Deep-learning model to improve histological grading and predict upstaging of atypical ductal hyperplasia / ductal carcinoma in situ on breast biopsy.

AIMS: Risk stratification of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), diagnosed using breast biopsy, has great clinical significance. Clinical trials are currently exploring the possibility of active surveillance for low-risk lesions, whereas axillary lymph node staging may be considered during surgical planning for high-risk lesions. We aimed to develop a machine-learning algorithm based on whole-slide images of breast biopsy specimens and clinical information to predict the risk of upstaging to invasive breast cancer after wide excision. METHODS AND RESULTS: Patients diagnosed with ADH/DCIS on breast biopsy were included in this study, comprising 592 (740 slides) and 141 (198 slides) patients in the development and independent testing cohorts, respectively. Histological grading of the lesions was independently evaluated by two pathologists. Clinical information, including biopsy method, lesion size, and Breast Imaging Reporting and Data System (BI-RADS) classification of ultrasound and mammograms, were collected. Deep DCIS consisted of three deep neural networks to evaluate nuclear grade, necrosis, and stromal reactivity. Deep DCIS output comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. Deep DCIS highly correlated with the pathologists' evaluations of both slide- and patient-level labels. All five parameters of Deep DCIS were significantly associated with upstaging to invasive carcinoma in subsequent wide excisional specimens. Using multivariate logistic regression, Deep DCIS predicted upstaging to invasive carcinoma with an area under the curve (AUC) of 0.81, outperforming pathologists' evaluation (AUC, 0.71 and 0.69). After including clinical and hormone receptor status information, performance further improved (AUC, 0.87). This combined model retained its predictive power in two subgroup analyses: the first subgroup included unequivocal DCIS (excluding cases of ADH and DCIS suspicious for microinvasion) (AUC, 0.83), while the second excluded cases of high-grade DCIS (AUC, 0.81). The model was validated in an independent testing cohort (AUC, 0.81). CONCLUSION: This study demonstrated that deep-learning models can refine histological evaluation of ADH and DCIS on breast biopsies, which may help guide future treatment planning.

Effect of swimming on the production of aldosterone in rats.

It has been demonstrated that exercise is one of the stresses known to increase the aldosterone secretion. Both potassium and angiotensin II (Ang II) levels are shown to be correlated with aldosterone production during exercise, but the mechanism is still unclear. In an in vivo study, male rats were catheterized via right jugular vein (RJV), and divided into four groups namely water immersion, swimming, lactate infusion (13 mg/kg/min) and pyruvate infusion (13 mg/kg/min) groups. Each group was treated for 10 min. Blood samples were collected at 0, 10, 15, 30, 60 and 120 min from RJV after administration. In an in vitro study, rat zona glomerulosa (ZG) cells were challenged by lactate (1-10 mM) in the presence or absence of Ang II (10(-8) M) for 60 min. The levels of aldosterone in plasma and medium were measured by radioimmunoassay. Cell lysates were analyzed by immunoblotting assay. After exercise and lactate infusion, plasma levels of aldosterone and lactate were significantly higher than those in the control group. Swimming for 10 min significantly increased the plasma Ang II levels in male rats. Administration of lactate plus Ang II significantly increased aldosterone production and enhanced protein expression of steroidogenic acute regulatory protein (StAR) in ZG cells. These results demonstrated that acute exercise led to the increase of both aldosterone and Ang II secretion, which is associated with lactate action on ZG cells and might be dependent on the activity of renin-angiotensin system.

Differences in cognitive process-related skills between taxi and non-taxi drivers between 50 and 70 years old.

This study investigated differences between 50- to 70-yr.-old taxi and non-taxi drivers with respect to cognitive process-related skills. Psychological indicators associated with perceptuomotor, attentional, and spatial memory recall abilities were collected for 173 taxi drivers (7 women, 166 men; M age = 57.5 yr.) and 175 non-taxi drivers (85 women, 90 men; M age = 58.2 yr.). The taxi drivers had shorter reaction times and motor times in response to stimuli in simple stimulus-response tasks. There was an age-related decline in monocular vision detection on both sides, processing speed for fovea stimuli, and higher-level cognition for drivers. Accordingly, the frontal visual information processing speed of the taxi drivers was superior to the non-taxi drivers, but a distinct age-related decline was observed for all drivers.

Diversity and wiring variability of visual local neurons in the Drosophila medulla M6 stratum.

