Screening for phenylketonuria in a totalitarian state.

Living under a totalitarian regime has many effects on the structure, way of thinking, and relations in a society. However, it is the impact on neonatal genetic screening that we discuss in this paper. Genetic screening functions at the interface between health services and society at large. Being involved for over a decade in setting up the Bulgarian PKU screening programme, we have had to deal with ways and attitudes which may be difficult for the western mind to grasp. Yet comprehension is very much needed in the new world we are trying to create.     

Informing on prenatal screening for Down syndrome prior to conception. An empirical and ethical perspective

In most Western countries, information on prenatal screening for Down syndrome is provided in the first-trimester of pregnancy. The purpose of this study was to examine whether this information should additionally be provided before pregnancy to improve the informed decision-making process. In an empirical study, we obtained data from pregnant women with respect to their preferences regarding information on prenatal screening preconceptionally. Questionnaire data (n?=?510) showed that 55.7% of responding women considered participating in prenatal screening for Down syndrome before pregnancy. 28.0% of women possessed information on prenatal screening preconceptionally. 84.6% preferred not to receive information preconceptionally in retrospect. In an ethical analysis, we elaborated on these preferences by weighing pros and cons. We considered two arguments against the provision of information on prenatal screening preconceptionally: women's preference to receive information in a step-by-step manner, and the risk of providing a directive message. We identified three reasons supporting its provision preconceptionally: the likelihood of making an informed decision could, firstly, be increased by "unchaining" the initial information from possible subsequent decisions, and, secondly, by providing women sufficient time to deliberate. Thirdly, the probability of equal access to prenatal screening may increase. To conclude with, we propose to incorporate an information offer on prenatal screening for Down syndrome in preconception care consultations. By offering information, instead of providing information, prospective parents are enabled to either accept or decline the information, which respects both their right to know and their right not-to-know.     

健康教育在唐氏综合征产前诊断工作中的重要性分析

唐氏综合征其发病率较高,患儿的出生给社会和家庭带来巨大经济负担,是严重的公共卫生问题之一,产前筛查诊断是最好的干预措施。随着科技发展,产前筛查技术也不断更新,从20年前的单一的血清学筛查,到二联、三联、四联,及目前大规模筛查研究推荐的早中孕联合筛查。在做好对孕产妇产前筛查健康教育的同时,如何对孕产妇进行健康教育是我们护理人员关心的问题。     

Genome-wide cfDNA screening: clinical laboratory experience with the first 10,000 cases

PurposeInvasive diagnostic prenatal testing can provide the most comprehensive information about the genetic status of a fetus. Noninvasive prenatal screening methods, especially when using cell-free DNA (cfDNA), are often limited to reporting only on trisomies 21, 18, and 13 and sex chromosome aneuploidies. This can leave a significant number of chromosomal and subchromosomal copy-number variations undetected. In 2015, we launched a new genome-wide cfDNA screening test that has the potential to narrow this detection gap.MethodsHere, we review the results from the first 10,000 cases submitted to the Sequenom clinical laboratory for genome-wide cfDNA screening.ResultsThe high-risk indication for this cohort differed compared with standard cfDNA screening. More samples were submitted with ultrasound indications (25% compared with 13% for standard cfDNA screening) and fewer for advanced maternal age (51% for genome-wide screening versus 68% for standard cfDNA screening). A total of 554 positive calls were made, of which 164 were detectable only via genome-wide analysis.ConclusionThis reports indicates a difference in utilization compared with standard cfDNA screening, where positivity rates are higher and a large subset of positive calls could not have been made using standard cfDNA screening.     

Coming to terms with Vietnam: the Viet/American Cervical Cancer Prevention Project

The Viet/American Cervical Cancer Prevention Project embraces a dual mission. We seek to develop sustainable, cost-effective cervical cancer prevention services for women in Vietnam. Because the problem of cervical cancer in Vietnam is in part a legacy of the Second Indochinese War, we also seek to examine obstacles to reconciliation by presenting what most acknowledge to be a remedy in advance of what some will perceive to be an accusation. Certain research and commercial interests have produced obstacles to our dual mission in Vietnam. The Alliance for Cervical Cancer Prevention, supported by the Bill and Melinda Gates Foundation, has failed to endorse Pap screening for developing countries and is conducting clinical trials which may further disaffect medically underserved groups. Visual screening techniques combined with immediate ablative treatment methods are incompatible with the requirements of "first do no harm." Because the Pap smear will probably be a component of any future human papillomavirus (HPV)-based or visual- based screening programs, it serves the interests of those promoting noncytologic screening methods to also support the development of Pap screening services. Research on HPV screening in developing countries raises concerns of commercial exploitation. Because Pap screening is feasible wherever cervical screening is appropriate, it is inappropriate to delay the development of Pap screening services pending research into HPV vaccines or alternative screening technologies. Quality management is the point at which public health and diagnostic pathology intersect and will remain an indispensable element of cervical screening programs irrespective of the screening test(s) eventually used. Pap screening in developing countries is an ethical imperative without a substantial political constituency and will benefit from the engagement of organized cytology.     

