Can 18 F FDG PET/CT metabolic parameters be used to noninvasively differentiate between different histopathological subtypes and Fuhrman grades of renal cell cancer?

AIM: To evaluate relationship between metabolic PET metabolic parameters and size of the primary tumor, various histopathological subtypes of renal cell carcinoma (RCC) and Fuhrman grade of the tumors. MATERIAL AND METHODS: Retrospective analysis of 93 biopsy-proven RCC patients who underwent pretreatment flourine 18 flourodeoxyglucose PET/computed tomography ( 18 F FDG PET/CT) was performed. Quantitative PET parameters, size of the primary tumor, histopathological subtypes and Fuhrman grades of the tumor were extracted. We tried to assess if there was any significant difference in the metabolic patterns of various histopathological subtypes of RCCs, Fuhrman grade of the tumors and size of the primary tumor. RESULTS: A significant correlation was noted between the size of primary tumor and maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) ( P  < 0.01, P  < 0.001 and P  < 0.001, respectively). SUV max values correlated significantly with the histopathological subtype ( P  < 0.001). Further sub-analyses was also done by segregating the patients into Low grade (Fuhrman grade 1 and 2) vs. High grade (Fuhrman grade 3 and 4). SUV max , MTV and TLG were significantly different between high grade vs. low grade tumors. ROC analysis yielded cut off values for SUV max , MTV and TLG to differentiate between high grade from low grade tumors. CONCLUSION: FDG PET/CT with the use of metabolic PET parameters can differentiate between different histopathological subtypes of RCC. Incorporation of metabolic parameters into clinical practice can potentially noninvasively identify patients with low-grade vs. high-grade RCC.

Automatic discovery and description of human planning strategies.

Scientific discovery concerns finding patterns in data and creating insightful hypotheses that explain these patterns. Traditionally, each step of this process required human ingenuity. But the galloping development of computer chips and advances in artificial intelligence (AI) make it increasingly more feasible to automate some parts of scientific discovery. Understanding human planning is one of the fields in which AI has not yet been utilized. State-of-the-art methods for discovering new planning strategies still rely on manual data analysis. Data about the process of human planning is often used to group similar behaviors together. Researchers then use this data to formulate verbal descriptions of the strategies which might underlie those groups of behaviors. In this work, we leverage AI to automate these two steps of scientific discovery. We introduce a method for automatic discovery and description of human planning strategies from process-tracing data collected with the Mouselab-MDP paradigm. Our method utilizes a new algorithm, called Human-Interpret, that performs imitation learning to describe sequences of planning operations in terms of a procedural formula and then translates that formula to natural language. We test our method on a benchmark data set that researchers have previously scrutinized manually. We find that the descriptions of human planning strategies that we obtain automatically are about as understandable as human-generated descriptions. They also cover a substantial proportion of relevant types of human planning strategies that had been discovered manually. Our method saves scientists' time and effort, as all the reasoning about human planning is done automatically. This might make it feasible to more rapidly scale up the search for yet undiscovered cognitive strategies that people use for planning and decision-making to many new decision environments, populations, tasks, and domains. Given these results, we believe that the presented work may accelerate scientific discovery in psychology, and due to its generality, extend to problems from other fields.

Regulation of Cytotoxic Immune Effector Function by AJ3 Probiotic Bacteria in Amyotrophic Lateral Sclerosis (ALS).

