This work presents a numerical simulation of a Hartmann-Shack wavefront sensor (WFS) that assesses the impact of integrated electronic circuitry on the sensor performance, by evaluating a full detection chain encompassing wavefront sampling, photodetection, electronic circuitry and wavefront reconstruction. This platform links dedicated C algorithms for WFS to a SPICE circuit simulator for integrated electronics. The complete codes can be easily replaced in order to represent different detection or reconstruction methods, while the circuit simulator employs reliable models of either off-the-shelf circuit components or custom integrated circuit modules. The most relevant role of this platform is to enable the evaluation of the applicability and constraints of the focal plane of a given wavefront sensor prior to the actual fabrication of the detector chip. In this paper, we will present the simulation results for a Hartmann-Shack wavefront sensor with an orthogonal array of quad-cells (QC) integrated along with active-pixel (active-pixel sensor (APS)) circuitry and analog-to-digital converters (ADC) on a “complementary metal oxide semiconductor” (CMOS) process and deploying a modal wavefront reconstructor. This extended simulation capability for wavefront sensors enables the test and verification of different photosensitive and circuitry topologies for position-sensitive detectors combined with the simulation of sampling microlenses and reconstruction algorithms, with the goal of enhancing the accuracy in the prediction of the wavefront-sensor performance before a detector CMOS chip is actually fabricated. Adaptive optics (AO) has emerged as a technology focused on improving the performance of optical systems, by reducing the deleterious effects caused by wavefront (WF) distortions. Adaptive optical systems (AOS) usually use several systems and components for the detection and dynamic compensation of aberrations, such as deformable mirrors, lasers, precision optical parts and wavefront sensors (WFS) . The appThe simulation contains every step in the WF detection and reconstruction process, from the generation of the input WFs to the computation of the reconstructed WFs and their respective resulting errors. It guides the designer through the evaluation of different WF sensing techniques and structures that composes a Hartmann-Shack WFS prior to device fabrication, as the scheme for the pixel read-out circuitry, as well as the topology of the microlens array. The Hartmann-Shack detection method was chosen since it is the most ubiquitously-used WF detection method ,15. The A WF is represented as a smooth and well-behaved two-dimensional mathematical function, whose optimal shape depends on the target application. Deviations from its optimal shape are considered as optical aberrations. Traditionally, methods for WF reconstruction are classified into zonal estimates , where dThe aforementioned Hartmann-Shack WFS is mainly composed of a microlens array and an optical detection plane, located at the focal plane of the microlens array. The latter is meant to sample and focus patches of the incident WF onto the detection plane, resulting in one light spot for each microlens on the sampling plane. The spot positions depend on the average local tilts of the sampled WF. If the WF is parallel to the microlens array a, the spIn this work, PSDs of the quad-cell (QC) type are used . A QC isIn this work, simulations and their interpretation will be presented in the context of ophthalmology. However, it is worth mentioning that the simulation can be easily adapted to any other application in AO, provided that reference WF statistics or databases are available.The computational structure to model the WF sensing flow is divided into six main blocks, as shown in The parameters used to initialize the simulation in Step 1 of r et al. . Next, iH), featuring homogeneous quantum efficiency on its surface; and the double quantum efficiency (QCD), which has two concentric regions with different quantum efficiencies [The amount of light over a single photodetector is translated as a proportional photocurrent signal. Any deviation from the QC center renders different signal values for each photodetector, according to the model presented in . Two kinciencies .In Step 5, the wavefront is reconstructed, and there are two possible paths to go through the simulation. In Path 5.1, WF reconstruction uses the position coordinates from the spots as obtained in Step 4, enabling the testing of how much the QCs, microlenses and photodiodes individually impact the reconstruction. Choosing Path 5.2, the electronic structures are incorporated, allowing the evaluation of different pixel topologies and add-on circuitry prior to any fabrication step, either on-chip or on a printed-circuit board. In this path, the photocurrent signals obtained from Step 4 are transferred to the SPICE simulator, where a model was built that emulates the WFS electronic interface, as presented in The top module in the SPICE schematics of All of the integrated components of the WFS that receive information about the photogenerated current (mulation . This phThe APS is composed of five transistors. The reset transistor (T1) works as a switch and when turned on is used to charge the photodetectors intrinsic capacitance, setting a reference voltage source level (VDD) at the sense node (SN). The buffer transistor (T2) buffers the signal to the selection transistor (T3), which is a switch that enables the selection of the pixel to be read. When turning off T1 and considering that the signal Tx at the transfer gate TG is on—where TG is a PMOS/NMOS complementary switch—the photodetector’s internal capacitance starts to discharge at a rate proportional to its photocurrent, reducing the voltage on the SN. Therefore, the voltage drop at the SN, which determines the output Vout, is a measure of the photocurrent’s intensity. When TG is turned off, the voltage at SN can be kept rather constant during a storage period for further readout purposes.The read-out voltage for each QC is sampled just after Tx is turned off, for instance at 151 ms for the first QC in n is the total number of points in the sampling grid in which the WF function is described, and the values The x and y spot-centroid coordinates enable the reconstruction of the wavefront. Either Step 5.2 or 5.1 of Both coefficients atistics , and CouH or QCD). All variables used in the simulations are shown in The simulation procedure described in the previous section enables the design of optimal electronic and optical parameters, in order to suit different applications, before the sensor is actually manufactured. Besides contributing to sensible decisions about the sensor design, the simulation also allows one to assess the separate and combined impact of optical, optoelectronic and electronic parameters in the sensor performance. To exemplify the importance of the platform, we have varied some parameters, combined with the presence or absence of the electronic circuitry, in order to observe their impact on the overall sensor performance. The chosen parameters were the number of microlenses in the microlens array and the type of PSD quadrant detector  and (f). The residual WF is the difference between the original WF and its reconstruction. Analysis of the residual values also helps in this evaluation, making the effect over the reconstruction RMS error more evident considering the electronic modules. The residual plots also show that the error along the borders is larger than that in the middle region of the WF, as expected since the wavefront aperture circumscribes the orthogonal microlens array area. However, when the signal passes through the electronic circuitry, the error is more pronounced in the central regions of the WF, where the tilts of the surface patches are smaller, and their respective light spots fall about the center of the QCs where it features a more linear response. In this case, the reconstructed spot positions are more susceptible to read-out noise of each of the four pixels in the QC, yielding a slightly larger reconstruction error. Moreover, the presented RMS error reconstruction in The simulations performed for a Hartmann-Shack WFS including integrated electronics serve as an advantageous auxiliary tool in designing the sensor, especially when a custom focal-plane chip is intended. The extension of the simulation to include electronics enables the performance assessment of different types of read-out circuits, position-sensitive detectors and imaging arrays prior to their manufacturing. It is important to observe that the RMS reconstruction error increases considerably when the electronic modules are taken into account, affecting the signals that are used by the reconstruction algorithm. The second important observation is that, even when the electronic modules are employed, it is possible to reduce the reconstruction error by properly designing the position-sensitive detector, being in this case a quad-cell with a double efficiency concentric structure (QCD). In addition, combining reliable integrated circuit simulation or that of discrete electronic components, to existing and more ample adaptive optics simulation platforms will not only contribute to enhancing the reconstruction fidelity featured by wavefront sensors, but also to the assessment of the complete adaptive optics system.