Processing of small molecule databases for automated docking

Virtual screening involves the mining of small molecule databases from various sources. The small molecule databases used in virtual screening are typically processed, from simple 2D representations, to maximize their information content and to optimize them for input to the particular virtual screening technology being used. Processing interprets or adds molecular information related to connectivity, stereochemistry, protonation, tautomers and conformation. For virtual screening with an automated docking protocol, a technique that relies on specific intermolecular atom-atom contacts for ranking molecules, it is expected that the pre-processing protocol can affect the results of the docking experiment. The possible effects of processing on docking results have not been extensively studied, and this topic has only recently emerged as a significant aspect of the docking-based virtual screening process. One recent report highlights significant effects of different processing procedures on docking enrichment, while another outlines a general ligand preparation strategy. Here we survey and comment on recent practice in the field.     

Description and performance of a flow cytometry apparatus: the EPICS

This is a report on our experience with the EPICS C (Coultronics) cytometric flux apparatus, a screening cell analyzer, employing a laser ray (2 or 5 watts); we obtained good results to analyze immunologically-tagged mononuclear blood cells with or without prior separation: for rhythm, repeatability, and contamination. The EPICS C machine proved to be effective to study the cell cycle using lymphoblastic cells, epithelial cells and cells from a breast cancer. Several screening trials were carried out with fluorescent ball bearings of various sizes; the quality of screening (purity and yield) appear optimal at a speed ranging from 500 to 1,000 bearings per second, using three parameters: the logarithm of green fluorescence, the integral function of green fluorescence, the diffraction of light to small angles. Thus, if results obtained for this analysis are entirely satisfactory, the screening function remains limited because it is slow.     

Western blot screening for monoclonal antibodies against human separase

Separase is a cysteine protease that participates in separation of sister chromatids during mitosis. Human separase is a 230-kDa enzyme that is inhibited by binding to its protein inhibitor securin, specific phosphorylation, and subcellular localization. To further characterize human separase, we raised monoclonal antibodies specific against a C-terminal fragment of the protein. A critical step in monoclonal antibody production procedure is the primary screening of hybridoma supernatants. Here we report primary screening protocol utilizing Western blot analysis. The described screening protocol is carried out using fusion of a human separase fragment with two different purification tags, maltose-binding protein (MBP) and glutathione S-transferase (GST). Immunization by MBP-fusion was followed by primary screening with both MBP- and GST-separase fusions combined in the same preparation separated in SDS-PAGE. This highly sensitive screening approach reduced the number of positive signals by eliminating antibodies specific for the purification tag used in the immunization procedure. The described separase-specific antibodies were suitable for detection of endogenous separase in crude extracts, immunoprecipitation, and immunofluorescent cell staining experiments. The presented procedure is fast, reproducible and could be adopted as a primary screening scheme for a variety of protein antigens.     

Simulation of sequential screening experiments using emerging chemical patterns

A method called "Emerging Chemical Patterns" (ECP) has recently been introduced as a novel approach to binary molecular classification (for example, "active" versus "inactive"). The underlying pattern recognition algorithm was first introduced in computer science and then adopted for applications in medicinal chemistry and compound screening. A special feature is its ability to accurately classify molecules on the basis of very small training sets containing only a few compounds. This feature is highly relevant for virtual compound screening when only very few experimental hits are available as templates. Here we adopt ECP calculations to simulate sequential screening using an experimental high-throughput screening (HTS) data set containing inhibitors of dihydrofolate reductase. In doing so, we focus on minimizing the number of database compounds that need to be evaluated in order to identify a substantial fraction of available hits. We demonstrate that iterative ECP calculations recover on average between approximately 19% and approximately 39% of available hits in the data set while dramatically reducing the number of compounds that need to be tested to between approximately 0.002% and approximately 9% of the screening database.     

Recent progress in the development of assays suited for histone deacetylase inhibitor screening

Histone deacetylase (HDAC) inhibitors have an unprecedented potential to occupy a major position in the future market of anticancer agents. However, progress in the development of these new chemotherapeutics is largely dependent on the existence of bioassays well-suited for inhibitor screening. Herein, we summarize recent developments in HDAC assay technology and, particularly, discuss different assay types with respect to their suitability for high-throughput screening programs.     

