values in patients deemed clinically disease-free postoperatively are indicative of residual disease and a poor prognosis. If and when effective therapy for bronchogenic carcinoma becomes available, monitoring of CEA values may be useful in some patients as an early indication of release. Further studies are required to determine if the extraordinarily poor prognosis associated with marked elevations of CEA may be used as an additional criterion of inoperability in such patients.