Quality control of pharmaceutical ingredients:developing a caking test for industry

Objectives - Powdered and granulated particulate materials make up most of the ingredients of pharmaceuticals and are often at risk of undergoing unwanted agglomeration, or caking, during transport or storage. This is particularly acute when bulk powders are exposed to extreme swings in temperature and relative humidity, which is now common as drugs are produced and administered in increasingly hostile climates and are stored for longer periods of time prior to use. This study explores the possibility of using a uniaxial unconfined compression test to compare the strength of caked agglomerates exposed to different temperatures and relative humidities. This is part of a longer-term study to construct a protocol to predict the caking tendency of a new bulk material from individual particle properties. The main challenge is to develop techniques that provide repeatable results yet are presented simply enough to be useful to a wide range of industries. Methods - Powdered sucrose, a major pharmaceutical ingredient, was poured into a split die and exposed to high and low relative humidity cycles at room temperature. The typical ranges were 20–30% for the lower value and 70–80% for the higher value. The outer die casing was then removed and the resultant agglomerate was subjected to an unconfined compression test using a plunger fitted to a Zwick compression tester. The force against displacement was logged so that the dynamics of failure as well as the failure load of the sample could be recorded. The experimental matrix included varying the number of cycles, the amount between the maximum and minimum relative humidity, the height and diameters of the samples, the number of cycles and the particle size. Results - Trends showed that the tensile strength of the agglomerates increased with the number of cycles and also with the more extreme swings in relative humidity. This agrees with previous work on alternative methods of measuring the tensile strength of sugar agglomerates formed from humidity cycling (Leaper et al 2003). Conclusions - The results show that at the very least the uniaxial tester is a good comparative tester to examine the caking tendency of powdered materials, with a simple arrangement and operation that are compatible with the requirements of industry. However, further work is required to continue to optimize the height/ diameter ratio during tests.

Pulse oximetry as a screening test for congenital heart defects in newborn infants: a test accuracy study with evaluation of acceptability and cost-effectiveness

Background: Screening for congenital heart defects (CHDs) relies on antenatal ultrasound and postnatal clinical examination; however, life-threatening defects often go undetected. Objective: To determine the accuracy, acceptability and cost-effectiveness of pulse oximetry as a screening test for CHDs in newborn infants. Design: A test accuracy study determined the accuracy of pulse oximetry. Acceptability of testing to parents was evaluated through a questionnaire, and to staff through focus groups. A decision-analytic model was constructed to assess cost-effectiveness. Setting: Six UK maternity units. Participants: These were 20,055 asymptomatic newborns at = 35 weeks’ gestation, their mothers and health-care staff. Interventions: Pulse oximetry was performed prior to discharge from hospital and the results of this index test were compared with a composite reference standard (echocardiography, clinical follow-up and follow-up through interrogation of clinical databases). Main outcome measures: Detection of major CHDs – defined as causing death or requiring invasive intervention up to 12 months of age (subdivided into critical CHDs causing death or intervention before 28 days, and serious CHDs causing death or intervention between 1 and 12 months of age); acceptability of testing to parents and staff; and the cost-effectiveness in terms of cost per timely diagnosis. Results: Fifty-three of the 20,055 babies screened had a major CHD (24 critical and 29 serious), a prevalence of 2.6 per 1000 live births. Pulse oximetry had a sensitivity of 75.0% [95% confidence interval (CI) 53.3% to 90.2%] for critical cases and 49.1% (95% CI 35.1% to 63.2%) for all major CHDs. When 23 cases were excluded, in which a CHD was already suspected following antenatal ultrasound, pulse oximetry had a sensitivity of 58.3% (95% CI 27.7% to 84.8%) for critical cases (12 babies) and 28.6% (95% CI 14.6% to 46.3%) for all major CHDs (35 babies). False-positive (FP) results occurred in 1 in 119 babies (0.84%) without major CHDs (specificity 99.2%, 95% CI 99.0% to 99.3%). However, of the 169 FPs, there were six cases of significant but not major CHDs and 40 cases of respiratory or infective illness requiring medical intervention. The prevalence of major CHDs in babies with normal pulse oximetry was 1.4 (95% CI 0.9 to 2.0) per 1000 live births, as 27 babies with major CHDs (6 critical and 21 serious) were missed. Parent and staff participants were predominantly satisfied with screening, perceiving it as an important test to detect ill babies. There was no evidence that mothers given FP results were more anxious after participating than those given true-negative results, although they were less satisfied with the test. White British/Irish mothers were more likely to participate in the study, and were less anxious and more satisfied than those of other ethnicities. The incremental cost-effectiveness ratio of pulse oximetry plus clinical examination compared with examination alone is approximately £24,900 per timely diagnosis in a population in which antenatal screening for CHDs already exists. Conclusions: Pulse oximetry is a simple, safe, feasible test that is acceptable to parents and staff and adds value to existing screening. It is likely to identify cases of critical CHDs that would otherwise go undetected. It is also likely to be cost-effective given current acceptable thresholds. The detection of other pathologies, such as significant CHDs and respiratory and infective illnesses, is an additional advantage. Other pulse oximetry techniques, such as perfusion index, may enhance detection of aortic obstructive lesions.