Human walking is usually conceived as the cyclic rotation of the limbs. The goal of lower-limb movements, however, is the forward translation of the body system, which can be mechanically represented by its center of mass (CoM). Lower limbs act as struts of an inverted pendulum, allowing minimization of muscle work, from infancy to old age. The plantar flexors of the trailing limbs have been identified as the main engines of CoM propulsion. Motion of the CoM can be investigated through refined techniques, but research has been focused on the fields of human and animal physiology rather than clinical medicine. Alterations in CoM motion could reveal motor impairments that are not detectable by clinical observation. The study of the three-dimensional trajectory of the CoM motion represents a clinical frontier. After adjusting for displacement due to the average forward speed, the trajectory assumes a figure-eight shape (dubbed the “bow-tie”) with a perimeter about 18 cm long. Its lateral size decreases with walking velocity, thus ensuring dynamic stability. Lateral redirection appears as a critical phase of the step, requiring precise muscle sequencing. The shape and size of the “bow-tie” as functions of dynamically equivalent velocities do not change from child to adulthood, despite anatomical growth. The trajectory of the CoM thus appears to be a promising summary index of both balance and the neural maturation of walking. In asymmetric gaits, the affected lower limb avoids muscle work by pivoting almost passively, but extra work is required from the unaffected side during the next step, in order to keep the body system in motion. Generally, the average work to transport the CoM across a stride remains normal. In more demanding conditions, such as walking faster or uphill, the affected limb can actually provide more work; however, the unaffected limb also provides more work and asymmetry between the steps persists. This learned or acquired asymmetry is a formerly unsuspected challenge to rehabilitation attempts to restore symmetry. Techniques of selective loading of the affected side, which include constraining the motion of the unaffected limb or forcing the use of the affected limb on split-belt treadmills which impose a different velocity and power to either limb, are now under scrutiny. A huge amount of research, a true odyssey , has beeThe body system as a whole may be represented, from a mechanical standpoint, by its CoM. The CoM of a distribution of mass is the unique point in space whose linear acceleration is determined only by the total external force acting on the system, without effects due to internal forces . When apTwo distinct viewpoints still characterize the study of human legged animals' walking .The earlier, yet still dominant, viewpoint considers walking to be a series of cyclic rotations of the limbs and trunk, referred to as the “segmental” approach or viewpoint from here on. To illustrate this concept, one can imagine a man walking on a treadmill; the cyclic nature of the joint rotations is apparent. The beginning of the cycle is a matter of convention; usually, but not exclusively, this is considered as the instant of heel strike. The series of events that takes place between subsequent heel strikes of opposite sides of the body is called a step. Two subsequent steps make a stride.The less widely accepted viewpoint highlights that walking has the primary goal of achieving forward translation of the body system as a whole (locomotion), although this results from the interplay between gravity and the coordinated and cyclic contraction of numerous muscles. In this view, the body system as a whole can be represented by its CoM. This will be referred to as the “system” viewpoint or approach from here on.The umbrella term “gait analysis” describes the synchronous recording of many segmental variables, which has become accessible to clinical settings in recent decades, due to the rapid progression of technology . HoweveAnthropometric studies have demonstrated that the CoM of quietly standing humans lies approximately a few centimeters in front of the lumbosacral joint, about 57% of the body height from the feet plants, in both children and adults . SophistHow to measure the motion parameters of the invisible CoM during walking has been a challenge for generations of researchers. A first approximation was reducing the body motion to the visible motion of the sacrum. This approximation is rather rough. In fact, the movement of the CoM is affected by the movement of individual body segments, while the sacral markers are not . HoweverA famous clinical article has suggested that smoothing the CoM oscillations is the aim of some of the segmental motions of the lower limbs, such as pelvic tilt and knee flexion, named the six “major determinants” of gait  Figure .The authors suggested that these six determinants deserved special attention in clinical observation. Unfortunately, measuring energy changes and displacements of the human CoM proved to be considerably more challenging than intuitively capturing the pendulum analogy.Nowadays, numerous and valid methods exist to observe and measure the CoM motion. In this review, articles based on the “sacral marker” simplification will be overlooked. Articles will be considered, based on the analysis of ground reaction forces  or on kinematic analysis of body segments  as per anthropometric modeling. Both methods provide reliable and very similar results with respect to the CoM motion. The corresponding technicalities and criticisms are summarized in the following paragraphs and in The 3D trajectory of the CoM is among the most recent outcomes of an old line of research. The only abstraction required to the clinician is subtracting the average forward velocity of the body: stated otherwise, one can imagine observing a subject walking on a treadmill, with zero average velocity with respect to the ground. The subject's trunk will show rhythmic back-forth, and left-right oscillations, with no average forward displacement. This approach, adopted here, will not require delving into the underlying principles of physics and engineering. Also, it might better fit the clinical assessment, still based mostly on visual observation of gait impairments.Figure 3).The pendulum-like CoM motion was usually analyzed in the sagittal plane although, in principle, the same technology could well be applied to the frontal and horizontal planes. On the other hand, most of the work to move the body system and its segments, and its largest displacements, can be observed in the sagittal plane  so that A systematic study of the 3D path of the CoM in healthy adults at various walking velocities, based on the double-integration method  as a function of the distance (arc-length) covered during one stride  shows evident peaks. The larger peak occurs during the single-stance period  as would be expected), the larger bc curvature peak is synchronous with a narrow peak of negative external power . In other words, the lateral oscillation of the CoM during the single-stance period requires active braking, followed by active propulsion . These events allow the CoM to be actively redirected toward the opposite side. It is known that lateral-externally oriented ground reaction forces occur throughout the entire double-stance and early single-stance periods but not during late stance  is defined as the minimum difference between the perimeter of the base of support and XCoM. In adult walking, the lateral MoS is much lower than would be predicted by considering the CoM alone  (where . 50 mm) . Computi. 50 mm) , 34–40. The potential clinical usefulness of the XCoM analysis, capturing the balance variable during walking, cannot be underestimated. Not surprisingly, technical efforts are ongoing to simplify its estimation during walking, e.g., through a limited set of optical markers  or even A recent study aimed to relate the CoM path to age in children (5–13 years old) and adults (23–48 years old) using metric distances normalized to subjects' height. Walking velocity was also normalized to height through the Froude number . Both thkf), to be transformed into the sum (Ev) of gravitational potential energy (Ep) and kinetic energy due to the upward velocity (Ekv). The changes of kinetic energy due to the lateral motion (Ekl) are much smaller than those observed in the sagittal and vertical directions. In an ideal pendulum the friction forces of the air and at the hinge are neglected, the time course of Ekf is the mirror image of the time course of Ev, and the sum of these energies, Etot, remains constant; the oscillation would be perpetual and no work would be necessary to keep it in motion with respect to the ground   of Wext. R can peak at 100% (no muscle work required) and reach 60% as a mean along a step, at “optimal” velocities around 1.3 m s−1. Increments of Etot, necessarily sustained by muscles, occur around the double stance (increment a) and during the single stance (increment b)  . Of courext, and to maximize R  and Rinst  occur and when the CoM is lifted (increment b). Both phase shift and size differences between its components may lead to increments of Etot. In general increment a is due to the fact that Ekf increases more than Ev decreases, while the opposite is true for increment b  and of muscle recruitment appears highly relevant. The sequence of activation of lower-limb muscles can be recorded using surface electromyography or fine-wire implanted electrodes ..tot . In. Intot, locities ; corresplocities  66)..tot, whiRecent research confirmed that the plantar flexors provide the highest power output during walking compared with other extensor muscles that act at the knee and hip , 67. Thiint. Given the methods that were used, these segmental interpretations did not consider the systemic role of the plantar flexors; however, they are compatible with a systemic interpretation. For instance, the braking action of the stretched plantar flexors during active lengthening cannot be ignored, yet it can be interpreted simultaneously with a mechanism that facilitates the remarkable production of positive ankle power during the successive shortening . These studies show that appropriate modeling of positive work  at lower-limb joints, considering both their rotational and translational energies, can explain the increments of Etot along a stride  to increment b. This is confirmed by the increased power production during ankle plantar flexion compared with other sagittal joint rotations  of the 3D path (the “bow-tie”) of the CoM. Timing of joint power and electromyographic patterns of the lower limb muscles also seem independent of age .