Telehealth solutions can improve the safety of ambulatory chemotherapy, contributing to the maintenance of patients at their home, hence improving their well-being, all the while reducing health care costs. There is, however, need for a practicable multilevel monitoring solution, encompassing relevant outputs involved in the pathophysiology of chemotherapy-induced toxicity. Domomedicine embraces the delivery of complex care and medical procedures at the patient’s home based on modern technologies, and thus it offers an integrated approach for increasing the safety of cancer patients on chemotherapy.The objective was to evaluate patient compliance and clinical relevance of a novel integrated multiparametric telemonitoring domomedicine platform in cancer patients receiving multidrug chemotherapy at home.Self-measured body weight, self-rated symptoms using the 19-item MD Anderson Symptom Inventory (MDASI), and circadian rest-activity rhythm recording with a wrist accelerometer (actigraph) were transmitted daily by patients to a server via the Internet, using a dedicated platform installed at home. Daily body weight changes, individual MDASI scores, and relative percentage of activity in-bed versus out-of-bed (I<O) were computed. Chemotherapy was administered according to the patient medical condition. Compliance was evaluated according to the proportions of (1) patient-days with all data available (full) and (2) patient-days with at least one parameter available . Acceptability was assessed using the Whole Systems Demonstrator Service User Technology Acceptability Questionnaire. Linear discriminant analysis was used to identify the combination of parameters associated with subsequent unplanned hospitalization.A total of 31 patients ; age range: 35-91 years) participated for a median of 58 days (38-313). They received a total of 102 chemotherapy courses (64.7% as outpatients). Overall full compliance was 59.7% (522/874), with at least one data available for 830/874 patient-days (95.0%), during the 30-day per-protocol span. Missing data rates were similar for each parameter. Patients were altogether satisfied with the use of the platform. Ten toxicity-related hospitalizations occurred in 6 patients. The combination of weighted circadian function (actigraphy parameter I<O), body weight change, and MDASI scores predicted for ensuing emergency hospitalization within 3 days, with an accuracy of 94%.Multidimensional daily telemonitoring of body weight, circadian rest-activity rhythm, and patient-reported symptoms was feasible, satisfactory, and clinically relevant in patients on chemotherapy. This domomedicine platform constitutes a unique tool for the further development of safe home-based chemotherapy administration. Incremental advances in the treatment of cancer are responsible for its progressive transformation into a chronic condition, with a similar level of impact on the individual patients’ quality of life, health, and well-being as other chronic diseases -3. HowevImprovements in treatment safety and patient well-being have been the mainstay for the development of the delivery methods that enable tailoring chemotherapy delivery according to circadian clocks in cancer patients. Toward this goal, cancer chronotherapy protocols use dedicated multichannel programmable-in-time pumps ,14. ThusRecent progress in information and communication technologies can provide health care professionals with continuous data flow on symptoms, quality of life, toxicity, behavior, and circadian function from remote patients remaining within their own environment . Toward Patients aged more than 18 years with any cancer type requiring chemotherapy for at least one month were screened for the study at the Chronotherapy Clinics in the Medical Oncology Department of Paul Brousse Hospital in Villejuif, France. Eligibility further required the availability of an Internet connection at home and signed written informed consent. The inCASA electronic platform and the related equipment were installed at the home of each registered patient for a minimum of 30 days. The platform was connected to the Internet Protocol network. Each patient was instructed on how to use the platform for the daily transfer of biomedical data, and was given a form with telephone contacts information for technical or health-related issues.While on study, patients could receive either conventional chemotherapy or chronotherapy according to medical decision. World Health Organization (WHO) Performance Status (PS) score was estimated for all patients before each treatment to support medical decision. WHO PS is a 0-5 score  used to quantify cancer patients’ well-being and functional status . All conThe study was approved by the local institutional review board and conducted according to the Declaration of Helsinki . Each paThe inCASA platform was composed of (1) a touch screen computer  equipped with the SARA software ; (2) a body weight scale , which was connected to the computer via Bluetooth through the SARA application; and (3) a wrist-watch accelerometer (actigraph) , whose collected data on wrist accelerations (per 1-min epoch) were transmitted via an infrared USB dongle connected to the computer a.The SARA software included an electronic version of the MD Anderson Symptom Inventory (MDASI) questionnaire for self-assessment of 13 frequent core symptoms and 6 items assessing interference with activities of daily living. Daily self-rated MDASI items, self-measured body weight, and 24-h rest-activity records were automatically transmitted to a server through the Internet via the SARA software and the LinkSmart Middleware b.Patients were instructed to weigh themselves each morning, fill out the on-screen MDASI questionnaire each evening, continuously wear the wrist actigraph, and download the data in the evening, before or after completing the questionnaire. All the data were then transmitted daily via the Internet to the secured central server. They could be securely accessed anytime by the oncology nursing or medical staff with a dedicated graphical display . The perPatients were asked to contact the hospital or their general practitioner (GP) as they would have normally done in case of a health concern. Nonetheless, in case of a lack of data transmission for more than 24 hours, high symptom severity, quick body weight loss, or apparent deterioration of the circadian activity pattern, the oncology nurse usually phoned the patient and organized any appropriate intervention. This could involve telephone reassurance, a home visit by a technician or a nurse, a patient visit to the GP or to the oncologist, or an emergency visit at the outpatient clinics or in hospitalization .The overall compliance to the platform was assessed by calculating longitudinal individual patient-day reporting rates. These were defined as the total number of days in which data were obtained divided by the duration of the period during which the platform was available for use for each participant. These rates were calculated for each parameter  separately, for at least one parameter per patient-day, and for all 3 parameters together. Furthermore, given the 3-day time frame for emergency hospitalization prediction, we also calculated the percentage of patients with a full set of data  available at least once during a sliding window of 3 days. Longitudinal analysis was performed during the initial 30 days (primary endpoint), and for the following 30 days (on-study days 31–60), whenever applicable.The study did not include specific and structured questioning about the reasons for missing data; however, during routine consultations, the medical oncologists  were encouraged to offhand discuss the noncompliance issue with the patients.Participants rated their perception and satisfaction regarding the service delivered using the Whole Systems Demonstrator Service User Technology Acceptability Questionnaire (SUTAQ)  at studyUnstructured, narrative interviews of the hospital nurses involved  were performed by the main study investigators  to evaluate their global perception of the clinical relevance of the platform and acknowledge specific issues.The daily percentage of body weight change was calculated with reference to baseline values obtained over at least three days before the initial course of on-study chemotherapy. The 19 MDASI item scores were used without any predefined threshold. The rest-activity pattern was analyzed using the Action 4 software (Ambulatory Monitoring Inc). The dichotomy index I<O was selected as being the most clinically relevant in cancer patients, according to prior work -31. I<O Descriptive analyses were performed for the overall distribution and individual longitudinal patterns of body weight change, of the 19 MDASI items separately, and of I<O.Time series were analyzed using Matlab , and ranked for relevance regarding prediction of emergency hospitalizations. First, handling missing data in each of the 21 time series  from each patient were interpolated according to their localization: missing data localized at the beginning (or at the end) of the time series were assumed as having the value of the first (or the last) measured value, respectively; a linear interpolation was used to compute missing data within two measured data segments. We initially tested several interpolation approaches  for our sensitivity analyses, but the final results were roughly similar to those using the simple linear method (data not shown). Second, we calculated the dynamic patterns of change over time by subtracting the parameter value of each day from the average of the same parameter on the three previous days. Finally, linear discriminant analysis (LDA) was used on these computed values to determine the combination of parameters whose 3-day dynamic patterns best predicted for an unplanned hospitalization (target event). The predefined time frame for prediction was set at the 3 days preceding each emergency hospitalization event.A total of 52 patients were screened as potentially eligible from October 2011 to August 2013 . Eight wPatients aged 35-91 years (median: 61 years) participated in the study for a median duration of 58 days (range: 38-313 days). Most of them were treated for colorectal, pancreatic, or breast cancer . The majDuring the initial 30-day period (per-protocol), patients provided complete daily data  for a total of 522 days out of the 874 theoretical patient-day data . Hence, overall full compliance was 59.7%. Individual general compliance for each parameter was as follows: 81.7% (714/874) for body weight, 78.1% (683/874) for MDASI, and 74.7% (653/874) for actigraphy. At least one parameter for each patient-day was available in 95.0% (830/874) cases. Moreover, at least one complete set of daily data for the 3 parameters was available at least once every 3 days in 77.2% of the cases. Altogether, compliance remained rather good and stable over the per-protocol 30-day span . HoweverIndividual patient compliance  ranged from 0% to 85.7%, with a median of 56.3%.The most common reasons for missing data, outside planned or emergency hospitalizations (125 patient-days), were informally reported to be technical problems, out-of-home trips, and patient forgetting or feeling too sick.Fifteen patients completed the SUTAQ questionnaire, which was offered at mid study course to 22 patients  chemotherapy courses in 6 patients (19%). Thus, 5 participants underwent a single unplanned hospitalization, and 1 patient was hospitalized 5 times. A global decrease in average