Effect of performance feedback on perceived knowledge and likelihood to pursue continuing education

The purpose of this study was to assess the effect of performance feedback on Athletic Trainers’ (ATs) perceived knowledge (PK) and likelihood to pursue continuing education (CE). The investigation was grounded in the theories of “the definition of the situation” (Thomas & Thomas, 1928) and the “illusion of knowing,” (Glenberg, Wilkinson, & Epstein, 1982) suggesting that PK drives behavior. This investigation measured the degree to which knowledge gap predicted CE seeking behavior by providing performance feedback designed to change PK. A pre-test post-test control-group design was used to measure PK and likelihood to pursue CE before and after assessing actual knowledge. ATs (n=103) were randomly sampled and assigned to two groups, with and without performance feedback. Two independent samples t-tests were used to compare groups on the difference scores of the dependent variables. Likelihood to pursue CE was predicted by three variables using multiple linear regression: perceived knowledge, pre-test likelihood to pursue CE, and knowledge gap. There was a 68.4% significant difference (t101=2.72, p=0.01, ES=0.45) between groups in the change scores for likelihood to pursue CE because of the performance feedback (Experimental group=13.7% increase; Control group=4.3% increase). The strongest relationship among the dependent variables was between pre-test and post-test measures of likelihood to pursue CE (F2,102=56.80, p<0.01, r=0.73, R2=0.53). The pre- and post-test predictive relationship was enhanced when group was included in the model. In this model [YCEpost=0.76XCEpre-0.34 Xgroup+2.24+E], group accounted for a significant amount of unique variance in predicting CE while the pre-test likelihood to pursue CE variable was held constant (F3,102=40.28, p<0.01, r=0.74, R2=0.55). Pre-test knowledge gap, regardless of group allocation, was a linear predictor of the likelihood to pursue CE (F1,102=10.90, p=.01, r=.31, R2=.10). In this investigation, performance feedback significantly increased participants’ likelihood to pursue CE. Pre-test knowledge gap was a significant predictor of likelihood to pursue CE, regardless if performance feedback was provided. ATs may have self-assessed and engaged in internal feedback as a result of their test-taking experience. These findings indicate that feedback, both internal and external, may be necessary to trigger CE seeking behavior.

(Table 1) Sample characteristics, test consolidations and calculated elastic parameters of ODP Sites 194-1193 and 194-1196

