Randomised Evaluation of New Technologies within the Population‐Based Cervical Cancer Screening Programme in Finland: Cross‐Sectional Performance and Validity

A randomised and population-based screening design with new technologies has been applied to the organised cervical cancer screening programme in Finland. In this experiment the women invited to routine five-yearly screening are individually randomised to be screened with automation-assisted cytology, human papillomavirus (HPV) test or conventional cytology. By using the randomised design, the ultimate aim is to assess and compare the long-term outcomes of the different screening regimens. The primary aim of the current study was to evaluate, based on the material collected during the implementation phase of the Finnish randomised screening experiment, the cross-sectional performance and validity of automation-assisted cytology (Papnet system) and primary HPV DNA testing (Hybrid Capture II assay for 13 oncogenic HPV types) within service screening, in comparison to conventional cytology. The parameters of interest were test positivity rate, histological detection rate, relative sensitivity, relative specificity and positive predictive value. Also, the effect of variation in performance by screening laboratory on age-adjusted cervical cancer incidence was assessed. Based on the cross-sectional results, almost no differences were observed in the performance of conventional and automation-assisted screening. Instead, primary HPV screening found 58% (95% confidence interval 19-109%) more cervical lesions than conventional screening. However, this was mainly due to overrepresentation of mild- and moderate-grade lesions and, thus, is likely to result in overtreatment since a great deal of these lesions would never progress to invasive cancer. Primary screening with an HPV DNA test alone caused substantial loss in specificity in comparison to cytological screening. With the use of cytology triage test, the specificity of HPV screening improved close to the level of conventional cytology. The specificity of primary HPV screening was also increased by increasing the test positivity cutoff from the level recommended for clinical use, but the increase was more modest than the one gained with the use of cytology triage. The performance of the cervical cancer screening programme varied widely between the screening laboratories, but the variation in overall programme effectiveness between respective populations was more marginal from the very beginning of the organised screening activity. Thus, conclusive interpretations on the quality or success of screening should not be based on performance parameters only. In the evaluation of cervical cancer screening the outcome should be selected as closely as possible to the true measure of programme effectiveness, which is the number of invasive cervical cancers and subsequent deaths prevented in the target population. The evaluation of benefits and adverse effects of each new suggested screening technology should be performed before the technology becomes an accepted routine in the existing screening programme. At best, the evaluation is performed randomised, within the population and screening programme in question, which makes the results directly applicable to routine use.

When and why threats go undetected: Impacts of event rate and shift length on threat detection accuracy during airport baggage screening

Objective: We aimed to assess the impact of task demands and individual characteristics on threat detection in baggage screeners. Background: Airport security staff work under time constraints to ensure optimal threat detection. Understanding the impact of individual characteristics and task demands on performance is vital to ensure accurate threat detection. Method: We examined threat detection in baggage screeners as a function of event rate (i.e., number of bags per minute) and time on task across 4 months. We measured performance in terms of the accuracy of detection of Fictitious Threat Items (FTIs) randomly superimposed on X-ray images of real passenger bags. Results: Analyses of the percentage of correct FTI identifications (hits) show that longer shifts with high baggage throughput result in worse threat detection. Importantly, these significant performance decrements emerge within the first 10 min of these busy screening shifts only. Conclusion: Longer shift lengths, especially when combined with high baggage throughput, increase the likelihood that threats go undetected. Application: Shorter shift rotations, although perhaps difficult to implement during busy screening periods, would ensure more consistently high vigilance in baggage screeners and, therefore, optimal threat detection and passenger safety.

Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a valid screening tool in chemotherapy outpatients