Local neurons in the vertebrate retina are instrumental in transforming visual inputs to extract contrast, motion, and color information and in shaping bipolar-to-ganglion cell transmission to the brain. In Drosophila, UV vision is represented by R7 inner photoreceptor neurons that project to the medulla M6 stratum, with relatively little known of this downstream substrate. Here, using R7 terminals as references, we generated a 3D volume model of the M6 stratum, which revealed a retinotopic map for UV representations. Using this volume model as a common 3D framework, we compiled and analyzed the spatial distributions of more than 200 single M6-specific local neurons (M6-LNs). Based on the segregation of putative dendrites and axons, these local neurons were classified into two families, directional and nondirectional. Neurotransmitter immunostaining suggested a signal routing model in which some visual information is relayed by directional M6-LNs from the anterior to the posterior M6 and all visual information is inhibited by a diverse population of nondirectional M6-LNs covering the entire M6 stratum. Our findings suggest that the Drosophila medulla M6 stratum contains diverse LNs that form repeating functional modules similar to those found in the vertebrate inner plexiform layer.

A comprehensive wiring diagram of the protocerebral bridge for visual information processing in the Drosophila brain.

How the brain perceives sensory information and generates meaningful behavior depends critically on its underlying circuitry. The protocerebral bridge (PB) is a major part of the insect central complex (CX), a premotor center that may be analogous to the human basal ganglia. Here, by deconstructing hundreds of PB single neurons and reconstructing them into a common three-dimensional framework, we have constructed a comprehensive map of PB circuits with labeled polarity and predicted directions of information flow. Our analysis reveals a highly ordered information processing system that involves directed information flow among CX subunits through 194 distinct PB neuron types. Circuitry properties such as mirroring, convergence, divergence, tiling, reverberation, and parallel signal propagation were observed; their functional and evolutional significance is discussed. This layout of PB neuronal circuitry may provide guidelines for further investigations on transformation of sensory (e.g., visual) input into locomotor commands in fly brains.

The response patterns of young bicyclists to a right-turning motorcycle: a simulator study.

This study was designed to assess how bicyclists (30 men, 30 women) responded to right-turning motorised vehicles, which is a risky situation for bicyclists, and employed a scenario in which a motorcycle made a right turn in front of a bicyclist. The factors of speed difference and cut-in time gap were generated to objectively investigate steering control, speed, and the associated collisions in a bicycle simulator. There was no effect for sex, but as expected, for shorter cut-in time gaps, the steering angles were smaller (deflected to the right to avoid the passing motorcycle), the speeds were lower, and the variations in the steering angle and speed were larger. Variations in the steering angle and speed were unexpectedly lower for larger speed differences than for smaller speed differences. Response patterns comprised 5 patterns: early response and quickly depress the brake, last-moment response and slowly depress the brake, late response and quickly depress the brake, very late response and quickly depress the brake, and no response. Larger speed differences and the no-response pattern resulted in two collisions. Individuals with less experience may not have associated speed differences with potential dangers.

Three-dimensional reconstruction of brain-wide wiring networks in Drosophila at single-cell resolution.

BACKGROUND: Animal behavior is governed by the activity of interconnected brain circuits. Comprehensive brain wiring maps are thus needed in order to formulate hypotheses about information flow and also to guide genetic manipulations aimed at understanding how genes and circuits orchestrate complex behaviors. RESULTS: To assemble this map, we deconstructed the adult Drosophila brain into approximately 16,000 single neurons and reconstructed them into a common standardized framework to produce a virtual fly brain. We have constructed a mesoscopic map and found that it consists of 41 local processing units (LPUs), six hubs, and 58 tracts covering the whole Drosophila brain. Despite individual local variation, the architecture of the Drosophila brain shows invariance for both the aggregation of local neurons (LNs) within specific LPUs and for the connectivity of projection neurons (PNs) between the same set of LPUs. An open-access image database, named FlyCircuit, has been constructed for online data archiving, mining, analysis, and three-dimensional visualization of all single neurons, brain-wide LPUs, their wiring diagrams, and neural tracts. CONCLUSION: We found that the Drosophila brain is assembled from families of multiple LPUs and their interconnections. This provides an essential first step in the analysis of information processing within and between neurons in a complete brain.

Measurement of auditory cues in drivers' distraction.