daily rest-activity I<O values was observed over the 2 weeks preceding an unplanned hospitalization a. No sucLDA identified the model with the relative weights for the dynamic patterns in circadian rest-activity I<O parameter, body weight change, and MDASI scores, which best predicted for a subsequent emergency hospitalization during the following 3 days . TestingContinuous telemonitoring of circadian rest-activity rhythm, jointly with daily body weight and self-reported symptoms, was implemented for the first time in the home of patients receiving chemotherapy for advanced cancer. The inCASA domomedicine platform was found to be adequate for such purpose, since it was well accepted by the patients and provided an unprecedented amount of multidimensional data over prolonged time spans. Furthermore, the integration of the subjective and objective data translated into accurate information able to predict subsequent emergency hospitalization . Thus, sThe inCASA platform was home located and Web-based, but it did not require to log-in, in contrast to other telehealth studies ,34-36. TAlthough the platform workflow was well accepted by patients altogether, some technological aspects could be refined to increase both comfort and convenience, thus further improving compliance rates in view of a prolonged use. For example, circadian rest-activity rhythm data could be automatically and seamlessly transmitted to the home-based platform, and thereupon to the central server, resulting in less end-user manipulations. Additionally, hospital nurses indicated the positive impact of timely technical support for the implementation of this patient-centered approach, confirming previous report . On someNotwithstanding these amendable technical issues, this study identified, for the first time, a combination of subjective and objective parameters whose dynamics predicted the occurrence of emergency hospitalization within 3 days from the event with an accuracy of 94%. Thus, the integrated multiparametric assessment, including body weight and circadian rest-activity rhythm jointly with subjectively rated symptoms, provided a novel framework for the early detection of severe adverse events that will require hospital admission within 3 days. These data allow foreseeing the timely triggering of proactive interventions to improve the safety of treatment administration at home while potentially reducing the financial burden on health care providers ,44. IndeThis pilot study was mainly observational; hence, no predefined decisional pathway or procedures were implemented according to telemonitored data. Notwithstanding, common sense and prudence led the investigators to off-protocol contact patients in case of missing data, mainly for reasons not requiring medical attention, or, less often, in case of parameter deterioration . In thisSuch hypothesis of patient benefit from a telemonitoring-guided proactive intervention is being tested within a multicenter domomedicine French study, using a second-generation platform (PiCADo) . The stuFinally, besides low I<O that defines altered circadian rhythms, the MDASI items most strongly associated with subsequent unplanned hospitalization have been linked to circadian disruption  ,26,27,45The inCASA solution allowed monitoring not only of patient-reported symptoms, but also of circadian rest-activity patterns and of body weight in cancer patients on chemotherapy, while they were at home. These unique and novel data provided useful information to health care and social care professionals for the follow-up of patient’s well-being. The ultimate paramount benefit of this approach is the increased safety of chemotherapy administration at home. In our experience, this multidimensional telemonitoring represented an effective, accurate, and refined tool for identifying patients at risk for emergency hospitalization, allowing in the future the development and timely triggering of preemptive, coordinated, and befitting interventions to prevent such unplanned admissions, within a domomedicine approach.


Asymmetrical gait and a reduction in weight bearing on the affected side are a common finding in chronic stroke survivors. The purpose of this pilot study was to determine the effectiveness of a shoe insole device that we developed, called Walk-Even, in correcting asymmetric gait in chronic stroke survivors. Six individuals with chronic (>6 months) stroke underwent 8 weeks of intervention with 2 sessions/week, each consisting of 20 minutes of gait training and 20 minutes of lower-extremity strength training. The 2 control participants underwent conventional gait training, while 4 participants underwent gait training using the Walk-Even. Following intervention, all the participants improved on most of the gait measures: peak pressure of the foot, time of transfer of weight from heel-to-forefoot, center of pressure (COP) trajectory, COP velocity, asymmetry ratio of stance, mean-force-heel, mean-force-metatarsals, Timed “Up and Go,” and Activities-specific Balance Scale. The improvement was more pronounced in the 4 participants that underwent training with Walk-Even compared to the control participants. This pilot study suggests that a combination of strength and gait training with real-time feedback may reduce temporal asymmetry and enhance weight-bearing on the affected side in chronic stroke survivors. A large randomized controlled study is needed to confirm its efficacy. Individuals after stroke are often left with disabling motor impairments and gait dysfunction, leading to reduced function and quality of life , 2. GaitTypically, conventional gait rehabilitation is provided by a physical therapist using hands-on activities to facilitate normal movement patterns . UsuallyMore recently, external feedback in the form of either auditory or sensory or visual guidance has been used to achieve symmetrical gait patterns in various populations with asymmetrical gait –19. For While the above-mentioned studies revealed preliminary evidence of improving gait performance using external feedback devices in chronic stroke survivors, no single intervention has yet emerged as being more effective than the others. More research is still needed for effective therapies that concentrate on retraining symmetrical gait in chronic stroke survivors. Thus, our objective was to test a novel device  that we developed to provide either (1) stance-feedback to increase the stance time on the affected side (thereby increasing load on the affected limb) or (2) swing-feedback to decrease the swing time on the affected side (thereby increasing load on the affected limb) in individuals with chronic stroke. We compared it with two participants who underwent conventional training. Thus, the purpose of this pilot study was to describe changes in the gait performance associated with an 8-week intervention of symmetrical gait retraining using the Walk-Even in chronic stroke survivors.Six participants after chronic stroke were recruited from the pro bono clinic within the Physical Therapy Department on the CSU Long Beach campus and were enrolled in the study. The inclusion criteria were as follows: first onset of stroke and onset duration of >6 months, no cognitive impairment  , abilityFor the intervention, we used our customized “Walk-Even” insole device to provide feedback-based gait training . The devμs to 250 μs in 12 settings to stimulate the sensory system alone. The stimulation intensity was adjusted to accommodate patient's tolerance. (3) Participants 5 and 6 underwent conventional gait training with regular physical therapy training.All participants underwent a total of 16 individualized sessions . For each 40-minute session, 20 minutes consisted of aerobic warm-up, isolated lower-extremity strengthening, and practice of functional tasks related to gait. The remaining 20 minutes consisted of separate gait training session as follows: (1) participants 1 and 2 received an auditory feedback during the affected limb stance that reminded the subject to put more weight and keep their affected foot on the ground in order to prolong their stance (stance-feedback). The audio feedback was activated when the affected leg established an initial contact and stopped at a predefined time period that was based on the averaged nonaffected limb stance time. The goal was to persuade the subject towards an increased symmetrical gait pattern by increasing the stance time on the affected limb. (2) Participants 3 and 4 received both audio and sensory feedback during the affected swing that encouraged the subject to shorten his/her prolonged swing (swing-feedback). The feedback was activated when the swing time of the affected limb exceeded a threshold obtained from the swing time of the nonaffected side. Specifically, when asymmetrical gait cycles were measured by the device, an auditory beep as well as a sensory stimulus on the thigh of the healthy limb encouraged the participant to immediately transfer their body weight over to the affected limb. The sensory feedback was given on the nonaffected thigh in the form of an electrical stimulation that was not high enough to activate a contraction of underlying muscle. The frequency of the stimulation was fixed at 250 Hz, but the pulse width was adjustable from 80 Both the strength and gait training were progressive. We used clinical judgment to decide when to progress the difficulty of the activity. For example, if the participant was completing level surface walking without the loss of intermittent balance, the surface was changed  to increase the difficulty.Participants were evaluated at baseline (1 week before the first training session) and at endpoint (1 week after the last training session). The gait parameters of all the participants were evaluated using the F-Scan in-shoe pressure sensor monitoring system  and the Walk-Even: at baseline and after intervention. The plantar pressures were measured using F-Scan research 7.0 program, with the pressure sensor insoles that had 960 force-sensing resistors (3.88 sensors per centimeter square) and were 0.16 mm thick. The insoles were embedded in sandals provided for the participants based on foot size . The sensors were calibrated to body weight. After practice and calibrating the F-Scan according to the manufacturer's protocol, participants were asked to walk 10 meters at their self-selected gait velocity . The recAll the evaluation signals were analyzed offline using the MATLAB program . The trajectory length and the velocity of the center of pressure (COP) were measured using the path of COP for the affected foot. For example, if the subjects progress from mid-stance neutral ankle position to terminal stance with weight shifting over the toes, we would expect a longer COP trajectory length. We also measured applied peak pressure for the total foot area, mean force of the heel during the first 50% of normalized gait cycle, and the mean force of the metatarsal during the terminal stance of the normalized gait cycle. In addition, the normalized time at which the body weight transferred from heel to forefoot was analyzed. Stance time asymmetry ratio was used to quantify the extent of temporal asymmetry between the two limbs, respectively. They were calculated as follows :(1)StancThis study was a pilot study that reported the treatment findings of a very small population with chronic stroke. Thus, the results were provided as pre- and posttest scores and percentile change scores, without the use of statistical analysis.Participant 1 was a 