Purpose In the oncology population where malnutrition prevalence is high, more descriptive screening tools can provide further information to assist triaging and capture acute change. The Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a component of a nutritional assessment tool which could be used for descriptive nutrition screening. The purpose of this study was to conduct a secondary analysis of nutrition screening and assessment data to identify the most relevant information contributing to the PG-SGA SF to identify malnutrition risk with high sensitivity and specificity. Methods This was an observational, cross-sectional study of 300 consecutive adult patients receiving ambulatory anti-cancer treatment at an Australian tertiary hospital. Anthropometric and patient descriptive data were collected. The scored PG-SGA generated a score for nutritional risk (PG-SGA SF) and a global rating for nutrition status. Receiver operating characteristic curves (ROC) were generated to determine optimal cut-off scores for combinations of the PG-SGA SF boxes with the greatest sensitivity and specificity for predicting malnutrition according to scored PG-SGA global rating. Results The additive scores of boxes 1–3 had the highest sensitivity (90.2 %) while maintaining satisfactory specificity (67.5 %) and demonstrating high diagnostic value (AUC = 0.85, 95 % CI = 0.81–0.89). The inclusion of box 4 (PG-SGA SF) did not add further value as a screening tool (AUC = 0.85, 95 % CI = 0.80–0.89; sensitivity 80.4 %; specificity 72.3 %). Conclusions The validity of the PG-SGA SF in chemotherapy outpatients was confirmed. The present study however demonstrated that the functional capacity question (box 4) does not improve the overall discriminatory value of the PG-SGA SF.

Review of Diagnostic Screening Instruments for Alcohol and Other Drug Use and Other Psychiatric Disorders

In recent years there has been a growing recognition that many people with drug or alcohol problems are also experiencing a range of other psychiatric and psychological problems. The presence of concurrent psychiatric or psychological problems is likely to impact on the success of treatment services. These problems vary greatly, from undetected major psychiatric illnesses that meet internationally accepted diagnostic criteria such as those outlined in the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association (1994), to less defined feelings of low mood and anxiety that do not meet diagnostic criteria but nevertheless impact on an individual’s sense of wellbeing and affect their quality of life. Similarly, the presence of a substance misuse problem among those suffering from a major psychiatric illness, often goes undetected. For example, the use of illicit drugs such as cannabis and amphetamine is higher among those individuals suffering from schizophrenia (Hall, 1992) and the misuse of alcohol in people suffering from schizophrenia is well documented (e.g., Gorelick et al., 1990; Searles et al., 1990; Soyka et al., 1993). High rates of alcohol misuse have also been reported in a number of groups including women presenting for treatment with a primary eating disorder (Holderness, Brooks Gunn, & Warren, 1994), individuals suffering from post-traumatic stress disorder (Seidel, Gusman and Aubueg, 1994), and those suffering from anxiety and depression. Despite considerable evidence of high levels of co-morbidity, drug and alcohol treatment agencies and mainstream psychiatric services often fail to identify and respond to concurrent psychiatric or drug and alcohol problems, respectively. The original review was conducted as a first step in providing clinicians with information on screening and diagnostic instruments that may be used to assess previously unidentified co-morbidity. The current revision was conducted to extend the original review by updating psychometric findings on measures in the original review, and incorporating other frequently used measures that were not previously included. The current revision has included information regarding special populations, specifically Indigenous Australians, older persons and adolescents. The objectives were to: ● update the original review of AOD and psychiatric screening/diagnostic instruments, ● recommend when these instruments should be used, by whom and how they should be interpreted, ● identify limitations and provide recommendations for further research, ● refer the reader to pertinent Internet sites for further information and/or purchasing of assessment instruments.

Screening for partner violence among family mediation clients: Differentiating types of abuse

Family mediation is mandated in Australia for couples in dispute over separation and parenting as a first step in dispute resolution, except where there is a history of intimate partner violence. However, validation of effective well-differentiated partner violence screening instruments suitable for mediation settings is at an early phase of development. This study contributes to calls for better violence screening instruments in the mediation context to detect a differentiated range of abusive behaviors by examining the reliability and validity of both established scales, and newly developed scales that measured intimate partner violence by partner and by self. The study also aimed to examine relationships between types of abuse, and between gender and types of abuse. A third aim was to examine associations between types of abuse and other relationship indicators such as acrimony and parenting alliance. The data reported here are part of a larger mixed method, naturalistic longitudinal study of clients attending nine family mediation centers in Victoria, Australia. The current analyses on baseline cross-sectional screening data confirmed the reliability of three subscales of the Conflict Tactics Scale (CTS2), and the reliability and validity of three new scales measuring intimidation, controlling and jealous behavior, and financial control. Most clients disclosed a history of at least one type of violence by partner: 95% reported psychological aggression, 72% controlling and jealous behavior, 50% financial control, and 35% physical assault. Higher rates of abuse perpetration were reported by partner versus by self, and gender differences were identified. There were strong associations between certain patterns of psychologically abusive behavior and both acrimony and parenting alliance. The implications for family mediation services and future research are discussed.