This study is based on rock mechanical tests of samples from platform carbonate strata to document their petrophysical properties and determine their potential for porosity loss by mechanical compaction. Sixteen core-plug samples, including eleven limestones and five dolostones, from Miocene carbonate platforms on the Marion Plateau, offshore northeast Australia, were tested at vertical effective stress, sigma1', of 0-70 MPa, as lateral strain was kept equal to zero. The samples were deposited as bioclastic facies in platform-top settings having paleo-water depths of <10-90 m. They were variably cemented with low-Mg calcite and five of the samples were dolomitized before burial to present depths of 39-635 m below sea floor with porosities of 8-46%. Ten samples tested under dry conditions had up to 0.22% strain at sigma1' = 50 MPa, whereas six samples tested saturated with brine, under drained conditions, had up to 0.33% strain. The yield strength was reached in five of the plugs. The measured strains show an overall positive correlation with porosity. Vp ranges from 3640 to 5660 m/s and Vs from 1840 to 3530 m/s. Poisson coefficient is 0.20-0.33 and Young's modulus at 30 MPa ranged between 5 and 40 GPa. Water saturated samples had lower shear moduli and slightly higher P- to S-wave velocity ratios. Creep at constant stress was observed only in samples affected by pore collapse, indicating propagation of microcracks. Although deposited as loose carbonate sand and mud, the studied carbonates acquired reef-like petrophysical properties by early calcite and dolomite cementation. The small strains observed experimentally at 50 MPa indicate that little mechanical compaction would occur at deeper burial. However, as these rocks are unlikely to preserve their present high porosities to 4-5 km depth, further porosity loss would proceed mainly by chemical compaction and cementation.

Effect of Performance Feedback on Perceived Knowledge and Likelihood to Pursue Continuing Education

The purpose of this study was to assess the effect of performance feedback on Athletic Trainers’ (ATs) perceived knowledge (PK) and likelihood to pursue continuing education (CE). The investigation was grounded in the theories of “the definition of the situation” (Thomas & Thomas, 1928) and the “illusion of knowing,” (Glenberg, Wilkinson, & Epstein, 1982) suggesting that PK drives behavior. This investigation measured the degree to which knowledge gap predicted CE seeking behavior by providing performance feedback designed to change PK. A pre-test post-test control-group design was used to measure PK and likelihood to pursue CE before and after assessing actual knowledge. ATs (n=103) were randomly sampled and assigned to two groups, with and without performance feedback. Two independent samples t-tests were used to compare groups on the difference scores of the dependent variables. Likelihood to pursue CE was predicted by three variables using multiple linear regression: perceived knowledge, pre-test likelihood to pursue CE, and knowledge gap. There was a 68.4% significant difference (t101= 2.72, p=0.01, ES=0.45) between groups in the change scores for likelihood to pursue CE because of the performance feedback (Experimental group=13.7% increase; Control group= 4.3% increase). The strongest relationship among the dependent variables was between pre-test and post-test measures of likelihood to pursue CE (F2,102=56.80, p<0.01, r=0.73, R2=0.53). The pre- and post-test predictive relationship was enhanced when group was included in the model. In this model [YCEpost=0.76XCEpre-0.34 Xgroup+2.24+E], group accounted for a significant amount of unique variance in predicting CE while the pre-test likelihood to pursue CE variable was held constant (F3,102=40.28, p<0.01,: r=0.74, R2=0.55). Pre-test knowledge gap, regardless of group allocation, was a linear predictor of the likelihood to pursue CE (F1,102=10.90, p=.01, r=.31, R2=.10). In this investigation, performance feedback significantly increased participants’ likelihood to pursue CE. Pre-test knowledge gap was a significant predictor of likelihood to pursue CE, regardless if performance feedback was provided. ATs may have self-assessed and engaged in internal feedback as a result of their test-taking experience. These findings indicate that feedback, both internal and external, may be necessary to trigger CE seeking behavior.

Foraminifera Mg/Ca, test weight and XDX for sediment core WIND28K

A record of deep-sea calcite saturation (D[CO3**-2]), derived from X-ray computed tomography-based foraminifer dissolution index, XDX, was constructed for the past 150 ka for a core from the deep (4157 m) tropical western Indian Ocean. G. sacculifer and N. dutertrei recorded a similar dissolution history, consistent with the process of calcite compensation. Peaks in calcite saturation (~15 µmol/kg higher than the present-day value) occurred during deglaciations and early in MIS 3. Dissolution maxima coincided with transitions to colder stages. The mass record of G. sacculifer better indicated preservation than did that of N. dutertrei or G. ruber. Dissolution-corrected Mg/Ca-derived SST records, like other SST records from marginal Indian Ocean sites, showed coolest temperatures of the last 150 ka in early MIS 3, when mixed layer temperatures were ~4°C lower than present SST. Temperatures recorded by N. dutertrei showed the thermocline to be ~4°C colder in MIS 3 compared to the Holocene (8 ka B.P.).

