Improving the promise of embedded pragmatic trials: Surmountable barriers encountered in an evaluation of home-based HPV self-sampling to increase cervical cancer screening in overdue women.

Despite increased attention on how to conduct pragmatic trials and their importance, there remains an under-appreciation for the reality of what they take to design, compete and secure funding and execute. Many barriers are surmountable through increased exposure to experiences from completed trials. This report summarizes our experience in designing, securing funding and implementing the Home-Based Options to Make screening Easier (HOME) pragmatic trial, which was designed to evaluate home human papillomavirus testing for cervical cancer screening in underscreened women (women who had not received a cervical cancer screening test in ≥3.5 years). This report highlights factors at the level of research teams, organizations seeking to conduct embedded research, reviewers and funding agencies that challenge pragmatic trial design and execution. There is an urgent need to train on peer-reviewers how to evaluate embedded trial grant proposals, for agencies to pursue more rapid and innovative funding strategies, and to consider strategies for reviewers and funders to evaluate stakeholder buy-in (beyond letters of support). These factors together are needed to realize the promise of pragmatic trials to more efficiently and effectively generate critical data that inform changes in health care delivery and benefit patients.

Trends in Clinical Breast Density Assessment From the Breast Cancer Surveillance Consortium.

Changes to mammography practice, including revised Breast Imaging Reporting and Data System (BI-RADS) density classification guidelines and implementation of digital breast tomosynthesis (DBT), may impact clinical breast density assessment. We investigated temporal trends in clinical breast density assessment among 2 990 291 digital mammography (DM) screens and 221 063 DBT screens interpreted by 722 radiologists from 144 facilities in the Breast Cancer Surveillance Consortium. After age-standardization, 46.3% (95% CI = 44.1% to 48.6%) of DM screens were assessed as dense (heterogeneously/extremely dense) during the BI-RADS 4th edition era (2005-2013), compared to 46.5% (95% CI = 43.8% to 49.1%) during the 5th edition era (2014-2016) (P = .93 from two-sided generalized score test). Among DBT screens in the BI-RADS 5th edition era, 45.8% (95% CI = 42.0% to 49.7%) were assessed as dense (P = .77 from two-sided generalized score test) compared to 46.5% (95% CI = 43.8% to 49.1%) dense on DM in BI-RADS 5th edition era. Results were similar when examining all four density categories and age subgroups. Clinicians, researchers, and policymakers may reasonably expect stable density distributions across screened populations despite changes to the BI-RADS guidelines and implementation of DBT.

Intracranial mapping of auditory perception: event-related responses and electrocortical stimulation.

OBJECTIVE: We compared intracranial recordings of auditory event-related responses with electrocortical stimulation mapping (ESM) to determine their functional relationship. METHODS: Intracranial recordings and ESM were performed, using speech and tones, in adult epilepsy patients with subdural electrodes implanted over lateral left cortex. Evoked N1 responses and induced spectral power changes were obtained by trial averaging and time-frequency analysis. RESULTS: ESM impaired perception and comprehension of speech, not tones, at electrode sites in the posterior temporal lobe. There was high spatial concordance between ESM sites critical for speech perception and the largest spectral power (100% concordance) and N1 (83%) responses to speech. N1 responses showed good sensitivity (0.75) and specificity (0.82), but poor positive predictive value (0.32). Conversely, increased high-frequency power (>60Hz) showed high specificity (0.98), but poorer sensitivity (0.67) and positive predictive value (0.67). Stimulus-related differences were observed in the spatial-temporal patterns of event-related responses. CONCLUSIONS: Intracranial auditory event-related responses to speech were associated with cortical sites critical for auditory perception and comprehension of speech. SIGNIFICANCE: These results suggest that the distribution and magnitude of intracranial auditory event-related responses to speech reflect the functional significance of the underlying cortical regions and may be useful for pre-surgical functional mapping.

How accurate are bedside hearing tests?

The accuracy of five bedside hearing tests was evaluated in 107 consecutive adults, using pure-tone audiometry as the standard reference. Bedside tests had poor sensitivity (< or =0.60), relatively good specificity (> or =0.74), and variable positive predictive value (0.24 to 1.0) for detecting hearing loss. Sensitivity improved when bedside tests were combined with case history. The diagnostic utility of bedside tests routinely administered by neurologists to detect hearing loss in adults requires further study.

