Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Validation of finite element models for orthodontic aligners.

PURPOSE: Clear thermoplastic aligners have become popular in orthodontics, but the biomechanics of these devices is not well understood. Neither is the tooth movement induced by such devices. The aim of this study was to develop and validate finite element (FE) models for clear thermoplastic teeth aligners for orthodontic force prediction. METHODS AND MATERIALS: FE models were created from Micro-CT scans of an aligner and a model arch of teeth with one of the incisors tipped buccal-lingually by 2.4°. The models were uniformly meshed with 0.3-mm long elements. Linear-elastic mechanical properties provided by the material manufacturers were used. Fitting of the two components was simulated using Abaqus's interference fit, followed by frictional surface-to-surface interaction. The assembled FE model was validated by comparing its prediction for the teeth-aligner gaps and aligner surface strains with experimental data. The experimental teeth-aligner gaps were obtained from the Micro-CT scans whereas the aligner surface strains were measured using a 2-camera digital image correlation (DIC) system. RESULTS: Good agreement between prediction and measurement was obtained for both the teeth-aligner gaps and aligner surface strains. The linear regression between prediction and measurement for teeth-aligner gaps sampled at different positions had a R2 value of 0.99. The mean difference between prediction and measurement for the aligner surface strains (von Mises) over 1544 nodes on the labial side and 1929 nodes on the lingual side was 0.07% and 0.01%, respectively, both being lower than the mean background noise. CONCLUSION: A FE model for clear thermoplastic teeth aligners has been successfully developed and validated. The model can therefore be used with confidence to predict the forces and moments applied to teeth by the aligners, thus improving our understanding of the biomechanics of such devices and the tooth movement they induce.

Dynamic Scaling and Island Growth Kinetics in Pulsed Laser Deposition of SrTiO_{3}.

We use real-time diffuse surface x-ray diffraction to probe the evolution of island size distributions and its effects on surface smoothing in pulsed laser deposition (PLD) of SrTiO_{3}. We show that the island size evolution obeys dynamic scaling and two distinct regimes of island growth kinetics. Our data show that PLD film growth can persist without roughening despite thermally driven Ostwald ripening, the main mechanism for surface smoothing, being shut down. The absence of roughening is concomitant with decreasing island density, contradicting the prevailing view that increasing island density is the key to surface smoothing in PLD. We also report a previously unobserved crossover from diffusion-limited to attachment-limited island growth that reveals the influence of nonequilibrium atomic level surface transport processes on the growth modes in PLD. We show by direct measurements that attachment-limited island growth is the dominant process in PLD that creates step flowlike behavior or quasistep flow as PLD "self-organizes" local step flow on a length scale consistent with the substrate temperature and PLD parameters.

Effect of orthodontic treatment with preadjusted edgewise appliances on the buccolingual inclination of mandibular canines: a CBCT study.

OBJECTIVES: To assess the effects of treatment with preadjusted edgewise appliances on the buccolingual inclination of mandibular canines and the intercanine distance. SETTING AND SAMPLE POPULATION: The Division of Orthodontics at the University of Minnesota. Thirty patients whose treatment included extraction of mandibular first premolars and 30 patients whose treatment did not include extractions. MATERIAL AND METHODS: The buccolingual inclination of mandibular canines and their linear distance were measured on cone beam computed tomograms before and after treatment in both patient groups. Differences between extraction and non-extraction groups and between pre- and post-treatment measurements were tested for statistical significance, and the correlation between the buccolingual inclination and the intercanine distance was computed. RESULTS: Post-treatment, the buccolingual inclination of mandibular canines was significantly greater in the non-extraction group than in the extraction group. In both groups, the canines became more lingually inclined with treatment (non-extraction group: -2.1°; extraction group: -4.1°). The intercanine distance increased significantly in the extraction group (+1.2 mm) but not in the non-extraction group (-0.5 mm). While there was a significant positive correlation between the buccolingual inclination and the mandibular intercanine distance in both groups before treatment, after treatment this correlation was significant only in the non-extraction group. CONCLUSION: Orthodontic treatment with preadjusted edgewise appliances results in more lingually inclined mandibular canines together with an increased intercanine distance, especially in patients whose treatment involves the extraction of mandibular first premolars.

Long-term reduction in poly(dimethylsiloxane) surface hydrophobicity via cold-plasma treatments.