The impact of descriptive norms on motivation to participate in cancer screening – Evidence from online experiments

ObjectiveThe current study tested in two online experiments whether manipulating normative beliefs about cancer screening uptake increases intention to attend colorectal screening among previously disinclined individuals.Methods2461 men and women from an Internet panel (Experiment 1 N = 1032; Experiment 2, N = 1423) who initially stated that they did not intend to take up screening were asked to guess how many men and women they believe to get screened for colorectal cancer. Across participants, we varied the presence/absence of feedback on the participant’s estimate, as well as the stated proportion of men and women doing the screening test.ResultsAcross the two experiments, we found that receiving one of the experimental messages stating that uptake is higher than estimated significantly increased the proportion of disinclined men and women becoming intenders. While, we found a positive relationship between the communicated uptake and screening intentions, we did not find evidence that providing feedback on the estimate has an added benefit.ConclusionScreening intention can be effectively manipulated through a high uptake message.Practice implicationsCommunication of high screening uptake is an easy and effective way to motivate disinclined individuals to engage in colorectal cancer screening.     

Can health screening damage your health?

This study set out to determine whether screening can be psychologically harmful to healthy adults. A prospective controlled study was carried out on 215 healthy adults attending a by-invitation coronary heart disease screening clinic in general practice. The general health questionnaire was used as an indicator of recent psychological distress. Patients attending the screening clinic had significantly lower subjective psychological distress than an unscreened group of 225 age-matched controls, indicating that we may well be screening an already psychologically healthy sub-group. The main finding was that patients' own assessment of their psychological distress was significantly increased three months after screening compared with that of controls, who showed a non-significant decrease. It is concluded that there is a real risk of causing distress by screening healthy adults and that this possibility has largely been ignored by previous studies. Possible explanations and implications of these findings are discussed, particularly in the light of increased pressure from many quarters for more screening services to be set up in general practice.     

An affective booster moderates the effect of gain- and loss-framed messages on behavioral intentions for colorectal cancer screening

Previous research has demonstrated that loss-framed messages are more effective than gain-framed messages in motivating detection behaviors such as screening. The present study examined whether affective context moderates the degree to which message frame is associated with behavioral intentions to engage in colorectal cancer screening. In particular, we buttressed a framing manipulation with an "affective booster" to increase anticipated and anticipatory emotions associated with the framed messages. Consistent with previous research, we found that loss-framed messages are more effective in increasing intentions to screen. However, we found that among individuals who received gain-framed messages (but not loss-framed messages), the affective booster increased message persuasiveness. This effect on intentions was partially mediated by self-efficacy for engaging in screening. This study indicates that in the presence of emotional boosters, loss-framed messages may lose their advantage over gain-framed messages in motivating detection behaviors, and that self-efficacy may partially explain these effects.     

Review of screening guidelines for non-AIDS-defining malignancies: evolving issues in the era of highly active antiretroviral therapy

HIV-associated morbidity and mortality have declined dramatically in the era of HAART. Through direct and indirect benefits of HAART, people with HIV/AIDS are living longer, developing less AIDS-defining cancers and more cancers commonly seen in the seronegative population. Herein, we review cancer screening strategies for people living with HIV and compare and contrast them with those of the general population. The most noticeable differences occur in anal and cervical cancer screening. Although anal cancer is uncommon in the general population, it is more prevalent in men who have sex with men and people at high risk for human papillomavirus infection, especially those infected with HIV. To address this, we recommend that a digital rectal exam and a visual inspection be performed annually. In addition, an anal Pap test should be performed soon after the diagnosis of HIV infection, with follow-up testing every six months until two normal tests. Abnormal cytological results are then investigated with high-resolution anoscopy and biopsy of suspicious lesions. In screening for cervical cancer, a Pap test should be performed during the anogenital exam after initial HIV diagnosis, with a second Pap six months later, then annually if the results are normal. A colposcopy should follow an abnormal result. Human papillomavirus testing as a screening method for cervical cancer in women with HIV can also be efficacious. In lung cancer screening, preliminary data suggest that low-dose computerized tomography may play an important role, but further research is needed. Screening for breast and colon cancer should follow guidelines for the general population. Early screening for prostate cancer based on a diagnosis of HIV lacks clear benefit.     

