The past decades have seen rapid and vast developments of robots for the rehabilitation of sensorimotor deficits after damage to the central nervous system (CNS). Many of these innovations were technology-driven, limiting their clinical application and impact. Yet, rehabilitation robots should be designed on the basis of neurophysiological insights underlying normal and impaired sensorimotor functions, which requires interdisciplinary collaboration and background knowledge.Recovery of sensorimotor function after CNS damage is based on the exploitation of neuroplasticity, with a focus on the rehabilitation of movements needed for self-independence. This requires a physiological limb muscle activation that can be achieved through functional arm/hand and leg movement exercises and the activation of appropriate peripheral receptors. Such considerations have already led to the development of innovative rehabilitation robots with advanced interaction control schemes and the use of integrated sensors to continuously monitor and adapt the support to the actual state of patients, but many challenges remain. For a positive impact on outcome of function, rehabilitation approaches should be based on neurophysiological and clinical insights, keeping in mind that recovery of function is limited. Consequently, the design of rehabilitation robots requires a combination of specialized engineering and neurophysiological knowledge. When appropriately applied, robot-assisted therapy can provide a number of advantages over conventional approaches, including a standardized training environment, adaptable support and the ability to increase therapy intensity and dose, while reducing the physical burden on therapists. Rehabilitation robots are thus an ideal means to complement conventional therapy in the clinic, and bear great potential for continued therapy and assistance at home using simpler devices.This review summarizes the evolution of the field of rehabilitation robotics, as well as the current state of clinical evidence. It highlights fundamental neurophysiological factors influencing the recovery of sensorimotor function after a stroke or spinal cord injury, and discusses their implications for the development of effective rehabilitation robots. It thus provides insights on essential neurophysiological mechanisms to be considered for a successful development and clinical inclusion of robots in rehabilitation. Rehabilitation robotics is a relatively young and rapidly growing field, with increasing penetration into the clinical environment . In the The idea of using machines for rehabilitation dates back much earlier. In a 1910 patent, Theodor Büdingen proposed a ‘movement cure apparatus’, a machine driven by an electric motor to guide and support stepping movements in patients with heart disease. In the 1930s, Richard Scherb developed the ‘meridian’, a cable-driven apparatus to move joints for orthopaedic therapy. This human-powered mechanotherapy machine already supported multiple interaction modes, ranging from passive to active-assisted and active-resisted movements. A first robotic rehabilitation system was based on the concept of continuous passive motion (CPM), a stiff interaction mode in which the robot moves the joints along a predefined trajectory, independent of the contribution of the patient .The first powered exoskeletons for therapeutic applications in SCI patients were introduced in the 1970s –5. TheseA new era of neurorehabilitation robotics began in 1989 with the development of the MIT-MANUS  and liftDevelopments of rehabilitation robots for the lower extremity began in 1994, with the design of the Lokomat , combiniThe decades since these pioneering developments have seen an explosion of novel rehabilitation robots for both the upper and lower extremities, which can broadly be classified into grounded exoskeletons, grounded end-effector devices, and wearable exoskeletons Fig. . These dThe number of new developments has been disproportionate to the penetration of these technologies into the clinical setting, likely due to the technology-driven approach of many engineering groups and the limited, albeit increasing, exchange of the field with therapists and clinicians. While a few randomized-controlled trials have confirmed efficacy of robot-assisted therapy equivalent to that of dose-matched conventional therapy –21, the For a successful inclusion of robots in rehabilitation, fundamental knowledge about the physiological basis of the recovery of function is required. This knowledge is widely distributed and difficult for engineers to access and translate into design considerations. Consequently, in our opinion and experience, a close cooperation between engineers, therapists and clinical neurophysiologists/neurorehabilitation scientists is required from the very beginning of a development, and was shown to be successful in previous developments .According to evidence from studies in cats , non-humThis review aims to provide historical and clinical background of relevance to the field of rehabilitation robotics for engineers, basic and clinical neurophysiologists and therapists interested in and entering this exciting field. It introduces the neurophysiological basis for upper and lower limb functions that should be considered for the design of effective rehabilitation robots, and underlines the need for transdisciplinary collaborations for future developments. Before addressing aspects specific to upper and lower limb rehabilitation, general neurophysiological considerations of relevance for the design of rehabilitation robots will be discussed.Stroke and spinal cord injury (SCI) are among the leading causes of adult long-term physical disability, with approximately 10 million people surviving a stroke and over 250′000 surviving a spinal cord injury (of which approximately 60% are incomplete) every year. Muscle weakness due to activation deficits represents the main disability following stroke and SCI, and frequently limits self-independence. Furthermore, following CNS damage, secondary effects such as spastic muscle tone (increased resistance to passive stretch) develop.The aim of neurorehabilitation is to improve outcome of function after damage to the CNS, such as stroke and SCI, through intensive physical therapy. This goal is, however, difficult to define as the effects of conventional therapy can hardly be separated from the spontaneous recovery of function that occurs in parallel to the effects of the rehabilitative treatment . In stroTherapy-induced recovery is mediated by neuroplasticity, and the goal of rehabilitation is thus to maximally exploit neuroplasticity in order to achieve an optimal outcome for the individual patient. However, neuroplasticity is limited, with most patients reaching a plateau after recovering approximately 70–80% of the initial impairment stroke: –30). Bas. Bas30])The recovery of function in persons with CNS lesion is much like a relearning process exploiting preserved sensorimotor circuits . The relThere are basic differences in the recovery of upper and lower limb function. For instance, the exploitation of neuroplasticity is quite limited for arm and hand movements after a stroke, especially when the corticospinal tract is damaged. In addition, there are differences between cerebral and spinal cord damage. For example, the success of rehabilitation depends on the integrity of cognitive function, which is often impaired in post-stroke subjects.Spasticity can contribute to the compensation of sensorimotor deficits –38, therThere is currently no consensus on the optimal therapy programs to promote recovery of motor function following CNS damage, and the understanding of recovery mechanisms is limited. Nevertheless, current evidence suggests that recovery requires active physical participation of patients during therapy . AdditioMost of the factors that influence rehabilitation outcome are based on evidence from experiments in post-stroke patients as they represent a much larger patient group than patients with SCI. However, findings made in stroke concerning lower limb, i.e. stepping function, are usually also valid in SCI and can be transferred to this patient population. For example, the positive effect of training intensity on the outcome of ambulation in stroke subjects  could reThe general neurophysiological considerations provide a strong basis for the application of robots in rehabilitation. Robot-assisted rehabilitation provides a standardized environment, in which both therapy intensity and dose can be increased. In a conventional setting, hemiparetic patients typically perform about 30 movement repetitions with their affected upper limb in a 45-min session , whereasSeverely affected patients can benefit from passive/highly-assisted movements and gravity support by exoskeletons that provide control over all relevant joints Figs.  and 3. IThe versatility and complexity of arm and hand movements with unique functions such as unimanual reaching, grasping and manipulation, as well as bimanual separate and cooperative movements, differ fundamentally from stepping movements with a more automatic movement control. Skilled hand and finger movements reflect cultural achievements in the evolution  that areIn general, the recovery of arm/hand function following CNS damage is limited when compared to gait in post-stroke  and cervIn post-stroke subjects, outcome of upper limb function critically depends on the integrity of the corticospinal tract (CST) , 69. A sIn contrast, the recovery in patients with an intact CST is proportional to the initial impairment, with patients recovering approximately 70–80% of the initial impairment  –30. SomeEarly after stroke flaccid arm muscle paresis prevails, i.e. the limbs are weak and do not resist passive displacement. With the development of some spastic muscle tone, needed to perform rudimentary grips, the training of residual muscle function can be initiated . In thisPatients typically compensate for their sensorimotor deficits through the involvement of the non-paretic arm/hand, leading to learned non-use of the paretic arm , 73. TheDuring the course of upper limb rehabilitation, the support provided should always be kept to a minimum in order to make the training challenging with a maximum of individual effort and contribution to movement performance by the patient (for review ). HoweveMany upper limb movements involve the use of both hands. However, only a few studies provide a neurophysiological basis for the training of bimanual movements . BimanuaThe involvement of the unaffected hemisphere in movement control of the paretic hand might be even stronger in a special type of bimanual movement, where one hand supports the action of the other one by generating equal but opposed forces/torques, e.g. when opening a bottle or cutting bread. Such cooperative hand movements are based on a task-specific control: a ‘neural coupling’ of the hemispheres, i.e. both ipsi- and contralateral hemispheres become involved in the control of each of the two hands during cooperative hand movements . ConsequFinally, while the recovery of finger function is limited, basic functions such as opening and closing the hand should also be trained, as most of the interaction with the environment during ADL involves grasping and releasing objects. Besides motor function, somatosensory function is also of importance during object grasping: shaping and maintaining a stable grasp during the manipulation of an object relies on the processing of somatosensory input, determined by the mechanical properties of the manipulated object . SomatosThe combination of kinematic complexity and functional impairment makes the design of robotic devices to train arm, hand and finger function after CNS damage particularly challenging. Following the initial developments based on stiff industrial manipulators, end-effector-based devices for planar  and 3D Independent of their kinematic configuration, all of these systems can partially or fully unload the arm against gravity. This approach reduces the effect of flexor synergies, and allows the performance of hand movements within a larger workspace. However, the complex structure and geared actuators of such devices with their reflected