Poly(dimethylsiloxane), PDMS, a versatile elastomer, is the polymer of choice for microfluidic systems. It is inexpensive, relatively easy to pattern, and permeable to oxygen. Unmodified PDMS is highly hydrophobic. It is typically exposed to an oxygen plasma to reduce this hydrophobicity. Unfortunately, the PDMS surface soon returns to its original hydrophobic state. We present two alternative plasma treatments that yield long-term modification of the wetting properties of a PDMS surface. An oxygen plasma pretreatment followed by exposure to a SiCl4 plasma and an oxygen-CCl4 mixture plasma both cause a permanent reduction in the hydrophobicity of the PDMS surface. We investigate the properties of the plasma-treated surfaces with X-ray photoelectron spectroscopy (XPS) and contact angle measurements. We propose that the plasma treated PDMS surface is a dynamic mosaic of high- and low-contact-angle functionalities. The SiCl4 and CCl4 plasmas attach polar groups that block coverage of the surface by low-molecular-weight groups that exist in PDMS. We describe an application that benefits from these new plasma treatments, the use of a PDMS stencil to form dense arrays of DNA on a surface.

Detection of skin cancer margins in Mohs excisions with high-speed strip mosaicing confocal microscopy: a feasibility study.

BACKGROUND: Fluorescence confocal mosaicing microscopy is an emerging technology for rapid imaging of nuclear and morphological detail directly in excised tissue, without the need for frozen or fixed section processing. Basal cell carcinomas (BCCs) can be detected with high sensitivity and specificity in Mohs excisions with this approach. For translation to clinical trials and towards potentially routine implementation, a new and faster approach called strip mosaicing confocal microscopy was recently developed. OBJECTIVES: To perform a preliminary assessment of fluorescence strip mosaicing confocal microscopy for detecting skin cancer margins in Mohs excisions. METHODS: Tissue samples from 17 Mohs cases were imaged in the form of strip mosaics. Each mosaic was divided into two halves (submosaics) and graded by a Mohs surgeon and a dermatologist who were blinded to the pathology. The 34 submosaics were compared with the corresponding Mohs pathology. RESULTS: The overall image quality was excellent for resolution, contrast and stitching in the 34 submosaics. Components of normal skin including the epidermis, dermis, dermal appendages and subcutaneous tissue were easily visualized. The preliminary measures of sensitivity and specificity were both 94% for detecting skin cancer margins. CONCLUSIONS: The new strip mosaicing approach represents another advance in confocal microscopy for imaging of large areas of excised tissue. Strip mosaicing may enable rapid assessment of BCC margins in fresh excisions during Mohs surgery and may serve as an adjunct to frozen pathology.

Producer survey of bird-livestock interactions in commercial dairies.

The objective of this producer survey was to identify and estimate damage caused by bird-livestock interactions in commercial dairies. The interactions between birds and livestock have previously been implicated in causing economic damage while contributing to the environmental dissemination of microorganisms pathogenic to livestock and humans. Very little research exists to help producers understand what bird species use dairies, why they use dairies, or the scope and nature of damage created as a result of bird-livestock interactions. To better characterize these interactions, we surveyed dairy operators within Pennsylvania, New York, and Wisconsin. Survey results suggest that the most common and destructive bird species found on commercial dairies are invasive to North America, and their use of dairies is associated with the loss of cattle feed, increased operating costs, and an increase in dairies self-reporting Salmonella spp. and Mycobacterium avium ssp. paratuberculosis. Cattle feed loss estimates generated from this survey were used to parameterize an input-output (IO) economic model using data from 10 counties in the state of Pennsylvania (Bedford, Berks, Blair, Bradford, Chester, Cumberland, Franklin, Lancaster, Lebanon, and Somerset). This IO model allowed us to estimate direct, indirect, and induced economic effects of feed loss from bird damage to dairies within these counties. The IO model output suggests that feed loss costs Pennsylvania between $4.11 and $12.08 million (mean $10.6 million) in total economic damage, with approximately 43 to 128 jobs (mean 112) forgone statewide in 2009.

Craniofacial and intraoral phenotype of Robinow syndrome forms.

Robinow syndrome (RS) is a rare genetic condition with two inheritance forms, autosomal dominant RS (DRS) and autosomal recessive RS (RRS). The characteristic features of this syndrome overlap in both inheritance forms, which make the clinical differential diagnosis difficult, especially in isolated cases. The objective of this study was to identify differences in the craniofacial and intraoral phenotype of patients with DRS and RRS. The characteristics and frequency of 13 facial and 13 intraoral clinical features associated with both DRS and RRS were assessed by direct dysmorphology examination and using a digital photographic analysis in 12 affected subjects. Although the phenotypic presentation varied and overlapped in the two forms of the syndrome, there were differences in the severity of the craniofacial and intraoral features. The craniofacial dysmorphology of RS was more severe in RRS. Nasal anomalies were the most frequent craniofacial features in both DRS and RRS. In contrast, intraoral features such as wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding and hypodontia were more severe in patients with DRS. Overall, facial characteristics appeared less pronounced in adult subjects compared to younger subjects. Craniofacial and intraoral findings are highly variable in RS, with abnormalities of the intraoral structures being more prominent in the DRS form. We propose that the difference in the alveolar ridge deformation pattern and severity of other intraoral characteristics could enhance the differential diagnosis of the two forms of this syndrome.