Dimensions of oral-health-related quality of life.

Oral-health-related quality of life (OHRQoL) is expected to have multiple dimensions. It was the aim of this study to investigate the dimensional structure of OHRQoL measured by the Oral Health Impact Profile (German version) (OHIP-G) and to derive a summary score for the instrument. Subjects (N = 2050; age, 16-79 yrs) came from a national survey. We used rotated principal-components analysis to derive a summary score and to explore the dimensional structure of OHIP-G. The first principal component explained 50% of the variance in the data. The sum of OHIP-G item responses was highly associated with the first principal component (r = 0.99). This simple but informative OHIP-G summary score may indicate that simple sums are also potentially useful scores for other OHRQoL instruments. Four dimensions (psychosocial impact, orofacial pain, oral functions, appearance) were found. These OHIP-G dimensions may serve as a parsimonious set of OHRQoL dimensions in general.

Modeling variability in cortical representations of human complex sound perception.

This study investigated methodological (task, stimulus) and intersubject variability in the cortical representation of auditory processing of complex sounds, including speech. Subjects were adult seizure patients undergoing left hemisphere electrocortical mapping (ECM). We tested auditory discrimination of complex sounds, including frequency-modulated tones and speech syllables (digitized, synthesized) contrasted by phonetic features and lexical status. To measure task effects, auditory comprehension was also tested. Within- and across-patient differences in the distribution of deficits induced by ECM were modeled statistically using the recently developed method of Template Mixture Modeling. Cortical representations of auditory discrimination were smaller, more localized, and less variable across subjects than auditory comprehension. Stimulus effects were observed only for speech-tone contrasts. When tasks and stimuli were held constant, two auditory discrimination centers were identified in the posterior temporal lobe. There was also an interaction between task and intersubject effects, with more intersubject variability in cortical maps of auditory comprehension than auditory discrimination. These results demonstrate the utility of using the statistical modeling approach of Template Mixture Modeling to quantify sources of variability in cortical functional organization.

Health beliefs and endoscopic screening for colorectal cancer: potential for cancer prevention.

BACKGROUND: Colorectal cancer can be prevented through endoscopic removal of adenomatous polyps. Because screening endoscopy rates are low, it is critical to identify correlates of screening behavior that are amenable to interventions to improve screening rates. Our purpose was to identify the correlates of endoscopic screening among persons at risk for colorectal cancer. METHODS: We surveyed 1,160 healthy, adult, first-degree relatives of colorectal cancer patients in 583 kindreds, for a 43% response rate. Using multiple logistic regression analysis, we tested the association between screening behavior and perceived risk for colorectal cancer, the belief that colorectal cancer can be prevented, demographic factors, strength of family history, and practical barriers to screening. RESULTS: Persons screened at least once were older, were male, had stronger family histories, had a regular doctor, and had health insurance. After these fixed factors were accounted for, the belief that colorectal cancer can be prevented and higher perceived risk were associated with significantly greater odds of screening. CONCLUSIONS: This study establishes the need for trials evaluating the cancer prevention potential of the link between screening behavior and health beliefs. Physicians must be aware of their patients' family colorectal cancer history and recommend appropriate endoscopic screening for those at increased risk, particularly women. Patients should be educated about their cancer risk and about preventing colorectal cancer.

Transcortical sensory aphasia: revisited and revised.

Transcortical sensory aphasia (TSA) is characterized by impaired auditory comprehension with intact repetition and fluent speech. We induced TSA transiently by electrical interference during routine cortical function mapping in six adult seizure patients. For each patient, TSA was associated with multiple posterior cortical sites, including the posterior superior and middle temporal gyri, in classical Wernicke's area. A number of TSA sites were immediately adjacent to sites where Wernicke's aphasia was elicited in the same patients. Phonological decoding of speech sounds was assessed by auditory syllable discrimination and found to be intact at all sites where TSA was induced. At a subset of electrode sites where the pattern of language deficits otherwise resembled TSA, naming and word reading remained intact. Language lateralization testing by intracarotid amobarbital injection showed no evidence of independent right hemisphere language. These results suggest that TSA may result from a one-way disruption between left hemisphere phonology and lexical-semantic processing.

Template mixture models for direct cortical electrical interference data.