Newborn screening for spinal muscular atrophy: The views of affected families and adults

Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant death worldwide. However, due to a lack of treatments, SMA has historically fallen short of Wilson‐Jungner criteria. While studies have explored the acceptability of expanded newborn screening to the general public, the views of affected families have been largely overlooked. This is in spite of the potential for direct impacts on them and their unique positioning to consider the value of early diagnosis. We have previously reported data on attitudes toward pre‐conception and prenatal genetic screening for SMA among affected families (adults with SMA [n = 82] and family members [n = 255]). Here, using qualitative interview [n = 36] and survey data [n = 337], we report the views of this same cohort toward newborn screening. The majority (70%) of participants were in favor, however, all subgroups (except adults with type II) preferred pre‐conception and/or prenatal screening to newborn screening. Key reasons for newborn screening support were: (1) the potential for improved support; (2) the possibility of enrolling pre‐symptomatic children on clinical trials. Key reasons for non‐support were: (1) concerns about impact on the early experiences of the family; (2) inability to treat. Importantly, participants did not view the potential for inaccurate typing as a significant obstacle to the launch of a population‐wide screening program. This study underscores the need to include families affected by genetic diseases within consultations on screening. This is particularly important for conditions such as SMA which challenge traditional screening criteria, and for which new therapeutics are emerging.     

Cancer Screening in Patients Infected with HIV

Non–AIDS-defining cancers are a rising health concern among HIV-infected patients. Cancer screening is now an important component of health maintenance in HIV clinical practice. The decision to screen an HIV-infected patient for cancer should include an assessment of individualized risk for the particular cancer, life expectancy, and the harms and benefits associated with the screening test and its potential outcome. HIV-infected patients are at enhanced risk of several cancers compared to the general population; anal cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, and lung cancer all have good evidence demonstrating an enhanced risk in HIV-infected persons. A number of cancer screening interventions have shown benefit for specific cancers in the general population, but data on the application of these tests to HIV-infected persons are limited. Here we review the epidemiology and background literature relating to cancer screening interventions in HIV-infected persons. We then use these data to inform a conceptual model for evaluating HIV-infected patients for cancer screening.     

When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective

This paper focuses on the question of, “When is the best time to identify an individual at risk for a treatable genetic condition?” In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a “Genomics Passbook” is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a “living document” that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.     

A semi-supervised approach using label propagation to support citation screening

Citation screening, an integral process within systematic reviews that identifies citations relevant to the underlying research question, is a time-consuming and resource-intensive task. During the screening task, analysts manually assign a label to each citation, to designate whether a citation is eligible for inclusion in the review. Recently, several studies have explored the use of active learning in text classification to reduce the human workload involved in the screening task. However, existing approaches require a significant amount of manually labelled citations for the text classification to achieve a robust performance. In this paper, we propose a semi-supervised method that identifies relevant citations as early as possible in the screening process by exploiting the pairwise similarities between labelled and unlabelled citations to improve the classification performance without additional manual labelling effort. Our approach is based on the hypothesis that similar citations share the same label (e.g., if one citation should be included, then other similar citations should be included also). To calculate the similarity between labelled and unlabelled citations we investigate two different feature spaces, namely a bag-of-words and a spectral embedding based on the bag-of-words. The semi-supervised method propagates the classification codes of manually labelled citations to neighbouring unlabelled citations in the feature space. The automatically labelled citations are combined with the manually labelled citations to form an augmented training set. For evaluation purposes, we apply our method to reviews from clinical and public health. The results show that our semi-supervised method with label propagation achieves statistically significant improvements over two state-of-the-art active learning approaches across both clinical and public health reviews.     

Rapid detection of beta-globin gene (HBB) mutations coupling heteroduplex and primer-extension analysis by DHPLC

Beta-thalassemia is a common inherited disease, resulting from one or more of a total of more than 200 different mutations in the beta-globin gene (HBB). Efficient and reliable mutation-screening methods are essential in order to establish appropriate prevention programs for at-risk populations based upon a molecular diagnosis. We have developed a rapid and highly-specific mutation screening test for the diagnosis of beta-thalassemia by coupling heteroduplex and primer-extension analysis based on the denaturing high performance liquid chromatography (DHPLC) system. A total of 161 healthy heterozygous Taiwanese carriers featuring 10 different HBB mutations and 30 patients exhibiting 12 different compound heterozygous or homozygous HBB mutations were subjected to DHPLC. The elution profile for the heteroduplex analysis of DHPLC could be successfully used to identify the common disease-causing mutations of HBB. To further confirm the sequence variants, we developed a technique combining multiplex primer-extension analysis coupled with DHPLC for the genotyping of eight common disease-causing mutations in the HBB gene. Overall, by coupling heteroduplex and primer-extension analysis based upon DHPLC, we were able to unambiguously identify the most-common beta-thalassemia mutations corresponding to more than 99% of HBB alleles among the Taiwanese population. In conclusion, compared to classic approaches to mutation screening for this malady, we suggest that DHPLC is an excellent technique to be applied to the genetic screening of prenatal and postnatal individuals as a part of a diagnosis program for beta-thalassemia and provides a more-efficient, economic, and sensitive means to undertake such a screening program.