inertia limit the interaction quality and the ability to adapt the level of support . The larRobot-assisted approaches should also consider the training of bimanual and cooperative movement tasks as they are important during ADL  approaches. These should also incorporate the training of basic hand function and interaction with virtual object dynamics that generate somatosensory feedback. In the future, it will be possible to at least partially compensate for remaining deficits with wearable assistive robotics.Locomotor movements are performed more automatically than arm and hand movements. Corticospinal control mainly serves the goal to voluntarily alter the stepping rhythm, e.g. to correct the stepping direction or amplitude to overcome obstacles. Accordingly, corticospinal projections to lower limb motoneurons in humans are stronger to the flexor than to the extensor muscles , 100. ThPassive orthoses can assist foot dorsiflexion in the swing phase of stepping. In SCI subjects, some proximal leg muscle activation is required for a successful locomotor training . BesidesThirty years ago, rehabilitation after CNS damage was focused on the strengthening of leg muscles to a level where patients were able to perform stepping movements on parallel bars with the support of their arms . In the Movement speed during locomotor training represents another factor that influences outcome. In ambulatory stroke patients, a successive increase (according to principles of sports physiology) of treadmill speed after a 4-week training period resulted in a better walking ability than conventional gait training . FurtherIn severely paralyzed patients with an SCI, automatic stepping movements can be induced, associated with a physiological leg muscle activation  patterns with reduced amplitude), when patients stand on a moving treadmill with the body unloaded up to 80% , 109. ThMost of the recovery of function occurs during the first three months after CNS damage. However, also in chronic patients with an incomplete SCI and stroke a significant gain in gait velocity, endurance, and performance can be achieved by an automated locomotor training . FurtherHip extension at the end of the stance phase is an essential stimulus for the leg muscle activation during locomotion, especially for initiating the stance to swing transition with an appropriate change in leg muscle activation . This isToday we know that bipeds use a quadrupedal coordination during locomotion, i.e. arm movements represent an integral part of locomotion , 119 andFunctional gait training positively affects the recovery of locomotor function, but is personnel-intensive and physically demanding for the therapists. This situation triggered the development of robotic devices to assist leg movements during stepping on a treadmill with the body partially unloaded . Robot-aDuring the course of rehabilitation, the physical support has to be continuously adapted to the actual needs of the patient, with the objective of maximizing active participation of the patient by reducing and selectively providing assistance . With thInitial developments for robot-assisted gait training were focused on patients with almost complete paralysis as a result of SCI, where training is most demanding for therapists. These patients can hardly actively contribute to the leg movements. Therefore, high assistive torques are required, typically resulting in robotic devices with high output impedance. With increased penetration of this technology into clinics, locomotor training using such devices was expanded to patients with a stroke or incomplete SCI, who require less and/or asymmetric assistance. However, this is difficult to achieve by devices with a high output impedance, as these behave more like a velocity than a torque source. Consequently, novel control approaches  and deviThe field of lower-extremity robot-assisted therapy is progressing towards wearable powered exoskeletons Fig. . These cWith the ability to partially support balance with wearable exoskeletons, the hands become free from holding crutches. This will facilitate arm swing, which represents an integral part of locomotion (for review see ). These In conclusion, in post-stroke patients training leads to a good recovery of stepping function using spastic muscle tone for body support. In SCI, some remaining proximal leg muscle function is required to allow a successful training and recovery of function. The activation of load (re-loading of the body as far as possible) and hip-joint related (hip extension) receptors leads to a physiological leg muscle activity pattern during stepping and, consequently, to dose-dependent training effects. Accordingly, devices are required which can adapt the support and impedance of individual joints according to patients’ impairment. The development of wearable robotic gait orthoses with integrated balance support will further promote functional training, engagement and motivation, and lead to systems that can provide long-term assistance in the home environment Fig. .Rehabilitation training of the upper and lower limb should be founded on neurophysiological insights, independent of whether it is performed conventionally, or with the support of robotic devices. After CNS damage, improvement of sensorimotor functions occurs to a large degree spontaneously and can further be achieved by an exploitation of neuroplasticity. This is reflected in a physiological limb muscle activation that might serve as a marker for the achievement of training effects. This requires voluntarily performed upper limb movements, or an activation of appropriate receptors for a purposeful activation of lower limb muscles, i.e. during stepping movements.The potential for a recovery of function differs not only between upper and lower limbs, but also between neurological disorders such as stroke and SCI, and requires the development of technology accounting for these differences. Table Training effects in upper compared to lower limbs are limited and are mainly determined by corticospinal tract integrity. Nevertheless, intensive, highly dosed training has beneficial effects, especially early after stroke. Training devices should unload  arm movements against gravity, incorporate hand function for reach and grasp training and use the motivating and cognitively engaging effects of virtual reality, with a focus on the ADL that are most important to the individual.For the lower limbs, the effects of training on the recovery of sensorimotor function seem to depend on both their intensity and dose. Rehabilitation robots are ideal tools to complement classical functional therapy by allowing a standardized and intensive training with individually and continuously adapted physical support. Grounded exoskeletons and end-effector devices as well as wearable exoskeletons seem to be equally effective in the improvement of function. However, their suitability depends on the phase of recovery, and the individual impairment Fig. .Rehabilitation robots should always provide targeted physical support adapted to the functional abilities of the patient in a way to enable functional movements. This has strong implications for the design, instrumentation and control of such systems. These should be able to adapt their output impedance and physical support to the actual state of the patient and the task at hand, without altering functional movement patterns through their apparent dynamics. Patients will likely train with different devices throughout the recovery phase during rehabilitation, to optimally adapt movement complexity and physical support to the current state and functional abilities of the patient (e.g. transitioning from left to right in Fig. There are currently a number of novel and exciting developments in and around the fields of rehabilitation engineering and rehabilitation sciences. Advances in material sciences will allow lighter, more customizable structures with more tightly integrated actuation and sensing. Furthermore, there is an increasing focus on combining robotics with non-invasive , 127 andA number of further challenges remain for the field of robot-assisted therapy and assistance, many of which will also require collaboration with industry and government bodies. Adoption of robotic devices is driven by cost and reimbursement systems, and research should therefore also focus on identifying the simplest, most effective technical solutions that can support the rehabilitation process.Finally, future rehabilitation approaches will not only profit from the inclusion of robots, but also from an advanced understanding of neurophysiological mechanisms underlying normal and impaired sensorimotor functions, enabled by the use of robots as scientific tools . Resulti


Estimate the demand for board‐certified nuclear medicine physicists in the next 5–10 years,Identify the critical issues related to supplying an adequate number of physicists who have received the appropriate level of training in nuclear medicine physics, andIdentify approaches that may be considered to facilitate the training of nuclear medicine physicists.The American Association of Physicists in Medicine (AAPM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) recognized the need for a review of the current state of nuclear medicine physics training and the need to explore pathways for improving nuclear medicine physics training opportunities. For these reasons, the two organizations formed a joint AAPM/SNMMI Ad Hoc Task Force on Nuclear Medicine Physics Training. The mission of this task force was to assemble a representative group of stakeholders to:As a result, a task force was appointed and chaired by an active member of both organizations that included representation from the AAPM, SNMMI, the American Board of Radiology (ABR), the American Board of Science in Nuclear Medicine (ABSNM), and the Commission for the Accreditation of Medical Physics Educational Programs (CAMPEP). The Task Force first met at the AAPM Annual Meeting in Charlotte in July 2012 and has met regularly face‐to‐face, online, and by conference calls. This manuscript reports the findings of the Task Force, as well as recommendations to achieve the stated mission.PACS number: 01.40.G‐ Since the earliest days of nuclear medicine over 60 years ago, the medical physicist has been an essential member of the nuclear medicine team. The development and implementation of nuclear counting and imaging instrumentation has required collaboration between the physicist and physician on the physical aspects of the technology and its best utilization in imaging the patient. Nuclear medicine physics is a unique area in medical physics, since a nuclear medicine physicist must be a specialist in the instrumentation associated with the measurement and imaging of radiopharmaceuticals, dosimetry for diagnostic and therapeutic procedures, and computer applications used in the imaging of radiopharmaceutical distributions. A nuclear medicine physicist must have a strong background in physics and physiology. They use their knowledge in these areas to work as part of the nuclear imaging team.An appropriate quality control program is essential to the success of nuclear imaging. Medical physicists receive specific education and training in quality control. When added to a sound understanding of imaging, radiation dose, and clinical needs, the nuclear medicine physicist is uniquely qualified to assume responsibility for the quality control program.The nuclear medicine physicist also understands the clinical use of the technology and can provide valuable assistance to clinical colleagues in assessing the trade‐offs to be considered to achieve a desired clinical result. The nuclear medicine physicist is often asked to provide estimates of the radiation dose received by certain patients  for different nuclear medicine protocols, and periodically to speak to patients and their families regarding the potential risks associated with nuclear medicine procedures. In addition, the nuclear medicine physicist is an expert in the dosimetric and radiation safety aspects of the therapeutic application of radiopharmaceuticals.It is important that nuclear medicine physics trainees understand the physical and physiological basis of