Evaluating cytology for the detection of invasive cervical cancer.

OBJECTIVE: To assess the sensitivity, the number needed to screen (NNS) and the positive predictive value (PPV) of cervical cytology for the diagnosis of cancer by age in a screening population. METHODS: A retrospective cohort of women with invasive cervical cancer nested within a census of cervical cytology. All (c. 8 million) women aged 20-64 years with cervical cytology (excluding tests after an earlier abnormality). From April 2007 to March 2010, 3372 women had cervical cancer diagnosed within 12 months of such cytology in England. The sensitivity of cervical cytology to cancer, NNS to detect one cancer and predictive values of cytology were calculated for various 'referral' thresholds. These were calculated for ages 20-24, 25-34, 35-49 and 50-64 years. RESULTS: The sensitivity of at least moderate dyskaryosis [equivalent to a high-grade squamous intraepithelial lesion (HSIL) or worse] for cancer of 89.4% [95% confidence interval (CI) 88.3-90.4%] in women offered screening was independent of age. At all ages, women with borderline-early recall or mild dyskaryosis on cytology (equivalent to ASC-US and LSIL, respectively, in the Bethesda system) had a similar risk of cervical cancer to the risk in all women tested. The PPV of severe dyskaryosis/?invasive and ?glandular neoplasia cytology (equivalent to squamous cell carcinoma and adenocarcinoma/adenocarcinoma in situ, respectively, in the Bethesda System) were 34% and 12%, respectively; the PPV of severe dyskaryosis (HSIL: severe dysplasia) was 4%. The NNS was lowest when the incidence of cervical cancer was highest, at ages 25-39 years, but the proportion of those with abnormal cytology who have cancer was also lowest in younger women. CONCLUSIONS: The PPV of at least severe dyskaryosis (HSIL: severe dysplasia) for cancer was 4-10% of women aged 25-64 years, justifying a 2-week referral to colposcopy and demonstrating the importance of failsafe monitoring for such patients. The sensitivity of cytology for cervical cancer was excellent across all age groups.

Change detection in the flicker paradigm: the role of fixation position within the scene.

Eye movements were monitored while participants performed a change detection task with images of natural scenes. An initial and a modified scene image were displayed in alternation, separated by a blank interval (flicker paradigm). In the modified image, a single target object was changed either by deleting that object from the scene or by rotating that object 90 degrees in depth. In Experiment 1, fixation position at detection was more likely to be in the target object region than in any other region of the scene. In Experiment 2, participants detected scene changes more accurately, with fewer false alarms, and more quickly when allowed to move their eyes in the scene than when required to maintain central fixation. These data suggest a major role for fixation position in the detection of changes to natural scenes across discrete views.

Thematic roles assigned along the garden path linger.

In the literature dealing with the reanalysis of garden path sentences such as While the man hunted the deer ran into the woods, it is generally assumed either that people completely repair their initial incorrect syntactic representations to yield a final interpretation whose syntactic structure is fully consistent with the input string or that the parse fails. In a series of five experiments, we explored the possibility that partial reanalyses take place. Specifically, we examined the conditions under which part of the initial incorrect analysis persists at the same time that part of the correct final analysis is constructed. In Experiments 1a and 1b, we found that both the length of the ambiguous region and the plausibility of the ultimate interpretation affected the likelihood that such sentences would be fully reanalyzed. In Experiment 2, we compared garden path sentences with non-garden path sentences and compared performance on two different types of comprehension questions. In Experiments 3a and 3b, we constructed garden path sentences using a small class of syntactically unique verbs to provide converging evidence against the position that people employ some sort of "general reasoning" or pragmatic inference when faced with syntactically difficult garden paths. The results from these experiments indicate that reanalysis of such sentences is not always complete, so that comprehenders often derive an interpretation for the full sentence in which part of the initial misanalysis persists. We conclude that the goal of language processing is not always to create an idealized structure, but rather to create a representation that is "good enough" to satisfy the comprehender that an appropriate interpretation has been obtained.

Misinterpretations of garden-path sentences: implications for models of sentence processing and reanalysis.

Theories of sentence comprehension have addressed both initial parsing processes and mechanisms responsible for reanalysis. Three experiments are summarized that were designed to investigate the reanalysis and interpretation of relatively difficult garden-path sentences (e.g., While Anna dressed the baby spit up on the bed). After reading such sentences, participants correctly believed that the baby spit up on the bed; however, they often confidently, yet incorrectly, believed that Anna dressed the baby. These results demonstrate that garden-path reanalysis is not an all-or-nothing process and that thematic roles initially assigned for the subordinate clause verb are not consistently revised. The implications of the partial reanalysis phenomenon for Fodor and Inoue's (1998) model of reanalysis and sentence processing are discussed. In addition, we discuss the possibility that language processing often creates "good enough" structures rather than ideal structures.

To see and remember: visually specific information is retained in memory from previously attended objects in natural scenes.