61-year-old man with cerebral infarct and sixty-three months' poststroke. He had right-sided hemiparesis and used an ankle-foot orthosis for walking assistance. Pressure distribution of the affected foot (before and after intervention) of the subject is shown . He undeParticipant 2 was a 48-year-old man with cerebral infarct and fifty months' poststroke. He had right-sided hemiparesis and did not use any walking assistance. He had a history of falls and underwent stance-feedback from the Walk-Even. Participant 3 was a 51-year-old man with cerebral infarct and twenty-four months' poststroke. He had left-sided hemiparesis and did not use any walking assistance and underwent swing-feedback from the Walk-Even. Participant 4 was a 58-year-old man with cerebral infarct and eighty-one months' poststroke. He had left-sided hemiparesis and did not use any walking assistance. The postintervention asymmetry ratio increased in participant 4. However, the COP trajectory distance, peak pressure, and mean force of metatarsals during terminal stance and CP all show positive change. He underwent swing-feedback from the Walk-Even. Participant 5 was a 56-year-old female with cerebral infarct and sixty months' poststroke. She had right-sided hemiparesis and did not use any walking assistance. She underwent conventional physical therapy training. Participant 6 was a 66-year-old female with cerebral infarct and sixty months' poststroke. She had right-sided hemiparesis and did not use any walking assistance. She underwent conventional physical therapy training. The main aim of this pilot study was to investigate an 8-week intervention using the Walk-Even device  to improve gait symmetry in six individuals with chronic stroke. Four of them received gait training by the Walk-Even, while two participants had conventional physical therapy gait training. Our findings indicate that the intervention improved not only symmetry (as measured by asymmetry ratio), motor control (as measured by FMA), and balance (as measured by the TUG and ABC), but also the weight bearing load and distribution on the affected limb . The improvement was more pronounced when the participants underwent gait training with the Walk-Even compared to the regular physical therapy training.The recovery process of a stroke can be lengthy and intensive, depending on its severity. After stroke, intrinsic feedback systems may be compromised, making it difficult for the person to determine what needs to be done to improve performance. Numerous research on focus of attention has consistently demonstrated that an external focus  enhances motor performance and learning relative to an internal focus  , 28. ExtAnother important consideration for the recovery process is the muscle weakness in chronic stroke survivors. In fact, muscle weakness is a major impairment that causes disability in stroke survivors . TherefoThe present study differs from earlier studies , 16–20 tAnother equal consideration is the duration of the intervention and its effect on the outcome. Kwakkel  reportedAlthough we attribute the positive changes to the “Walk-Even” feedback training, the observed changes might have been solely due to the lower-extremity strength training. Another limitation is the lack of long-term follow-up measures after the training. In addition, the small size of this study's sample may limit the strength of conclusions that can be drawn, but all participants who underwent the Walk-Even intervention clearly show the increased stance loading on affected side compared to the control group. Although the data is encouraging, further randomized controlled studies with various subgroups of stroke survivors are needed to provide a definite conclusion on the advantages of using the Walk-Even intervention.The Walk-Even device has been designed to provide external feedback that might be useful in correcting the asymmetry of gait in chronic stroke survivors. Large scale investigations are needed to elucidate which types of feedback (stance versus swing) and therapeutic interventions  provide best rehabilitative practice for correcting gait asymmetry and weight bearing for individuals in the chronic stages of recovery from stroke. Another major potential application is to see this intervention in postacute phase of recovery in stroke survivors where there is maximal potential for recovery and plasticity changes. The important improvements seen after intervention in our small sample suggest that this technique could be used to improve gait symmetry and increased affected-side stance loading in chronic stroke survivors.


Attended speech is comprehended better not only if more acoustic detail is available, but also if it is semantically highly predictable. But can more acoustic detail or higher predictability turn into disadvantages and distract a listener if the speech signal is to be ignored? Also, does the degree of distraction increase for older listeners who typically show a decline in attentional control ability? Adopting the irrelevant-speech paradigm, we tested whether younger (age 23–33 years) and older (60–78 years) listeners’ working memory for the serial order of spoken digits would be disrupted by the presentation of task-irrelevant speech varying in its acoustic detail (using noise-vocoding) and its semantic predictability (of sentence endings). More acoustic detail, but not higher predictability, of task-irrelevant speech aggravated memory interference. This pattern of results did not differ between younger and older listeners, despite generally lower performance in older listeners. Our findings suggest that the focus of attention determines how acoustics and predictability affect the processing of speech: first, as more acoustic detail is known to enhance speech comprehension and memory for speech, we here demonstrate that more acoustic detail of ignored speech enhances the degree of distraction. Second, while higher predictability of attended speech is known to also enhance speech comprehension under acoustically adverse conditions, higher predictability of ignored speech is unable to exert any distracting effect upon working memory performance in younger or older listeners. These findings suggest that features that make attended speech easier to comprehend do not necessarily enhance distraction by ignored speech. Selective attention enables the cognitive system to select and prioritize relevant information from the environment and to filter out irrelevant information . In the noise-vocoding technique is frequently used, which parametrically degrades the spectral content  but leaves the coarse temporal structure  of the speech signal largely intact  and semantic predictability of task-irrelevant sentence endings (low or high) were varied. We asked whether more preserved acoustic detail but also higher predictability would enhance distraction by task-irrelevant speech; and whether the effects of more acoustic detail and higher predictability would be stable in the group of older listeners.A sample of 22 participants, comprising 12 younger  and 10 older participants , took part in this study. All participants were recruited from the participant database of the Max Planck Institute for human cognitive and brain sciences in Leipzig, Germany. None of the participants reported any history of neurological diseases or significant hearing problems. Experimental procedures were approved by the local ethics committee of the University of Leipzig Medical faculty.For the to-be-memorized stimuli, we used recordings of German spoken digits from 1 to 9 from a previous study . Digits SD: 0.2 s). The task-irrelevant sentences were spoken by the same female voice  as the digits.For the task-irrelevant speech, we used a German version of the speech in noise (SPIN) sentences  adopted The task-irrelevant sentences varied along two orthogonal dimensions: first, sentences were spectrally degraded using 2, 8, or 32 frequency channels  for noise-vocoding. In detail, 2, 8, or 32 Butterworth filters (6th order) were used to band-pass filter the speech signal. The filter centre frequencies were logarithmically spaced according to Greenwood’s cochlear frequency position function  and spanFor attended speech materials, a higher number of frequency channels results in enhanced intelligibility , which hFigure 1). 0.5 s after the offset of the final digit, three unconnected, task-irrelevant spoken sentences were presented. On an individual trial, the three task-irrelevant sentences were equally noise-vocoded and had an equal predictability of the sentence final words. The three task-irrelevant sentences were presented with an onset-to-onset delay of 2.76 s. This resulted in a retention period of 8.28 s, during which participants retained the serial order of spoken digits in memory and ignored the task-irrelevant speech. During the presentation of speech stimuli, participants fixated a cross on the screen. After the presentation of task-irrelevant speech, participants saw a number pad with the digits from 1 to 9 on the computer screen. The ordering of digits on the number pad was randomly determined on each trial. They used the computer mouse to select the digits in the order of presentation. After the selection of an individual digit, the respective digit disappeared from the number pad. After the selection of all 9 digits from the number pad, an additional mouse click was required to start the next trial.In the present study, we used an adapted irrelevant-speech paradigm e.g., . On eachPrior to the experiment, participants were instructed to internally rehearse the spoken digits in their order of presentation during the presentation of task-irrelevant speech in order to keep the memory decay low. Participants were instructed to not close their eyes and to not speak the digits out loudly during a trial. Participants performed approximately 10 practice trials in order to familiarize with the task. After completion of the practice trials participants approved that they understood all instructions and were able to perform the task.All acoustic stimuli were presented over Sennheiser HD-25 headphones. Each participant completed 120 trials, 20 for each condition in the 3  × 2  design. Individual task-irrelevant sentences could occur more than once (at most three times) during the experiment, however, not more than once in an individual trial. The entire experiment took approximately 1 h to complete.On a small proportion of trials , participants selected an individual digit more than once during the serial recall. These trials were removed from all further analyses.noise-vocoding of task-irrelevant speech , predictability , and digit position (1–9); between-subject factor age group ]. In case of violation of sphericity , we report Greenhouse-Geisser’s (GG) epsilon (ε), and GG-corrected p-values. As effect sizes, we report the partial eta-squared  detail but also higher predictability would enhance the degree of distraction of task-irrelevant speech. Furthermore, we tested whether the degree of distraction by acoustic detail and predictability would change in a group of older (aged 60–78 years) compared with a group of younger listeners (aged 23–33 years). To this end, proportions of correctly recalled digits in the irrelevant-speech task were submitted to a repeated-measures ANOVA [within-subject factors BayesFactor package). In detail, when comparing two statistical models, the BF indicates how many times more likely the observed data are under the alternative compared to the null-model. The BF ranges