Artificial intelligence and breast screening: French Radiology Community position paper.

The objective of this article was to evaluate the evidence currently available about the clinical value of artificial intelligence (AI) in breast imaging. Nine experts from the disciplines involved in breast disease management - including physicists and radiologists - convened a meeting on June 3, 2019 to discuss the evidence for the use of this technology in plenary and focused sessions. Prior to the meeting, the group performed a literature review on predefined topics. This paper presents the consensus reached by this working group on recommendations for the future use of AI in breast screening and related research topics.

HPV self-sampling or the Pap-smear: a randomized study among cervical screening nonattenders from lower socioeconomic groups in France.

Today in France, low attendance to cervical screening by Papanicolaou cytology (Pap-smear) is a major contributor to the 3,000 new cervical cancer cases and 1,000 deaths that occur from this disease every year. Nonattenders are mostly from lower socioeconomic groups and testing of self-obtained samples for high-risk Human Papilloma virus (HPV) types has been proposed as a method to increase screening participation in these groups. In 2011, we conducted a randomized study of women aged 35-69 from very low-income populations around Marseille who had not responded to an initial invitation for a free Pap-smear. After randomization, one group received a second invitation for a free Pap-smear and the other group was offered a free self-sampling kit for HPV testing. Participation rates were significantly different between the two groups with only 2.0% of women attending for a Pap-smear while 18.3% of women returned a self-sample for HPV testing (p ≤ 0.001). The detection rate of high-grade lesions (≥CIN2) was 0.2‰ in the Pap-smear group and 1.25‰ in the self-sampling group (p = 0.01). Offering self-sampling increased participation rates while the use of HPV testing increased the detection of cervical lesions (≥CIN2) in comparison to the group of women receiving a second invitation for a Pap-smear. However, low compliance to follow-up in the self-sampling group reduces the effectiveness of this screening approach in nonattenders women and must be carefully managed.

Vaginal self-sampling is an adequate means of screening HR-HPV types in women not participating in regular cervical cancer screening.

In France, about 40% of women aged 25-65 years do not participate in regular screening and thus are at high risk (HR) of cervical cancer. Human papillomavirus (HPV) vaginal self-sampling is a valuable alternative in this population. This study aimed to assess the prevalence of HR and LR (low-risk) HPV infection in 3767 women aged >35 years from mid-socioeconomic backgrounds who carried out HPV vaginal self-sampling at home. HPV vaginal self-sampling was better accepted than the Pap-test in women aged 35-69 years who were previously non-responders to individual invitation. From the 933 self-collected swabs studied (24.7%), 62 were HPV-infected (6.6%), and 73 HPV types were found. HPV 16 was the most frequently found (43.5%), followed by 53 (23.2%), 18 (12.3%), 66 (12.3%), 31 (6.8%), 33 (5.4%) and 58 (2.7%). Ten women (16.2%) were infected by multiple HR-HPV types. Median HPV 16 load was 104.000 copies/10(6) cells and median HPV 18 load was 833 copies/10(6) cells. Six women (9.3%) harboured LR-HPV types. The 12-month follow-up of 43 HR-HPV positive women (69.3%) revealed CIN2-3 lesions in three women (6.9%), all HPV 16 infected, and harbouring an HPV 16 load >5 log(10) copies/10(6) cells. Women harbouring HR-HPV types other than HPV 16/18 were older than women harbouring HPV 16/18 types (55 years vs. 46.9 years, p 0.0008). The high frequency of HR-HPV types in women >50 years deserves further investigation to elucidate the mechanism involved (re-infection or reactivation).

[Digital mammography: performance evaluation parameters and available systems in France]. / La mammographie numérique: paramètres utiles à l'évaluation des systèmes et offre industrielle en France.

The purpose of this article is to review the features of digital mammography systems available in France. This article includes three parts: definition of the different components of a digital mammography system, description of different performance evaluation parameters, and review of systems currently available in France. Data from the literature as well as questionnaires from different manufacturers were used. The following vendors agreed to participate: Agfa, Fujifilm, GE Healthcare, Hologic-Lorad, IMS, Kodak, Konica Minolta, Philips, Planmed, Sectra, Siemens. For each vendor, the type of detector, type of available mammographic units and workstation, optional features (CAD), archival and printing possibilities (when vendors specifically offer dedicated solutions).