(Table 1) Average sea surface temperature, average sea surface salinity, C37 concentration, palmitic acid concentration, Uk'37, C37/C38 ratio, dD of water, dD of C37 and dD of palmitic acid of water samples from a transect across the Amazon Plume

The stable hydrogen isotope composition of lipid biomarkers, such as alkenones, is a promising new tool for the improvement of palaeosalinity reconstructions. Laboratory studies confirmed the correlation between lipid biomarker dD composition (dDLipid), water dD composition (dDH2O) and salinity; yet there is limited insight into the applicability of this proxy in oceanic environments. To fill this gap, we test the use of the dD composition of alkenones (dDC37) and palmitic acid (dDPA) as salinity proxies using samples of surface suspended material along the distinct salinity gradient induced by the Amazon Plume. Our results indicate a positive correlation between salinity and dDH2O, while the relationship between dDH2O and dDLipid is more complex: dDPAM correlates strongly with dDH2O (r2 = 0.81) and shows a salinity-dependent isotopic fractionation factor. dDC37 only correlates with dDH2O in a small number (n = 8) of samples with alkenone concentrations > 10 ng L**-1, while there is no correlation if all samples are taken into account. These findings are mirrored by alkenone-based temperature reconstructions, which are inaccurate for samples with low alkenone concentrations. Deviations in dDC37 and temperature are likely to be caused by limited haptophyte algae growth due to low salinity and light limitation imposed by the Amazon Plume. Our study confirms the applicability of dDLipid as a salinity proxy in oceanic environments. But it raises a note of caution concerning regions where low alkenone production can be expected due to low salinity and light limitation, for instance, under strong riverine discharge.

An R-package for the Estimation and Testing of Multiple Covariates and Biomarker Interactions for Survival Data Based on Local Partial Likelihood

When we study the variables that a ffect survival time, we usually estimate their eff ects by the Cox regression model. In biomedical research, e ffects of the covariates are often modi ed by a biomarker variable. This leads to covariates-biomarker interactions. Here biomarker is an objective measurement of the patient characteristics at baseline. Liu et al. (2015) has built up a local partial likelihood bootstrap model to estimate and test this interaction e ffect of covariates and biomarker, but the R code developed by Liu et al. (2015) can only handle one variable and one interaction term and can not t the model with adjustment to nuisance variables. In this project, we expand the model to allow adjustment to nuisance variables, expand the R code to take any chosen interaction terms, and we set up many parameters for users to customize their research. We also build up an R package called "lplb" to integrate the complex computations into a simple interface. We conduct numerical simulation to show that the new method has excellent fi nite sample properties under both the null and alternative hypothesis. We also applied the method to analyze data from a prostate cancer clinical trial with acid phosphatase (AP) biomarker.

An Objective Framework to Test the Quality of Candidate Indicators of Good Environmental Status

Large efforts are on-going within the EU to prepare the Marine Strategy Framework Directive’s (MSFD) assessment of the environmental status of the European seas. This assessment will only be as good as the indicators chosen to monitor the eleven descriptors of good environmental status (GEnS). An objective and transparent framework to determine whether chosen indicators actually support the aims of this policy is, however, not yet in place. Such frameworks are needed to ensure that the limited resources available to this assessment optimize the likelihood of achieving GEnS within collaborating states. Here, we developed a hypothesis-based protocol to evaluate whether candidate indicators meet quality criteria explicit to the MSFD, which the assessment community aspires to. Eight quality criteria are distilled from existing initiatives, and a testing and scoring protocol for each of them is presented. We exemplify its application in three worked examples, covering indicators for three GEnS descriptors (1, 5 and 6), various habitat components (seaweeds, seagrasses, benthic macrofauna and plankton), and assessment regions (Danish, Lithuanian and UK waters). We argue that this framework provides a necessary, transparent and standardized structure to support the comparison of candidate indicators, and the decision-making process leading to indicator selection. Its application could help identify potential limitations in currently available candidate metrics and, in such cases, help focus the development of more adequate indicators. Use of such standardized approaches will facilitate the sharing of knowledge gained across the MSFD parties despite context-specificity across assessment regions, and support the evidence-based management of European seas.