nuclear medicine, as well as an understanding of the current state‐of‐the‐art instrumentation. If trainees are well versed in the fundamentals, they will be better prepared to understand future advancements in the field such as the recent development of hybrid PET/magnetic resonance (MR) scanners. Additionally, an understanding of the fundamentals of molecular imaging is essential for nuclear medicine physicists. This requires, for example, the determination of the best approaches of kinetic modeling to provide parametric images of receptor ligands.It has recently become evident that a structured clinical training experience is an essential component for a qualified medical physicist (QMP).A diagnostic medical physicist has some basic training in nuclear medicine physics, but may not have the in‐depth knowledge necessary for answering a variety of questions in the nuclear medicine clinic. Much of the general scope of knowledge is the same for both the diagnostic and nuclear medical physicist, including image science, image reconstruction, cross‐sectional imaging, display, and analysis. However, there are areas of knowledge unique and essential to nuclear medicine physics that cannot be covered in the time allotted to nuclear medicine in a diagnostic medical physics residency program.Determining the number of practicing nuclear medicine physicists and the number needed in the future was one of the missions of this Task Force. Data were collected from several sources including the Conference of Radiation Control Program Directors (CRCPD), SNMMI, ABR ABSNM, and the AAPM. No single source, or any combination of sources, provided the Task Force with the information needed to completely address this issue.The CRCPD maintains a national qualified medical physicist (QMP) registry. This database identifies the board that certified the individual and the year of certification. Certification boards such as the ABR and the ABSNM provide data directly to the CRCPD. As of March 3, 2014, there were 184 physicists listed as having certification in Nuclear Medicine Physics, 94 with certification in Nuclear and Diagnostic Medical Physics, and another 9 who were certified in Nuclear and Therapeutic Medical Physics. In addition, there were 61 individuals listed as having certification in Nuclear Medicine Physics and Instrumentation by the ABSNM. ABSNM has an initial certification process that is similar to initial certification by the ABR in Nuclear Medicine Physics. Eight of the 61 individuals listed by the ABSNM were also board certified in Nuclear Medicine Physics by the ABR.Based on these data, it appears that there are currently about 340 board‐certified nuclear medicine physicists. There was one final group of 200 physicists in the CRCPD database who were listed as Medical Physicists. These may be individuals who are certified by the ABR in all three areas of medical physics. Of note for this group is that the certifications ran from about 1954 through 1997. Approximately 20% of the individuals were board certified prior to 1970. Although some are surely practicing nuclear medicine physics, it is most likely a small number. An attempt was made to verify the accuracy of the CRCPD data by making comparisons to the ABR and ABSNM databases. The ABR supplied information that indicated it has 294 board‐certified nuclear medicine physicists. The ABSNM has several certifications, but the list of diplomates includes names but not certifications. The SNMMI is the professional society for persons who have a strong interest in or are actively involved in nuclear medicine. The SNMMI reviewed its membership records and determined that there were approximately 600 members who identified themselves as medical physicists when renewing their membership. This number is much larger than the number from the CRCPD database, which suggests a range of clinical responsibility from none  to full‐time clinical nuclear medicine physics responsibilities. Only a fraction of these individuals are board certified in nuclear medicine physics, most likely because there has historically been little motivation to pursue board certification.n=5,467) who reside in the United States or Canada as of the end of 2012. The response rate was 61% . From this information, we were able to obtain the information in 340(206/.61) board‐certified nuclear medicine physicists. This compares very well with the estimated total of 340 from the CRCPD database. There are some issues with this comparison in that the data in AAPM collects data through the AAPM professional survey  about the number of physicists, their degrees and board certifications, years of experience, and the area of medical physics that is their primary specialty. The survey was sent to all AAPM full, junior, and resident members  dedicated nuclear medicine physicists.In addition to the numbers of nuclear medicine physicists, the Task Force was interested in ascertaining the number that would be needed in the future. No data are available at this time regarding future needs. The data in The data clearly show that nuclear medicine physicists comprise a small fraction of the total number of QMPs. This Task Force was not able to accurately determine the total number of board‐certified nuclear medicine physicists. However, it is likely the number is in the range of about 350–450, or slightly less than 10% of those receiving the AAPM Professional Survey. It is clear that better information is required to address the future need for nuclear medicine physicists. Without accurate information regarding the number of nuclear medicine physicists, it is very difficult to estimate the future needs.ABR certification of newly trained medical physicists requires successful completion of three examinations — a Part I examination, which includes a general section and a clinical section, a Part II examination following the completion of a CAMPEP approved residency, and a Part III  examination, which is taken about 10 months following passage of Part II. Part II and Part III are specific to the field of medical physics to which the applicant is seeking certification. Initial exams are given once per year. Conditioning retakes are given in May/June and October of a given year. ABR certificates are conditional; they are valid contingent on meeting the requirements of Maintenance of Certification (MOC).Graduate Medical Physics ProgramMedical Physics Certificate ProgramMedical Physics ResidencyNew applicants for the Part I general and clinical exams must be enrolled in (or graduates of) one of the following CAMPEP Accredited Programs:Candidates enrolled in CAMPEP accredited programs must be in good standing, and the enrollment must be attested to by the program director. Part I general and clinical exams are given at Pearson VUE Centers throughout the U.S. and Canada.New applicants for the Part II Exam must have completed a CAMPEP‐accredited residency and passed the Part I Exam. Applicants for the Part II Nuclear Medical Physics board exam must have obtained clinical experience in nuclear medicine physics during their residency, and their program director must attest that they have had appropriate didactic and clinical training in nuclear medicine physics. When an applicant is approved for Part II, they become “Board Eligible”. This is an official ABR and American Board of Medical Specialties (ABMS) status, and candidates may describe themselves as “Board Eligible”. The ABR will report the candidate as “Board Eligible” on the ABR website. Newly approved candidates for the Part II exam must become board certified within six years of approval or seek additional training. Part II Exams are given at Pearson VUE Centers throughout the U.S. and Canada.New applicants for the Oral Exam must have passed the Part II Exam. Applicants will be examined sequentially by five medical physicists who are board certified in nuclear medicine physics. Examinees respond orally to 25 nuclear medicine physics questions, in five categories, over 2.5 hours. The oral examination questions emphasize practical clinical aspects of nuclear medicine physics.There are some candidates in the ABR medical physics board certification pathway from previous years. ABR usually allows candidates to finish under the requirements that were in place when they began. Candidates from 2011 and earlier do not require a CAMPEP‐accredited education. Candidates from 2013 and earlier can still use the “36‐month clinical experience” pathway and are not required to complete a CAMPEP‐accredited residency.Thirty‐seven medical physicists have been granted ABR certification in Nuclear Medical Physics in the last five years . There iEssentials and Guidelines for Clinical Medical Physics Residency Training Programs Section 3.5.Any ABR diplomate certified in at least one discipline of medical physics  may pursue ABR board certification in additional medical physics disciplines. In applying for ABR certification in an additional discipline, the diplomate must demonstrate that he or she has the equivalent of at least one year of clinical experience in that discipline. An ABR diplomate, certified in the discipline for which the diplomate is seeking additional certification, must attest that the diplomate has the requisite one year of clinical experience in that discipline. The clinical experience need not be obtained in a full‐time position, but should be consistent with one year or more of total time committed to clinical experience in the discipline. One year is defined as at least 80% FTE effort. For nuclear medical physics, the clinical experience must address the competencies listed in AAPM Report 249: Upon ABR acceptance of the application, the diplomate will be admitted into the Part 2 and Part 3  examination process. Once the diplomate is approved for Part 2 in an additional discipline, he or she is considered “Board Eligible” in the additional discipline and is allowed six years to complete the certification process. If certification is not completed within six years, the candidate's “Board Eligible” status expires and the candidate has to complete at least one year of additional training at an institution that has a CAMPEP‐approved residency program before a new application can be filed.Diplomates who apply for a second or third certification must receive approval to take Part 2 within four years or the ABR will remove the application from the certification process. In this case, the diplomate has to complete a year of clinical experience at an institution that has a CAMPEP‐approved residency program before a new application can be filed.http://www.theabr.org/ic‐rp‐landing#Additional Certifications). The diplomate and a supervisor must develop clinical experience and supervision plans prior to the initiation of the clinical experience. The supervisor must be an ABR‐certified medical physicist certified in the discipline for which the diplomate is seeking additional certification.Beginning in 2019, the clinical experience for additional certifications must be prospective  of the new ABR‐certified nuclear medical physicists were physicists who were adding nuclear medical physics certification as an additional ABR certification.A certificate is issued to each candidate who meets the educational and training requirements of the ABSNM and passes the two examinations, as outlined below. The certificate indicates that its holder has adequate training in the Specialty of Nuclear Medicine Science and has demonstrated knowledge adequate to practice Nuclear Medicine Science in the specialty of Physics and Instrumentation.The ABSNM certification requires successful completion of two examinations: a Part I examination which covers general nuclear medicine concepts, and a Part II examination which covers more detailed nuclear medicine procedures, physics, and instrumentation. There is no oral examination for the ABSNM certification. Both examinations are given on the same day and are administered once per year. The examination is usually administered in conjunction with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) annual meeting, which is normally in June. Currently, ABSNM certificates are lifetime certificates; diplomates, however, are highly encouraged to participate in MOC programs. Applicants