What is the nature of the representation formed during the viewing of natural scenes? We tested two competing hypotheses regarding the accumulation of visual information during scene viewing. The first holds that coherent visual representations disintegrate as soon as attention is withdrawn from an object and thus that the visual representation of a scene is exceedingly impoverished. The second holds that visual representations do not necessarily decay upon the withdrawal of attention, but instead can be accumulated in memory from previously attended regions. Target objects in line drawings of natural scenes were changed during a saccadic eye movement away from those objects. Three findings support the second hypothesis. First, changes to the visual form of target objects (token substitution) were successfully detected, as indicated by both explicit and implicit measures, even though the target object was not attended when the change occurred. Second, these detections were often delayed until well after the change. Third, changes to semantically inconsistent target objects were detected better than changes to semantically consistent objects.

Object identification is isolated from scene semantic constraint: evidence from object type and token discrimination.

Two models of the interaction between scene meaning and object identification were tested: the description enhancement model and the criterion modulation model. The former proposes that the early activation of a scene schema facilitates the initial perceptual analysis of schema-consistent objects, the latter that schema activation modulates the amount of information necessary to indicate the presence of an object of a particular perceptual type. In Experiment 1, we employed a forced-choice, type-discrimination paradigm. Participants were asked to determine which of two semantically consistent objects or which of two semantically inconsistent objects had appeared in a briefly presented scene. Contrary to the prediction derived from both of these models, discrimination performance was better for semantically inconsistent versus consistent objects. In Experiments 2 and 3 we introduced a forced-choice, token-discrimination paradigm to further test the description enhancement model. Contrary to the prediction of that model, discrimination performance was no better for semantically consistent versus inconsistent tokens. These results suggest that both the initial perceptual analysis of an object and the matching of an object's constructed visual description to stored descriptions are isolated from stored knowledge about real-world contingencies between scenes and objects.

High-level scene perception.

Three areas of high-level scene perception research are reviewed. The first concerns the role of eye movements in scene perception, focusing on the influence of ongoing cognitive processing on the position and duration of fixations in a scene. The second concerns the nature of the scene representation that is retained across a saccade and other brief time intervals during ongoing scene perception. Finally, we review research on the relationship between scene and object identification, focusing particularly on whether the meaning of a scene influences the identification of constituent objects.

Does consistent scene context facilitate object perception?

The conclusion that scene knowledge interacts with object perception depends on evidence that object detection is facilitated by consistent scene context. Experiment 1 replicated the I. Biederman, R. J. Mezzanotte, and J. C. Rabinowitz (1982) object-detection paradigm. Detection performance was higher for semantically consistent versus inconsistent objects. However, when the paradigm was modified to control for response bias (Experiments 2 and 3) or when response bias was eliminated by means of a forced-choice procedure (Experiment 4), no such advantage obtained. When an additional source of biasing information was eliminated by presenting the object label after the scene (Experiments 3 and 4), there was either no effect of consistency (Experiment 4) or an inconsistent object advantage (Experiment 3). These results suggest that object perception is not facilitated by consistent scene context.

Scintigraphic assessment of drug delivery from the Ultrahaler dry powder inhaler.

A new dry powder inhaler, the Ultrahaler, has been developed to deliver nedocromil sodium for the prophylaxis of asthma. This study was performed to compare the lung deposition of nedocromil sodium inhaled from the Ultrahaler at two different inhaled flow rates with that from a pressurised metered dose inhaler (MDI). A scintigraphic study was conducted in 12 healthy volunteers. On each study day, volunteers received a single 4.2 mg dose of nedocromil sodium from the Ultrahaler, using either an optimal (fast) inhaled flow rate or a suboptimal (slow) inhaled flow rate, or two doses of 2 mg nedocromil sodium from an MDI using an optimal (slow) inhaled flow rate. Used optimally, the Ultrahaler deposited significantly more (p < 0.05) of the metered dose in the lungs than either the Ultrahaler used suboptimally or the MDI used optimally [mean (SD) lung deposition values of 13.3 (4.8)%, 9.8 (3.5)%, and 7.5 (2.9)%, respectively]. Oropharyngeal deposition averaged over 80% of the dose for all three treatment regimens. This scintigraphic study demonstrated in vivo proof of concept for the Ultrahaler dry powder inhaler, and provided quantitative data on the relationship in lung deposition between the Ultrahaler and MDI which differed from that predicted by the in vitro fine particle fraction.

The relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers--implications for in vitro testing.

Despite the fact that powder inhaler devices have been available for over 3 decades there is still very little fundamental information as to how powder inhaler design interacts with the airway dynamics of patients. This paper documents the results of human volunteer investigations designed to elucidate this interaction. These data indicates that if 'maximum' inhalation effort is employed the flow rate attained through an inhaler is controlled by the maximum pressure drop developed by the chest muscles. If a moderate or 'comfortable' effort is used, however, the relationship is more complex. An equation for defining the 'respirable fraction' of an inhalation aerosol cloud as a function of inhalation flow rate is also proposed.