−1 elderly subjects were unable to simultaneously increase the velocity of the CoM forward and upward. Once the lower velocity and lower step length were taken into account, the lower-limb joint dynamics and estimated roles of individual muscles in propulsion of the CoM were found to be superimposable between young (24 years old on average) and elderly (74 years old on average) subjects  tend to adopt a lower average velocity and, for any given velocity, a shorter step length, compared to their adult counterpart. These features appear to compensate for weakness, in particular, of the plantar flexors, and for subclinical balance impairment. A recent study confirmed the existence of age-related differences in terms of propulsion from the trailing leg  by compasubjects . More resubjects . The prosubjects . As a cosubjects  may prevsubjects .In summary, once the inverted pendulum mechanism is established, the role of individual muscles in CoM motion seems to remain largely unchanged from infancy to old age although the plantar flexors seem to become less dominant compared to the proximal muscles at advanced age. The main adaptations of walking to body size and shape, muscle strength and joint mobility are related to velocity and the step length that is adopted and attainable .Human walking impairments are varied but, for simplicity, here they can be divided into symmetric and asymmetric forms, depending on the mechanical events observed during each of the two steps within a stride. A key concept, nearly a paradox, emerging from the Literature is that walking impairments may be associated with an overall normal total energy expenditure per unit distance, which in turn reflects a normal efficiency of the pendulum-like mechanism as an average between subsequent steps. Evidence is provided in the following paragraphs and is further discussed in ext,m and/or a normal 3D path of the CoM (see below) can be observed in symmetric impairments. This has been found to be the case in scoliosis , al, al91), ext and R between the subsequent steps is generated. As a third unexpected finding, there is a tendency for external work and power asymmetries to compensate between the two subsequent steps, with the result that means along the whole stride and hence, per unit distance, can remain normal. This raises a critical challenge to rehabilitation aiming at restoring symmetry, as will be clarified later on.This agreement between segmental and systemic dynamic asymmetries is expected. However, from analyzing the results in the literature, at least three unexpected findings could be identified. The first is that the effects of most asymmetric diseases on the mechanics of the CoM may be surprisingly similar. The second is that when kinematic effects are minor, the asymmetries of the CoM motion may be large nonetheless. For instance, both in post-stroke , 93 and ext,m is only mildly increased (step is about 30% lower) in children with cerebral palsy compared with their healthy counterparts. However, it must be noted that patients with cerebral palsy walked more slowly and with a higher step frequency, making it difficult to assess the isolated effect of spasticity. A normal Wext, step is obtained through a higher Rstep in adolescents with mild obesity and Prader-Willi syndrome, as demonstrated by comparison of the Froude-normalized walking velocities of patients and controls  syndrome seen in various unilateral impairments, spanning from hemiparesis to cerebellar ataxia, to poliomyelitis, peripheral neuropathies, and myopathies.  of the impaired lower limb in the case of asymmetric walking has a deeply studied precedent in strabismus. A child that squints will commit visual acuity to the unaffected eye. Amblyopia will be much more likely than realignment. On the other hand, monocular vision will be more effective, from a behavioral standpoint, than diplopia. The analogy with the non-use observed in case of upper or lower limb impairments is quite strong . MaintaiIn split-belt walking, the subject walks on a force treadmill constructed with two parallel independent belts that can rotate at different velocities, hence the terms split- or dual-belt treadmill. Velocity ratios between the belts range from 1.5 to 4, depending on the study. Splitting causes a sudden escape limp in healthy subjects; within a few strides, the stance time and the “anterior” step length are reduced on the faster belt. The split-belt paradigm was introduced in a study on the capacities for early adaptation of the (supposed) spinal circuitries which underlie human walking . More reThe literature on split-belt walking as a rehabilitation treatment is increasing rapidly, despite the fact that some basic issues remain controversial. Initial studies were based only on kinematic observations. The analogy between experimental claudication in healthy subjects and true pathological claudication during ground walking is only valid for the stance duration, which is shorter for the faster leg of healthy subjects on the treadmill and for the paretic leg of patients during ground walking. This analogy is not valid for step length see . Differeext and/or of the plantar flexors' power and how these are achieved. Unfortunately, the time courses of Etot and R during split gait have not yet been described.Additional insight may come by raising the question: does increased symmetry of the power of the plantar flexors translate into a more symmetric translation of the body system as a whole ? Despite the recent shift of interest from purely kinematic to dynamic analyses at the level of the lower limb, energy changes of the CoM during split-belt walking have not been directly addressed to date. Evaluation of this factor might clarify whether the primary aim of late adaptation is the minimization of WThere is only one report that describes an experiment in which the subject is given visual feedback of the oscillations of the CoM in the frontal plane during treadmill walking . This waGait analysis is still striving to become a routine method of assessment of walking impairments. This goal is far from being achieved despite continuous educational efforts by dedicated scientific societies .The main obstacles to clinical applications of gait analysis, in the authors' opinions, are neither the cost nor the technical skills required. Many other diagnostic technologies common in medicine are complicated and expensive . The key point is that, in most clinical conditions, gait analysis seems to add little to a skilled visual assessment, with respect to conventional clinical decision making . By greaa priori hypotheses should be conceived, focused questions should be raised, and the analysis should be run according to a confirmatory  logic, as one would for any diagnostic procedure. Unfortunately, walking in general and the CoM motion in particular are rarely considered as specific, trans-disciplinary chapters of medical education. By contrast, understanding the CoM motion might help to interpret the focal alterations. First, the CoM cannot be directly observed, but signs of alterations of its path can be visually detected  may be rewarded by a more efficient pendulum mechanism. In asymmetric gaits the CoM perspective is particularly enlightening. On one hand, it seems clear that any attempt to restore symmetry by treating the affected side will be at high risk for failure, as the successful adaptation of CoM motion will be jeopardized. On the other hand, asymmetry leads to troubles in the long run, so that treatments that aim to rebalance the work between the affected and unaffected lower limbs are justified. These treatments need a conceptual advance in rehabilitation medicine and should be driven by monitoring the effects on CoM motion. The idea of forced-use through spilt-belt treadmills looks a promising paradigm of a system-and-segments approach for the diagnosis and treatment of asymmetric walking impairments. Other approaches that directly target the CoM, cited above, might be effective as well. As a final speculation, going perhaps beyond the scope of the present review, the potential role of non-invasive electric or magnetic brain stimulation can be alluded to. A variant (and perhaps one of the neurophysiologic bases) of the “acquired non-use” model is represented by the model of interhemispheric inhibition. Evidence is growing that the preference for an asymmetric locomotion is reflected by the asymmetry in excitability between the two hemispheric motor cortices, both in orthopedic and neurological impairments , 130. NoLT and VR discussed and contributed to writing the article. LT designed and wrote the content of the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