Efficacy of computer technology-based HIV prevention interventions: a meta-analysis.

OBJECTIVES: To conduct a meta-analysis of computer technology-based HIV prevention behavioral interventions aimed at increasing condom use among a variety of at-risk populations. DESIGN: Systematic review and meta-analysis of existing published and unpublished studies testing computer-based interventions. METHODS: Meta-analytic techniques were used to compute and aggregate effect sizes for 12 randomized controlled trials that met inclusion criteria. Variables that had the potential to moderate intervention efficacy were also tested. RESULTS: The overall mean weighted effect size for condom use was d = 0.259 (95% confidence interval = 0.201, 0.317; Z = 8.74, P < 0.001; N = 4639), indicating a statistically significant impact of the interventions. This effect size compares favorably to previously tested interventions delivered by human facilitators. Statistically significant effect sizes were also found for frequency of sexual behavior, number of partners, and incident sexually transmitted diseases. In addition, interventions were significantly more efficacious when they were directed at men or women (versus mixed sex groups), utilized individualized tailoring, used a Stages of Change model, and had more intervention sessions. CONCLUSION: Computer technology-based HIV prevention interventions have similar efficacy to more traditional human-delivered interventions. Given their low cost to deliver, ability to customize intervention content, and flexible dissemination channels, they hold much promise for the future of HIV prevention.

[Population dynamics of glochidia of the freshwater pearl mussel Margaritifera margaritifera L., parasitizing on juvenile Salmonidae fishes in northern water reservoirs].

This paper presents data on the population dynamics of glochidia of the freshwater pearl mussel Margaritifera margaritifera L. (1758) (a declining species of European fauna), parasitizing on juvenile Salmonidae fishes in rivers of northern Europe. It was found that the number of glochidia parasitizing on gills of juvenile salmon and trout in explored water reservoirs are stimulated by negative binomial distribution. Estimation of the distribution parameter allows us to obtain statistically valid data on the population number of pearl mussel and to judge the stable character of interactions in the host-parasite system (balance of host specimens that are resistant and nonresistant to infection).

Effects of revised diagnostic recommendations on malaria treatment practices across age groups in Kenya.

OBJECTIVE: The recent change of treatment policy for uncomplicated malaria from sulfadoxine-pyrime-thamine to artemether-lumefantrine (AL) in Kenya was accompanied by revised malaria diagnosis recommendations promoting presumptive antimalarial treatment in young children and parasitological diagnosis in patients 5 years and older. We evaluated the impact of these age-specific recommendations on routine malaria treatment practices 4-6 months after AL treatment was implemented. METHODS: Cross-sectional, cluster sample survey using quality-of-care assessment methods in all government facilities in four Kenyan districts. Analysis was restricted to the 64 facilities with malaria diagnostics and AL available on the survey day. Main outcome measures were antimalarial treatment practices for febrile patients stratified by age, use of malaria diagnostic tests, and test result. RESULTS: Treatment practices for 706 febrile patients (401 young children and 305 patients > or =5 years) were evaluated. 43.0% of patients > or =5 years and 25.9% of children underwent parasitological malaria testing (87% by microscopy). AL was prescribed for 79.7% of patients > or =5 years with positive test results, for 9.7% with negative results and for 10.9% without a test. 84.6% of children with positive tests, 19.2% with negative tests, and 21.6% without tests were treated with AL. At least one antimalarial drug was prescribed for 75.0% of children and for 61.3% of patients > or =5 years with a negative test result. CONCLUSIONS: Despite different recommendations for patients below and above 5 years of age, malaria diagnosis and treatment practices were similar in the two age groups. Parasitological diagnosis was under-used in older children and adults, and young children were still tested. Use of AL was low overall and alternative antimalarials were commonly prescribed; but AL prescribing largely followed the results of malaria tests. Malaria diagnosis recommendations differing between age groups appear complex to implement; further strengthening of diagnosis and treatment practices under AL policy is required.

Nonresonant inelastic x-ray scattering and energy-resolved Wannier function investigation of d-d excitations in NiO and CoO.