who fail either part of the examination are allowed to retake that part of the exam the following year.A certificate from the ABSNM indicates that its holder has successfully completed certain requirements of study and professional experience which the ABSNM considers necessary to constitute an adequate foundation in nuclear medicine science. It also indicates that the candidate has passed an examination for ability and competence in the field of nuclear medicine science.General Education: Amaster's or a doctorate degree in physics, medical physics, engineering, applied mathematics, or other physical sciences from an accredited college or university, andunder the supervision of a medical physicist who is certified in medical physics by a specialty board recognized by the U.S. Nuclear Regulatory Commission (NRC) or an Agreement State, and who will provide a letter of reference attesting to the candidate's experience and competency; orin clinical nuclear medicine facilities providing diagnostic and/or therapeutic services under the direction of physicians who meet the requirements for authorized users in 10 CFR §35.290 and 10 CFR §35.390, and who will provide a letter of reference attesting to the candidate's experience and competency. Training/Work Experience: Two years (doctorate candidates) or three years (master's candidates) of full‐time practical training and/or supervised experience in medical physics:Individuals who complete their education  and certifications from another country must first be evaluated for U.S Equivalency by the World Education Services (WES) or other similar service.Any ABSNM diplomate certified in at least one specialty of a board  might pursue board certification in another specialty. In applying for ABSNM certification in an additional specialty, the diplomate must fulfill the same requirements as a new applicant in both areas: education and training/work experience. These same requirements also apply to diplomates of other boards.Thirty‐four physicists certified in Nuclear Medicine Physics and Instrumentation over the last five years by the ABSNM, as illustrated in (3) An institution or organization wishing to become CAMPEP‐accredited must demonstrate that the proposed program meets CAMPEP Residency Standards. The method for evaluating a program requires the submission of a Self Study.With the small numbers of certified Nuclear Medicine medical physicists, there is a critical need for CAMPEP‐accredited Nuclear Medicine Physics Training Programs within the U.S. In recent years, CAMPEP has developed detailed standards and specific targeted competencies for each of the three medical physics training programs: imaging, nuclear medicine, and therapy.An institution or organization can submit an appropriate Self Study that meets the standards and competencies for nuclear medicine for CAMPEP review. Upon successful completion of a review by the CAMPEP Residency Education Program Review Committee, a CAMPEP site visit, and final positive approval by the CAMPEP Board of Directors, an institution or organization can be granted a Provisional Accreditation for a Nuclear Medicine Physics Residency. An application for CAMPEP accreditation can be submitted without a resident in the program, but a site visit will only be scheduled after a resident is in the program for one year. Medical physics students with a MS and/or PhD, who complete a CAMPEP accredited nuclear medicine physics residency or DMP program whose program includes a nuclear medicine residency, will be allowed to sit for Part II of the ABR Certification Exam in Nuclear Medicine Physics. A variation of this option are residency programs that offer the option for a resident to decide at the end of the first year of residency whether to complete the second year of residency in nuclear medicine physics or in diagnostic radiology physics. With this model, the resident will be eligible to sit for Part II in the content area selected. For example, if they selected nuclear medicine physics in their second year, they would be eligible for the ABR Part II in Nuclear Medicine Physics only.2+1 residency program option. This 2+1 program allows for the following:* with an additional 12 months of Nuclear Medicine Physics training to its residents, orA CAMPEP‐accredited two‐year Imaging Residency ProgramA CAMPEP‐accredited two‐year Nuclear Medicine Residency Program with an additional 12 months of imaging specific training to its residents.With the current need for qualified nuclear medicine physicists, CAMPEP has approved the 2+1 Residency Programs provided the program meets CAMPEP Residency Standards for both Imaging and Nuclear Medicine.In point 1 above, the resident would be eligible to sit for Part II of the ABR's Diagnostic Medical Physics Exam at the end of 24 months, and then sit for Part II of the ABR's Nuclear Medical Physics Exam at the end of 36 months. In point 2 above, the resident would be eligible to sit for Part II of the ABR's Nuclear Medical Physics Exam at the end of 24 months, and then sit for Part II of the ABR's Diagnostic Medical Physics Exam at the end of 36 months. CAMPEP has agreed to accredit such 2+1) Model is that the institutional overhead for the department offering the training program may be substantially reduced.Presently four‐year DMP programs combine a two‐year accredited didactic medical physics education  with a two‐year accredited residency program. For those DMP programs that offer an imaging (diagnostic) track, it is very reasonable that a student would choose to remain an additional 12 months and obtain the training credentials in nuclear medicine physics to qualify for Part II of the ABR Nuclear Medical Physics Exam. This would require that the DMP‐accredited imaging residency program would need to meet CAMPEP standards for both imaging and nuclear medicine training of residents. An advantage of the DMP  However, no Nuclear Medicine physics residency programs are explicitly listed.The Self Study required by CAMPEP may be perceived to be burdensome to complete. However, the actual Self Study requires approximately 10 to 15 pages to complete; most of the Self Study involves documentations such as clinical rotation schedules and faculty curricula vitae. Additionally, other barriers to submission of a Self Study include: administrative organization/support, equipment, total numbers of clinical procedures including special procedures, and nuclear medicine physicist mentor support.On November 28, 2012, the AAPM Board of Directors approved $560,000 in funding for new imaging physics residencies in either diagnostic or nuclear medicine. The Radiological Society of North America (RSNA) is providing an additional $560,000. Each institution awarded a grant will receive $35,000 per year for four years in matching support for each of two residents.Beginning in 2012, a joint RSNA and AAPM Imaging Physics Residency Workgroup created an application process, and advertised and reviewed grant applications for two consecutive years. Eight new imaging physics residency programs have received these grants. Each residency program is expected to apply for CAMPEP accreditation. None of these residency positions are specifically identified as nuclear medicine physics.The SNMMI has developed a Nuclear Medicine Physics Residency Training grant that was launched in January 2014. The grant was created to encourage the establishment and enhancement of clinical nuclear medicine physics training programs, specifically to increase the number of CAMPEP accredited programs available for nuclear medicine physicists seeking board certification. The grant was implemented also to encourage new and established imaging residency training programs to expand their scope to include training in nuclear medicine physics. Currently, the grant provides funding for one full‐time equivalent  at one institution. Funding will be awarded to the residency training program — either CAMPEP‐accredited or applying for CAMPEP accreditation — which would then identify a resident to receive the grant. This program is in a two‐year trial period. If successful, the SNMMI plans to extend the program for an additional two years. The SNMMI has asked the AAPM to consider matching its commitment in support of nuclear medicine physics residency training.http://frwebgate.access.gpo.gov/cgi‐bin/getdoc.cgi?dbname=2001_register&docid=01‐909‐filed.pdf Questions may be answered by contacting local Centers for Medicare and Medicaid Services (CMS) Regional Office or by contacting the Medicare Fiscal Intermediary.Since 2001, Medicare has offered funding for Nursing and Allied Education, which applied to medical physics. Specific criteria are defined in 42 CFR Part 413.85 and can be reviewed at The Joint AAPM‐SNMMI Task Force has studied the training needs for nuclear medicine physicists. While board‐certified Nuclear Medicine Physicists represent about 10% of the AAPM membership, a large number are nearing retirement age and relatively few have become certified in recent years. The shortage of residency programs, the associated overhead of applying for residency program accreditation, and lack of funding have been identified as obstacles to the creation of CAMPEP‐accredited residency programs that specifically address nuclear medicine physics.The AAPM and the RSNAhave established a seed‐funding program for the establishment of new imaging medical physics residencies. The SNMMI has recently introduced a grant mechanism to assist with the funding of nuclear medicine physics training within new or established residency programs. By themselves, however, these funding mechanisms are not sufficient to sustain the field. Therefore, substantial effort and support by the host institutions is required. In this report, several models of training programs were presented with the intent that a site seeking to build a residency program can make best use of local resources.This report should be provided as a guidance document for future efforts. At a minimum, this report should be distributed to the relevant professional societies  as well as certifying  and accreditation bodies .This report should also be made widely available to interested individuals, perhaps through the websites of the above professional organizations.All nuclear medicine physics certifying bodies should incorporate formal residency training as a requirement for board certification as well as maintenance of qualification program.The Joint Task Force reviewed current data regarding the state of the field, but was not able to provide an evaluation of future needs. Therefore, a nuclear medicine physics work force committee should be formed to evaluate future needs in the field, perhaps under the AAPM Work Force Assessment Committee.Relevant professional organizations should continue to fund residency training in nuclear medicine physics to encourage new and established imaging residency programs to incorporate nuclear medicine physics training into their programs.Therefore, the recommendations of the Joint AAPM‐SNMMI Task Force are:the high median age of qualified nuclear medicine physiciststhe poorly understood training and certification processesthe shortage of formal training programsThe above recommendations are based on a combination of several factors:This report reviewed the current state of the field and educational requirements and proposes several models to meet work force needs in the near future. However, professional organizations such as the AAPM and the SNMMI, as well as others, must continue to support the training of nuclear medicine physicists and continue to evaluate the needs of the field in a changing clinical and professional environment. To remain a vital and progressive field, nuclear medicine needs well‐trained medical physicists to meet the complex requirements of quality patient care and to advance the field. If there are not enough qualified nuclear medicine physicists, nuclear medicine as a whole will see a negative impact.The members of the Task Force wish to acknowledge Lynne Fairobent, Senior Manager for Government Relations at the AAPM, for her excellent support of this project and the support of Angela Keyser and Virginia Pappas, the Executive Directors of the AAPM and SNMMI, respectively.