An Objective Framework to Test the Quality of Candidate Indicators of Good Environmental Status

Large efforts are on-going within the EU to prepare the Marine Strategy Framework Directive’s (MSFD) assessment of the environmental status of the European seas. This assessment will only be as good as the indicators chosen to monitor the eleven descriptors of good environmental status (GEnS). An objective and transparent framework to determine whether chosen indicators actually support the aims of this policy is, however, not yet in place. Such frameworks are needed to ensure that the limited resources available to this assessment optimize the likelihood of achieving GEnS within collaborating states. Here, we developed a hypothesis-based protocol to evaluate whether candidate indicators meet quality criteria explicit to the MSFD, which the assessment community aspires to. Eight quality criteria are distilled from existing initiatives, and a testing and scoring protocol for each of them is presented. We exemplify its application in three worked examples, covering indicators for three GEnS descriptors (1, 5 and 6), various habitat components (seaweeds, seagrasses, benthic macrofauna and plankton), and assessment regions (Danish, Lithuanian and UK waters). We argue that this framework provides a necessary, transparent and standardized structure to support the comparison of candidate indicators, and the decision-making process leading to indicator selection. Its application could help identify potential limitations in currently available candidate metrics and, in such cases, help focus the development of more adequate indicators. Use of such standardized approaches will facilitate the sharing of knowledge gained across the MSFD parties despite context-specificity across assessment regions, and support the evidence-based management of European seas.

Broad-scale patterns of sex ratios in Patella spp.: a comparison of range edge and central range populations in the British Isles and Portugal

Sex change, or sequential hermaphroditism, occurs in the plant and animal kingdoms and often determines a predominance of the first sex. Our aim was to explore changes in sex ratios within the range of the species studied: Patella vulgata and Patella depressa. The broad-scale survey of sex with size of limpets covered a range of latitudes from Zambujeira do Mar (southern Portugal) to the English Channel. Indirect evidence was found for the occurrence of protandry in P. vulgata populations from the south of England, with females predominating in larger size-classes; cumulative frequency distributions of males and females were different; sex ratios were biased towards males and smallest sizes of males were smaller than the smallest sizes of females. In contrast in Portugal females were found in most size-classes of P. vulgata. In P. depressa populations from the south coast of England and Portugal females were interspersed across most size-classes; size distributions of males and females and size at first maturity of males and females did not differ. P. depressa did, however, show some indications of the possibility of slight protandry occurring in Portugal. The test of sex ratio variation with latitude indicated that P. vulgata sex ratios might be involved in determining the species range limit, particularly at the equatorward limit since the likelihood of being male decreased from the south coast of England to southern Portugal. Thus at the southern range limit, sperm could be in short supply due to scarcity of males contributing to an Allee effect.

Broad-scale patterns of sex ratios in Patella spp.: a comparison of range edge and central range populations in the British Isles and Portugal

Sex change, or sequential hermaphroditism, occurs in the plant and animal kingdoms and often determines a predominance of the first sex. Our aim was to explore changes in sex ratios within the range of the species studied: Patella vulgata and Patella depressa. The broad-scale survey of sex with size of limpets covered a range of latitudes from Zambujeira do Mar (southern Portugal) to the English Channel. Indirect evidence was found for the occurrence of protandry in P. vulgata populations from the south of England, with females predominating in larger size-classes; cumulative frequency distributions of males and females were different; sex ratios were biased towards males and smallest sizes of males were smaller than the smallest sizes of females. In contrast in Portugal females were found in most size-classes of P. vulgata. In P. depressa populations from the south coast of England and Portugal females were interspersed across most size-classes; size distributions of males and females and size at first maturity of males and females did not differ. P. depressa did, however, show some indications of the possibility of slight protandry occurring in Portugal. The test of sex ratio variation with latitude indicated that P. vulgata sex ratios might be involved in determining the species range limit, particularly at the equatorward limit since the likelihood of being male decreased from the south coast of England to southern Portugal. Thus at the southern range limit, sperm could be in short supply due to scarcity of males contributing to an Allee effect.