A driving simulator was used to examine the effects on driving performance of auditory cues in an in-vehicle information search task. Drivers' distraction by the search tasks was measured on a peripheral detection task. The difficulty of the search task was systematically varied to test the distraction caused by a quantified visual load. 58 participants completed the task. Performance on both search tasks and peripheral detection tasks was measured by mean response time and percent error. Analyses indicated that in-vehicle information search performance can be severely degraded when a target is located within a group of diverse distractors. Inclusion of an auditory cue in the visual search increased the mean response time as a result of a change in modality from auditory to visual. Inclusion of such an auditory cue seemed to influence distraction as measured by performance on the peripheral detection task; accuracy was lower when auditory cues were provided, and responses were slower when no auditory cues were provided. Distraction by the auditory cue varied according to the difficulty of the search task.

Octopamine neuromodulatory effects on a social behavior decision-making network in Drosophila males.

Situations requiring rapid decision-making in response to dynamic environmental demands occur repeatedly in natural environments. Neuromodulation can offer important flexibility to the output of neural networks in coping with changing conditions, but the contribution of individual neuromodulatory neurons in social behavior networks remains relatively unknown. Here we manipulate the Drosophila octopaminergic system and assay changes in adult male decision-making in courtship and aggression paradigms. When the functional state of OA neural circuits is enhanced, males exhibit elevated courtship behavior towards other males in both behavioral contexts. Eliminating the expression of the male form of the neural sex determination factor, Fruitless (Fru(M)), in three OA suboesophageal ganglia (SOG) neurons also leads to increased male-male courtship behavior in these same contexts. We analyzed the fine anatomical structure through confocal examination of labeled single neurons to determine the arborization patterns of each of the three Fru(M)-positive OA SOG neurons. These neurons send processes that display mirror symmetric, widely distributed arbors of endings within brain regions including the ventrolateral protocerebra, the SOG and the peri-esophageal complex. The results suggest that a small subset of OA neurons have the potential to provide male selective modulation of behavior at a single neuron level.

Integration of optical clearing and optical sectioning microscopy for three-dimensional imaging of natural biomaterial scaffolds in thin sections.

The intrinsic turbidity of scaffolds formed by natural biomaterials such as collagen fibers prevents high-resolution light microscopy in depth. In this research, we have developed a new method of using light microscopy for penetrative three-dimensional (3-D) visualization of scaffolds formed by collagen, chitosan, or cellulose. First, we applied an optical-clearing solution, FocusClear, to permeate and reduce the turbidity of the scaffolds. The improved photon penetration allowed fluorophores for efficient excitation and emission in the FocusClear solution. Confocal microscopy was applied to achieve cellular-level resolution up to 350 microm for both the fibroblast/collagen and the osteoblast/chitosan constructs and micrometer-level resolution up to 40 microm for the cellulose membrane. The depth of imaging of the cellulose membrane was further improved to 80 microm using two-photon microscopy. Significantly, these voxel-based confocal/two-photon micrographs allowed postrecording image processing via Amira projection algorithms for 3-D visualization and analysis of the scanned region. Although this optical method remains limited in viewing block scaffolds in thin sections, our approach provides a noninvasive way to microscopically examine the scaffold structure, which would be a valuable tool to studying biomaterials and their interactions with the molecule/cell of interest within the scaffold in an integrated fashion.

Responses in a manual tracking and visual detection task.

To investigate interference between the sustained and occasional attention required in driving, performance of 36 participants engaged in a focal manual tracking task and a peripheral detection task, representing sustained and occasional attention, respectively, was studied. Error ratio, tracking distance, tracking speed, and root mean squared tracking distance error were taken for manual tracking, and response times were measured on the detection task. Analysis indicated that multiple tasks or highly sustained attentional demands preceded lower performance on sustained attention tasks. Performance on occasional attention tasks after multiple tasks may also decrease, but occasional attention performance improved when the participants were engaged concurrently in a task involving higher sustained attention. Furthermore, the association between sustained and occasional attention was strengthened as the number of tasks or the demands of sustained attention increased.

Driving performance assessment: effects of traffic accident location and alarm content.