between 0 and infinity, and a BF close to 1 indicates that the data are equally likely under both models. By convention,  could either stem from the absence of an effect or from the insensitivity of an analysis in detecting the effect . To enhavention, , a BF > Note that this approach also helps to overcome some of the limitations associated with the comparably small sample size available here: using a Bayes-Factor-based testing approach is recommended to specifically circumvent questions of whether the sample was simply too small to detect an effect. For instance, one recommended Bayesian procedure  of interest and, second, the null-model lacking the factor (or combination of factors) of interest. For instance, to follow up on the non-significant main effect of predictability of task-irrelevant speech, we compared the alternative model  vs. the null model with participant as the only factor.In this study, the to-be-compared models in the Bayes-Factor comparisons comprised a selection of the following factors: random factor Figure 2 shows average proportions of correctly recalled digits as a function of digit position. Across experimental conditions, the proportion of correctly recalled digits was highest for digits presented at initial positions  and at the final position , giving rise to a significant main effect of digit position  shows that proportions of correctly recalled digits decreased with more acoustic detail of task-irrelevant speech for younger participants  and for older participants . The main effect of acoustic detail was highly significant . Across the two age groups, mean proportions of correctly recalled digits were lower for task-irrelevant speech with 8ch compared to 2ch  and for 32ch compared to 2ch , but not significantly different for 32ch vs. 8ch . Thus, participants were less successful in the recall of digits from memory when the to-be-ignored speech was spectrally more intact and thus more intelligible.F16,320 = 3.24; GG’s ε = 0.5; p = 0.002;Furthermore, the stronger memory disruption for spectrally rich vs. degraded task-irrelevant speech was particularly evident for digits presented at later positions, underlined by a significant digit position × noise-vocoding interaction , which provides evidence against any effect of predictability of sentence endings of task-irrelevant speech on performance in the irrelevant-speech task.High- and low-predictable task-irrelevant sentence endings did not differentially affect the proportion of correctly recalled digits . Thus, predictability of task-irrelevant sentences is not only ineffective in influencing task performance in and by itself, but is also unable to modulate the degree to which more acoustic detail of task-irrelevant speech decreases task performance.Furthermore, we found no significant interaction of noise-vocoding and predictability on the proportion of correctly recalled digits .A major question in this study was whether more acoustic detail and higher predictability of task-irrelevant speech would be more performance-detrimental in older compared with younger participants. As readily visible from SE: 0.61 ± 0.03) than in the group of older participants (mean proportion correct ± SE: 0.48 ± 0.03), resulting in a significant main effect of age group . Furthermore, the interaction of age group and digit position was significant  but not at remaining positions .Irrespective of our experimental manipulations of noise-vocoding and predictability of task-irrelevant speech, the average overall performance was higher in the group of younger participants (mean proportion correct ± In the present study we investigated the disruption of younger and older listeners’ working memory for target speech by acoustic as well as semantic features of task-irrelevant speech. Our results can be summarized as follows: (i) Memory distraction is enhanced by higher acoustic  detail of task-irrelevant speech, but (ii) not by higher predictability of the task-irrelevant speech. (iii) Despite an overall performance decline, older listeners do not differ from younger listeners in their susceptibility to acoustic detail  and predictability  of task-irrelevant speech.Figure 2). This is in agreement with one previous study by We found that listeners’ serial recall of digits from memory was more impaired when task-irrelevant speech with more acoustic detail (with a higher number of channels used for noise-vocoding) was presented during memory retention . Importantly, a Bayesian model comparison (see Results) allows us to conclude that this result is to be interpreted as positive evidence for the lack of such an effect . After the experiment, participants usually report to be well aware of the acoustic but not of the predictability manipulation. We consider it possible that for a stronger semantic manipulation such as well-formed sentences  vs. semantic violations  the semantic violation might draw attention away from the rehearsal of digits in memory and thus might impede memory performance.It remains a possibility that our predictability manipulation was simply not potent enough (in contrast to our acoustic detail manipulation) to affect the distraction of task-irrelevant speech. In our high-predictable sentences  only the sentence final words were predictable from the sentence context. Thus far we have tested It is important to note that the three task-irrelevant sentences on each trial in our study were unconnected. Therefore, predictability between sentences was always low whereas we manipulated solely the predictability within an individual sentence. It is thus an open question for future research whether the predictability of a single sentence or multiple connected sentences would leave distraction from task-irrelevant speech unaffected as well. Furthermore, it will be important to test the temporal dynamics of distraction from task-irrelevant speech in future studies. In the present study, the first high- vs. low-predictable sentence final word occurred more than approximately 1.5 s after the onset of the task-irrelevant speech. This is relatively late compared to the manipulation of acoustic detail, which affected the task-irrelevant speech from beginning on. We can thus not exclude that the present predictability manipulation occurred too late during memory retention to disrupt already consolidated memory content.Figure 2). This is in line with previous studies that found no age-differences regarding the degree of distraction in the irrelevant-speech task  decreases at older age (e.g., In general, the ability to focus attention on target stimuli and to ignore irrelevant information (i.e., ge e.g., . Does thThe presentation of task-irrelevant speech can disrupt memory for relevant information. We show here that the features that make attended speech easier to process are not the same that render ignored speech more distracting. That is, only a higher degree of acoustic detail but not higher predictability enhance the degree of distraction by to-be-ignored speech. This finding is preserved even if the attentional control ability decreases in healthy aging.MW and JO designed research; MW performed research; MW analyzed data; MW and JO wrote the paper.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.


We show that the tumor-toxic effects of gene dosage changes of onco-passenger genes are compensated by the uncoupling of their copy number variations from their expression by means of selective DNA methylation. For example, collateral co-amplification of genes in tumor suppressor pathways, such as the TGF-β and inflammatory signaling pathways, are compensated by DNA hypermethylation to suppress their overexpression, while collateral deletion of pro-oncogenic genes are compensated by DNA hypomethylation to promote their expression from the single remaining allele. Our work reveals an important tumorigenic mechanism of regulation of toxic gene copy number imbalance in tumor cells arising from chromosomal instability, and suggests that targeting the DNA methylation machinery may prevent compensatory regulation of onco-passenger gene expression in chromosomally unstable cancers, and re-activate dormant tumor suppressor pathways for effective therapy.Chromosomal instability is a hallmark of human cancers, and is characterized by large structural variations in the genome. Such large structural variations are expected to create intrinsic collateral stress due to gene dosage changes in many genes that are co-deleted or co-amplified in large chromosomal segments ( PTEN tumor suppressor in many cancers is often accompanied by the loss of the entire chromosome 10 p-arm. Similarly, amplification of the MYC oncogene is usually associated with the amplification of the entire q-arm of chromosome 8, leading to the copy number gains of many hundreds of genes , have resulted in the identification of a large number of driver genes and processes in cancers [TP53 on chromosome 17 in human cancers also have important roles in tumor suppression [Transformation to malignancy partly relies on the innovation of novel gene expression programs by tumor cells. A common mechanism employed by tumor cells to acquire novel gene expression programs is by structural genomic variations (SGVs). Many cancers are characterized by extensive genomic structural rearrangements that result in the gain or loss of chromosomal segments , 2. Suchof genes . We call cancers , signifi cancers , 7. A moERBB2 (Chromosome 17), CCND1 (Chromosome 11) and MYC (Chromosome 8) oncogenes are frequently observed . We measured the extent to which the transcriptomes of breast tumors with amplifications of ERBB2, MYC or CCND1 oncogenes are due to the accompanying onco-passenger CNVs. To this end, we calculated two genome-wide metrics for each of the oncogenes above: 1) co-amplification profile: the correlation of its amplification with the CNV of every other gene in the genome (CNV-CNV correlation), and 2) co-expression profile: correlation of its amplification with the mRNA expression of every other gene in the genome (CNV-mRNA correlation). In the first, we measure the correlation of CNV of the oncogene of interest  with the CNV of every other gene in the genome, and in the second, we measure the correlation of CNV of the oncogene with the mRNA levels of every other gene in the genome. The first metric captures the repertoire of co-amplified genes (onco-passengers) with the respective oncogenes, and the second metric captures the transcriptomic changes associated with each oncogene amplification. A correlation of the two metrics, therefore, is expected to reveal the extent to which the transcriptomics changes associated with an oncogene amplification (e.g. ERBB2) are due to the accompanying onco-passenger CNVs, as opposed to downstream pathway effects of the oncogene activation . Intriguingly, we found that the two metrics have a very high correlation in each case  and in other cancers as well (ERBB2 on Chromosome 17). These observations suggest that tumors actively uncouple the expression of many onco-passenger genes from their CNVs, perhaps due to selective tumorigenic advantage.It is conceivable that onco-passenger genes associated with the amplifications of large chromosomal segments may contain genes that are deleterious to tumor viability. Similarly, deletions of large chromosomal segments may result in the co-deletion of genes with essential roles in tumor progression. In both of these cases, the expression of respective onco-passenger genes is expected to be actively uncoupled from