We hypothesized that by increasing the temperature of the alkaline pre-extraction step in water or ethanol, we could reduce the inputs required during Cu-AHP pretreatment and enzymatic hydrolysis without significant loss in sugar yield. We also performed technoeconomic analysis to determine if ethanol or water was the more cost-effective solvent during alkaline pre-extraction and if the expense associated with increasing the temperature was economically justified.When applied to recalcitrant lignocellulosic feedstocks, multi-stage pretreatments can provide more processing flexibility to optimize or balance process outcomes such as increasing delignification, preserving hemicellulose, and maximizing enzymatic hydrolysis yields. We previously reported that adding an alkaline pre-extraction step to a copper-catalyzed alkaline hydrogen peroxide (Cu-AHP) pretreatment process resulted in improved sugar yields, but the process still utilized relatively high chemical inputs  compared to the 30 °C NaOH-H2O pre-extraction (55%) carried out in a previous study. Consequently, increasing the temperature of the alkaline pre-extraction step to 120 °C in both ethanol and water allowed us to decrease bipyridine and H2O2 during Cu-AHP and enzymes during hydrolysis with only a small reduction in sugar yields compared to 30 °C alkaline pre-extraction. Technoeconomic analysis indicated that 120 °C NaOH-H2O pre-extraction has the lowest installed ($246 million) and raw material ($175 million) costs compared to the other process configurations.After Cu-AHP pretreatment of 120 °C NaOH-H2O pre-extraction was superior to both 120 °C NaOH-EtOH and 30 °C NaOH-H2O pre-extraction.We found that by increasing the temperature of the alkaline pre-extraction step, we could successfully lower the inputs for pretreatment and enzymatic hydrolysis. Based on sugar yields as well as capital, feedstock, and operating costs, 120 °C NaOH-HThe online version of this article (10.1186/s13068-018-1124-x) contains supplementary material, which is available to authorized users. Increasing energy demands, the desire for energy independence, and growing concern over greenhouse gas emissions and global warming have encouraged the search for renewable, eco-friendly sources of energy, including biofuels produced from lignocellulosic biomass . LignoceA diverse range of pretreatment technologies have been investigated that are capable of overcoming this recalcitrance, and several studies have used aqueous or organic solvents to effectively pretreat the lignocellulosic biomass for its improved conversion –10. ReleMulti-stage pretreatments offer the potential to provide a synergistic interaction in order to improve and/or generate high-yield, high-purity fractions of cell wall biopolymers and are commonly used in the forest products industry. For example, an acidic “pre-hydrolysis” coupled to an alkaline delignification is employed in the production of viscose pulps and is capable of yielding acetate and hemicellulose-derived compounds  in the first stage and a high-purity cellulose pulp suitable for the production of cellulose derivatives . Compara2O2) during pretreatment and enzyme loadings during hydrolysis to achieve the reported yields. We hypothesized that by increasing the severity of the alkaline pre-extraction step, we could increase delignification while still retaining most of the xylan, thereby allowing us to reduce both the chemical inputs required during Cu-AHP pretreatment and the enzyme loadings utilized during hydrolysis.We previously demonstrated that a copper-catalyzed alkaline hydrogen peroxide (Cu-AHP) pretreatment process resulted in a substantial improvement of sugar yields following enzymatic hydrolysis compared to AHP-only pretreatment , 24. FurAlthough increasing the severity of alkaline pre-extraction conditions would almost certainly improve glucose yields following Cu-AHP pretreatment and enzymatic hydrolysis, an economic evaluation of pretreatment process economics is needed, as increasing the severity would also increase the processing costs. Technoeconomic analysis (TEA) evaluates both the economic and technological aspects of pretreatment technologies. In addition to understanding the total costs associated with producing ethanol from lignocellulosic feedstocks, TEA also analyzes the effects of changes in chemical input or feedstock costs, evaluates process design to maximize energy usage and recovery, and identifies process bottlenecks that might inhibit industrial-scale feasibility. As a process development tool, TEA has been applied to many pretreatment technologies including, but not limited to, dilute acid , 26, AFEIn this manuscript, we compare the impact that water and ethanol alkaline pre-extraction steps have on the effectiveness of Cu-AHP pretreatment of hybrid poplar. Importantly, we report that by increasing the temperature of the alkaline pre-extraction step to 120 °C, we can improve the process performance while simultaneously reducing the chemical and enzyme inputs in the second stage that are required to achieve high sugar yields following enzymatic hydrolysis. Finally, we perform economic analysis to identify areas of the pretreatment process to target for further improvements.Populus nigra var. charkoviensis × caudina cv. NE-19) grown at the University of Wisconsin Arlington Agricultural Research Station was used for this study. Debarked and air-dried hybrid poplar logs were split to approximately 1.5″ × 2″ x 12″ wedges, chipped by an Earthwise 15-Amp Electric Garden Chipper/Shredder (Model GS70015), and sieved by shaking for 15 min in a LABTECH Chip Classifier with round-hole screens. Chips that passed through the 7-mm round-hole screen but were retained on the 3-mm round-hole screen were shipped to Michigan State University for use in this study.Eighteen-year-old hybrid poplar (2SO4 (0.6 mL/min) and the operating temperature was 65 °C. The xylose measured from the samples were reported as a cumulative percentage of xylose, mannose, and galactose as the HPX-87H column is unable to resolve these sugars.Prior to compositional analysis, wood chips were ground to pass through a 1-mm screen on a Christy Turner lab mill . A two-stage acidolysis method from the National Renewable Energy Laboratory  was used2O PE) in a 100 mL volume capacity Parr reactor (4560 Mini Benchtop reactor). After incubation, the remaining insoluble biomass was thoroughly washed with deionized water and air dried. Prior to Cu-AHP pretreatment, the alkaline pre-extracted wood chips were milled to 1 mm using a Christy Turner lab mill .For the pre-extraction step, a 5 g sample (1–2% moisture content) of 3–7 mm of hybrid poplar wood chips was heated without mixing at 120 °C for 1 h (plus a 15 min heat-up time and a 10-min cool-down time) with 250 mM NaOH (100 mg/g biomass) and either 50 mL (~ 10% wt/vol solids loadings) of 95% (vol/vol) ethanol (120 °C NaOH-EtOH pre-extraction (PE)) or water (120 °C NaOH-H2O2 [2+ (added as CuSO4·5H2O) and 2 mM for 2,2′-bipyridine (bpy), respectively.  The H2O2 and NaOH loadings were both set at 100 mg/g of hybrid poplar biomass. Fed-batch addition of H2O2 was performed over a 10-h period to achieve a final oxidant loading of 100 mg/g pre-extracted biomass.Following ethanol or water alkaline pre-extraction, the milled hybrid poplar biomass was subjected to Cu-AHP pretreatment with fed-batch addition of H2O2 . The pre2SO4 followed by the addition of 0.25 mL of 1 M citric acid buffer (pH 5.0). To complete enzymatic hydrolysis, Cellic CTec3 (197.3 mg/g) and HTec3 (170.5 mg/g), provided by Novozymes A/S , were added into the reaction mixture, each at a loading of 15 mg protein/g glucan from pre-extracted biomass, for a total protein loading of 30 mg/g. The enzyme content was supplied by the manufacturer. The total aqueous volume of the reaction was then adjusted to 5 mL by adding deionized water to attain solids loading of 5% (wt/vol). The samples were incubated at 50 °C for 72 h with orbital shaking at 210 rpm. The sugars obtained following enzymatic hydrolysis were quantified by high-performance liquid chromatography following a procedure described previously [Following 23 h of Cu-AHP pretreatment, the pH of the pretreatment mixture was adjusted to 5.0 with 72% (w/w) Heviously . The sugth plant assumptions was performed to assess economic improvements resulting from the two-stage Cu-AHP pretreatment conditions that were evaluated experimentally. Three processes were considered to precede Cu-AHP pretreatment: 1) 30 °C NaOH-H2O PE [2O PE (as described above), and 3) 120 °C NaOH-EtOH PE (as described above). Process flow diagrams of each process and biorefinery are provided in Additional file A technoeconomic analysis (TEA) based on nH-H2O PE , 2) 120 CP is the total capital cost and CCF is the capital charge factor calculated to be 0.1061 for an interest rate (r) of 10% and a plant life of 30 years. OC is calculated as the summation of raw material and fixed operating costs minus revenues from selling byproducts. Annual fixed operating costs are assumed to be 5.1% of total capital costs [The 2011 NREL biorefinery model , designeal costs .We have previously demonstrated the improved hydrolysis yields of the Cu-AHP pretreatment process in treating hybrid poplar compared to both alkaline-only and alkaline hydrogen peroxide-only treatments when all pretreatments were conducted at 30 °C , 23, 24.i.e., ethanol and water. Additionally, we performed the alkaline pre-extraction step on larger sized poplar wood chips (3–7 mm) that were then milled to 20 mesh (0.85 mm) screen size using a Wiley mill prior to Cu-AHP pretreatment. Studies have shown that pretreating wood chips prior to milling to a size appropriate for enzymatic hydrolysis can reduce energy consumption compared to milling prior to pretreatment [Based on this promising yield increase, we hypothesized that by increasing severity of the alkaline pre-extraction, we could further reduce the chemical costs during Cu-AHP while still maintaining high sugar yields. Therefore, the current study focused on further improvements to Cu-AHP pretreatment by performing alkaline pre-extraction at high temperature in two different solvent systems, reatment , 41.To test the hypothesis that increasing the temperature of the alkaline pre-extraction would allow us to reduce inputs during Cu-AHP, hybrid poplar biomass was mixed with the solvent (ethanol or water) in the presence of alkali and incubated at 120 °C for 1 h instead of at 30 °C, as in our previous studies. After completing Cu-AHP pretreatment and enzymatic hydrolysis, we observed between 93 and 98% conversion of glucan and xylan of pre-extracted biomass to glucose and xylose  compared to 120 °C NaOH-EtOH PE (~ 16%). Compositional analysis of treated biomass demonstrated that ~ 27% of the original xylan and ~ 28% of the original lignin was solubilized during 120 °C NaOH-H2O PE compared to ~ 20% xylan and 19% lignin solubilization for 120 °C NaOH-EtOH PE-treated biomass  [While both 120 °C pre-extraction steps resulted in some lignin removal, the majority of the delignification occurred when the pre-extracted biomass was further subjected to Cu-AHP pretreatment. After Cu-AHP pretreatment of 120 °C NaOH-HPE (55%) .2O2, enzymes, and NaOH are the major raw material costs (other than feedstocks) in the overall conversion process. Therefore, the first set of experiments were carried out at reduced bpy loadings while Cu2+ concentrations were maintained at 1 mM. High glucose yields (~ 90%) were still observed when the bpy concentration was reduced to 0.75 mM with 120 °C NaOH-H2O PE/Cu-AHP, but slightly lower yields (~ 80%) were noted for 120 °C NaOH-EtOH PE/Cu-AHP , Cu2+ (1 mM) and enzymes loadings  were kept constant  and xylose yields (2–6% increase) compared to 120 °C NaOH-EtOH PE/Cu-AHP at all peroxide loadings. Further, H2O2 could be reduced to 40 mg/g biomass while still maintaining high glucose yields for both 120 °C NaOH-H2O PE/Cu-AHP (86%) and 120 °C NaOH-EtOH PE/Cu-AHP (81%). The biomass treated with just 20 mg H2O2/g biomass and subjected to 120 °C NaOH-H2O PE/Cu-AHP still resulted in just over 80% glucose yields. The complete elimination of H2O2, however, resulted in only ~ 50% glucose yields for both 120 °C NaOH-H2O PE and 120 °C NaOH-EtOH PE.In the second set of experiments, we reduced H2O2 (100 mg/g glucan), Cu2+ (1 mM) and bpy loadings (2 mM) were held constant . Increased enzymes also lead to increased sugar costs for onsite enzyme production, as 30 °C NaOH-H2O PE sugar cost ($48.2 MM/year) is about double that of 120 °C NaOH-H2O PE ($27.1 MM/year) and 120 °C NaOH-EtOH PE ($26.1 MM/year). Finally, 120 °C NaOH-EtOH PE requires a larger amount of heat to recover ethanol used in the pre-extraction reactors. More troubling, the heat obtained from combusting the solid residues of fermentation and the biogas from wastewater treatment is insufficient to meet the heat demands, requiring that purchased natural gas be burned (about $1.84 MM/year) to provide the necessary process heat. Consequently, 120 °C NaOH-EtOH PE does not produce excess steam for power production and must purchase grid electricity costing $12.3 MM/year.Simulation results were used to calculate the raw material and variable operating cost of each process. A detailed list of the annual raw material cost for the three processes, E/Cu-AHP , 120 °C 2O PE and 120 °C NaOH-H2O PE because of the capital costs attributed to ethanol recovery, the reboiler, and air-cooled condensers. Overall, 30 °C NaOH-H2O PE resulted in $100 MM higher capital costs than the other processes, primarily because of higher capital costs for enzyme production. Consequently, UPC for 30 °C NaOH-H2O PE/Cu-AHP, 120 °C NaOH-H2O PE/Cu-AHP, and 120 °C NaOH-EtOH PE/Cu-AHP was calculated as 4.09, 3.57, and 3.85 $/gal, respectively. This indicates that compared to the other process, 120 °C NaOH-H2O PE has the better economics because of its lower operating and investment cost  for each process is shown in Table S4 , 30 mg/g glucan (to 20 mg/g glucan), and 2 mM (to 1 mM), respectively, without meaningfully lowering the glucose and xylose yields. To gauge the impact of altering these three variables on process economics, a hypothetical case was formulated by assuming no interaction effects. If H2O2, enzyme, and bpy loadings can be reduced in concert without lowering the fermentable sugar yield, then the overall impact of these changes reduced the total raw material cost of the process and capital costs of the enzyme production unit by about 25% and 16% to $131.7 MM/year and $25.6 MM, respectively. The excess electricity sold to the grid also increased from $3.6 to $5.2 MM/year, a 44% increase. Overall, these changes reduced UPC from $3.57 to $2.82/gal, which is a 21% decrease. Figure 2O PE hypothetical case that benefits from lowering H2O2, enzyme, and bpy loadings in concert. As expected, reductions in raw materials used by 120 °C NaOH-H2O PE results in significant reductions in operating costs, and to a lesser degree, capital costs. Of course, interaction effects could alter these predictions positively or negatively; future experiments should be designed to simultaneously vary multiple factors and measure the influence of interaction on costs.Using the 120 °C NaOH-HAnother possible option to further reduce the raw material cost would be lowering the current bpy price ($59/kg) by mass production. A five- and ten-fold reduction in bpy cost will reduce the annual raw material cost for high-temperature water PE by about $22.7 and $25.5 MM/year, respectively, which is a significant decrease. However, this option assumes future economies of scale for the production of bpy. Therefore, scenarios that include bpy recycling or onsite production should be considered in future studies.A complete life cycle analysis, which would provide a more detailed picture of the environmental impact of the three process configurations, was not performed. However, several observations can be made based solely on the mass and energy balances. For example, as a consequence of the higher electricity and natural gas inputs, the process utilizing 120 °C NaOH-EtOH PE would result in higher fossil fuel input and greenhouse gas emissions per unit of biofuel generated than either of the other two process configurations. On the other hand, the 120 °C NaOH-EtOH PE process requires less process water per unit of biofuel produced. Further analysis is needed to fully understand these tradeoffs.2O2, and enzyme loadings to be decreased without causing as large of a reduction in glucose and xylose yields as was seen with a 30 °C NaOH-H2O PE. Additionally, sugar yields with 120 °C NaOH-H2O PE were greater than those for 120 °C NaOH-EtOH PE. TEA revealed that 30 °C NaOH-H2O PE was the most expensive of the three pre-extraction methods, and that 120 °C NaOH-H2O PE had the lowest investment and operating costs. Further experimental work, coupled with TEA, will be required to identify the optimal severity of the alkaline pre-extraction step relative to the Cu-AHP extraction and the reduction of non-feedstock inputs.In conclusion, we found that increasing the temperature of the alkaline pre-extraction step to 120 °C prior to Cu-AHP pretreatment allowed bpy, HAdditional file 1: Table S1. Raw material prices considered in the technoeconomic analysis. Table S2. Operating conditions considered for technoeconomic assessment of industrial scale bioethanol plant utilizing two stage Cu-AHP preteatments. The first three columns use data that were collected during this investigation. Entries in the fourth column, for the best-case, assume that glucose and xylose yields from the “120 °C NaOH-H2O PE + Cu-AHP case” remain unchanged when hydrogen peroxide, 2,2ʹ-bipyridine (bpy), and enzyme loadings are reduced. Table S3. Comparison of raw material costs (MM $/year) for 60 MM gal/year bioethanol plant utilizing two-stage Cu-AHP pretreatments. Table S4. Total capital investments of 60 MM gal/year bioethanol plant utilizing two-stage Cu-AHP pretreatments. Figure S1. Block flow diagram of the biorefinery. Figure S2. Process flow diagram of pretreatment unit including first stage (a) 30 °C NaOH-H2O PE, (b) 120 °C NaOH-H2O PE, and (c) 120 °C NaOH-EtOH PE followed by second stage Cu-AHP pretreatment.