Our recent studies indicated that amyotrophic lateral sclerosis (ALS) patients suffer from significantly elevated levels of interferon-gamma (IFN-γ) secretion by natural killer (NK) and CD8+ T cells, which may be responsible for the immune-pathologies seen in central nervous system and in peripheral organs of the patients. In order to counter such elevated induction of IFN-γ in patients we designed a treatment strategy to increase anti-inflammatory cytokine interleukin-10 (IL-10) by the use of probiotic strains which significantly increase the levels of IL-10. Therefore, in this paper we demonstrate disease specific functions of Al-Pro (AJ3) formulated for the adjunct treatment of auto-immune diseases including ALS, and compared the function with CA/I-Pro (AJ4) for the treatment of cancer and viral diseases, and NK-CLK (AJ2) for maintenance of immune balance and promotion of disease prevention. The three different formulations of probiotic bacteria have distinct profiles of activation of peripheral blood mononuclear cells (PBMCs), NK, and CD8+ T cells, and their induced activation is different from those mediated by either IL-2 or IL-2 + anti-CD16 monoclonal antibodies (mAbs) or IL-2 + anti-CD3/CD28 mAbs. IL-2 + anti-CD16 mAb activation of PBMCs and NK cells had the highest IFN-γ/IL-10 ratio, whereas IL-2 combination with sAJ4 had the next highest followed by IL-2 + sAJ2 and the lowest was seen with IL-2 + sAJ3. Accordingly, the highest secretion of IFN-γ was seen when the PBMCs and NK cells were treated with IL-2 + sAJ4, intermediate for IL-2 + sAJ2 and the lowest with IL-2 + sAJ3. The levels of IFN-γ induction and the ratio of IFN-γ to IL-10 induced by different probiotic bacteria formulation in the absence of IL-2 treatment remained much lower when compared to those treated in the presence of IL-2. Of note is the difference between NK cells and CD8+ T cells in which synergistic induction of IFN-y by IL-2 + sAJ4 was significantly higher in NK cells than those seen by CD8+ T cells. Based on these results, sAJ3 should be effective in alleviating auto-immunity seen in ALS since it will greatly regulate the levels and function of IFN-γ negatively, decreasing overactivation of cytotoxic immune effectors and prevention of death in motor neurons.

Laparoscopic peritoneal dialysis catheter insertion: an oasis harnessed-experience and results at a tertiary care centre in India.

BACKGROUND: Peritoneal dialysis is a life sustaining renal replacement therapy for patients with end stage renal disease. In comparison to hemodialysis it offers better mobility and independence to patients. A number of techniques including open, laparoscopic and fluoroscopy guided, and their modifications, have been described for intraperitoneal catheter insertion. We describe our technique and results of laparoscopic peritoneal dialysis (PD) catheter insertion at a tertiary care centre in India. CASE SERIES: 48 patients were referred from the department of nephrology at our centre for laparoscopic PD catheter insertion. A two port technique was used in 37 patients and three port technique was implemented in the rest for simultaneous adhesiolysis and/or omentectomy. A straight tip catheter was tunneled through the rectus muscle in all patients. Two patients had incisional hernia from a previous abdominal surgery which was repaired concomitantly with onlay meshplasty. RESULTS: The operative time ranged between 20 and 35 min under general anaesthesia. Three patients were subjected to urgent start dialysis of which one patient developed peridrain leak as an early complication which was managed conservatively. All other patients were commenced on peritoneal dialysis two weeks after surgery. There was no other surgical site occurrence or episodes of peritonitis reported in a 6 month follow up period with the department of nephrology. CONCLUSION: In the era of minimal access surgery, the laparoscopic approach is feasible for widespread and safe use for PD catheter insertion. The benefits of PD can thus be made available to patients at civil hospitals even with a basic laparoscopy setup.

High-Resolution PM2.5 Emissions and Associated Health Impact Inequalities in an Indian District.

Health and livelihood impacts from ambient air pollution among populations in developing countries are disproportional. These disparities are often overlooked due to a lack of information on microlevel emission data, especially in smaller cities and rural areas. The current work in an Indian district, Saharanpur, proposes the use of novel data sets to estimate microlevel emissions from air-polluting infrastructure sectors in urban and rural areas for use in pollutant transport models. Health impacts estimated based on the surface PM2.5 concentration suggest that the rate of premature deaths is 158 (95% CI: 122-163) and 143 (95% CI: 65-151) deaths per 100 000 people in urban and rural areas, respectively. Sixty-eight percent of the 6372 (95% CI: 3321-6987) annual premature deaths occurs in rural areas. Depicting higher contribution-exposure disparities among socioeconomic groups, the study observed that compared to their contribution to air pollution, low socioeconomic status (SES) groups in the region experience 6,7, 7, and 26% more premature deaths from PM2.5 exposure for industries, household cooking fuel burning, open waste burning, and transportation, respectively. The majority of disability-adjusted life years (DALYs) in the study domain are observed in economically weaker worker categories. Reduced income due to the loss of these life years will significantly impact these groups due to their dependence on daily wages for basic life necessities. Microlevel pollution mitigation policies with a focus on these inequalities are critical for promoting environmental equity and justice.