their CNVs in tumors to allow for successful tumor progression. Indeed, for example in V Figure . A simil as well . To test as well , a patte as well . Moreove as well , with a ERBB2 showed that while the expression of CR-high genes predicted poor survival, and hence more malignant cancer phenotype, expression of the CR-low gene had a better clinical prognosis, indicating less malignant cancer phenotype  and CR-low (STAC2)  . Catecholamines, such as epinephrine, signal through β-adrenergic receptors to activate the Gs-PKA pathway, which further supports the hypothesis that GPCR-PKA signaling plays a major role in breast cancers.In addition, a large subnetwork of CR-high genes in BRCA was involved in G-protein coupled receptor (GPCR) signaling through GPathways associated with CR-low genes, on the other hand, were often involved in innate and adaptive immune signaling . For methylation data, the Infinium 27 k array data were used for all, except SKCM (where 27 k data were not available), datasets. For SKCM, Infinium 450 k data were used with the 27 k probes for consistency with other datasets. Datasets used and their sample sizes are shown in All of the datasets were obtained from TCGA data portal. CNV of genes were obtained from the segmentation data of SNP 6.0 arrays by survival (coxph function).In all analyses, genes with CNV gain were defined as those that had 90%-ile  CNV (log ratio as measured in SNP6 array) of > 0.50, and those with CNV loss were defined as genes that had 10%-ile CNV of < −0.50. To exclude genes that are constitutively suppressed in a given cancer type, only genes that have expression > 30 normalized counts in at least 10% of the tumor samples were included in the analysis. Survival analyses were conducted with COX regression analysis using R package r-values of > 0.4, were transformed by substracting 0.4 (f(x) = x – 0.4), so that CR-high genes now have positive values and CR-low genes have negative values (for more intuitive separation of CR-high and CR-low genes/pathways). Then, the data were transformed by xf(x) = 2 prior to NetWalk to make the data positive and centered around 1 (a requirement of NetWalk, see ref.Pathway analyses were conducted in NetWalker  using th


Over 90% demonstrated MTM knowledge and 68.2% completed MTM learning activities. APPE experiences significantly improved students’ overall self-confidence (pre-APPE = 3.27 (0.85 SD), post-APPE = 4.02 (0.88), p < 0.001). Students engaging in MTM learning opportunities had higher self-confidence post-APPE (4.20 (0.71)) vs. those not reporting MTM learning opportunities (3.64 (1.08), p = 0.05). Post-APPE, fewer students reported MTM was patient-centric or anticipated engaging in MTM post-graduation. APPE learning opportunities increased student self-confidence to provide MTM services. However, the reduction in anticipated engagement in MTM post-graduation and reduction in sensing the patient-centric nature of MTM practice, may reveal a gap between practice expectations and reality.To determine the impact of advanced pharmacy practice experiences (APPE) on student self-confidence related to medication therapy management (MTM), fourth-year pharmacy students were surveyed pre/post APPE to: identify exposure to MTM learning opportunities, assess knowledge of the MTM core components, and assess self-confidence performing MTM services. An anonymous electronic questionnaire administered pre/post APPE captured demographics, factors predicted to impact student self-confidence (Grade point average (GPA), work experience, exposure to MTM learning opportunities), MTM knowledge and self-confidence conducting MTM using a 5-point Likert scale . Sixty-two students (26% response rate) responded to the pre-APPE questionnaire and  In the United States, the Medicare Modernization Act of 2003 led to the creation of Medicare Part D prescription medication coverage along with the introduction of medication therapy management (MTM) as a required patient-centric service for high-risk beneficiaries with multiple prescription medications . MTM seeAs demand for MTM services increases, colleges of pharmacy and the profession seek to educate students on the business, care delivery, and policy aspects of MTM prior to graduation to ensure preparedness for practice ,8,9. U.SAt our institution, MTM is taught and practiced at various points throughout the didactic curriculum, with the American Pharmacists Association Delivering Medication Therapy Management Services (APhA-MTM) certificate program offered as an elective opportunity. There are several MTM-focused APPEs offered by both faculty and non-faculty preceptors, enabling about 15% of our students to engage in direct patient care MTM learning opportunities. The core required community pharmacy APPE also provides a venue for students to engage in MTM services and completion of a CMR is required during this rotation. However, much remained unclear about the extent to which our students were exposed to and delivering MTM during APPEs and if these learning opportunities increased their self-confidence to deliver specific core components of MTM service delivery. A survey developed to measure the impact of APPEs on student self-confidence did not address MTM specific activities . AssessmAn exploratory study was undertaken to determine the ability of our APPE experiences to provide MTM learning opportunities, develop student knowledge of MTM service provision and enhance student self-confidence to deliver MTM services. Specifically, the APPE experiences of fourth year (P4) student pharmacists were assessed in a pre/post APPE framework to: 1. identify student exposure to MTM learning opportunities; 2. assess the student pharmacists’ knowledge of the core components of MTM service delivery; and 3. assess student pharmacists’ self-confidence in their ability to perform MTM services. The goal was to identify how students’ didactic and APPE experiences affected their understanding and practical application of MTM, to guide future instructional design for faculty and experiential education opportunities related to MTM service delivery. In addition, we hope to use this formative research to finalize a systematic tool to evaluate MTM-focused APPEs for our institution.A survey-based evaluation was conducted at the completion of the P3 year and repeated at the end of the P4 year for students who graduated from our institution in 2015. All students from both our main and satellite campuses were invited to participate in the study. The study was approved by the Institutional Review Board at the Albany College of Pharmacy and Health Sciences (#13-007) prior to implementation and subjects were provided informed consent at the onset of the survey.The self-administered, electronic survey was constructed by the research team to address the 3 study objectives  for these open-ended responses from established MTM definitions ,3,4. TwoThe final survey section asked students to self-assess, using a Likert scale, their overall self-confidence to provide MTM services to patients and their self-confidence engaging in 10 components of MTM service delivery . These represent components of the pharmacy practice faculty investigators’ (KC and JC) MTM-focused APPE syllabi (learning objectives and outcomes) developed from the CMS Medicare and pharmacy profession definitions of MTM, in conjunction with Doctor of Pharmacy accreditation standards and curricular outcomes ,4,5,8,9.n = 20) who had completed a MTM-related rotation and who were available for an in-person interview during the study period. Each pilot participant was asked to complete the survey, and then a member of our team trained in interviewing techniques and group facilitation (WP) assessed the participants’ understanding of the instrument and ability to respond to the survey. Finding no major hurdles in the usability testing, several minor revisions were made to the survey and it was developed in an electronic, web-based program, REDCap (Research Electronic Data Capture) , for secure, anonymous data collection.Because of the unique nature of the questions and the students’ limited exposure to this method of data collection, a usability pilot study was conducted with 5 student pharmacists, in person, to verify the clarity and understandability of the survey questions, as well as to estimate a time requirement for the survey implementation. These 5 students were randomly chosen from a pool of P4 Class of 2014 student pharmacists  and at the end of the APPE year . Two reminder e-mails were sent during both data collection periods and surveys were held open for 3–4 weeks each time. Survey respondents were not individually matched pre- and post-APPE year, as surveys were not linked to an individual, and no names, dates of birth, student IDs or other identifiable information were collected to ensure anonymity. Students could provide their names and email addresses at the conclusion of the survey (stored separately from survey data) to be entered into a raffle for one of five $25 gift cards as an incentive for participation.® (9.4). All tests were evaluated at a 5% level of significance.Results were tabulated for the pre- and post-assessment separately and, when appropriate, a t-test for a test of significance was computed to evaluate the differences between the assessments or between relevant sub-groups within an assessment for continuous data. Chi-square tests were used to evaluate difference in proportions between the pre- and post-test responses. Analysis was completed via SASThere were 238 graduates in 2015, with 180 on the main campus and 58 at the satellite campus. Responses were received from 62 students, representing a 26% response rate in the pre-test; 44 responses were received in the post-test (18% response rate). Respondent demographics are provided in Nearly all respondents indicated they were aware of MTM and most learned about it in classes or from faculty . Although not statistically significant, there was a trend toward reduction in agreement with the statement that MTM “allows for an interactive person-to-person, patient and provider conversation” .Student pharmacists defined ‘MTM’ in two ways to demonstrate their knowledge of the topic , via opep < 0.0001) demonstrating the desired impact of APPE learning experiences. There were significant increases in self-confidence of student pharmacists’ abilities, assessed via the Likert scale noted earlier, to prepare for and conduct a CMR and to prepare patient deliverables , to communicate with the patient and providers regarding MRPs, to offer evidence-based, individualized recommendations, and to discuss MRPs verbally and in writing. Before respondents completed their APPEs, around 90% of people indicated that they would provide MTM in the future, but only 77% of respondents indicated they expected to practice MTM in the future in the post-test assessment (p = 0.07).Students were asked to provide a self-assessment of their overall confidence to engage in MTM and the ten specific components of MTM . StudentTo evaluate what experiences might be helpful in enhancing MTM skills, subgroup analyses were conducted based on factors related to increased self-confidence in MTM abilities . StudentEnsuring pharmacy graduates are adequately prepared to provide MTM services is important to meet the needs of the patient population. Popovich eloquently stated that pharmacy students need exposure to new information (knowledge and skills) and then, need to experience the application of that information to cultivate