Nonresonant inelastic x-ray scattering measurements on NiO and CoO show that strong dipole-forbidden d-d excitations appear within the Mott gap at large wave vectors. These dominant excitations are highly anisotropic, and have [001] nodal directions for NiO. Theoretical analyses based on a novel, energy-resolved Wannier function (within the local density approximation+Hubbard U) show that the anisotropy reflects the local exciton wave functions and local point-group symmetry. The sensitivity to weak symmetry breaking in particle-hole wave functions suggests a wide application to strongly correlated systems.

The financial and clinical implications of adult malaria diagnosis using microscopy in Kenya.

OBJECTIVE: A recent observational study undertaken at 17 health facilities with microscopy in Kenya revealed that potential benefits of malaria microscopy are not realized because of irrational clinical practices and the low accuracy of routine microscopy. Using these data, we modelled financial and clinical implications of revised clinical practices and improved accuracy of malaria microscopy among adult outpatients under the artemether-lumefantrine (AL) treatment policy for uncomplicated malaria in Kenya. METHODS: The cost of AL, antibiotics and malaria microscopy and the expected number of malaria diagnosis errors were estimated per 1,000 adult outpatients presenting at a facility with microscopy under three scenarios: (1) current clinical practice and accuracy of microscopy (option A), (2) revised clinical practice with current accuracy of microscopy (option B) and (3) revised clinical practice with improved accuracy of microscopy (option C). Revised clinical practice was defined as performing a blood slide for all febrile adults and prescribing antimalarial treatment only for positive results. Improved accuracy of routine microscopy was defined as 90% sensitivity and specificity. In the sensitivity analysis, the implications of changes in the cost of drugs and malaria microscopy and changes in background malaria prevalence were examined for each option. RESULTS: The costs of AL, antibiotics and malaria microscopy decreased from 2,154 dollars under option A to 1,254 dollars under option B and 892 dollars under option C. Of the cost savings from option C, 72% was from changes in clinical practice, while 28% was from improvements in the accuracy of microscopy. Compared with 638 malaria overdiagnosis errors per 1,000 adults under option A, 375 and 548 fewer overdiagnosis errors were estimated, respectively, under options B and C. At the same time, the number of missed malaria diagnoses remained generally low under all options. Sensitivity analysis showed that both options B and C are robust to a wide range of assumptions on the costs of drugs, costs of blood slides and malaria prevalence. CONCLUSIONS: Even with the imperfect microscopy conditions at Kenyan facilities, implementation of revised clinical practice (option B) would substantially reduce the costs and errors from malaria overdiagnosis. Additional interventions to improve the accuracy of microscopy (option C) can achieve further benefits; however, improved microscopy in the absence of revised clinical practice is unlikely to generate significant cost savings. Revision of guidelines to state explicitly age-specific indications for the use and interpretation of malaria microscopy is urgently needed. Further prospective studies are required to evaluate the effectiveness and costs of interventions to improve clinical practice and the accuracy of malaria microscopy.

Nonequilibrium interlayer transport in pulsed laser deposition.

We use time-resolved surface x-ray diffraction measurements with microsecond range resolution to study the growth kinetics of pulsed laser deposited . Time-dependent surface coverages corresponding to single laser shots were determined directly from crystal truncation rod intensity transients. Analysis of surface coverage evolution shows that extremely fast nonequilibrium interlayer transport, which occurs concurrently with the arrival of the laser plume, dominates the deposition process. A much smaller fraction of material, which is governed by the dwell time between successive laser shots, is transferred by slow, thermally driven interlayer transport processes.

Cold-plasma modification of oxide surfaces for covalent biomolecule attachment.

While many processes have been developed to modify the surface of glass and other oxides for biomolecule attachment, they rely primarily upon wet chemistry and are costly and time-consuming. We describe a process that uses a cold plasma and a subsequent in vacuo vapor-phase reaction to terminate a variety of oxide surfaces with epoxide chemical groups. These epoxide groups can react with amine-containing biomolecules, such as proteins and modified oligonucleotides, to form strong covalent linkages between the biomolecules and the treated surface. The use of a plasma activation step followed by an in vacuo vapor-phase reaction allows for the precise control of surface functional groups, rather than the mixture of functionalities normally produced. By maintaining the samples under vacuum throughout the process, adsorption of contaminants is effectively eliminated. This process modifies a range of different oxide surfaces, is fast, consumes a minimal amount of reagents, and produces attachment densities for bound biomolecules that are comparable to or better than commercially available substrates.

Influence of physical activity on urinary leakage in primiparous women.