[Digital mammography and computer assisted diagnosis]. / La mammographie numérique: technique, applications et apport de l'aide informatisée au diagnostic.

Until recently, the film has remained the only medium of information in mammography. The film is used to record, to exploit, to store and to transmit the image. Computerization of images allows to dissociate and to optimize these different functions. Among classical factors of image quality (spatial resolution, contrast, noise), new factors should be added like the detective quantum efficiency and the conversion factor. Radioluminescent screens, then digital sensors for breast stereotactic imaging have been marketed. Manufacturers are now testing full field digital mammographs. Digital imaging allows many applications (computed-aided diagnostic, 3D imaging.) and permits the easy transfer of images for diagnosis and teaching. Three parts are presented in this chapter. The first one describes the different imaging modalities and gives a reminder of the different elements related to image quality. The second one is related to the practical aspects of full field mammography, the reading of mammograms on a review station, ergonomy in full field mammography and to possible changes for screening mammography. The third part is devoted to computed aided diagnosis and its possible application in screening.

The zinc finger protein DIE-1 is required for late events during epithelial cell rearrangement in C. elegans.

The mechanism by which epithelial cells undergo directed rearrangement is central to morphogenesis, yet the regulation of these movements remains poorly understood. We have investigated epithelial cell rearrangement (intercalation) in the dorsal hypodermis, or embryonic epidermis, of the C. elegans embryo by analyzing the die-1(w34) mutant, which fails to undergo normal intercalation. Dorsal hypodermal cells of die-1(w34) homozygous embryos initiate but fail to complete the process of intercalation. Multiphoton microscopy reveals that intercalating cells extend monopolar, basolateral protrusions in their direction of migration; posterior dorsal hypodermal cells in die-1(w34) mutants appear to extend protrusions normally, but fail to translocate their cell bodies to complete rearrangement. Despite abnormal intercalation, the subsequent morphogenetic movements that enclose the embryo with epithelial cells and the process of dorsal cell fusion still occur. However, elongation of the embryo into a wormlike shape is disrupted in die-1(w34) embryos, suggesting that intercalation may be necessary for subsequent elongation of the embryo. Actin filaments are not properly organized within the dorsal hypodermis of die-1(w34) embryos, consistent with intercalation's being a necessary prerequisite for elongation. The die-1 gene encodes a C2H2 zinc finger protein containing four fingers, which likely acts as a transcriptional regulator. DIE-1 is present in the nuclei of hypodermal, muscle, gut, and pharyngeal cells; its distribution suggests that DIE-1 acts in each of these tissues to regulate morphogenetic movements. die-1(w34) mutants display morphogenetic defects in the pharynx, gut, and muscle quadrants, in addition to the defects in the dorsal hypodermis, consistent with the DIE-1 expression pattern. Mosaic analysis indicates that DIE-1 is autonomously required in the posterior dorsal hypodermis for intercalation. Our analysis documents for the first time the dynamics of protrusive activity during epithelial cell rearrangement. Moreover, our analysis of die-1 shows that the events of epithelial cell rearrangement are under transcriptional control, and that early and later phases of epithelial cell rearrangement are genetically distinguishable.

The internal phosphodiesterase RegA is essential for the suppression of lateral pseudopods during Dictyostelium chemotaxis.

Dictyostelium strains in which the gene encoding the cytoplasmic cAMP phosphodiesterase RegA is inactivated form small aggregates. This defect was corrected by introducing copies of the wild-type regA gene, indicating that the defect was solely the consequence of the loss of the phosphodiesterase. Using a computer-assisted motion analysis system, regA(-) mutant cells were found to show little sense of direction during aggregation. When labeled wild-type cells were followed in a field of aggregating regA(-) cells, they also failed to move in an orderly direction, indicating that signaling was impaired in mutant cell cultures. However, when labeled regA(-) cells were followed in a field of aggregating wild-type cells, they again failed to move in an orderly manner, primarily in the deduced fronts of waves, indicating that the chemotactic response was also impaired. Since wild-type cells must assess both the increasing spatial gradient and the increasing temporal gradient of cAMP in the front of a natural wave, the behavior of regA(-) cells was motion analyzed first in simulated temporal waves in the absence of spatial gradients and then was analyzed in spatial gradients in the absence of temporal waves. Our results demonstrate that RegA is involved neither in assessing the direction of a spatial gradient of cAMP nor in distinguishing between increasing and decreasing temporal gradients of cAMP. However, RegA is essential for specifically suppressing lateral pseudopod formation during the response to an increasing temporal gradient of cAMP, a necessary component of natural chemotaxis. We discuss the possibility that RegA functions in a network that regulates myosin phosphorylation by controlling internal cAMP levels, and, in support of that hypothesis, we demonstrate that myosin II does not localize in a normal manner to the cortex of regA(-) cells in an increasing temporal gradient of cAMP.