A Study on the liquefaction risk in seismic design of foundations

A fully coupled non-linear effective stress response finite difference (FD) model is built to survey the counter-intuitive recent findings on the reliance of pore water pressure ratio on foundation contact pressure. Two alternative design scenarios for a benchmark problem are explored and contrasted in the light of construction emission rates using the EFFC-DFI methodology. A strain-hardening effective stress plasticity model is adopted to simulate the dynamic loading. A combination of input motions, contact pressure, initial vertical total pressure and distance to foundation centreline are employed, as model variables, to further investigate the control of permanent and variable actions on the residual pore pressure ratio. The model is verified against the Ghosh and Madabhushi high acceleration field test database. The outputs of this work is aimed to improve the current computer-aided seismic foundation design that relies on ground’s packing state and consistency. The results confirm that on seismic excitation of shallow foundations, the likelihood of effective stress loss is greater in deeper depths and across free field. For the benchmark problem, adopting a shallow foundation system instead of piled foundation benefitted in a 75% less emission rate, a marked proportion of which is owed to reduced materials and haulage carbon cost.

Non-contact test set-up for aeroelasticity in a rotating turbomachine combining a novel acoustic excitation system with tip-timing

Due to trends in aero-design, aeroelasticity becomes increasingly important in modern turbomachines. Design requirements of turbomachines lead to the development of high aspect ratio blades and blade integral disc designs (blisks), which are especially prone to complex modes of vibration. Therefore, experimental investigations yielding high quality data are required for improving the understanding of aeroelastic effects in turbomachines. One possibility to achieve high quality data is to excite and measure blade vibrations in turbomachines. The major requirement for blade excitation and blade vibration measurements is to minimize interference with the aeroelastic effects to be investigated. Thus in this paper, a non-contact-and thus low interference-experimental set-up for exciting and measuring blade vibrations is proposed and shown to work. A novel acoustic system excites rotor blade vibrations, which are measured with an optical tip-timing system. By performing measurements in an axial compressor, the potential of the acoustic excitation method for investigating aeroelastic effects is explored. The basic principle of this method is described and proven through the analysis of blade responses at different acoustic excitation frequencies and at different rotational speeds. To verify the accuracy of the tip-timing system, amplitudes measured by tip-timing are compared with strain gage measurements. They are found to agree well. Two approaches to vary the nodal diameter (ND) of the excited vibration mode by controlling the acoustic excitation are presented. By combining the different excitable acoustic modes with a phase-lag control, each ND of the investigated 30 blade rotor can be excited individually. This feature of the present acoustic excitation system is of great benefit to aeroelastic investigations and represents one of the main advantages over other excitation methods proposed in the past. In future studies, the acoustic excitation method will be used to investigate aeroelastic effects in high-speed turbomachines in detail. The results of these investigations are to be used to improve the aeroelastic design of modern turbomachines.

PREVALENCE AND FACTORS ASSOCIATED WITH THE PERFORMANCE OF MAMMOGRAPHY AND PAP SMEAR TEST

Objective: To estimate the prevalence and factors associated with the performance of mammography and pap smear test in women from the city of Maringá, Paraná. Methods: Population-based cross-sectional study conducted with 345 women aged over 20 years in the period from March 2011 to April 2012. An interview was carried out using a questionnaire proposed by the Ministry of Health, which addressed sociodemographic characteristics, risk factors for chronic noncommunicable diseases and issues related to mammographic and pap screening. Data were analyzed using bivariate analysis, crude analysis with odds ratio (OR) and chi-squared test using Epi Info 3.5.1 program; multivariate analysis using logistic regression was performed using the software Statistica 7.1, with a significance level of 5% and a confidence interval of 95%. Results: The mean age of the women was 52.19 (±5.27) years. The majority (56.5%) had from 0 to 8 years of education. Additionally, 84.6% (n=266) of the women underwent pap smear and 74.3% (n=169) underwent mammography. The lower performance of pap smear test was associated with women with 9-11 years of education (p=0.01), and the lower performance of mammography was associated with women without private health insurance (p<0.01). Conclusion: The coverage of mammography and pap smear test was satisfactory among the women from Maringá, Paraná. Low education level and women who depended on the public health system presented lower performance of mammography.