the intellectual confidence required to enable action . The conThis present study demonstrated that our students’ didactic learning opportunities provided a good foundation to engage in MTM service delivery upon entering APPE with baseline knowledge of the process. Most students (68%) were engaged in MTM-related activities during APPEs, which significantly increased their self-confidence to practice MTM above those who did not report receiving MTM learning opportunities during APPEs. This demonstrates the activities are developing the confidence desired, however, it indicates a potential need to increase experiential exposure to MTM services above 68%, as all our students should garner patient-centered care experiences. Or, is it possible that there were additional students who participated in delivery of MTM services during APPEs, but who did not indicate such during the self-reported exposure? For example, students in ambulatory settings who were in fact conducting CMRs with patients and collaborating with providers at the site to optimize medication therapy, may not have defined the activity as MTM, perhaps because they were not billing for the service as “MTM” using the web-based platforms typically used to provide the services, which were discussed in the classroom and/or used in their work place. Disparate definitions of what activities constitute MTM may have affected student response to individual questions or completing the survey overall. In the US, the profession itself struggles with defining and identifying the services or activities which constitute MTM and how to define and represent pharmacist patient care activities in the electronic medical record . We idenSeveral efforts were made to reduce the possibility of response bias through a broad-based email invite asking for feedback overall on APPEs, by making the surveys anonymous at each point and completing the interviews online in an environment less likely to encourage social desirability. Additionally, the invite came from a member of the research team not within the school/program of pharmacy on campus, so there is limited reason to believe students would be trying to ‘say the right thing’ given they were unlikely to know that faculty member personally. Researchers attempted to achieve a good response rate by using the designated college email system (to avoid the email being marked trash or spam) and two email reminders. The low response rate could have been impacted by the survey coming from a faculty member who students may not have been familiar with. An additional factor impacting response could have been the first email for distribution of the survey was sent to students in the final week of the didactic curriculum when students find themselves busy with final exam preparation.Following APPEs, student confidence to engage in MTM improved consistent with the desired accreditation standards and practice expectations, demonstrating the impact of the APPEs ,10,11,15Two specific findings from this study leave us with more questions. Why did students indicate they are less likely to provide MTM after graduation? Why did fewer students indicate that MTM is patient-centric in the post survey? While students grew more self-confident in their abilities to deliver the core components of MTM service delivery, they ended the APPE year with fewer indicating likelihood to practice MTM post-graduation, even among those who gained MTM confidence and experience . This coThe reduction in the perception that MTM is interactive and patient-centric may reflect how MTM is practiced by pharmacists and experienced by the students in the real-world setting. Many regional pharmacists and students engage in targeted interventions for specific medication-related problems or telephonic adherence/refill reminder programs considered part of MTM service provision. While these activities constitute a component of MTM service delivery, they do not represent the highly interactive pharmacist-patient-prescriber communications typical of a CMR ,4,5,6. SStudents gained self-confidence to engage in the core components of MTM following the opportunity to engage in MTM related activities during APPEs. Therefore, colleges should continue to verify the availability of high level APPE MTM learning opportunities for all students. To ensure systematic integration of MTM across the curriculum and set appropriate practice expectations, we recommend that pharmacy curriculums continue to emphasize a consensus definition of MTM as disparate definitions of what constitutes “MTM” may cloud expectations.


The study evaluated clinical efficacy of intensity modulated radiation therapy (IMRT) in treating patients with thyroid-associated ophthalmopathy (TAO) and defined predictive factors that associated with treatment response. A total of 178 TAO patients were treated with retro-orbital IMRT with radiation dose of 20 Gy in 10 fractions. The immediate and long-term treatment response and complications were evaluated. Besides, logistic-regression analysis was conducted to identify possible predictive factors. TAO symptom score significantly fell from the initiation to 6-month post-treatment (P < 0.001). 134 patients (73.2%) had mild to significant response to IMRT, and 172 patients (96.6%) achieved stabilization of TAO without future progression. Current smoker  and symptom duration longer than 18 months  were identified as independent predictive factors for non-response of TAO to retro-orbital IMRT. Immediate complications were slight and self-limited, and long-term complications mainly included chronic xerophthalmias in12 patients (6.74%) and cataract formation in 4 patients (2.25%). The study suggested that IMRT was a viable option for treating TAO patients, with a satisfactory symptom control ability and acceptable post-treatment complications. The subsequent edema of the EOMs and fats increased volume within the bony orbital cone, and led to typical symptoms of TAO including orbital pain, proptosis, tearing, EOM dysfunction, diplopia, sight loss, exposure keratitis, corneal ulceration and even blindness.Thyroid-associated ophthalmopathy (TAO), an inflammatory fibrosing pathology of retro-orbital contents, is the most common extrathyroidal manifestation of autoimmune hyperthyroidism (Graves’ disease). It is an autoimmune disease caused by production of auto-antibodies that activate the thyroid stimulating hormone receptors (TSHR), which is primarily located in thyroid tissues but also expressed in adipose and connective tissues within the retro-orbital area. These auto-antibodies induced inflammatory and fibrotic responses of the retro-orbital fat and extraocular muscles (EOMs), characterized by T cell infiltration and fibroblastic glycosaminoglucan accumulation5. Besides, the usage of corticoids is also restricted by its multiple side-effects including hyperglycemia, hypertension and immune system compromise.The treatment TAO aimed at preserving vision, reducing diplopia, relieving orbital pain and improving cosmetic appearance. For patients whose TAO symptoms are not relieved after normalization of thyroid function, glucocorticoids have been traditionally considered as the first-line treatment method. About 65% of these patients could benefit from the corticoids, but relapse of TAO symptoms is common when the corticoids are reduced or withdrawn6. In fact, there are previous reports concluding that RT should be used as the first-line therapy for TAO, although controversy still existed in the field8. The mechanism of RT in treating TAO is mainly through its non-specific anti-inflammatory effects, suppressing radiosensitive lymphocytes and inhibiting fibroblast proliferation and glycosaminoglucan secretion9. Despite RT is slower than corticoids to reveal its curative effects, it could provide a more prolonged protection period10.Radiation therapy (RT) is an established modality for the treatment of TAO, and is particularly useful in treating patients who are insensitive to or cannot tolerate corticoidsTraditionally, lateral opposing fields (LOF) technique has been utilized by radiation oncologists in treating TAO for its simple set-up and prompt delivery procedures. However, one of the most obvious drawbacks of the technique is that, to minimize the dose to lenses, beams are either blocked to anterior portion of the globes or titled 5 degrees posteriorly, which would lead to inadequate dose to the EOM insertions and anterior portion of the retro-orbital fats that are commonly involved in TAO process. Besides, dose distribution within the target is hard to reach homogeneous by the LOF technique. Afterwards, new techniques including three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiation therapy (IMRT) emerged, and have been regarded as the current standard radiation technique for head and neck tumors. Nevertheless, the clinical outcomes of using these techniques in treating TAO patients have not been reported.13. As a result, IMRT may be more applicable in the retro-orbital radiation because of the quite irregular target volume of the retro-orbital structures. Indeed, Lee et al. identified the dosimetric superiority of IMRT in the retro-orbital radiation in his dosimetric study involving 10 TAO patients undergoing IMRT treatment14. IMRT was found to have a significantly superior conformity index and homogeneity index than 3DCRT and LOF, and could provide better dose sparing to globes, lenses and optic nerves. Nevertheless, as it is a dosimetric study, no treatment outcomes were reported, and the number of patients undergoing IMRT was limited. Moreover, no other studies has been done concerning the clinical outcomes of the retro-orbital IMRT in treating TAO patients.IMRT, as an evolutionary form of 3DCRT, is capable to deliver a dose distribution around a more irregular and complex target volume. Besides, it could achieve steeper dose gradients between the target and normal structures, thus reducing the dose to surrounding tissues without compromising the planning target coverageTherefore, the primary goal of the current study is to evaluate the therapeutic efficacy of the retro-orbital IMRT in treating TAO, as well as the accompanying acute and long-term complications; the secondary goal is to identify possible predictive factors that associate with the treatment response to the retro-orbital IMRT.Our research is in accordance with the Helsinki Declaration and approved by the medical ethics committee of West China Hospital, Sichuan University. Written informed consent has been obtained from all individual participants included in the study.The study is a retrospective study based on prospective collection of treatment data. The data of disease severity, therapeutic response and complications were prospectively collected in clinic when we treated TAO patients with retro-orbital IMRT technique between July 2010 and December 2014. Patients were included in the study with the following inclusion criteria: (1) Patients were diagnosed with TAO. The diagnosis of TAO was confirmed at the Department of Ophthalmology, West China Hospital after a complete neuro-ophthalmologic examination. The full workup included history and physical examination, thyroid disease history, thyroid laboratory tests, and CT and/or MRI imaging used to rule out other diseases including infection and tumor. (2) The TAO was treated with IMRT technique at our department. (3) Medical records and laboratory reports of the patients were complete. (4) The patients had regular follow-up visits and