The impact of physical activity on urinary leakage (UL) has previously been considered, but not in relation to first pregnancy and delivery. The aim of this study was to describe physical activity and urinary leakage before, during and after the first childbirth. The subjects who were invited to participate in the study were taken consecutively from nine maternity clinics in the northwest part of Stockholm County, and the study group included 665 primiparous women. The mean age of the women was 28 (range 17-43) years. The women answered one questionnaire during the 36th gestation week and another 1 year post partum. Physical activity/exercises were classified according to their impact on the pelvic floor, and the women were divided into three groups: high-impact exercise (n=327), low-impact exercise (n=84) and the inactive group (n=254). The results showed a high intensity and frequency of physical activity in the participating primiparous women. Risk factors for UL were symptoms of a dysfunctional pelvic floor and connective tissue disorders and high-impact physical activity before pregnancy, while low-impact activity seemed to promote continence. If urinary leakage was present before pregnancy, it persisted in most women during pregnancy and 1 year post partum.

Polychromatic X-ray microdiffraction studies of mesoscale structure and dynamics.

Polychromatic X-ray microdiffraction is an emerging tool for studying mesoscale structure and dynamics. Crystalline phase, orientation (texture), elastic and plastic strain can be nondestructively mapped in three dimensions with good spatial and angular resolution. Local crystallographic orientation can be determined to approximately 0.01 degree and elastic strain tensor elements can be measured with a resolution of approximately 10(-4) or better. Complete strain tensor information can be obtained by augmenting polychromatic microdiffraction with a monochromatic measurement of one Laue-reflection energy. With differential-aperture depth profiling, volumes tens to hundreds of micrometers below the surface are accessible so that three-dimensional distributions of crystalline morphology including grain boundaries, triple points, second phases and inclusions can all be mapped. Volume elements below 0.25 microm3 are routinely resolved so that the grain boundary structure of most materials can be characterized. Here the theory, instrumentation and application of polychromatic microdiffraction are described.

Quantitative analyses of GFRalpha-1 and GFRalpha-2 mRNAs and tyrosine hydroxylase protein in the nigrostriatal system reveal bilateral compensatory changes following unilateral 6-OHDA lesions in the rat.

Copy numbers of mRNAs for GFRalpha-1 and GFRalpha-2, the preferred receptors for glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) were determined by real-time quantitative RT-PCR (QRT-PCR). Receptor expression was assessed in striatum (ST) and substantia nigra (SN) of normal rats and rats acutely or progressively lesioned by 6-OHDA injected into the medial forebrain bundle or ST, respectively. GFRalpha-1 mRNA was clearly detected in normal ST. In normal SN, significantly higher expression of both receptors was observed. At 4 weeks after acute lesion, GFRalpha-2 mRNA was markedly decreased in SN bilaterally, whereas GFRalpha-1 mRNA in SN and ST was not affected. A progressive lesion resulted in a progressive decrease of GFRalpha1 mRNA in ST bilaterally. In SN, levels of GFRalpha-1 mRNA were not significantly affected by a progressive lesion, whereas GFRalpha-2 mRNA was markedly decreased bilaterally. Quantitative western blotting standardized against tyrosine hydroxylase (TH) protein from PC12 cells revealed the expected decrease in TH protein in lesioned SN, but also significant increases in TH protein in contralateral, unlesioned SNs at 4 weeks after both acute and progressive lesions. These data suggest that previously unrecognized compensatory changes in the nigrostriatal system occur in response to unilateral dopamine depletion. Since the changes observed in receptor expression did not always parallel loss of dopamine neurons, cells in addition to the nigral dopamine neurons appear to be affected by a 6-OHDA insult and are potential targets for the neurotrophic factors, GDNF and NTN.

Differential-aperture X-ray structural microscopy: a submicron-resolution three-dimensional probe of local microstructure and strain.

A recently developed differential-aperture X-ray microscopy (DAXM) technique provides local structure and crystallographic orientation with submicron spatial resolution in three-dimensions; it further provides angular precision of approximately 0.01 degrees and local elastic strain with an accuracy of approximately 1.0 x 10(-4) using microbeams from high brilliance third generation synchrotron X-ray sources. DAXM is a powerful tool for inter- and intra-granular studies of lattice distortions and lattice rotations on mesoscopic length scales of tenths of microns to hundreds of microns that are largely above the range of traditional electron microscopy probes. Nondestructive, point-to-point, spatially resolved measurements of local lattice orientations in bulk materials provide direct information on geometrically necessary dislocation density distributions through measurements of the lattice curvature in plastically deformed materials. This paper reviews the DAXM measurement technique and discusses recent demonstrations of DAXM capabilities for measurements of microtexture, local elastic strain, and plastic deformation microstructure.