This paper introduces a statistical approach for high-level spatial analysis when there is little prior information about the shape or location of the region of interest in the underlying image and limited spatial resolution of the available data. Our work was motivated by a functional brain mapping technique called direct cortical electrical interference (DCEI) that gives binary observations at multiple sites throughout the brain. We estimate an underlying, binary spatial response function using a mixture of an unknown number of simple geometrical shapes (e.g. circles) with unknown centers and sizes to be estimated. Inference is made using reversible jump Markov chain Monte Carlo. The approach is illustrated with simulated examples and a real example with DCEI data.

Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation.

OBJECTIVE: To determine whether cortical electrical stimulation can terminate bursts of epileptiform activity in humans, we used afterdischarges (ADs) as a model of epileptiform activity. METHODS: Cortical stimulation was performed for clinical localization purposes using subdural electrodes implanted in patients undergoing preresection evaluations for treatment of medically intractable seizures. We used 0.3-millisecond pulses of alternating polarity, repeated at 50 pulses/second. When stimulation produced AD, we often applied short additional brief bursts of pulse stimulation (BPS). We examined the effectiveness of BPS in aborting ADs in 17 patients using survival analysis. RESULTS: With BPS, ADs stopped within 2 seconds in 115 cases, 2 to 5 seconds in 22 cases, and in more than 5 seconds in 89 cases. Without BPS, ADs stopped within 2 seconds in 21 cases, 2 to 5 seconds in 114 cases, and in more than 5 seconds in 340 cases. BPS was an effective method to abort ADs (Cox proportional hazards model: p<0.0001). At any time during the course of ADs, the instantaneous rate of stopping ADs within 2 seconds after BPS was applied was 4.6 times greater than when BPS was not applied (95% CI = 3.7, 5.7). In eight cases, ADs progressed to the occurrence of clinical seizures, always when BPS was not applied. CONCLUSIONS: Afterdischarges significantly decreased in duration after we applied brief bursts of pulse stimulation. Although afterdischarges are not identical to spontaneous epileptiform activity, these results support the idea that electrical stimulation, applied in an appropriate manner at seizure onset, could abort seizures in humans.

Language recovery after left hemispherectomy in children with late-onset seizures.

We investigated the language capabilities of the isolated right hemisphere in 6 children (age, 7-14 years) after left hemidecorticectomy for treatment of Rasmussen's syndrome. Patients were right-handed before surgery and had at least 5 years of normal language development before the onset of seizures. Language testing included speech sound (phoneme) discrimination, single word and phrasal comprehension, repetition, and naming. Within 4 to 16 days after surgery, patients showed improved phoneme discrimination compared with their performance shortly before surgery. Other language functions remained severely impaired until at least 6 months after surgery. By 1 year after surgery, receptive functions were comparable with, or surpassed, patient presurgery performance. Although word repetition was intact by 1 year after surgery, naming remained impaired, and patient speech was limited largely to production of single words. These results suggest that the right hemisphere is innately capable of supporting multiple aspects of phoneme processing. Recovery of higher level receptive and, to a lesser extent, expressive language functions is attributed to plasticity of the right hemisphere, which appears to persist beyond the proposed critical period for language acquisition and lateralization.

Attitudes toward colon cancer gene testing: factors predicting test uptake.

OBJECTIVES: Genetic discoveries in hereditary nonpolyposis colorectal cancer (HNPCC) have made possible genetic testing to determine susceptibility to this form of colorectal cancer (CRC). This study measured the uptake of genetic testing for HNPCC among first-degree relatives of CRC patients and conducted a preliminary analysis of the predictors of test uptake. MATERIALS AND METHODS: We compared 77 test acceptors and 181 decliners on demographic, medical history, and psychological characteristics, controlling for distance from the testing center. The psychological factors studied were risk perception for CRC, frequency of cancer thoughts, and perceived ability to cope with unfavorable genetic information. RESULTS: In the final regression model, after accounting for all variables, the significant predictors of test uptake were increased risk perception, greater perceived confidence in ability to cope with unfavorable genetic information, more frequent cancer thoughts, and having had at least one colonoscopy. The association between risk perception and uptake was dependent on frequency of cancer thoughts. Among those who thought about getting CRC more often, the probability of testing increased as perceived risk increased to approximately 50% likelihood of getting CRC and then leveled off. In contrast, among those who never or rarely thought about getting CRC, risk perception was unrelated to testing decision. CONCLUSIONS: Our findings are consistent with the associations reported between psychological factors and other cancer screening behaviors.