the corresponding clinic data were available. Patients were excluded in the following conditions: (1) lost to follow-up or died because of other diseases; (2) had received radiotherapy for TAO or decompressive surgery before enrollment; (3) treated with other radiotherapy techniques including LOF and 3DCRT; (4) only patients with hyperthyroidism were included to achieve a more homogenous background, those with hypothyroidism were excluded; and also, (5) patients with single-eye irradiation were excluded.15. However, due to several limitations of the NPSPECS system16, a more comprehensive TAO symptom evaluation system was utilized in the current study, which included additional symptom categories of diplopia, orbital pain and tearing in evaluation17. Each category, except for the tearing, was assigned a score of 0, 1 or 2 representing no symptoms, mild to moderate symptoms, and severe symptoms, respectively. Tearing was allocated a score of 0 (no tearing) or 1 (tearing). Total TAO symptom score was the cumulative score of all the listed categories and ranged from 0 to 15.Patients’ TAO symptoms were classified into 5 general categories according to the NOSPECS system: soft tissue signs, proptosis, EOM dysfunction, corneal involvement, and sight lossTreatment response of the TAO symptom was based on the score difference between the baseline score and 6-month post-treatment score, which was calculated as [(baseline score – 6-month post-treatment score)/baseline score], and categorized as follows: >66% - significant response, 33% to 66% - moderate response, 10% to 33% - mild response, 0% to 10% - no response and <0% - progression. Treatment response in the individual symptom categories was defined as complete response (CR) if the symptom was completely resolved, or partial response (PR) if the symptom was improved but not completely resolved.All patients received retro-orbital radiation with linear accelerator based step-and-shoot IMRT technique. Patient was immobilized with a custom-made thermoplastic mask, and then they underwent CT scan with slice sickness of 2.5 mm for image acquisition and target contouring. The origins to insertions of the EOMs and the retro-orbital fatty spaces within the main bulk were encompassed as the clinical target volume (CTV) Fig. . LacrimaThe statistical analyses were performed using SPSS Statistics version 22.0. Descriptive statistics were utilized to characterize the patient population, treatment outcomes and complications. The symptom scores at different treatment periods were compared by Kruskal-Wallis test and Mann-Whitney U test, and illustrated in Box plots. Pearson’s Chi-squared test and Fisher’s exact test were conducted to identify the variables predictive of non-response to IMRT, and a multivariate logistic-regression analysis was performed to determine the independent risk factors. All the statistical analyses were considered significant at two-tailed P < 0.05.The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. All data generated or analysed during this study are included in this published article.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The characteristics of these patients were presented in Table The immediate response of the whole symptom severity to IMRT has been shown in Fig. The response to IMRT in the categories of individual symptoms at 6-month post-treatment was shown in Table In the aspect of acute complications, slight hair loss around sideburns and increased milphosis or madarosis were the most common complications after retro-orbital IMRT, which occurred in 26 patients (14.6%) and 32 patients (17.9%), respectively. The symptoms commonly appeared from 1-month to 4-month post-IMRT, and could be in remission spontaneously by 6 months after the treatment. Unilateral or bilateral eye redness also occurred in 12 patients (6.74%), within the period from start of radiotherapy to 4 months post-treatment. Similarly, the eye redness could be spontaneously relieved or eliminated within a week. Particularly, a total of 21 patients (11.8%) informed of increased orbital pain accompanying with self-consciously progressed proptosis after the treatment, but their symptoms achieved PR or CR at the 6 months’ follow-up visit. This may be caused by temporary edema of the retro-orbital tissues after RT.The symptom score of these patients at the last follow-up was not significantly different from the 6-month post-treatment score, with the same median score of 3 points. For the 134 patients who had immediate treatment reactions of mild, moderate and significant response, only 7 patients (5.2%) had obvious exacerbation or recurrence of TAO symptoms, and the disease of the rest 127 patients (94.8%) was maintained or continued to improve. It needs to mention that, 5 of the 7 patients with recurrent TAO symptoms were current smokers and refused to quit smoking. For the 44 patients with immediate treatment reactions of no response or progression, no obvious improvement of the disease severity happened during the subsequent follow-ups, and surgery intervention was recommended by ophthalmologists to those meeting the operation indication.As for complications, the intermittent eye redness, slight sideburns hair loss, and increased milphosis or madarosis were not presented in the cohort at the last follow-up visit. A total of 12 patients (6.74%) developed chronic xerophthalmias, and were well-controlled with administration of artificial tears. Cataracts occurred in 4 patients (2.25%), and were treated successfully with cataract removal and lens replacement. No radiation retinopathy or secondary malignancy has been detected in the cohort.Table To our knowledge, the current study based on 178 patients with TAO firstly evaluated the overall efficacy and treatment outcomes of retro-orbital IMRT in treating TAO symptoms, and identified possible risk factors predictive of non-response to the treatment method. Our findings demonstrated that IMRT was a feasible option for treating TAO patients, with a satisfactory disease control ability and acceptable post-RT complications. In addition, current smoking and duration of TAO longer than 18 months were identified as independent risk factors for poor response of TAO to IMRT.19. All our patients received a total dose of 20 Gy in 10 fractions to both retro-orbital contents, which is the most adopted radiation protocols in previous studies. However, it should be noted that the 20 Gy/10-fraction protocol was established as a balance of efficacy and toxicity based on LOF technique. In other words, 20 Gy in 10 fractions was identified by previous reports as the most efficacious and minimally toxic treatment dose in treating TAO patients when using the LOF technique. As IMRT could achieve a better dose differentiation between tumor target and normal tissues, the protocol may not be the most optimized protocol for IMRT. Considering that it has not been established that whether 20 Gy was adequate for the retro-orbital contents to reach plateau of relief, IMRT may provide a chance to further raise the dose of the target volume to achieve a higher symptom control ability without causing more complications, and the optimal RT protocol is needed to be clarified in future studies.Overall, the retro-orbital IMRT exhibited satisfactory therapeutic effects in our cohort. The total symptom score significantly fell from the initiation of the treatment to 4-month post-RT. Although the 6-month score was not statistically different from the 4-month score, a decreasing trend could still be found. In the aspect of patients, 73.2% of them had mild to significant response to IMRT, and 96.6% of them achieved stabilization of TAO without future progression. Compared with previous studies utilizing LOF technique, the proportions in the current cohort are at a relatively high level17, and our results were in accordance with the previous studies that the two symptom categories had relatively high improvement rates  in the cohort experienced self-conscious aggravation of TAO symptoms after the start of retro-orbital IMRT, but the aggravated symptoms disappeared afterwards. The pseudo-progression mostly occurred in patients with higher levels of initial symptom severity scores, and it is possibly caused by the temporary edema of the retro-orbital tissues after radiotherapy.28. For patients who received a lens dose of 1500 cGy fractioned during a treatment course, the probability of cataract formation was 12% at 5 years18. Secondly, that IMRT could provide a well preservation to adjacent normal structures may also contribute to the low rate of cataract formation. With appropriate field volume designed to protect the lens, the lens dose was estimated to be under 700 cGy, fractioned in 10 fractions during 2 to 3 weeks. Thus, the risk of cataract development after IMRT for TAO is supposed to be small.In the aspect of long-term complications, our study suggested satisfactory safety of IMRT in treating TAO. Only 4 patients (2.25%) in the cohort developed cataracts. Considering that the advancing age was also correlated with increased risk for cataract, the possibility of cataract directly caused by IMRT was actually further less. The low dose in treating TAO is one of the reasons. According to previous data from orbital lymphoma patients, RT-induced cataract formed after a single fraction of 200 cGy29. The risk of radiation retinopathy is tightly associated with total dose, dose rate, use of radiation sensitizers (e.g. chemotherapeutic agents) and the presence of systematic disease (e.g. diabetes)30. The radiation dose which can cause up to 5% radiation retinopathy within 5 years was estimated to be 45 Gy28. The radiation dose in our patients is much less than 45 Gy and chemotherapy is not needed, thus it is reasonable that no patients in our cohort suffered from radiation retinopathy. Secondary malignancy is another major concern. The excess lifetime risk of RT-induced cancer after treating TAO was calculated to be 0.7% in previous reports31, and the estimation was based on LOF technique. IMRT could significantly reduce the dose sparing to bone marrow and brain, however, the radiation dose in the painting area was larger than the conventional irradiation as IMRT used multiple fields with different intensity modulation for each beam. The soft tissues or muscles within or near the target area were susceptible to the development of radiation-induced secondary malignancy. Besides, some dosimetric studies reported increased risk of secondary malignancy in soft tissues which were exposed to low-dose radiation brought by IMRT. As a result, although no secondary malignancy was detected in our cohort, the risk of secondary malignancy development when utilizing IMRT technique in treating TAO patients should be paid attention and re-evaluated in future studies.Because cataract is easily to be dealt with eye operation, some other possible complications are clinically more severe. Radiation retinopathy is a sight-limiting complication induced by ophthalmic RT, which is characterized by vascular closure, vascular incompetence and resultant loss of visionIn conclusion, the study demonstrated that retro-orbital IMRT was a viable option for treating TAO patients, with a satisfactory symptom control ability and acceptable complications. In addition, current smoking and duration of TAO longer than 18 months were identified as independent risk factors for poor response of TAO to IMRT.Informed consent was obtained from all individual participants included in the study.