However, the definition and annotation of miRNAs have been changed significantly across different versions of miRBase. The changes cause inconsistency in miRNA related data between different databases and articles published at different times. Several tools have been developed for different purposes of querying and converting the information of miRNAs between different miRBase versions, but none of them individually can provide the comprehensive information about miRNAs in miRBase and users will need to use a number of different tools in their analyses.miRBaseConverter, an R package integrating the latest miRBase version 22 available in Bioconductor to provide a suite of functions for converting and retrieving miRNA name (ID), accession, sequence, species, version and family information in different versions of miRBase. The package is implemented in R and available under the GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/miRBaseConverter/). A Shiny-based GUI suitable for non-R users is also available as a standalone application from the package and also as a web application at http://nugget.unisa.edu.au:3838/miRBaseConverter. miRBaseConverter has a built-in database for querying miRNA information in all species and for both pre-mature and mature miRNAs defined by miRBase. In addition, it is the first tool for batch querying the miRNA family information. The package aims to provide a comprehensive and easy-to-use tool for miRNA research community where researchers often utilize published miRNA data from different sources.We introduce miRBaseConverter and the Shiny-based web application are presented to provide a suite of functions for converting and retrieving miRNA name, accession, sequence, species, version and family information in different versions of miRBase. The package will serve a wide range of applications in miRNA research and could provide a full view of the miRNAs of interest.The Bioconductor package The online version of this article (10.1186/s12859-018-2531-5) contains supplementary material, which is available to authorized users. In the following, we introduce the built-in database and the main functions of miRBaseConverter in detail.miRBaseConverter to include the miRNA information from miRBase version 6 to version 22 (the latest version). The miRNA names, accessions, sequences, families, species and other information in the different versions of miRBase are organized and stored in an index structure. Each of the same types of miRNA data  is summarised together and each entry is assigned a unique index. Then the mapping tables between different data types are generated based on the indexes of entries. The stored information in the database can be greatly reduced by only keeping one copy of the same information in different versions of miRBase. Finally, the database is compressed to have a very small size (We have constructed a built-in database for miRBaseConverter can be applied to fast check the miRNA status (Alive or Dead), the most probable miRBase version number, and the family information of a list of miRNAs. Due to the limitations at the time when a miRBase version was created, there were some misannotated and duplicated sequences included in different versions of miRBase. These misdefined miRNAs were always killed in the following updated miRBase versions. However, some databases or research works may still include the results related to these misdefined miRNAs. There is a demand for addressing this issue to rapidly screen dead miRNAs. The version number for a list of miRNAs is the valuable knowledge for downstream analysis. miRBaseConverter provides the function to check the most probable miRBase version for the input miRNA list and gives the matched proportions in all miRBase versions. Meanwhile, miRBaseConverter is the first tool for batch querying miRNA family information, which is important for functional enrichment research of miRNAs. The defined functions in miRBaseConverter for miRNA check are checkMiRNAAlive, checkMiRNAVersion and checkMiRNAFamily.miRBaseConverter provides five kinds of miRNA conversion functions for all species: miRNA name to accession, accession to name, name to name in different versions, precursor name to mature name and mature name to precursor name. The corresponding functions are miRNA_NameToAccession, miRNA_AccessionToName, miRNAVersionConvert, miRNA_PrecursorToMature and miRNA_MatureToPrecursor. The fast batch conversion between miRNA name and accession is the basic need for miRNA research. An accession is the unique and fixed identifier assigned to a sequence record of a miRNA and therefore miRNA accessions are adopted in most miRNA-related databases. However, miRNA names have better readability than accessions for researchers in most cases. Meanwhile, there is a great demand for the conversion of miRNA names in different versions. For example, Tarbase v7 [miRBaseConverter offers a wide range of conversion tools. A number of examples illustrating the conversions are provided in the manual of the package.rbase v7  and miRTrbase v7  use miRBgetAllMiRNAs, getAllSpecies, getAllVersionInfo, getMiRNAHistory, getMiRNASequence, and getMiRNATable. By calling the functions implemented in miRBaseConverter to retrieve the information of a miRNA or a list of miRNAs, it is easy to get the particularly detailed knowledge of the miRNAs of interests.We implement functions for the retrieval of all kinds of miRNA information, including the basic statistical information of all miRBase versions, the species information involved in all miRBase versions, the detailed history information of a miRNA in all miRBase versions, the family information of miRNAs, the sequence information of miRNAs and the complete data table of all miRNAs in a specified miRBase version. The defined functions for miRNA information retrieval are miRBaseConverter provides two functions goTo_miRBase and goTo_miRNAFamily to redirect users to miRBase web server for retrieving more detailed information (miRNA webpages and miRNA family webpages) of miRNAs. The operation of miRNA online information retrieval gives a comprehensive perspective of the miRNAs of interest and greatly helps with understanding the miRNAs.miRBaseConverter package implemented in R is designed for the miRNA research community to assist with converting and retrieving miRNA information in different versions of miRBase. miRBaseConverter provides a suite of functions for querying miRNA name, accession, sequence, species, version and family information. The package is released under under the General Public License (GPLv2) and freely available from Bioconductor (3.5) repository [miRBaseConverter, the shiny-based web application and two typical case studies to demonstrate the applications of miRBaseConverter with different purposes. The relevant datasets for the case studies are provided as supplementary data and available at https://taoshengxu.github.io/ExperimentData/miRBaseConverter.The pository . In addimiRBaseConverter provides a detailed document to illustrate how to use each of the functions of the package, which can be accessed in the Bioconductor repository. Here we demonstrate a use case of the miRBaseConverter R package for the version upgrade of a list of miRNAs. The original miRBase version of the candidate miRNAs is always missing or is not provided in most actual cases. The function checkMiRNAVersion can be applied firstly to check the most probable miRBase version number for the list of miRNAs. Then we use the miRNA accession (as the transforming bridge) to exactly match each of the miRNAs which might have been defined in different miRBase versions. The following are the code chunks and the output for converting a list of miRNAs to the latest miRBase version 22. The detailed user manual can be accessed via Bioconductor website .The user manual of miRBaseConverter can successfully process the input precursor and mature miRNAs from different species at the same time. For example, the precursor miRNA is hsa-mir-103-1-as in miRBase version 16 converted to hsa-mir-103b-1 in miRBase version 22, and the mature miRNA mmu-miR-1274a in miRBase version 16 is removed in miRBase version 22. More examples for miRNA information retrieval and version conversion is presented in the vignette of miRBaseConverter, which is available in Additional file The above example shows that miRBaseConverter package which runs in web browsers. The GUI adopts a left-right structure with a concise performance as shown in Fig. We have designed a web application with a GUI to provide non-R users a convenient way to retrieve and convert miRNA information in different versions of miRBase without depending on R runtime environment. The Shiny-based web application provides a shell for the miRBaseConverter R package. In the third step, a additional parameter which is the target miRBase version is needed for some of the main functions listed in the second step. After finalising all the three steps, the “Run” button is used for submitting the input content to server for result retrieval.There are three main steps for the retrieval of a list of miRNAs as shown in the left pane of the GUI in Fig. miRBaseConverter R package are called when users submit the retrieving or converting request from the web GUI, so the retrieval and conversion via the web application also have the quick response as using miRBaseConverter in the R environment.On the right-hand side of the GUI, there is a result table presenting the retrieval and conversion information of the input miRNA list. The records in the result table strictly correspond to the order of the miRNAs in the input list. The miRNA accessions or family accessions in the result table are implanted hyperlinks to easily redirect users to the miRBase web server for the detailed information about the miRNAs of interest. In addition, the web application provides the function to export the miRNA result table (a.csv file) for further study. The functions in the miRBaseConverter for constructing a gene regulatory network including mRNAs, TFs and miRNAs based on a variety of interaction databases. There are quite a number of experimentally confirmed and putative databases that reveal the regulatory relationships among biological molecules. Information from these databases can be integrated together to form a comprehensive biological regulatory network. However, the miRNA names in different databases are inconsistent as they use different versions of miRBase for the miRNA annotation. Therefore, a unified miRNA annotation is the foundation for constructing the gene regulatory network. miRBaseConverter offers a handy tool in high throughput workflow to unify the miRNA names for various miRNA interaction databases. Here we choose some representative databases used for each type of interactions in our analysis. The detailed information of the interaction databases is summarised in Table In this scenario, we present the use of miRBaseConverter. miRecords is a resource for animal miRNA-target interactions [miRBaseConverter and the org.Hs.eg.db package to retrieve the miRNA accessions and gene Entrez IDs, respectively. TransmiR is a database of TF-miRNA regulations [miRBaseConverter is an appropriate tool for the conversion of miRNA precursor names and mature names. The ENCODE research work [http://encodenets.gersteinlab.org/. Similar to miRecords, we apply miRBaseConverter and the org.Hs.eg.db package to retrieve the miRNA accessions and Entrez IDs for the interaction data, respectively. We get the information in Transcriptional Regulatory Element Database (TRED) [https://github.com/slowkow/tftargets).miRTarbase is an experimentally validated and widely used miRNA-target interaction database. miRTarbase v7 collects 502652 records of human miRNA-mRNA interaction pairs, where miRNA names and the gene symbol and Entrez ID information of the target mRNAs are provided . But it ractions . We use ulations . The TF rch work  providese (TRED)  and ENCOmiRNA_NameToAccession in miRBaseConverter. Before the conversion, we apply the checkMiRNAVersion function to have a double-check on the miRBase version of the miRNA name list to be processed. Then the functions miRNA_NameToAccession and miRNA_AccessionToName are used for converting the miRNAs involved in miRecords v4 (miRBase v16) to the names and accessions in miRBase v21. For the miRNAs in other databases, we process them in the similar way to have a consistent miRBase version for downstream integration analysis.Due to the fact that miRTarbase v7 adopted the relatively new miRBase version (v21) than the other miRNA-related databases, we unify the miRNAs in all the miRNA interaction databases to miRBase v21. Firstly, the large number of miRNA names in miRTarbase v7 can be converted to the corresponding miRNA accessions using the function miRBaseConverter and other gene annotation R packages, all the miRNAs and genes involved in the interaction databases have been adopted their own unified annotation, respectively. Therefore, the regulatory interactions from all the databases are combined together to form a two-column data table representing the complex gene regulatory network. The two-column data table structure is the most common representation of a gene regulatory network. A directed graph can be generated to visualize the gene regulatory network. The nodes are the biological features  and the edges are the regulatory interactions between the features. For illustration, in Fig. By applying checkMiRNAVersion in miRBaseConverter to cope with the miRNA name conversion for miRNA expression dataset in TCGA and unify the miRNA version of TargetScan 7.0 and miRTarBase v7 to miRBase v21.In this scenario, we would like to predict miRNA targets in Breast cancer with a computational method, e.g. Pearson correlation using expression data from TCGA BRCA together with the target binding information from TargetScan. We then use miRTarBase v7 to validate the predictions of miRNA targets. The obstacle is the inconsistent annotations of miRNAs from different sources. The annotations of miRNAs in TCGA miRNA illumina Hiseq platform are precursors, and the annotations of miRNAs in TargetScan 7.0 and miRTarBase v7 come from different miRBase versions. We apply the miRBaseConverter to check the miRBase version number and convert precursor names to the corresponding mature names. The miRNA annotations of TargetScan 7.0 and miRTarBase v7 are based on miRBase version 17 and version 21, respectively. Here we apply miRBaseConverter to transform the all miRNA names to the names used in the latest miRBase version 22. So all the experiments data are consistent with the same miRBase version.The Level 3 TCGA BRCA RNASeqv2 and miRNAHiseq data are downloaded from the Broad GDAC Firehose using TCGA Assembler . We extrmiRLAB package to predict the targets of a miRNA base on expression data. The miRLAB package provides a complete set of pipelines for predicting miRNA-mRNA regulatory relationships using expression data [hsa-miR-224-5p predicted by the Pearson correlation method. There are 8 predicted miRNA-mRNAs interactions confirmed in miRTarbase v7, as shown in Table For demonstration, we apply the method of Pearson Correlation implemented in the ion data . To evalhsa-miR-224-5p and some of its confirmed target mRNAs are positive or near zero, while the common knowledge is that miRNAs down-regulate their target mRNAs and hence negative correlation should be expected. The results suggest that the predicted targets by Pearson correlation may include false discoveries. On the other hand, due to the incompleteness of miRTarbase v7, some targets predicted by the Pearson correlation method (the ones with negative correlation coefficients) are not validated by miRTarBase v7. Therefore, follow-up analyses and/or experiments should be conducted. miRNA regulates gene expression by binding to the target mRNAs. Therefore, the miRNA sequence information is very important for predicting target mRNAs by studying the presence of mRNA conserved sites that match the seed region of each miRNA. In the case that one would like to see the sequence of miRNAs and check with the sequence of predicted mRNAs, the user can simply use the function getMiRNASequence in miRBaseConverter for obtaining the multiple sequence of the interest miRNAs. We provide the complete processing scripts in online supplementary data.Based on the validation result, the correlation between miRBaseConverter R package which has been released in the Bioconductor repository. A Shiny-based web application of miRBaseConverter has also been presented in the paper for non-R users. The Bioconductor package and the Shiny-based web application provide a suite of functions for converting and retrieving miRNA name, accession, sequence, species, version and family information in different miRBase versions. To our knowledge, there was previously no available tool that could conduct the batch retrieval of miRNA family information, thus representing a challenge in the miRNA-related research. miRBaseConverter is a full-scale tool for converting and retrieving information of all miRNAs defined in miRBase. We also have demonstrated the use of the main functions using examples and some case studies. We believe that the package will serve a wide range of applications in miRNA research and provide a full view of the miRNAs of interest.In this paper, we have presented the framework and the usages of the Project name: miRBaseConverterProject home page:http://bioconductor.org/packages/miRBaseConverter/Operating system(s): Platform independentProgramming language: ROther requirements: R (>= 3.4)License: GNU GPL-2Any restrictions to use by non-academics: noneAdditional file 1The vignette of miRBaseConverter. (PDF 150 kb)


The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. Its 18,000 members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine. In addition to publishing journals, newsletters, and books, the SNMMI also sponsors international meetings and workshops designed to increase the competencies of nuclear medicine practitioners and to promote new advances in the science of nuclear medicine. The European Association of Nuclear Medicine (EANM) equally is an international scientific and professional organization promoting the nuclear medicine with about 3,500 members specializing in the research and practice of nuclear medicine. The EANM was founded in 1987.The SNMMI/EANM will periodically define new procedural recommendations for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients. Existing practice guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated.Each procedural recommendation, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI/EANM recognizes that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills, and techniques, as described in each document.These procedural recommendations are an educational tool designed to assist practitioners in providing appropriate care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI and the EANM caution against the use of these procedural recommendations in litigation in which the clinical decisions of a practitioner are called into question.The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician in light of all the circumstances presented. Thus, an approach that differs from the procedural recommendations, standing alone, does not necessarily imply that the approach was below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the procedural recommendations when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the procedural recommendations.The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognized that adherence to these procedural recommendations will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these procedural recommendations is to assist practitioners in achieving this objective.With the increasing use of sonography, dilatation of the pelvicalyceal system  or ureter  is the most common abnormality of the urinary tract detected in utero or after birth. Common causes of congenital HN and HUN include vesicoureteric reflux (VUR), ureteropelvic junction (UPJ) stenosis, ureterovesical junction (UVJ) stenosis, posterior urethral valve (PUV), ectopic ureter with or without duplication, ectopic ureterocele, and primary nonobstructive dilatation. Some of the affected children present with urinary tract infection or an abdominal mass, but most of them remain asymptomatic for a long time. The natural course of HN/HUN in infants and children is variable. In some patients, HN/HUN improves or resolves completely, but in others, it remains stable or gradually gets worse and, depending on the underlying cause and without timely surgical intervention, may result in silent loss of renal function or recurrent episodes of abdominal/flank pain. Therefore, the aim for imaging evaluation of these infants and children should be to identify the kidneys that are at risk for loss of function and prevent loss of function by timely surgical intervention.Conventional dynamic renal scintigraphy provides information about the function of the affected kidney and supplements the ultrasound findings. Diuresis renography is a safe and widely available provocative test that, in addition to evaluating the renal function, allows evaluation of the extent and pattern of clearance of the radiopharmaceutical from the dilated urinary tract under high diuresis ,2. The rThe purpose of this guideline is to assist nuclear medicine practitioners in performing, interpreting, and reporting the results of diuresis renography in a manner that is effective in the detection of the kidneys at risk for loss of function and helps the referring physician in the patient’s management.Hydronephrosis (HN) and hydroureteronephrosis (HUN): These terms denote dilatation of the pelvicaliceal system or pelvicalyceal system and ureter, respectively, that may or may not be due to obstruction.Ureteropelvic