In vitro study found androgen‐response element (ARE) activity descends with AR‐Qs length (Q13 > Q25 > Q35), whereas BaP suppresses ARE activities in EMCA cells. Furthermore, AR‐Q13  enhances BaP‐induced dioxin‐responsive element (DRE) activity. Lastly, AR‐Q13 exerts higher colony‐forming capacity than other AR‐Qs, and knock‐down AhR abolished AR‐Q13‐mediated colony numbers. This study demonstrated a possible interaction of gene (AR‐Q polymorphism) and environmental toxins (e.g. BaP) to affect cancer progression. A large‐scale epidemiology and public health survey on the interaction of environmental toxin and AR poly‐Q in EMCA is suggested.The androgen receptor (AR) poly‐glutamine polymorphism (AR‐Q) was reported to play role in endometrial cancer (EMCA) development, yet controversial. Environmental factors interact with genetic variation have been reported in EMCA. Aerosol toxins, polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP), are EMCA facilitators. This report examined the interplay between AR‐Qs and BaP in EMCA. During analysing patient AR‐Q polymorphism and Aryl hydrocarbon Receptor (AhR) expressions, we found overall survival (OS) benefit is ascending with AR‐Q lengths (5‐year OS of 61.3% in Q length <20 and 88% in Q length >23). And AhR is higher expressed in short AR‐Q tumour compared to that in long AR‐Q patient.  EMCA is one of the most common gynaecologic cancers in the Western world The AR gene is located on the X chromosome q11.2–q12), spans 90 kb, contains 8 exons and encodes for a protein of around 917 amino acids .2–q12, sversus 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin  on human uterine cell migration Environmental toxins have been shown to involve human malignancies including EMCA in vitro studies support this speculation. Björk et al. et al. et al. in vitro.There is increasing interest in studying the interaction of genes and environmental cues in human disease progression including EMCA. This study is particularly interesting to the AR poly‐Q polymorphism and AhR ligands interplay in EMCA. Several Here, we conducted a hospital‐based cohort study to associate AR gene poly‐Q polymorphism to disease OS and to relate AhR expression in EMCA patients. Furthermore, we introduced a patient‐related AR poly‐Q cDNAs to co‐treat with AR ligand  or AhR ligands (BaP or TCDD). This shows molecular interactions by measuring ARE or dioxin‐response element (DRE) activities in HEC‐1A EMCA cells. Finally, we knocked down AhR by short‐hairpin RNA to observe colony‐formation capacity to test this hypothesis on the cellular level.Specimens  analysed in this study were obtained from patients diagnosed with EMCA from 2003 to 2006 at the China Medical University . Patients were identified from a single cohort registered in the Cancer Registry Database of the hospital, and EMCA pathology was classified according to World Health Organization pathology classification. Access to the tissue samples was approved by the Internal Review Board of the China Medical University Hospital (#DMR101‐IRB2‐276). A total of 100 Taiwanese patients with EMCA were recruited, and the patient demographic characteristics are shown in Table Genomic DNA was extracted from peripheral blood using the QIAamp DNA Blood Mini Kit  and stored at −80°C until the time of study. The method for analysing AR poly‐Q polymorphism has been described in detail previously (rapid and accurate determination of (CAG) repeats in the AR gene using a polymerase chain reaction and automated fragment analysis). Bharaj BS, Vassilikos EJ, Diamandis EP. Clin Biochem. 1999 Jul;32(5):327–32.). The amplified products were separated on the denaturing polyacrylamide gel using an ABI 3730 genetic analyzer and analysed by size using the GeneMapper software .Freshly excised tumour samples (1 × 1 cm) were immediately immersed in 10% PBS‐buffered formaldehyde. The protocols of tissue processing, slicing, de‐waxing, haematoxylin–eosin staining and immunohistochemistry followed previous publications 2. The TCDD  and BaP  had final concentrations of 5 nM and 10 μM, respectively, in the individual experiments.The human EMCA cell line HEC‐1A was purchased from ATCC  into pWPXL lentiviral‐based vector  with the cloning/releasing restriction enzyme Pmel. The sequencing results showed that the cDNA and Q‐lengths are correct (data not shown). The ARQ25 cDNA were amplified from the previously used pBabe‐AR plasmid : 386–394). This was subcloned into the pWPXL vector at the Pmel site.2 for 48 hrs. Media containing virus was collected by centrifugation and filtered through a 0.45‐μm filter. Media containing 0.8 mg/ml polybrene (Sigma‐Aldrich) was then added to culture dishes containing 106 HEC‐1A cells. After 16‐hrs infection, the media containing the virus was replaced with fresh DMEM/10% FBS medium, and the cells were maintained at 37°C in a humidified incubator in an atmosphere of 5% CO2 for 48 hrs. Infected cells were then collected and analysed. The green fluorescence protein (GFP) + cells were measured with flow cytometry  to determine infection efficiencies. GFP+ cells with infection efficiencies greater than 85% were subjected to the following experiments.The lentiviral production and infection procedures were carried out as reported previously with minor modifications.The infected HEC‐1A cells were plated onto 10‐cm dishes and treated with puromycin (6 μg/ml) for 3 weeks to form single colonies. The cells were then subcultured, and AR expressions were examined with an immunoblotting assay as described below. After confirming AR poly‐Q expression, the cells were frozen and subjected to cellular and molecular experiments.Protein extraction and the immunoblot assay were performed as previously described The assay was performed as previously described . Crystal violet cell staining was then performed. After 1 hr, crystal violat was washed from the cell culture dish and cell colonies were photographed.The cells were seeded onto 6‐cm plates (200 cells/dish) with DMEM in 10% CDFBS and incubated for 14 days. In one set of cells, 1000 μl of 4% formaldehyde solution was added to fixed cells, and the cells were allowed to incubate at room temperature for 1 hrt‐test, respectively. The Kaplan–Meier method was used to compare the influence of AR poly‐Q lengths on OS, and the significance was determined using the log‐rank test. Univariate and multivariate analyses to determine the interdependency of AR poly‐Q polymorphisms and clinical risk factors such as age, histological type, grade and stage were carried out using Cox regression t‐test was used for other experiments, and the standard error of mean (S.E.M.) served as an experimental variation and P‐values less than 0.05 were considered to be statistically significant.The associations of patient clinic‐pathologic characteristics with OS and AR poly‐Q lengths were assessed by a log‐rank test and Student's P ≤ 0.003). Five categories were associated with 5‐year OS: age of diagnosis (≤53 or >53 years old), BMI , histology type (endometroid or non‐endometroid), grade (grade 1 + 2 or 3) and stage (stage I+II or III+IV). The higher grade (P < 0.001) and staging (P = 0.003) are significantly associated with poorer OS in the study population. The AR poly‐Q length was measured separately on each strand and the frequency distribution of AR poly‐Q lengths in our series. There were 19 different lengths . The median number of the repeats was 22. Four of the poly‐Q repeats  had an overall frequency of 53%. The AR poly‐Q length presented a normal distribution in the study population . There were 12 patients who died from EMCA during the median follow‐up time of 36.4 months. Higher grade and stage of the disease were significantly associated with OS  transfected cells  that was stably expressed in EMCA HEC‐1A cells  with the calibre of turn on ARE, a short AR‐Q exerts itself better than the AR‐activating capacity  Short AR‐Q synergizes BaP‐AhR activation to activate target genes containing DRE  et al.  et al. 2003; Japan; ~300 patients) et al.  et al.  et al.  et al.  The AR poly‐Q polymorphism roles in EMCA have been studied since 2000. There are inconsistencies in the literature, and the most controversial part is in the risks of EMCA occurrence. For example, Sasaki In reviewing the related studies, we cannot find particular factors that are involved in the data discrepancies, for example ethnicity, location and study population, that might cause these data variations. Recently, there are several trials to pursue AR roles in EMCA, but from expression angle. Unfortunately, those reports still controversy that AR expressions could either be promoter et al. et al. AR can interact with AhR to alter cancer cell behaviour. For example, Ghotbaddini et al. et al. versus environmental toxin interaction, particular in EMCA patients. From this information, one can image the complexity of environmental toxins and gene polymorphism. To the best of our knowledge, there are no epidemiological studies regarding the environmental toxins of AR gene polymorphism in association with endometrial malignancy. Although the environmental toxin and gene interaction is extremely complex, this report details evidence that BaP‐AhR action might interact with short AR‐Q to affect EMCA progression.In this report, we found treatments of DHT on EMCA cells showed an interaction of AR‐AhR signalling to affect EMCA progression. However, there is also one possibility of androgen interaction with oestrogen receptors (ERs) to affect AhR function, therefore interferes AhR activation and ultimately EMCA progression. For example, Steckelbroeck In this report, we show that shorter AR‐Q has poorer EMCA prognosis. This phenomenon is reversely correlated with AhR expression. We also demonstrate that short AR‐Q facilitates BaP‐mediated AhR activation, which might explain the inconsistencies of AR‐Qs in EMCA development. Therefore, it is suggested that large‐scale epidemiological survey on AR‐Q polymorphism, genome‐wide screening on gene mutation, detecting tumour abundance of environmental toxins and the initiation of public health surveys on EMCA patients are important. Future in‐depth studies would help explain the aetiology, prevention and precision medicine needs for EMCA.