A computational process-tracing method for measuring people's planning strategies and how they change over time.

One of the most unique and impressive feats of the human mind is its ability to discover and continuously refine its own cognitive strategies. Elucidating the underlying learning and adaptation mechanisms is very difficult because changes in cognitive strategies are not directly observable. One important domain in which strategies and mechanisms are studied is planning. To enable researchers to uncover how people learn how to plan, we offer a tutorial introduction to a recently developed process-tracing paradigm along with a new computational method for measuring the nature and development of a person's planning strategies from the resulting process-tracing data. Our method allows researchers to reveal experience-driven changes in people's choice of individual planning operations, planning strategies, strategy types, and the relative contributions of different decision systems. We validate our method on simulated and empirical data. On simulated data, its inferences about the strategies and the relative influence of different decision systems are accurate. When evaluated on human data generated using our process-tracing paradigm, our computational method correctly detects the plasticity-enhancing effect of feedback and the effect of the structure of the environment on people's planning strategies. Together, these methods can be used to investigate the mechanisms of cognitive plasticity and to elucidate how people acquire complex cognitive skills such as planning and problem-solving. Importantly, our methods can also be used to measure individual differences in cognitive plasticity and examine how different types (pedagogical) interventions affect the acquisition of cognitive skills.

Addressing Surface Effects at the Particle-Continuum Interface in a Molecular Dynamics and Finite Elements Coupled Multiscale Simulation Technique.

Atomistic-to-continuum coupling methods are used to unravel molecular mechanisms of polymers and polymer composites. These multiscale techniques advantageously combine the computational efficiency of continuum approaches while keeping the accuracy of particle-based methods. The Capriccio method [Pfaller et al. Comput. Methods Appl. Mech. Eng. 2013, 260, 109-129.] is a well-proven multiscale technique, which connects finite elements (FE) with molecular dynamics (MD) in a partitioned-domain approach. A vital aspect of these multiscale methods is to provide physically sound boundary conditions to the particle domain suppressing any interface effects at the domain boundary occurring due to the coupling. These interfacial coupling artifacts still pose a significant problem, especially for amorphous polymers due to their highly irregular microstructure. We solve this problem by extending the particle-continuum interface by a layer of passive atoms which move with the outer continuum, thereby providing the missing interactions with a surrounding polymer bulk to the inner particle region. This solution allows us to successfully reproduce structural and mechanical properties obtained under conventional periodic boundary conditions, like density, stress, Young's modulus, and Poisson's ratio. Furthermore, we demonstrate the application of a nonaffine deformation by means of a simple bending test. In general, our revised method provides a framework to apply complex deformations for molecular scientists, while it allows the engineering community to examine challenging phenomena such as fracture behavior at a molecular level.

Leveraging artificial intelligence to improve people's planning strategies.

SignificanceMany bad decisions and their devastating consequences could be avoided if people used optimal decision strategies. Here, we introduce a principled computational approach to improving human decision making. The basic idea is to give people feedback on how they reach their decisions. We develop a method that leverages artificial intelligence to generate this feedback in such a way that people quickly discover the best possible decision strategies. Our empirical findings suggest that a principled computational approach leads to improvements in decision-making competence that transfer to more difficult decisions in more complex environments. In the long run, this line of work might lead to apps that teach people clever strategies for decision making, reasoning, goal setting, planning, and goal achievement.

High resolution vehicular exhaust and non-exhaust emission analysis of urban-rural district of India.

Air quality deterioration due to vehicular emissions in smaller Indian cities and rural areas remains unacknowledged, even though the situation is alarmingly similar to megacities. The resulting lack of knowledge on travel behavior and vehicle characteristics impacts accuracy of emission studies in these regions. This study uses a novel approach and appropriate primary and secondary data sets to allocate vehicular activities (vehicle population and vehicle kilometer travelled) and associated emissions at a high spatial resolution for estimation and dispersion analysis of vehicular exhaust and non-exhaust PM2.5 emission in an Indian urban-rural landscape. The study indicates that using approaches that do not allocate vehicles kilometers travelled to areas of their expected travel results in underestimating the percent share of PM2.5 emissions from rural roads and motorways while overestimating overall PM2.5 emissions. Particulate matter resuspension is the dominant form of PM2.5 emissions from the vehicular sector on all road types, constituting an even higher fraction on rural roads. Two-wheelers contribute a high fraction of PM2.5 emissions (exhaust and non-exhaust combined), followed by heavy commercial vehicles and four-wheelers on urban roads. Light commercial vehicles, especially agricultural tractors dominate these emissions on rural roads. PM2.5 hotspots are prevalent in urban areas, but several rural areas also experience heavy particulate matter concentrations. Thus, vehicle movement incorporation results in more accurate emission estimation, especially in an urban-rural landscape.