Mass spectrometry and n-in-one analytics in early drug discovery: Combinatorial chemistry libraries, lipophilicity and absorption screening

This thesis describes current and past n-in-one methods and presents three early experimental studies using mass spectrometry and the triple quadrupole instrument on the application of n-in-one in drug discovery. N-in-one strategy pools and mix samples in drug discovery prior to measurement or analysis. This allows the most promising compounds to be rapidly identified and then analysed. Nowadays properties of drugs are characterised earlier and in parallel with pharmacological efficacy. Studies presented here use in vitro methods as caco-2 cells and immobilized artificial membrane chromatography for drug absorption and lipophilicity measurements. The high sensitivity and selectivity of liquid chromatography mass spectrometry are especially important for new analytical methods using n-in-one. In the first study, the fragmentation patterns of ten nitrophenoxy benzoate compounds, serial homology, were characterised and the presence of the compounds was determined in a combinatorial library. The influence of one or two nitro substituents and the alkyl chain length of methyl to pentyl on collision-induced fragmentation was studied, and interesting structurefragmentation relationships were detected. Two nitro group compounds increased fragmentation compared to one nitro group, whereas less fragmentation was noted in molecules with a longer alkyl chain. The most abundant product ions were nitrophenoxy ions, which were also tested in the precursor ion screening of the combinatorial library. In the second study, the immobilized artificial membrane chromatographic method was transferred from ultraviolet detection to mass spectrometric analysis and a new method was developed. Mass spectra were scanned and the chromatographic retention of compounds was analysed using extract ion chromatograms. When changing detectors and buffers and including n-in-one in the method, the results showed good correlation. Finally, the results demonstrated that mass spectrometric detection with gradient elution can provide a rapid and convenient n-in-one method for ranking the lipophilic properties of several structurally diverse compounds simultaneously. In the final study, a new method was developed for caco-2 samples. Compounds were separated by liquid chromatography and quantified by selected reaction monitoring using mass spectrometry. This method was used for caco-2 samples, where absorption of ten chemically and physiologically different compounds was screened using both single and nin- one approaches. These three studies used mass spectrometry for compound identification, method transfer and quantitation in the area of mixture analysis. Different mass spectrometric scanning modes for the triple quadrupole instrument were used in each method. Early drug discovery with n-in-one is area where mass spectrometric analysis, its possibilities and proper use, is especially important.

A new ELISA plate based microtiter well assay for mycobacterial topoisomerase I for the direct screening of enzyme inhibitory monoclonal antibody supernatants

Antigen specific monoclonal antibodies present in crude hybridoma supernatants are normally screened by ELISA on plates coated with the relevant antigen. Screening for inhibitory monoclonals to enzymes would require the evaluation of purified antibodies or antibody containing supernatants for their inhibition of enzyme activity in a separate assay. However, screening for inhibitory antibodies against DNA transacting enzymes such as topoisomerase I (topo I) cannot be done using hybridoma supernatants due to the presence of nucleases in tissue culture media containing foetal calf serum which degrade the DNA substrates upon addition. We have developed a simple and rapid screening procedure for the identification of clones that secrete inhibitory antibodies against mycobacterial topo I using 96 well ELISA microtiter plates. The principle of the method is the selective capture of monoclonal antibodies from crude hybridoma supernatants by topo I that is tethered to the plate through the use of plate-bound polyclonal anti-topo I antibodies. This step allows the nucleases present in the medium to be washed off leaving the inhibitor bound to the tethered enzyme. The inhibitory activity of the captured antibody is assessed by performing an in situ DNA relaxation assay by the addition of supercoiled DNA substrate directly to the microtiter well followed by the analysis of the reaction products by agarose gel electrophoresis. The validity of this method was confirmed by purification of the identified inhibitory antibody and its evaluation in a DNA relaxation assay. Elimination of all enzyme-inhibitory constituents of the culture medium from the well in which the inhibitory antibody is bound to the tethered enzyme may make this method broadly applicable to enzymes such as DNA gyrases, restriction enzymes and other DNA transaction enzymes. Further, the method is simple and avoids the need of prior antibody purification for testing its inhibitory activity. (C) 2010 Elsevier B.V. All rights reserved.