The effect of genetic variants on aspirin resistance (AR) remains controversial. We sought to assess the association of genetic variants with AR and early clinical outcomes in patients with acute ischemic stroke (IS).COX-1, COX-2, GPIb, GPIIIa, P2Y1 and P2Y12 were determined using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). The primary outcome was early neurological deterioration (END) within 10 days of admission. The secondary outcome was a composite of early recurrent ischemic stroke (ERIS), myocardial infarction (MI) and death within 10 days of admission.A total of 850 acute IS patients were consecutively enrolled. Platelet aggregation was measured before and after a 7–10 day aspirin treatment. The sequences of 14 variants of 175 (20.6%) patients were AR, 45 (5.3%) were aspirin semi-resistant, 121 (14.2%) developed END, 17 (0.2%) had ERIS, 2 (0.2%) died, and 6 (0.7%) had MI. Single locus analysis indicated that only rs1371097 was associated with AR. However, GMDR analysis indicated that the following three sets of gene-gene interactions were significantly associated with AR: rs20417CC/rs1371097TT/rs2317676GG; rs20417CC/rs1371097TT/rs2317676GG; rs20417CC/rs1371097CT/rs2317676AG. END occurred significantly more frequently in patients with AR or high-risk interactive genotypes. Moreover, AR and high-risk interactive genotypes were independently associated with END.Sensitivity of IS patients to aspirin and END may be multifactorial and is not significantly associated with a single gene polymorphism. Combinational analysis may useful for further insight into the genetic risks for AR. Stroke is one of the leading causes of human mortality and disability . Early nAspirin acts by inhibiting platelet cyclooxygenase enzymes (COX), preventing generation of thromboxane A2 (TXA2) from arachidonic acid (AA). TXA2 binds to glycoprotein coupled receptor (GPIIb/IIIa) leading to phospholipase C activation and platelet aggregation . The plaCOX and the above mentioned receptors genes. For example, polymorphisms in COX-1, COX-2, GPIIIa, P2Y1, P2Y12 were reported to contribute to AR [COX-1, COX-2, GPIb, GPIIIa, P2Y1, P2Y12 in AR remains controversial [A number of studies have assessed the association of AR with single nucleotide polymorphisms (SNPs) in te to AR . Howeverte to AR –20. Thusoversial . These coversial , 23. HowWe hypothesize that the interaction of particular genetic variants may contribute to AR and END in IS patients. In this study, we assessed the potential contribution of fourteen variants in six genes to AR and END in acute IS patients using GMDR analysis.The study protocol was approved by the Ethics Committee of the People’s Hospital of Deyang City and the Third Affiliated Hospital of Wenzhou Medical University. Written informed consent was obtained from each patient prior to study enrollment.9/L or >450 × 109/L; 10) asthma or severe cardiovascular, liver, or renal disease.We consecutively enrolled 850 acute IS patients between August 2010 and August 2014. These patients had their first IS and were admitted to the participating hospitals within 72 h of stroke onset. The inclusion criteria were: 1) age ≥ 40 years old; 2) IS was confirmed using brain magnetic resonance imaging; 3) stroke etiology was atherothrombotic or small artery disease subtype according to a previously described Acute Stroke Treatment classification system ; 4) NatiAll patients received standard therapies , 25, incVenous blood (3 mL) was drawn from each patient’s antecubital vein before and after 7–10 days of aspirin treatment. Platelet aggregation was measured by light transmittance aggregometry (LTA), as described previously , 5, 18. COX-1 , COX-2 , TXAS1 , P2Y1 , P2Y12 , and GPIIIa  were selected from the NCBI database (http://www.ncbi.nlm.nih.gov/SNP), based on the following criteria: (i) SNPs that have been assessed in previous studies [A total of 14 variants in six genes, including  studies ; (ii) SNa priori into two groups based on whether they possessed at least one mutant allele.Whole blood (3 mL) was drawn from the antecubital vein into a sterile tube containing ethylenediaminetetraacetic acid and stored at -80 °C. Genotypes for the 14 variants were assessed using a matrix-assisted laser desorption/ionization time of flight mass spectrometry as previously described . Each alThe clinical outcomes of IS patients were assessed within the first 10 days of admission. The primary outcome was END, defined as an increase in NIHSS score of ≥ 4 points within 10 days of admission, after exclusion of hemorrhagic transformation of infarct or a new infarct in another vascular territory as previously described . The secχ2-test. Difference in genotype frequencies between the AR + ASR group and AS group were also compared using the χ2-test. Baseline and clinical characteristics were compared using the χ2 test or Fisher exact test  and the Student’s t test (continuous variables). Gene–gene interactions were assessed using the GMDR program  as previously reported [All statistical analyses were performed using SPSS 16.0 . Deviation of Hardy-Weinberg equilibrium for genotype frequencies was analyzed by reported , 23.P < 0.05 indicated statistical significance.Significant independent predictors of AR were analyzed by logistic regression analysis. The relative risk of a genotype with AR was expressed as odds ratio (OR) with 95% confidence interval (CI). The Cox proportional-hazards model was used to describe the risk for primary outcome and calculate the hazard ratio (HR) with 95% CI. The variables entered into the model were the variables that differed significantly between the AR + ASR group and AS group. All tests were two-sided, and the threshold level of P = 0.02, Table Of the 850 patients taking aspirin, AR was detected in 175 (20.6%), ASR was detected in 45 (5.3%), and AS was detected in 630 (74.1%). Diabetes mellitus, LDL-C and fasting glucose levels and female gender were significantly associated with ASR + AR in univariate analysis (P > 0.05). The frequency of TT + CT genotypes for rs1371097 was significantly higher in the AR + ASR group than in AS group . The one-locus model was computed for each variant and the prediction accuracy of these one-locus models was 0.5634, 0.5395 and 0.5237 , and a minimum P value was 0.9428. The significance of this interaction was then confirmed using a permutation test (P = 0.019), indicating that together these three genetic variants significantly contribute to ASR + AR. Further analysis demonstrated that, in comparison to patients harboring wild-type genotype rs20417GG, rs1371097CC, and rs2317676AA, the gene interactions contributing most significantly to this model were rs20417CC, rs1371097TT, and rs2317676GG; rs20417CC, rs1371097TT, and rs2317676GG/AG; rs20417CC, rs1371097CT, and rs2317676AG  after adjusting for other covariates , had higher glucose levels at baseline , and had a higher prevalence of diabetes mellitus  compared with patients without END. Furthermore, END was more common in patients carrying high-risk interactive genotypes than those with no such interactive genotypes . Cox regression analysis revealed that high-risk interactive genotypes , AR + ASR , and high glucose level  were independent risk factors for END  developed END, 17 (0.2%) had ERIS, 2 (0.2%) died, and 6 (0.7%) had MI within 10 days of admission. The frequency of END was higher in the AR + ASR group than that in AS group , we found no significant differences in the distribution of the other variants between the AR + ASR group and AS group. However, a high-risk interactive genotype, involving rs20417, rs1371097, rs2317676, was independently associated with AR and END.In the present study, we used the GMDR approach to investigate the potential contribution of fourteen variants in six genes to AR and END in 850 patients with acute IS. We found that the prevalence of AR and ASR was 20.6 and 5.3%, respectively, and that diabetes mellitus was associated with AR. These findings were in accordance with previous studies , 27. FurThe mechanisms underlying AR have not yet been fully elucidated. Previous studies have suggested that AR is correlated with gender, age, absorption or metabolic dysfunction, drug compliance, drug interactions, diabetes mellitus, aspirin dose, cholesterol levels, and inflammatory markers , 29. FurCOX and its receptors are involved in platelet activation and aggregation, and are inhibited by aspirin. Polymorphisms in COX-2 rs20417 and COX-1 C50T have been reported to be associated with impaired aspirin responsiveness [P2Y12 and P2Y1 polymorphisms; but Goodman et al.[GPllb/llla variants are associated with AR [With the advances in next generation sequencing and genetic association analysis, accumulating evidence has suggested that genetic factors may be associated with AR. siveness , 14. Howsiveness  and thissiveness . Grinshtan et al. did not  with AR , 37, whe with AR . This la with AR . These cIn this study, the frequency of END was 14.2%, and high-risk interactive genotypes and AR were independently associated with END. While the mechanisms underpinning END have not been fully understood. Thrombosis is one of the causes of ischemic stroke, and platelet activation plays a key role in thrombosis , IS and Recurrent ischemic stroke is common in IS patients. In this study, the frequencies of ERIS, MI and death did not significantly differ between the AR + ASR group and AS group. Furthermore, we found that high-risk interactive genotypes did not increase the risk of recurrent stroke.Our conclusions are limited by the scope of this particular study. Firstly, we enrolled a relatively small sample size, including only two centers, and the follow up period was relatively short. Our findings will need be validated in larger, multi-center studies that follow patients for longer. Secondly, although we genotyped multiple functional variants in known aspirin-relevant genes, some rare functional variants may have been overlooked; thus, we are not able to exclude the role of other polymorphisms in the regulation of AR. Finally, although the main aim of this study was to assess the occurrence of AR, and the association of genetic variants with AR and early clinical outcomes in acute ischemic stroke, we did not include the relevant negative control to allow the association of these gene variants with ischemic stroke to be analyzes. We therefore could not eliminate the possibility that these gene variants interact to contribute to acute stroke themselves. Thus, it will be essential to include a non-stroke group taking aspirin in future studies.We assessed the contribution of fourteen variants from six genes with AR and END in acute IS patients using the GMDR approach. We found that combinations of rs20417CC, rs1371097TT, and rs2317676GG; rs20417CC, rs1371097TT, and rs2317676GG/AG; rs20417CC, rs1371097CT, and rs2317676AG were associated with a higher risk of AR in IS patients. Moreover, AR and high-risk interactive genotypes were independently associated with END. Our findings suggest that the genetic basis for AR is complex, and that genotyping of multiple relevant genes may be necessary to predict AR risk and manage IS patients.