The use of reservoir devices for the simultaneous delivery of two metered-dose aerosols.

Many patients benefit from using metered-dose inhalers (MDIs) with spacer or reservoir devices. Concomitant therapy with separate MDI doses of cromolyn sodium and a beta-agonist is common practice. If two puffs from each drug could be placed into a chamber, the patient could administer both medications at once, enhancing compliance. A multistage liquid impinger (a four-stage inertial impaction device incorporating an inlet bend and an absolute filter, which separates an aerosol cloud into six fractions) was used to investigate such a possibility. Cromolyn sodium and albuterol MDIs were used with an Aerochamber (Monaghan Medical Corp., Plattsburgh, N.Y.) and an Inspirease (Schering Corp., Kenilworth, N.J.). Results are reported by analyzing milligrams of cromolyn sodium per actuation retrieved. With the Aerochamber, two puffs of cromolyn sodium followed by two puffs of albuterol resulted in the total "dose to patient" being reduced by 75% (0.19 versus 0.05 mg) and the effective dose of fine particles (less than 6.5 microns) being reduced by 80% (0.13 versus 0.03 mg) compared to two puffs of cromolyn sodium alone. With the Inspirease, total dose was decreased by 80% (0.32 versus 0.06 mg), whereas the effective dose of fine particles was reduced by 60% (0.19 versus 0.05 mg) compared to one puff of cromolyn sodium alone. The use of cromolyn sodium and albuterol MDIs in a multipuff combination with the Aerochamber or the Inspirease is not recommended because this leads to a loss of the dose delivered compared to a single administration.

Octadeca-9,11-dienoic acid in cervical intraepithelial neoplasia: a colposcopic study.

488 women were studied to evaluate the use of the molar ratio (%MR) of octadeca-9,11-dienoic acid (18:2(9, 11] to linoleic acid (18:2(9, 12] as a new screening method for cervical cancer and pre-cancer. A combination of Papanicolaou cytology, colposcopy and %MR 18:2(9, 11)/18:2(9, 12) were employed. 86 women (17.6%) were found to have histologically proven cervical intraepithelial neoplasia (CIN). The %MR was obtained in 452 cases (92%). There was no significant difference in %MR in cervical cell scrapes from women with or without CIN. The %MR of cervical scrapes in some women with anaerobic vaginosis was significantly elevated suggesting bacterial generation of 18:2(9, 11). The %MR of 18:2(9, 11)/18:2(9, 12) is unsuitable for the diagnosis of cervical intraepithelial neoplasia.

Possible cofactors in the etiology of cervical intraepithelial neoplasia. An immunopathologic study.

Previous work in our department demonstrated a reduction in the numbers of Langerhans' cells in cervical epithelium showing histologic changes of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN). In conjunction with a localized reversal of the T4:T8 ratio of T-lymphocytes, that finding provides evidence of the association of epithelial immunosuppression with both HPV infection and CIN. To investigate whether that phenomenon occurs primarily because of HPV alone or might be caused by a cofactor (e.g., cigarette smoking, oral contraceptive use, chlamydial infection), we performed a study of the effect of those cofactors on the immune defenses of the cervical epithelium. In a study of Langerhans' cells we showed that infection with HPV type 16 and current cigarette smoking both exert effects that cause a reduction in those cells. That diminution of the major antigen-presenting cells in cervical epithelium may constitute a mechanism that explains the observed role of those agents in the etiology of cervical neoplasia.

Cytological status and lesion size: a further dimension in cervical intraepithelial neoplasia.

Quantitative histological study of 84 laser cone biopsies showed a highly significant correlation between the grade of a cervical smear and the size of the lesion for all grades of cervical intraepithelial neoplasia (CIN) (CIN I P = 0.004; CIN II P = 0.0001; CIN III P = 0.003; total CIN P less than 0.0001); 10 of 34 (29%) of women with CIN III and mild dyskaryosis or less had significantly smaller lesions than 23 of 36 (63%) of women with CIN III and moderate or severe dyskaryosis. Repeat cytology identified as severe dyskaryosis all those with large CIN III lesions. Lesion size has been neglected in studies of the natural history of CIN and in the assessment of cytological screening, but offers an explanation for the apparent discrepancies between cytological, colposcopic and histological assessment of progression of CIN.

An explanation for the problem of false-negative cervical smears.

False-negative cervical cytology due to sampling error is a well-recognized problem. Forty-seven women with histologically proven cervical intraepithelial neoplasia (CIN) were studied. All had two cervical smears performed at a mean interval of 3 months. At the time of the second smear, cervicography, colposcopy and biopsy were performed. The area of acetowhite cervical lesions and of the total visible atypical transformation zone (ATZ) were measured from the cervical photographs. The 17 women in whom one or both smears showed no dyskaryosis were found to have a significantly smaller proportion of their ATZ affected by CIN. It is suggested that this finding can account for the sampling error which causes false-negative cervical cytology. New screening techniques, such as cervicography, may offer a method of detecting and assessing these relatively smaller cervical lesions.