junction (UPJ) obstruction: Usually refers to partial obstruction at the uretero-pelvic junction due to intrinsic narrowing or extrinsic compression by a crossing vessel. Complete obstruction of the proximal ureter during fetal development leads to nonfunctional kidney.Ureterovesical junction (UVJ) obstruction: Usually refers to partial obstruction and is due to narrowing of the distal ureter, duplication with ectopic ureterocele, or ectopic insertion of the ureter.Acute UPJ obstruction: This condition usually occurs in older children, manifested by sudden onset of severe flank/abdominal pain associated with nausea/vomiting (Dietl’s crisis). These episodes are often recurrent and are usually due to intermittent obstruction without urinary calculi. Nephrolithiasis is uncommon in children, but it may cause acute urinary tract obstruction (UPJ or UVJ). Acute UPJ obstruction occasionally occurs during diuresis renography.F-0 protocol: A diuresis renography technique with simultaneous administration of furosemide and radiopharmaceutical.F+(20 or 30) protocol: Diuresis renography techniques with administration of furosemide 20 or 30 min after administration of radiopharmaceutical.Initial evaluation of renal function and drainage in asymptomatic infants and children with sonographic diagnosis of HN/HUN and voiding cystourethrography demonstrating either no evidence of VUR or findings suggestive of coexistent reflux and UPJ obstruction.Serial follow-up examinations in patients with an inconclusive initial study to detect changes in the renal function or progressive worsening of postdiuresis drainage in an attempt to detect the kidneys at risk for loss of function.Older children with recurrent abdominal pain and HN to diagnose intermittent UPJ obstruction as the cause of the symptoms. Diuresis renography in these patients would be most informative if it is done during or within 24 h after an episode of pain .Evaluation of renal function and postdiuresis drainage after surgical interventions.In the United States, see Section V of the SNMMI Guideline for General Imaging. In Europe, the certified nuclear medicine physicians who perform the study and sign the report are responsible for the procedure, according to national laws and rules.Parent information  The parents should be given detailed information about the examination at the time of scheduling. Preparation before arrival in the department is usually not necessary if the procedure protocol includes routine administration of intravenous hydration. Otherwise, oral hydration before arrival and while in the department should be encouraged. Fasting is unnecessary and should be avoided. In rare cases, when the study will be done under sedation, the guidelines of the institution must be followed and the patient must be hydrated during examination by intravenous administration of fluid (see below).Before the examination  The supervising nuclear medicine physician should review all available clinical, laboratory, and imaging data. In particular, knowledge of relevant urologic procedures and surgeries such as presence of nephrostomy tube, ureteral stent, and urinary diversion is essential in the technical planning of the test and interpretation of the results. The nephrostomy tube should be clamped before examination.Patient education  The procedure should be explained to the parents and children old enough to understand. The parents should be encouraged to stay with the child throughout the examination.Anesthetic cream  Application of an anesthetic cream or spray on the potential venous access site(s) is advised.Intravenous access  With the F-0 technique, the tracer and furosemide can be injected through a butterfly needle of appropriate size. With the F+(20 or 30 min) technique, however, it is necessary to establish a secure intravenous access using an intracath to be used for initial injection of the tracer and subsequent injection of furosemide in a timely fashion (see D-5), as well as infusion of intravenous fluid per protocol.Hydration  Adequate hydration before or during examination is essential to achieve optimal postfurosemide diuresis and prevent dehydration. This is particularly important in infants and young children. Intravenous hydration with 5% dextrose in 0.33 normal saline or any other solution per the institution’s policy is essential in patients who cannot or will not comply with oral intake of fluids. The suggested volume of intravenous fluid is 15–20 mL/kg (about two thirds of it should be given before furosemide injection). However, many children can achieve adequate hydration by age-appropriate oral intake of fluids  when clear instructions are presented to them (or to their caregivers) and when compliance with these instructions can be monitored.Eliminating/minimizing potential effects of a full bladder  A full bladder may result in significant increase in intravesical pressure and cause delayed drainage from the renal pelvis. In toilet-trained children, a full bladder may also cause premature interruption of the study due to the need of the patient to void. Therefore, it is important to eliminate or minimize overdistention of the bladder during the examination. This could be achieved by insertion of an indwelling bladder catheter allowed to drain freely into a closed collection bag. An additional advantage of continuous drainage of the radioactive urine from the bladder is significant reduction in gonadal radiation dose. However, catheterization, for the child, is an invasive and unpleasant procedure. Therefore, its routine use is controversial. But it is advised in infants and children with HUN, PUV, known VUR, or neuropathic bladder. In the absence of an indwelling bladder catheter, all toilet-trained patients should be asked to empty their bladder before acquisition of the dynamic images. All boys who are able and willing to void while supine, using a urinal without moving, should be asked to void a few times during the dynamic acquisition of data. All gravity-assisted drainage images should also be obtained after the patient voids (see D-6).99mT-labeled tubular agents, because they are much more efficiently extracted by the kidney than the glomerular agents. This is particularly important in neonates and in children with severely dilated collecting systems or impaired renal function.The preferred radiopharmaceuticals for diuresis renography are 99mTc-MAG3 (tubular secretion)1. 99mTc-mercaptoacetyltriglycine (MAG3) is highly protein-bound and is removed from the plasma primarily by the proximal renal tubules  (see below). A small fraction of the administered activity of 99m Tc-MAG3 is excreted via the hepatobiliary system. Therefore, visualization of the tracer in the gallbladder or small bowel on the delayed images is a normal physiologic finding and should not be mistaken for retention in the right renal pelvis or urine leak.   tubules . The ext99mTc-EC (tubular secretion)2. 99mTc-l,l- and -d,d-ethylenedicysteine (EC) are enantiomers. Both are excellent renal radiopharmaceuticals with clearances slightly higher than 99mTc-MAG3 3. 99mTc-DTPA is purely filtered by the glomeruli  set to produce a pixel size of less than 4 mm should be used. γ-camera quality control should follow national rules or manufacturer’s instructions. For further guidance on routine quality control procedures for γ-cameras, refer to the SNMMI Guideline for General Imaging and the EANM guideline on routine quality control for nuclear medicine instrumentation.Patient position The images are acquired with the patient supine on the imaging table.Camera position The camera is usually under the table for acquisition of dynamic and static posterior images of normally positioned kidneys. If the affected kidney is a horseshoe variant or in an ectopic location, the posterior images alone would not be adequate for accurate calculation of the differential renal function (DRF). In this situation, if it is feasible, the initial images should be acquired with a dual-detector camera for geometric mean calculation of the DRF, but posterior images are adequate for evaluation of the postdiuresis drainage. The images for evaluation of HN in transplanted kidneys must be acquired anteriorly.Administered activity All administered activities in children should be scaled down according to the tables provided by either the EANM or the SNMMI  are obtained for 20 min  are acquired for 20 or 30 min, followed by intravenous administration of furosemide and acquisition of a second set of dynamic images (10–15 s per image) for 20 or 30 min. However, furosemide should ideally be injected after the entire dilated collecting system is filled with radioactive urine and there is adequate residual tracer activity for a meaningful evaluation of postdiuresis drainage parameters. Therefore, in the following situations it may be necessary to modify the timing of furosemide administration:Gravity-assisted and postvoid drainagea. Static 1-min posterior images are obtained before and after the patient is kept upright for a standardized period of time .b. Static 1-min image is obtained at a standardized time period (60 min or longer) after the radiopharmaceutical injection. Regardless of the protocol used, the quality of drainage must be assessed both visually and semiquantitatively at the end of the postfurosemide dynamic imaging because drainage could be affected by the supine position of the patient and, in the absence of indwelling bladder catheter, by varying degrees of bladder filling. Therefore, if drainage at the end of dynamic imaging is insufficient , it must be reassessed after the patient is kept upright for a standardized period of time and, in the absence of indwelling bladder catheter, after he/she empties his/her bladder . The folCalculation of DRF  Calculation of the DRF should be based on the summed image with the maximum accumulation of the radiopharmaceutical in the parenchyma and no radiopharmaceutical in the pelvicalyceal system, usually the second minute 60–120 s) images. The renal region of interest (ROI) should include only the entire functioning renal tissue. The preferred ROI for background subtraction is, around and slightly separated from the renal ROI, excluding the hilum of the kidney. This C-shaped ROI appropriately includes the contributing counts from the liver and spleen