Hormone replacement therapy and screening mammography: analysis of the results in the Bouches du Rhône programme.

OBJECTIVE: To evaluate the effectiveness of a mass screening programme for breast cancer in a French population where hormone replacement therapy (HRT) is common and where mammography is prescribed outside the programme for asymptomatic women. METHODS: From 1993 to 1996 inclusive, 41,062 women underwent a first test and 48,275 a second or third test in the Bouches du Rhône programme. Their HRT status was ascertained at the time of the test. False positive and false negative tests were identified at one year follow up. The incidence of interval cancers was estimated up to three years after the screening test. RESULTS: The odds of being detected at screening rather than as an interval cancer within one year of the test was five times greater among non-users of HRT than among users (odds ratio (OR) 5.14 (confidence interval 2.5 to 11.8)). This high reduction in sensitivity among users (71% v 92%) was associated with a very small reduction in specificity at the incident screen only. The incidence of interval cancers among HRT users was 3.5 times that of non-users within the first year after the test and 1.7 times during the following two years. CONCLUSIONS: When the early results of a programme have been used to measure its effectiveness they should be reassessed in populations where HRT is in widespread use. As interval cancers had better prognostic factors in HRT users than in non-users, the efficacy of a screening programme in such populations should be the subject of further studies.

The cellular mechanism of epithelial rearrangement during morphogenesis of the Caenorhabditis elegans dorsal hypodermis.

The mechanism by which epithelial cells rearrange is a process that is central to epithelial morphogenesis, yet remains poorly understood. We have investigated epithelial cell rearrangement in the dorsal hypodermis of the Caenorhabditis elegans embryo, in which two rows of epithelial cells rearrange in a morphogenetic process known as dorsal intercalation. The intercalating cells extend basal protrusions which squeeze between their opposing neighbors beneath their adherens junctions. As the intercalating cells move forward, these protruding tips become broader in the anterior-posterior and dorsoventral dimensions, effectively "plowing through" the adherens junctions and forcing an opening for the remainder of the intercalating cell to insert between the contralateral cells. These cell movements are dependent upon intact cytoarchitecture, since the pharmacological disruption of microtubules or actin filaments blocks cell rearrangement. The cells appear to intercalate independently of immediately adjacent neighboring hypodermal cells because dorsal intercalation is not blocked by the ablation of the progenitors for either half of the lateral hypodermal cells or the posterior half of the dorsal hypodermis. This is the first case in which the protrusive mechanism underlying epithelial cell rearrangement has been characterized, and we propose a model describing how epithelial cells rearrange within the confines of an epithelial monolayer, and discuss the mechanisms that may be guiding these directed cell movements.

end-1 encodes an apparent GATA factor that specifies the endoderm precursor in Caenorhabditis elegans embryos.

The endoderm in the nematode Caenorhabditis elegans is clonally derived from the E founder cell. We identified a single genomic region (the endoderm-determining region, or EDR) that is required for the production of the entire C. elegans endoderm. In embryos lacking the EDR, the E cell gives rise to ectoderm and mesoderm instead of endoderm and appears to adopt the fate of its cousin, the C founder cell. end-1, a gene from the EDR, restores endoderm production in EDR deficiency homozygotes. end-1 transcripts are first detectable specifically in the E cell, consistent with a direct role for end-1 in endoderm development. The END-1 protein is an apparent zinc finger-containing GATA transcription factor. As GATA factors have been implicated in endoderm development in other animals, our findings suggest that endoderm may be specified by molecularly conserved mechanisms in triploblastic animals. We propose that end-1, the first zygotic gene known to be involved in the specification of germ layer and founder cell identity in C. elegans, may link maternal genes that regulate the establishment of the endoderm to downstream genes responsible for endoderm differentiation.