Right hemisphere speech perception revealed by amobarbital injection and electrical interference.

OBJECTIVE: To investigate the right hemispheric speech perception capabilities of an adult right-handed patient with seizures. METHODS: Consecutive, unilateral, intracarotid sodium amobarbital injections and left hemispheric electrical interference mapping were used to determine lateralization and localization of speech perception, measured as syllable discrimination. RESULTS: Syllable discrimination remained intact after left and right intracarotid sodium amobarbital injections. Language otherwise strongly lateralized to the left hemisphere. Despite evidence of bilateral speech perception capabilities, electrical interference testing in the left posterior temporal lobe impaired syllable discrimination. CONCLUSIONS: The results suggest a functionally symmetric, parallel system in the adult brain with preferential use of left hemispheric pathways for speech perception.

Temporal dynamics of verbal object comprehension.

Knowledge of the stage composition and the temporal dynamics of human cognitive operations is critical for building theories of higher mental activity. This information has been difficult to acquire, even with different combinations of techniques such as refined behavioral testing, electrical recording/interference, and metabolic imaging studies. Verbal object comprehension was studied herein in a single individual, by using three tasks (object naming, auditory word comprehension, and visual word comprehension), two languages (English and Farsi), and four techniques (stimulus manipulation, direct cortical electrical interference, electrocorticography, and a variation of the technique of direct cortical electrical interference to produce time-delimited effects, called timeslicing), in a subject in whom indwelling subdural electrode arrays had been placed for clinical purposes. Electrical interference at a pair of electrodes on the left lateral occipitotemporal gyrus interfered with naming in both languages and with comprehension in the language tested (English). The naming and comprehension deficit resulted from interference with processing of verbal object meaning. Electrocorticography indices of cortical activation at this site during naming started 250-300 msec after visual stimulus presentation. By using the timeslicing technique, which varies the onset of electrical interference relative to the behavioral task, we found that completion of processing for verbal object meaning varied from 450 to 750 msec after current onset. This variability was found to be a function of the subject's familiarity with the objects.

Short-term consistency in self-reported physical functioning among elderly women: the Women's Health and Aging Study.

The assessment of physical functioning and disability is integral to population-based and clinical research carried out among elderly people. Typically, functional status is measured through self-reported responses to questions of the form "Do you have difficulty [doing a specific task]?" Knowledge of the reliability and validity of these self-report measures is key to the interpretation of many research efforts, but data on these measurement parameters are sparse. This paper addresses this deficiency through analyses of data from the Weekly Substudy of the Women's Health and Aging Study, a cohort of Baltimore-area women aged > or =65 years with moderate to severe physical disability. Self-reported data on 20 activities, obtained weekly over a 6-month period in 1993 or 1994, were analyzed to investigate how time intervals between assessments and a subject's age and baseline level of disability influenced the consistency of self-reports of disability at both the population level and the individual level. The prevalence of self-reported difficulty increased with baseline disability and, to a lesser extent, with age group. Consistency for all items was very high over short time intervals, but it decreased substantially with increasing intervals between responses (although associations between responses remained significant at 24 weeks). Consistency did not vary with age or baseline disability. Graphic techniques and statistical methods for use with repeated binary data are also illustrated.

Functional mapping of human sensorimotor cortex with electrocorticographic spectral analysis. I. Alpha and beta event-related desynchronization.