18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Postsurgical and Postprocedural Setting in Thorax and Abdominopelvic Malignancies: A Pictorial Essay (Part II).

This pictorial essay depicts normal appearances, complications and residual or recurrent disease on fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) studies in the postsurgical and postprocedural setting, other than head and neck malignancy. Reading and reporting FDG PET/CT in this scenario is daunting due to the multiple confounding false positives seen during this period. This article which is the second part in this series will familiarize the readers with the normal appearance and pitfalls seen in FDG PET/CT studies in thoracic and abdominopelvic malignancies during the postoperative and postprocedural period so as to avoid misinterpretations.

18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Postsurgical Setting in Head and Neck Cancers - A Pictorial Essay.

This pictorial essay depicts normal appearances, complications, and findings of residual and/or recurrent disease on fluorodeoxyglucose positron emission tomography/computed tomography (18F- FDG PET/CT) studies in the postsurgical setting. Reading and reporting 18F- FDG PET/CT in the postoperative scenario is demanding due to the multiple false positives seen during this period. This article which contains two parts will familiarize the readers with the normal appearance and pitfalls seen in 18F- FDG PET/CT studies during the postoperative period so as to avoid misinterpretations. This pictorial will discuss 18F- FDG PET/CT in the postoperative scenario in head and neck cancers.

68-gallium Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography Detects Rare Testicular Metastasis from Prostate Cancer.

Testicular metastases from solid tumors is a rare entity. We describe one such case where a patient on treatment for prostate cancer presented with a right scrotal swelling. For restaging, whole-body 68-gallium prostate-specific membrane antigen positron emission tomography/computed tomography (PET/CT) was performed. Fused PET/CT images demonstrated intense uptake in the testicular lesion. Unique anatomic and functional information provided by hybrid PET/CT helped in reliably establishing the testicular mass as the site of metastases from prostate cancer, which had a major impact on patient management.

Brain FET PET tumor-to-white mater ratio to differentiate recurrence from post-treatment changes in high-grade gliomas.

BACKGROUND AND PURPOSE: Highergrade glial neoplasms undergo standard treatment with surgery, radiotherapy, and alkylating agents. There is often a clinical/neuroimaging dilemma in the post-treatment setting to differentiate disease recurrence from treatment-related changes. FET (fluoro-ethyl-tyrosine) PET has emerged as a molecular imaging modality for cases where MR imaging is inconclusive. This study aims to develop a cutoff on FET PET for differentiating true recurrence from post-treatment changes. METHODS: We retrospectively analyzed72 patientswith post-treatment grade 3 or 4 brain gliomas. Five to six mCi of 18 F-FET was injected and static imaging of the brain was performed at 20 min. A tumor-to-white matter (T/Wm) ratio was used as semiquantitative parameter. A T/Wm cutoff of 2.5 was used for image interpretation. Imaging findings were confirmed by either histopathologic diagnosis in a multidisciplinary joint clinic or based on follow-up of clinical and neuroimaging findings. RESULTS: Forty-one of 72 patients (57%) showed recurrent disease on FET PET. Thirty-five of them were confirmed to have tumor recurrence; six patients showed post-treatment changes. Thirty-one of 72 patients (43%) showed post-treatment changes on FET PET; 27 were confirmed as post-treatment change and four patients had tumor recurrence on subsequent MR imaging. An optimum T/Wm cutoff of 2.65 was derived based on receiver operating characteristic analysis with a sensitivity of 80% and specificity of 87.5%. CONCLUSION: Static FET PET can be used as problem-solving imaging modality with a T/Wm cutoff of 2.65 to differentiate late recurrence from post-treatment changes in grade 3 or 4 brain gliomas with equivocal MR features.