According to accident statistics for Taiwan, the two most common traffic accident locations in urban areas are roadway segments and intersections. On roadway segments, most collisions are due to drivers not noticing the status of leading vehicle. At intersections, most collisions are due to the other driver failing to obey traffic signs. Using a driving simulator equipped with a collision warning system, this study investigated driving performance at different accident locations and between different alarm contents, and identified the relationship between crash occurrences and driving performance. Thirty participants, aged 20-29 years, were recruited in this study. Driving performance measures were perception-reaction time, movement-reaction time, speed and a crash. Experimental results indicated that due to different demands for processing information under different traffic conditions, driving performance differed at the two traffic accident locations. On a roadway segment, perception-reaction time for a beep was shorter than the time for a speech message. Nevertheless, at an intersection, a speech message was a great help to drivers and, thus, perception-reaction time was effectively reduced. In addition, logistic regression analysis indicates that perception-movement time had the greatest influence on crash occurrence.

Resistance rate to antibiotics of Helicobacter pylori isolates in eastern Taiwan.

BACKGROUND AND AIM: Prevalence of Helicobacter pylori (H. pylori) strains resistant to metronidazole, clarithromycin and amoxicillin is increasing worldwide. The aim of this study was to determine the antibiotic susceptibility patterns in H. pylori strains isolated from eastern Taiwan. METHODS: One strain each of H. pylori was isolated from 133 symptomatic patients and subjected to determination of the minimal inhibitory concentration (MIC) by the Epsilometer test (E-test) for four antibiotics commonly used in the treatment of H. pylori infections. RESULTS: None of the strains were resistant to tetracycline. Resistance to metronidazole (8 microg/mL), clarithromycin (1 microg/mL) and amoxicillin (8 microg/mL) was found in 51.9%, 13.5% and 36.1% of the isolates, respectively. Metronidazole-resistant strains were isolated more frequently from women (49/78; 62.8%) than from men (20/55; 36.4%). Resistance to at least two antimicrobial agents was detected in 33.8% of the isolates. There was a high rate of resistance to both metronidazole and amoxicillin (18.1%). CONCLUSIONS: Clarithromycin and tetracycline may provide useful components of treatment regimens in eastern Taiwan. In addition, pretreatment microbial susceptibility testing rather than empiric therapy is highly recommended for eradication of H. pylori infection.

Internal representations of smell in the Drosophila brain.

Recent advances in sensory neuroscience using Drosophila olfaction as a model system have revealed brain maps representing the external world. Once we understand how the brain's built-in capability generates the internal olfactory maps, we can then elaborate how the brain computes and makes decision to elicit complex behaviors. Here, we review current progress in mapping Drosophila olfactory circuits and discuss their relationships with innate olfactory behaviors.

Application of a virtual reality-enhanced exercise protocol in patients after coronary bypass.

OBJECTIVE: To determine whether, by using training enhanced by virtual reality (VR) displays, patients who had undergone coronary artery bypass graft (CABG) surgery could more effectively attain long-term cardiopulmonary results than those not using VR technology. DESIGN: Randomized controlled trial. SETTING: Exercise testing laboratory in a medical center. PARTICIPANTS: Consecutive sample of 32 patients who had undergone CABG surgery. INTERVENTIONS: All subjects were randomly assigned to 1 of 2 submaximal endurance programs, with or without simulated training. In all other respects, the 2 programs were identical. Each section lasted for 30 minutes and was conducted twice a week for about 3 months. Graded exercise tests, conducted before and after training, evaluated cardiorespiratory changes. MAIN OUTCOME MEASURES: The cardiorespiratory and hemodynamic parameters were evaluated at both peak and submaximal exertion. RESULTS: At the follow-up exercise tests (performed at 5.4 mo after surgical intervention), the VR group achieved significantly higher value in peak oxygen consumption (VO2peak), peak metabolic equivalents (METS), and amount of VO2 at anaerobic threshold than the non-VR group. Significant gain was attained in VO2peak and peak MET value accrued to those who participated in simulation-based aerobic training. CONCLUSIONS: Our study outcomes clearly support the perceived benefits of rehabilitation programs that incorporate VR to augment patients' recovery of their physical capacity.

Clinical Relevance of the vacA, iceA, cagA, and flaA genes of Helicobacter pylori strains isolated in Eastern Taiwan.

The genotypes of Helicobacter pylori flaA, cagA, vacA, and iceA were determined for DNA isolated from patients with chronic gastritis or peptic ulcer in eastern Taiwan. The vacA gene encoding the s1a subtype was found to predominate in peptic ulcer patients, and the iceA1 genotype was associated with chronic gastritis. cagA and flaA genes were not found to be associated with these types of disease.