Human scalp EEG studies have shown that event-related desynchronization (ERD) in the alpha (8-13 Hz) and beta (15-25 Hz) bands may be used to detect functional activation of sensorimotor cortex. However, in most previous studies somatotopy has not been examined in detail and brief, self-paced movements, focusing on the planning of motor output, have been used. We recorded electrocorticographic (ECoG) signals in five clinical subjects during a visual-motor decision task that was designed to activate the representations of different body parts in sensorimotor cortex. To focus more on execution of motor output than on its planning, subjects were instructed to make sustained isometric muscle contractions in different body parts (tongue protrusion, fist-clenching or foot dorsiflexion) in response to randomized visual stimuli depicting each action. ECoG spectral analysis utilized a mixed-effects analysis of variance model in which within-trial temporal dependencies were taken into account, and the magnitude and statistical significance of alpha and beta ERDs were mapped onto a surface rendering of each subject's brain MRI. Cortical electrical stimulation was performed in all subjects for clinical purposes, and the resulting maps of sensorimotor function were compared with those generated by ECoG spectral analysis. During the early phases of the motor responses, alpha ERD commonly occurred in a diffuse spatial pattern that was not somatotopically specific. During the late phases, the spatial pattern of alpha ERD usually became more focused and somatotopically specific. Maps of alpha ERD were closer to cortical stimulation maps when alpha ERD was sustained throughout the late phases of the motor responses. Thus, the topography of alpha ERD more resembled traditional somatotopy when its temporal profile approximated that of the motor response. The topography of beta ERD was often more discrete and somatotopically specific than that of alpha ERD, but beta ERD was often transient and sometimes absent. Sometimes, unilateral limb movement produced sustained alpha and beta ERD over bilateral sensorimotor cortices, with overlapping patterns for different body parts. The topographical spread of alpha ERD beyond expected functional-anatomical boundaries during early (and sometimes late) phases of motor responses invites a re-examination of traditional assumptions about sensorimotor functional neuroanatomy, as well as the role of alpha ERD as an index of cortical activation. We agree with others that the somatotopic representations of different body parts overlap more than previously thought. Also, unilateral limb movements may be associated with both contralateral and ipsilateral activation of sensorimotor cortex. We conjecture that alpha ERD may reflect activity within a broad synaptic network with distributed cortical representations.

Functional mapping of human sensorimotor cortex with electrocorticographic spectral analysis. II. Event-related synchronization in the gamma band.

It has been shown in animals that neuronal activity in the 'gamma band' (>30 Hz) is associated with cortical activation and may play a role in multi-regional and multi-modal integration of cortical processing. Studies of gamma activity in human scalp EEG have typically focused on event-related synchronization (ERS) in the 40 Hz band. To assess further the gamma band ERS further, as an index of cortical activation and as a tool for human functional brain mapping, we recorded subdural electrocorticographic (ECoG) signals in five clinical subjects while they performed visual-motor decision tasks designed to activate the representations of different body parts in sensorimotor cortex. ECoG spectral analysis utilized a mixed-effects analysis of variance model in which within-trial temporal dependencies were accounted for. Taking an exploratory approach, we studied gamma ERS in 10-Hz-wide bands (overlapping by 5 Hz) ranging from 30 to 100 Hz, and compared these findings with changes in the alpha (8-13 Hz) and beta (15-25 Hz) bands. Gamma ERS (observed in three out of subjects) occurred in two broad bands-'low gamma' included the 35-45 and 40-50 Hz bands, and 'high gamma' the 75-85, 80-90, 85-95 and 90-100 Hz bands. The temporal and spatial characteristics of low and high gamma ERS were distinct, suggesting relatively independent neurophysiological mechanisms. Low gamma ERS often began after onset of the motor response and was sustained through much of it, in parallel with event-related desynchronization (ERD) in the alpha band. High gamma ERS often began during, or slightly before, the motor response and was transient, ending well before completion of the motor response. These temporal differences in low and high gamma suggest different functional associations with motor performance. Compared with alpha and beta ERD, the topographical patterns of low and high gamma ERS were more discrete and somatotopically specific and only occurred over contralateral sensorimotor cortex during unilateral limb movements (alpha and beta ERD were also observed ipsilaterally). Maps of sensorimotor function inferred from gamma ERS were consistent with maps generated by cortical electrical stimulation for clinical purposes. In addition, different task conditions in one subject produced consistent differences in both motor response latencies and onset latency of gamma ERS, particularly high gamma ERS. Compared with alpha and beta ERD, the topography of gamma ERS is more consistent with traditional maps of sensorimotor functional anatomy. In addition, gamma ERS may provide complementary information about cortical neurophysiology that is useful for mapping brain function in humans.

Predictors of psychological adjustment to genetic testing for Huntington's disease.

In the present study the authors assessed predictors of adjustment to genetic testing for Huntington's disease. Fifty-two genetically positive and 108 genetically negative persons were studied for 1 year following testing. Adjustment, defined by hopelessness and depressive symptoms, was measured at 3, 6, 9, and 12 months after disclosure and was within normal limits for both groups. Those less well adjusted had tested positive, were married, had no children, or were closer to their estimated ages of onset. The study delineated risk factors for psychological distress that should be considered by people contemplating testing for Huntington's disease.