The SL1 trans-spliced leader RNA performs an essential embryonic function in Caenorhabditis elegans that can also be supplied by SL2 RNA.

Covalent joining of leader RNA exons to pre-mRNAs by trans-splicing has been observed in protists and invertebrates, and can occur in cultured mammalian cells. In the nematode Caenorhabditis elegans, approximately 60% of mRNA species are trans-spliced to the 22-nucleotide SL1 leader, and another approximately 10% of mRNAs receive the 22-nucleotide SL2 leader. We have isolated deletions that remove the rrs-1 cluster, a gene complex that contains approximately 110 tandem copies of a repeat encoding both SL1 RNA and 5S rRNA. An SL1-encoding gene alone rescues the embryonic lethality caused by these deletions. Mutations within the Sm-binding site of SL1 RNA, which is required for trans-splicing, eliminate rescue, suggesting that the ability of the SL1 leader to be trans-spliced is required for its essential activity. We observe pleiotropic defects in embryos lacking SL1 RNA, suggesting that multiple mRNAs may be affected by the absence of an SL1 leader. We found, however, that SL1-receiving messages are expressed without an SL1 leader. Surprisingly, when overexpressed, SL2 RNA, which performs a distinct function from that of SL1 RNA in wild-type animals, can rescue the lethality of embryos lacking SL1 RNA. Moreover, in these mutant embryos, we detect SL2 instead of SL1 leaders on normally SL1-trans-spliced messages; this result suggests that the mechanism that discriminates between SL1 and SL2-trans-splicing may involve competition between SL1 and SL2-specific trans-splicing. Our findings demonstrate that SL1 RNA is essential for embryogenesis in C. elegans and that SL2 RNA can substitute for SL1 RNA in vivo.

Kinetic analysis of the hydrodynamic transition accompanying protein folding using size exclusion chromatography. 1. Denaturant dependent baseline changes.

Size exclusion profiles of proteins with persistent conformations exhibit broad asymmetric peaks whose shape and elution times are dependent on denaturant concentration. The collective elution profiles were precisely simulated by an apparent binding model that treats the denaturant dependence in terms of an apparent matrix binding. The model requires three experimentally measurable parameters: the elution time for the unbound protein, an apparent association equilibrium constant for binding, and an apparent exchange time for binding. The denaturant dependence for each of these parameters is related to the accessible surface area of the protein.

A kinetic study of the folding of staphylococcal nuclease using size-exclusion chromatography.

The kinetics of the hydrodynamic volume change accompanying the reversible unfolding of staphylococcal nuclease have been observed by size-exclusion chromatography at 4 degrees C and pH 7.0 using the denaturant guanidine hydrochloride. The observed chromatographic profiles have been simulated by a six-component unfolding/refolding mechanism using a consistent set of equilibrium and kinetic parameters. The native protein is an equilibrium mixture of the cis and trans isomers of the peptide bond preceding proline-117. The native conformation containing the cis isomer dominates the equilibrium mixture, is more stable, and unfolds more slowly at its transition midpoint. The denatured protein is an equilibrium mixture of at least four components, the cis/trans isomers of proline-117 and one of the five remaining prolines. The dominant refolding pathway is initiated from the denatured component containing the trans isomer of proline-117. The six-component mechanism is consistent with tryptophan fluorescence kinetic measurements of the wild-type protein and with chromatographic measurements of a mutant P117G protein.

Congenital renal abnormalities in infants with in utero cocaine exposure.

To determine the incidence of renal abnormalities among infants exposed to cocaine in utero, we performed ultrasound studies of the genitourinary tract in 100 consecutive infants admitted to the full-term nursery whose mothers had a history of cocaine use during pregnancy and/or a maternal toxicology screen was positive for cocaine. Mean gestational age of the newborns was 38.4 +/- 2.1 weeks. Mean birth weight was 2,846 +/- 561 gm.; 26% of the patients were less than 2,500 gm. and 18% were small for gestational age. Symptoms of drug withdrawal were present in 47 patients. Two newborns had murmurs consistent with a ventricular septal defect. On ultrasonography, 1 newborn had a unilateral multicystic/dysplastic kidney and 1 had kidneys that were 2 standard deviations below normal in size. Based on our results routine renal ultrasound studies do not appear to be indicated in full-term newborns exposed in utero to cocaine.