Age Estimation in Mixed-dentition Children, Using Cameriere's European Formula and Demirjian's Method: A Comparative Pilot Study.

AIM: The objective of the present investigation is to compare the accuracy of two methods of age estimation, Cameriere's European formula and Demirjian's method, in estimating the age of mixed-dentition children in Telangana. MATERIALS AND METHODS: Digital orthopantomographs (OPGs) of 36 children between the age of 7 years and 12 years were subject to analysis. All the OPGs were analyzed for dental age using both Cameriere's and Demirjian's methods for mixed dentition. Chronological age was calculated by subtracting the date of births from the date on which the OPGs were taken. STATISTICAL ANALYSIS: descriptive analysis was performed. The accuracies of both the methods (Cameriere's and Demirjian's) were evaluated by calculating the mean prediction error. Wilcoxon signed-rank test was performed for both methods of dental age estimation with chronological age and for boys and girls. Significance threshold was set at 5%. RESULTS: Cameriere method resulted in a mean prediction error of 0.579 for girls and 0.483 for boys. Demirjian's method resulted in a mean prediction error of 2.228 for girls and 2.046 for boys. CONCLUSION: In conclusion, as far as accuracy is concerned, Cameriere's European formula proved to be more accurate, according to the current investigation. SIGNIFICANCE: The significance of age estimation is reflected in various fields such as pediatric endocrinology, orthodontics, law, anthropology, archeology, and forensics where identification of unascertained human bodies is required (crime investigations, mass disasters). Demirjian's method is commonly employed for dental age estimation in pediatric dentistry, orthodontics, and forensic dentistry. Cameriere's method may serve as a more accurate and reliable method for dental age estimation. Key message: Cameriere's European formula proved to be better, in terms of accuracy, in determining the chronological age of mixed-dentition children in the region of Telangana, according to the current investigation.

Estimation of Dental Anxiety Levels Before and After Dental Visit in Children with Visual Impairment Using Modified Dental Anxiety Scale in Braille Text.

OBJECTIVE: Dental anxiety and fear of dental treatment in special children has been recognized as a public health dilemma. Dental anxiety (being the fear of unknown in a dental setting) would definitely have a substantial effect on the children with visual impairment. Assessment of the dental anxiety makes it possible to design intervention programs aimed at reducing the anxiety levels in children with visual impairment. Thus, the aim of this study was to assess the dental anxiety levels before and after dental visit in children with visual impairment using Modified Dental Anxiety Scale (MDAS) printed in braille. MATERIALS AND METHODS: A total of 144 institutionalized children with visual impairment in the age group of 6-13 years, residing at an institutionalized blind school, participated in the study. Dental anxiety was assessed pre- and post-dental-screening visit using MDAS printed in braille. Statistical analysis was performed using the Wilcoxon matched-pairs signed rank test. RESULTS: Of 144 children, just before dental screening visit, 78 (54.1%) had severe dental anxiety, 52 (36.11%) had mild anxiety, and 14(9.72%) reported no anxiety, whereas after dental education, only 28 (19.44%) had severe anxiety, 22 (16.66%) had mild anxiety, and 94 (63.88%) reported no anxiety. CONCLUSION: In our study, there was a significant decrease in dental anxiety after dental screening and education. Therefore, proper behavior management techniques and dental health education programs would decrease dental anxiety in children with visual impairment.

Distribution of Periodontal Pockets Among Smokers and Nonsmokers in Patients with Chronic Periodontitis: A Cross-sectional Study.