blood-pool activity. Background-subtracted counts in each kidney are used for calculation of the DRF by using the integral method (area under the curve) or the Rutland-Patlak plot 0 s image.Calculation of drainage parameters Motion correction. The dynamic images must be displayed in a cinematic form to detect and correct for patient movement during the acquisition time. The ROI for generation of the postdiuresis time–activity curve must include the entire dilated system. In the case of HN, it should include the entire dilated pelvicalyceal system. But if the ureter is also dilated, it must be included in the ROI (single ROI). However, in a small percentage of cases of HUN, the level of obstruction, if any, may not be clear. For example, if the pelvicalyceal system is disproportionately more dilated than the ureter, it is important to exclude UPJ obstruction by adding a separate ROI for the pelvicalyceal system (double ROIs) or even a third ROI for dilated ureter (triple ROIs). The images with maximal dilatation of the collecting system must be chosen for drawing the ROI for generation of the postdiuresis time–activity curve. After injection of furosemide, the dilated renal pelvis may gradually become more dilated and if the early postfurosemide images are chosen for drawing the ROI, the entire dilated pelvis will not be included in the ROI on all images and the resultant time–activity curve would not be true representative of postdiuresis clearance of the tracer from the dilated pelvis.a. Generation of time–activity curves. Postfurosemide dynamic images are used for evaluation of the pattern and speed of clearance of the radiotracer from the dilated pelvicalyceal system and ureter. Attention must be paid to the following crucial points in the processing of the postdiuresis data and generation of the time–activity curves: Processing of the time–activity curves. Basic semiquantitative indices derived from the postdiuresis drainage time–activity curve, using commercially available softwares, are the washout half-time (T1/2) and the percentage drainage at the end of 20- or 30-min \dynamic acquisition. A more robust measurement of postdiuresis drainage is expressing residual counts in the renal parenchyma and the dilated pelvicalyceal system/ureter over a period of 1 min at the end of dynamic imaging as percentage of the renal counts in the second minute after injection of the radiopharmaceutical  ,17. Gravity-assisted drainage = (counts in the preupright image ROI) minus (counts in the postupright image ROI) divided by (counts in the preupright image ROI). With the technique using a single delayed image (see D-6b), the gravity-assisted/postvoid drainage is assessed either visually or by NORA. Evaluation of gravity-assisted/postvoid drainage. With the technique using static pre- and postupright images obtained shortly after completion of dynamic imaging (see D-6a), the gravity-assisted drainage is simply calculated by using the total counts in the ROIs drawn around the entire dilated system on both images and using the following formula (background activity and decay factor are negligible):The dynamic pre- and postfurosemide images should be reformatted and displayed as 1- or 2-min images for visual evaluation of the kidney morphology, cortical clearance, and postdiuresis drainage as well as associated anomalies such as duplication.The image demonstrating the DRF should include the time–activity curve of dynamic images, the summed image of the kidneys, and the ROIs used for calculation of the DRF.The postdiuresis drainage result should include the summed image, the ROIs, and the drainage time–activity curve. Depending on the protocol used, all semiquantitative indices should be included.The gravity-assisted drainage data should include the pre- and postupright static images with the ROIs and calculated percentage drainage or NORA depending on the acquisition technique.The interpreting physician should carefully review all the images, the shape of the drainage curve (drainage pattern), the quality of cortical clearance of the tracer, and all available semiquantitative indices . The scintigraphic findings and semiquantitative drainage parameters are interrelated, and none of them should be interpreted in isolation. This is particularly true for T1/2. Interpretation of the result must be based on the constellation of the findings and in the clinical context –20.On any single study, diagnosis of high likelihood for critical partial obstruction and eventual loss of function can be made only if there is a flat or rising drainage curve with little or no clearance in the upright position, particularly if there is unilateral delayed cortical clearance of the tracer throughout the study or initial good clearance but with reaccumulation of the tracer in the renal cortex after furosemide administration . OtherwiThe report should include patient demographics, clinical indication for the study, prior surgical interventions, and the pertinent results of other imaging studies. If hydration is administered in the department, its volume and route of administration should be recorded. The volume of total urine output during the examination, if known, should be reported. The presence of a nephrostomy tube with the information about the time interval that it was clamped during the study must be reported. The administered activity and the dosage and timing of furosemide during the procedure must be clearly cited.The size, shape, and position of the kidneys and any focal defect in cortical uptake should be described. Locations of noteworthy tracer retention in parenchyma, calyces, renal pelvis, and ureters on pre- and/or postfurosemide images should be noted.The DRF and all calculated drainage parameters including the basic indices such as T1/2 and the percentage drainage at the end of dynamic imaging as well as any additional quantitative measurements of drainage such as gravity-assisted drainage and NORA should be reported. The shape of the abnormal postfurosemide time–activity curves  should be described.The absence or presence and location of pain during examination must be documented because the presence of diuretic-induced flank pain may increase the likelihood that obstruction is present. Inclusion of an impression/conclusion at the end of the report is recommended.Inclusion of a statement about radiation burden should follow national rules.Quality control issues and potential pitfalls have been reviewed in previous sections.See the SNMMI Guideline for General Imaging.See International Commission on Radiological Protection publications 23, 26, and 38 –24 and a


Monostable vibration can eliminate dynamic bifurcation and improve system stability, which is required in many microelectromechanical systems (MEMS) applications, such as microbeam-based and comb-driven resonators. This article aims to theoretically investigate the monostable vibration in size-effected MEMS via a low dimensional model. An improved single degree of freedom model to describe electrically actuated microbeam-based resonators is obtained by using modified couple stress theory and Nonlinear Galerkin method. Static displacement, pull-in voltage, resonant frequency and especially the monostable dynamic behaviors of the resonators are investigated in detail. Through perturbation analysis, an approximate average equation is derived by the application of the method of Multiple Scales. Theoretical expressions about parameter space and maximum amplitude of monostable vibration are then deduced. Results show that this improved model can describe the static behavior more accurately than that of single degree of freedom model via traditional Galerkin Method. This desired monostable large amplitude vibration is significantly affected by the ratio of the gap width to mircobeam thickness. The optimization design results show that reasonable decrease of this ratio can be beneficial to monostable vibration. All these analytical results are verified by numerical results via Differential Quadrature method, which show excellent agreement with each other. This analysis has the potential of improving dynamic performance in MEMS. Microbeam-based structures are widely applied in MEMS, such as microactuator/sensor ,2,3, eneWith the reduction of the scale of the MEMS, classic continuum mechanics theories are unable to describe the size effects , thus hiStatic/dynamic behaviors of electrically actuated microbeams have been studied a lot by using different models and approaches. These investigations can be divided into two groups. The first group focuses on lumped-mass model and establishes single degree of freedom equation. Then, perturbation method is introduced to study dynamic behaviors of microbeam, which provides theoretical guidance for engineering ,22,23,24The Nonlinear Galerkin method and the well-known Galerkin method can be used to obtain the low dimensional manifold by some projection onto a sub manifold ,36. HoweIt can be concluded from the above analysis that monostable vibration can eliminate dynamic bifurcation, improve system stability and increase the output of energy, which is desired in many MEMS applications. However, to the best of our knowledge, there are fewer effective methods to study monostable large amplitude vibration behaviors via the low dimensional model. This paper aims to obtain an improved single degree of freedom model by using modified couple stress theory and Nonlinear Galerkin method and deduce theoretical expressions about parameter space and maximum amplitude of monostable vibration.The rest of this paper is organized as follows. In Here, we consider a clamped-clamped microbeam-based resonator, as shown in itten as .A and I are the area and moment of inertia of the cross section; d is the gap width; N corresponds to a tensile or compressive axial load, depending on whether it is positive or negative. l is introduced into Equation (1) as the material length scale parameter that has the capability to physically model properties of the couple stress effect. The last term in Equation (1) represents the parallel-plate electric actuation which is composed of DC and AC components. Here, DC voltage can cause a static deflection in the microbeam. There is a limit for the applied DC voltage called the static pull-in voltage [The first term on