Screening Cycles

We demonstrate how endogenous information acquisition in credit markets creates lending cycles when competing banks undertake their screening decisions in an uncoordinated way, thereby highlighting the role of intertemporal screening externalities induced by lending market competition as a structural source of instability. We show that uncoordinated screening behavior of competing banks may be not only the source of an important financial multiplier, but also an independent source of fluctuations inducing business cycles. The screening cycle mechanism is robust to generalizations along many dimensions such as the lending market structure, the lending rate determination and the imperfections in the screening technology.

A novel two sources ultrasound modulated optical tomographic system for screening breast cancer through elasticity characterization

The study of non-invasive characterization of elastic properties of soft biological tissues has been a focus of active researches since recent years. Light is highly scattered by biological tissues and hence, sophisticated reconstruction algorithms are required to achieve good imaging depth and a reasonable resolution. Ultrasound (US), on the otherhand, is less scattered by soft tissues and it has been in use for imaging in biomedical ultrasound systems. Combination of the contrast sensitivity of light and good localization of ultrasound provides a challenging technique for characterization of thicker tissues deep inside the body non-invasively. The elasticity of the tissues is characterized by studying the response of tissues to mechanical excitation induced by an acoustic radiation force (remotely) using an optical laser. The US modulated optical signals which traverse the tissue are detected by using a CCD camera as detector array and the pixel map formed on the CCD is used to characterize the embedded inhomogeneities. The use of CCD camera improves the signal-noise-ratio (SNR) by averaging the signals from all of the CCD pixels.

Neonatal screening for amino acidaemias in Karnataka, south India

Consanguineous marriages are strongly favoured among the peoples of South India. Because of the potential genetic risks resulting from inbreeding, a neonatal screening project was established in 1980 in the state of Karnataka for the identification of amino acidaemias. To date, blood samples obtained by toe-stab from 98,256 neonates have been tested by thin layer chromatography, with 46 single and 70 general amino acidaemias detected. The coefficients of inbreeding (F) for the two groups of neonates were 0.0336 and 0.0350, by comparison with a previously determined F value for the general, new-born population of 0.0298. The most common single abnormality detected was tyrosinaemia, with spontaneous resolution in the majority of cases.

Introduction of high-content screening method for studying drug-induced mitochondrial dysfunction in hepatocytes

Drug induced liver injury is one of the frequent reasons for the drug removal from the market. During the recent years there has been a pressure to develop more cost efficient, faster and easier ways to investigate drug-induced toxicity in order to recognize hepatotoxic drugs in the earlier phases of drug development. High Content Screening (HCS) instrument is an automated microscope equipped with image analysis software. It makes the image analysis faster and decreases the risk for an error caused by a person by analyzing the images always in the same way. Because the amount of drug and time needed in the analysis are smaller and multiple parameters can be analyzed from the same cells, the method should be more sensitive, effective and cheaper than the conventional assays in cytotoxicity testing. Liver cells are rich in mitochondria and many drugs target their toxicity to hepatocyte mitochondria. Mitochondria produce the majority of the ATP in the cell through oxidative phosphorylation. They maintain biochemical homeostasis in the cell and participate in cell death. Mitochondria is divided into two compartments by inner and outer mitochondrial membranes. The oxidative phosphorylation happens in the inner mitochondrial membrane. A part of the respiratory chain, a protein called cytochrome c, activates caspase cascades when released. This leads to apoptosis. The aim of this study was to implement, optimize and compare mitochondrial toxicity HCS assays in live cells and fixed cells in two cellular models: human HepG2 hepatoma cell line and rat primary hepatocytes. Three different hepato- and mitochondriatoxic drugs (staurosporine, rotenone and tolcapone) were used. Cells were treated with the drugs, incubated with the fluorescent probes and then the images were analyzed using Cellomics ArrayScan VTI reader. Finally the results obtained after optimizing methods were compared to each other and to the results of the conventional cytotoxicity assays, ATP and LDH measurements. After optimization the live cell method and rat primary hepatocytes were selected to be used in the experiments. Staurosporine was the most toxic of the three drugs and caused most damage to the cells most quickly. Rotenone was not that toxic, but the results were more reproducible and thus it would serve as a good positive control in the screening. Tolcapone was the least toxic. So far the conventional analysis of cytotoxicity worked better than the HCS methods. More optimization needs to be done to get the HCS method more sensitive. This was not possible in this study due to time limit.