Context Cigarette smoking is a well-established risk factor for periodontitis and carries an increased risk for loss of periodontal attachment as well as bone loss. Aims The purpose of the present study was to investigate whether disease severity differs between smokers and nonsmokers in a group of chronic periodontitis patients by assessing the periodontal probing depth (PPD) and bleeding on probing (BOP). Materials and methods The study included 150 individuals, 75 smokers and 75 nonsmokers, in the age group of 35-60 years. Subjects with chronic periodontitis were selected and included in the study. Periodontal evaluation, including periodontal probing pocket depths and bleeding on probing, was performed on all four quadrants and at six sites per tooth using the Williams periodontal probe. The data were pooled from the anterior sextant and the posterior sextant as well as from the facial and lingual surfaces. Statistical analysis Comparisons were made between smokers and nonsmokers using the z-test (two-tailed test). Probing pocket depth categories 0-3 mm, 4-5 mm, 6-7 mm, and ≥8 mm and the proportion of sites having a pocket depth of ≥5 mm were used in the analysis. Results The mean percentage of sites that bleed upon probing was higher for nonsmokers as compared with smokers. Smokers had less shallow pockets (0-3 mm) than nonsmokers and more pockets of 4-7 mm (categories 4-5 mm, 6-7 mm). No significant differences were detected in the prevalence of pockets ≥8 mm. In the anterior, premolar, and molar regions, pockets of 6-7 mm were significantly more prevalent in smokers. The buccal and lingual sides also showed that smokers had more sites with deep probing depths ≥5 mm than nonsmokers. The data also showed that in the upper jaw, in the anterior and premolar teeth, the largest differences were found between smokers and nonsmokers. Conclusions From the results, it can be concluded that cigarette smoking results in periodontal tissue destruction in the different areas of the oral cavity, with the maximum periodontal destruction in the maxillary anterior and premolar region.

Estimation Dynamic Distance Direct Ophthalmoscopy (eDDDO): A novel, objective method for the quantitative assessment of accommodation in young children.

Purpose: To describe estimation dynamic distance direct ophthalmoscopy (eDDDO) and compare it with the monocular estimation method of dynamic retinoscopy (eDR) for the assessment of accommodation in children. Methods: In this prospective observational cohort study, an ophthalmologist performed eDDDO followed by eDR in children with normal eyes, and then under the partial effects of cyclopentolate and tropicamide to assess performance of eDDDO with eDR under the condition of pharmacologically induced accommodation failure. Only one eye of each child was recruited in the study. To study the inter-observer variation, two masked pediatric ophthalmology fellows performed eDDDO in the similar manner. Results: For the comparison of eDDDO with eDR, 60 eyes of 60 patients were recruited. The mean age of the patients was 10.4 years. The mean accommodation on eDDDO was 3.0D, 5.1D, 9.8D, and 11.3D at 40 cm, 25 cm, 10 cm, and 8 cm, respectively and 3.0D, 5.0D, 9.5D, and 11.0D on eDR. The eDDDO overestimated accommodation by a mean 0.17D (95% CL 0-0.48D, P = 0.5). The correlation of eDDDO with eDR was excellent (Pearson r 0.98, T value 76.0). The inter-observer difference with eDDDO was not significant (mean 1D, 95% CL 0-2.6D, P = 0.9) and the correlation between two observers was excellent (Pearson r 0.9, T value 12.7). The eDDDO and eDR were also performed on 12 eyes of 6 children with a mean age of 8.5 years (range 8-12 years) under the partial effect of cyclopentolate and tropicamide, where eDDDO overestimated the accommodation by a mean 0.3D (95% CL 0- 1.2D, P = 0.7) and the correlation was excellent (Pearson r 1.0, T value 45). Conclusion: eDDDO is a simple, reliable, quantitative, and objective technique of accommodation assessment for children. Further studies with larger sample are required to assess its performance in disorders of accommodation affecting younger children and in children with ocular comorbidities.

Structured multimaterial filaments for 3D printing of optoelectronics.

Simultaneous 3D printing of disparate materials; metals, polymers and semiconductors with device quality interfaces and at high resolution remains challenging. Moreover, the precise placement of discrete and continuous domains to enable both device performance and electrical connectivity poses barriers to current high-speed 3D-printing approaches. Here, we report filaments with disparate materials arranged in elaborate microstructures, combined with an external adhesion promoter, to enable a wide range of topological outcomes and device-quality interfaces in 3D printed media. Filaments, structured towards light-detection, are printed into fully-connected 3D serpentine and spherical sensors capable of spatially resolving light at micron resolution across its entire centimeter-scale surface. 0-dimensional metallic microspheres generate light-emitting filaments that are printed into hierarchical 3D objects dotted with electroluminescent pixels at high device resolution of 55 µm not restricted by surface tension effects. Structured multimaterial filaments provides a path towards custom three-dimensional functional devices not realizable by existing approaches.