the right hand of Equation (1) represents the axial force and mid-plane stretching effects. Here,  voltage . AC voltμ is Lame’s constant that is defined by Young’s modulus E and Poisson’s ratio ν asIn the relations above, For convenience, the following non-dimensional variables are introducedSubstituting the non-dimensional variables into Equations (1) and (2), yields the following non-dimensional equation of motion of the micro-resonatorThe parameters appearing in Equation (5) areCompared with the Linear Galerkin method, the Nonlinear Galerkin method can describe the dynamic behaviors of the system more accurately. In this section, we introduce the Nonlinear Galerkin method to deal with Equation (5) and obtain an improved one degree of freedom model .Firstly, considering the Galerkin procedure, we discretize Equation (5) into a finite-degree-of-freedom system consisting of ordinary differential equations. This technique and its application to nonlinear systems were discussed by Abdel-Rahman et al. .i-th linear undamped mode shape of the straight microbeam, normalized such that i-th natural frequency of the microbeam. Equations (9) and (10) represent a boundary-value problem that can be solved by using a combination of Shooting method and a bisection procedure for each pair of mode shape and natural frequency [The solution of Equation (5) can be expressed asrequency .x = 0–1, yieldThen, Equation (5) is multiplied by (1−w)2 , so thatVdc>>Vac , (Vdc+VaEquation (11) represents a discretized system consisting of ordinary-differential equations, which contain all nonlinearities up to fifth order. The above is the Linear Galerkin method for dimensionality reduction. Most researchers utilized the derived reduced-order models to simulate the static behavior and dynamic response of microbeam-based MEMS devices. However, the way is not conducive to theoretical analysis. Here, the Nonlinear Galerkin method is introduced to deal with the above equations.M spatial dimension corresponding with Equation (11).Starting with an abstract setting, a nonlinear dynamical system is separated into the linear and the higher order nonlinear partHere, we assume the solution Substituting Equation (13) into Equation (12), multiplying by Combination with the dynamic response of microbeam, Substituting Equation (15) into Equation (14), we can obtainBoth low-frequency part and high-frequency part are introduced in Equation (16). It is considered that the high-frequency vibration has little impact on system dynamics under primary resonance condition. So, we set To obtain dynamic equation of single degree of freedom, we set subspace dimension equal to 2.M equal to 3 and only keep linear part of the high dimensional space variables. The relationship between the high-frequency part and low-frequency part is obtained, as shown belowIn order to simplify the calculation, we set Substituting Equation (17) into Equation (11) and keeping all nonlinearities up to fifth order, yield the following novel single degree of freedom equationThe above is the Nonlinear Galerkin method for dimensionality reduction. The previous single degree of freedom model obtained by the Linear Galerkin method only contains the first mode. In this paper, the Nonlinear Galerkin method is introduced to obtain the improved single degree of freedom model that contains the first mode and the third mode, which improves the accuracy of the model.This paper aims to study monostable large amplitude vibration. With the increase of amplitude, the advantage of the improved model becomes more and more obvious.Static analysis is significant in the MEMS. Through it, equilibrium position, pull-in voltage and pull-in location of the system can be obtained. Each of the DC voltage corresponds to a static displacement and the perturbation method is used to obtain an approximate solution near the equilibrium position. We assume To indicate the significance of each term in the equation of motion, ε is introduced as a small non-dimensional bookkeeping parameter. Considering the electrostatic force term To express the relationship between the excitation frequency and the natural frequency, we introduce a detuning parameter d T4=ε4t  and expaSubstituting Equation (22) into Equation (21) and equating coefficients of like powers of order order order order order The solution of Equation (23) can be expressed asA in the polar form Expressing the amplitude Then, the steady-state frequency response can be obtained by solving the following frequency response equationThe relationship between the resonance frequency shift and the maximum amplitude of oscillation is derived asσ as the bifurcation parameter and taking By inspection, when the g et al.  and Nayfg et al.  studied The amplitude frequency curve can be decomposed into two parts, as the followingThe monostable vibration appears when the frequency In this section, Differential Quadrature method and Finite Element method are introduced to verify the accuracy of the model. Meanwhile, with unfolding analysis and optimization theory, parameter space and maximum amplitude of the monostable vibration are obtained.Convergence is a key problem. With the traditional single degree of freedom model, static displacement curve cannot be obtained accurately. To solve the problem, higher dimensional model was introduced in previous studies . Here, tIn Besides, pull-in voltage is obtained by using those three methods under different gap width. As shown in Thus, our model is superior to the traditional single degree of freedom model. It can predict static displacement, natural frequency and pull-in voltage more accurately and convergence problem is also solved by our model.In this section, scale effect and axial stress are considered. The static deflection and static pull-in voltage of microbeam are calculated with our model. Meanwhile, Differential Quadrature method is introduced to handle Equation (5) for numerical verification. The calculated static deflections of the microbeam with What’s more, the calculation formula of the pull-in voltage can be obtained easily.From Equation (19), the relationship between static displacement When pull-in occurs, both branches collide and destroy each other with one eigenvalue tending to zero. Thus, the pull-in voltage corresponds to a saddle-node bifurcation. So, the pull-in occurs when The monostable vibration is desired for many applications, such as microbeam resonator . Here, pIn Three types of parameters  are taken from softening area, hardening area and boundary as shown in κ1 < 0 in the case of Due to the existence of nonlinear electrostatic force and geometric nonlinearity, it is hard to realize the monostable large amplitude vibration. The traditional single degree of freedom model is not enough to characterize the frequency response under the large amplitude vibration. In this section, we try to qualitatively study the monostable large amplitude vibration with the improved single degree of freedom model. To verify the validity of the results, the Differential Quadrature method is used to compare with the Nonlinear Galerkin method.Then, from Equation (35), parameter space of the monostable vibration with the different specification will be studied. As shown in Besides, the AC voltage of the peak decreases as the ratio of the gap width to the mircobeam thickness increases, which can be explained with The ratio of the gap width to the mircobeam thickness is the key to realize monostable large amplitude vibration and it decides the maximum amplitude that can be realized with appropriate DC and AC voltage. Reasonable decreasing the ratio of the gap width to the mircobeam thickness, the system can realize monostable large amplitude vibration. As we know, monostable large amplitude vibration is desired for many applications, such as microbeam resonator, which can eliminate the dynamic bifurcation phenomenon and increase the vibration energy.To verify the validity of the results, the Differential Quadrature method is proposed to compare with the Nonlinear Galerkin method. Here, the frequency response is calculated with sweeping up the frequency and sweeping down the frequency by Differential Quadrature method. As shown in (a)Under monostable vibration, (b)The maximum amplitude of approximate linear vibration is proportional to exciting force that is decided with the product of DC voltage and AC voltage.(c)Optimization parameters, which can realize the maximum amplitude of monostable vibration, are taken near the peak regions in The formula of maximum amplitude We take a rectangular area near the peak region and discretize it into many points as shown in In this section, the improved single degree of freedom model can describe monostable large amplitude vibration qualitatively. Although, when amplitude exceeds half of the gap, the error between reduced-order model and continuum model becomes obvious, our proposed model is significant to study the relationship between maximum amplitude and physical parameter.With the Nonlinear Galerkin method, we propose a novel approach to generate an improved single degree of freedom model for electrically actuated microbeam-based MEMS and use it to study the static and dynamic behaviors of these devices. Specially, the monostable vibration is theoretically investigated in size effected MEMS via the low dimensional model. The proposed theoretical results maintain a good situation consistency with the results obtained by Differential Quadrature method. Besides, the Finite element results of case studies are used to verify the accuracy of the model. Compared with the results obtained by the Linear Galerkin method, the model has obvious superiority.What’s more, the monostable large amplitude vibration eliminates dynamic bifurcation phenomenon, improves the stability of the system and increases the vibration energy, which is desired for many applications. Parameter space and maximum amplitude of the monostable vibration are obtained by using unfolding analysis and optimization theory for the first time. It is found that reasonable decreasing the ratio of the gap width to the thickness of the mircobeam is the key to realize monostable large amplitude vibration. Besides, the Nonlinear Galerkin method gives a way to convert partial differential equation into ordinary differential equation.