Self-efficacy, defined as confidence in the ability to carry out behavior to achieve a desired goal, is considered to be a prerequisite for behavior change. Self-efficacy correlates with cardiovascular health although optimal timing to incorporate self-efficacy strategies is not well established. We sought to study the effect of an empowerment approach implemented in the introductory phase of a multicomponent lifestyle intervention on cardiovascular health outcomes.Prospective intervention cohort study.Patients in the Integrative Cardiac Health Project Registry, a prospective lifestyle change program for the prevention of cardiovascular disease were analyzed for behavioral changes by survey, at baseline and one year, in the domains of nutrition, exercise, stress management and sleep. Self-efficacy questionnaires were administered at baseline and after the empowerment intervention, at 8 weeks.Of 119 consecutive registry completers, 60 comprised a high self-efficacy group (scoring at or above the median of 36 points) and 59 the low self-efficacy group (scoring below median). Self-efficacy scores increased irrespective of baseline self-efficacy but the largest gains in self-efficacy occurred in patients who ranked in the lower half for self-efficacy at baseline. This lower self-efficacy group demonstrated behavioral gains that erased differences between the high and low self-efficacy groups.A boost to self-efficacy early in a lifestyle intervention program produces significant improvements in behavioral outcomes. Employing empowerment in an early phase may be a critical strategy to improve self-efficacy and lower risk in individuals vulnerable to cardiovascular disease. Cardiovascular disease (CVD) is the leading cause of death in Westernized nations . PatientThe main strategy in CVD prevention is to identify and improve risk factors . SustainHowever, awareness alone is not adequate to change lifestyle behaviors affecting CVD risk , Scotto. For behIntegral to a collaborative care model for chronic disease is patient empowerment, which is defined as helping patients to develop the inherent capacity to be responsible for one’s own life . EmpowerThere is an inverse relationship between self-efficacy and CVD risk factor profiles , Eliass. HoweverIn the present study, we investigated the impact of an intervention designed to enhance self-efficacy by giving patients an early boost using an empowerment approach to improve adherence to healthy lifestyle behaviors. The empowerment intervention was implemented as part of a cardiovascular (CV) health program targeting behaviors in the areas of nutrition, exercise, perceived stress and sleep.The Integrative Cardiac Health Project (ICHP) is a prospective registry of patients enrolling in a 12-month CV health program. The study has been registered with clinicaltrials.gov and may be found using identifier NCT01975181. All patients give informed consent for participation in the registry and the study is being conducted according to the principles stated in the Declaration of Helsinki.Patients are self-referred or referred by a healthcare provider to assess their CVD risks and to learn how those risks can be improved through lifestyle behavior changes. Patients participating in ICHP are men and women over 17 years of age who are eligible for care in the Department of Defense Healthcare System. Participants are comprised of active duty service members, dependents of service members, and retirees from active service along with their dependents. As such, the participants in ICHP include both genders with a broad spectrum of ages, races and ethnicities. Some patients entering ICHP have diagnosed coronary heart disease but the large majority is seeking to reduce CV risk factors.Upon entry to ICHP, patients meet with a nurse practitioner (NP) to undergo a CV-focused history and physical examination and submit a cardiac-relevant laboratory panel of tests. Based on this baseline assessment, patients are categorized as low, intermediate, or high risk for CVD by the Framingham Risk Score, the most widely used CVD risk estimator. Family history of premature CVD was collected and defined as a parent or sibling who had a CV event before the age of 55 in men and 65 in women. Patients also complete a series of validated questionnaires to determine their individual pattern of lifestyle behaviors.Specific questionnaires focus on the domains of the program and are administered at baseline and at program completion, at 12 months: nutrition (Rate Your Plate), exercise (minutes of continuous exercise per week), stress , and sleep . A CV-relevant Self-Efficacy Questionnaire is administered at baseline and after an empowerment workshop, at 8 weeks from baseline See .Self-Efficacy Questionnaire: Self-efficacy was measured with the adapted diabetes mellitus type 2 self-efficacy scale. Since most self-management tasks apply generally to chronic diseases as a whole, this scale was used to measure the level of confidence people have about their ability to perform the self-management tasks necessary to reduce vascular risk. The 9-item questionnaire is scored on a 5-point Likert scale, with a higher self-efficacy score corresponding with better self-efficacy. Reliability of the questionnaire was tested with a Cronbach’s alpha of 0.69  . The tool, which currently forms the foundation of current primary prevention guidelines, uses age, gender, total cholesterol, HDL cholesterol, smoking history and blood pressure (BP) to calculate the risk of coronary heart disease outcomes (MI and coronary death) over the subsequent 10 years. Scores are categorized as low (<10), medium (11-19) and high (>20).Rate Your Plate (RYP): This ICHP-modified 26-item nutrition questionnaire, originally developed in 1983 by the Pawtucket Heart Health Program (PHHP), consists of questions focusing on foods that contribute the most fat, saturated fat, and cholesterol to the American nutrition. In a calibration study, the RYP was compared with the widely used Willet food frequency questionnaire (FFQ). When the RYP was administered prior to the Willet FFQ, Pearson product-moment correlations ranged between -0.45 and -0.65 on fat variables and nutrition cholesterol , thus having the capacity to quantitatively reflect intake of fat and saturated fat . Essentially, a global score of greater than 5 indicates a poor sleeper. Sleep perturbations can be categorized by scores as follows: 0 to 5 is a good sleep score; 6 to 10 shows mild sleep difficulty; 11 to 15 moderate sleep difficulty, and 16 to 21 severe sleeping difficulty.interval . NineteeFatigue Visual Analog Scale: This scale is borrowed from the Stanford Patient Education Research Center where it was tested on 122 patients, with mean value of 4.89 and standard deviations of 2.71 (Stanford Patient Education Research Center). This fatigue scale asks patients to express their experience of fatigue from 0 to 10 for the previous 2 week period. Patients who circle 5 to 6 express mild fatigue, 7 to 8 moderate fatigue, and 9 to 10 severe fatigue.Empowerment Intervention: Empowerment strategies for patients are comprised of a comprehensive risk assessment report with detailed lifestyle recommendations for optimizing risk reduction generated by the NP. After two initial NP appointments which allow patients to problem-solve barriers to lifestyle change, clarify goals and identify motivations, patients attend a multi-disciplinary educational workshop. The workshop is comprised of an interactive healthy food demonstration and stress management experience and focus on the impact of actionable behaviors on health. For the remainder of the program and after the workshop, patients receive ongoing motivational advice by health coaches in order to achieve healthy goals in the program’s domains as established by the NP in the first two weeks.Statistics: Sample size calculation indicated that a sample of 100 participants would provide a stabilized and generalizable set of data. Plans were made to enroll approximately 115 patients to allow for a 15 percent rate of drop-out for failure to complete surveys properly. Data are presented as means with standard deviations or proportions. A median score was used to split patient Self-Efficacy Scores into two groups of nearly equal size allowing comparisons between high and low scoring groups. Demographic and survey health variables were compared using chi-square test for categorical variables, and Student’s t-test for continuous variables. Pearson product-moment correlation coefficients were used to measure correlations because the data sets were normally distributed as seen on inspection of population histograms. All tests assumed p < 0.05 as statistical significance.The study population is comprised of 119 consecutive graduates of the ICHP CV program. The demographic variables of the group are provided in Inspection of a histogram of the self-efficacy scores revealed that these were normally distributed. The median score (36 points) of the self-efficacy questionnaire measured at entry to ICHP was used to divide the participants into high (n=60) and low scorers (n=59). Demographic variables were not different for high and low self-efficacy subgroups See . FramingAt baseline, the low self-efficacy group entered the ICHP program with lower scores for a healthy nutrition, less exercise minutes per week, higher levels of perceived stress, poorer sleep quality and greater fatigue See .These findings were corroborated with Pearson r product-moment correlations which showed a strong correlation of nutrition scores and moderately strong correlations of exercise minutes, lower stress scores, and better sleep quality with total self-efficacy scores See .The Pearson r coefficients show a strong correlation between baseline self-efficacy score and nutrition score and moderately strong correlations for exercise, stress and sleep.In response to the empowerment intervention of the ICHP program, 98 of the total 119 patients (82%) showed gains in self-efficacy with an average improvement of 7.2 ± 4.4 points; 11 (9%) showed no change; and 10 (8%) decreased their self-efficacy an average of 2.0 ± 1.2 points. In the group of 59 patients with low self-efficacy at program entry, 58 (98%) showed improvements averaging 9.4 ± 4.4 points in self-efficacy and only one (2%) decreased self-efficacy by 2.0 points.Among all 119 participants, only three (3%) were active tobacco smokers, each reporting current smoking of 2 cigarettes per day. Nineteen other patients were former smokers, having an average 1 pack per day history of smoking, and having quit an average of 26 years prior. Since tobacco use occurred so infrequently in the study population, further analysis of tobacco use was not performed.The salient finding of the current study is that a boost to self-efficacy early in a lifestyle intervention program produces substantial improvements in behavioral outcomes. The overwhelming majority of patients responded with improved self-efficacy scores. Self-efficacy scores increased irrespective of baseline self-efficacy.Though patients in both the low and the high self-efficacy groups showed improvements in self-efficacy and behavioral survey scores, the largest gains in self-efficacy occurred in patients who ranked in the lower half for self-efficacy at baseline. This lower self-efficacy group also demonstrated behavioral improvements that erased differences between the high and low self-efficacy groups or at least provided a substantial “catch-up” such that the scores on completion of the program were approaching or better than baseline scores for the high self-efficacy group.Our findings agree with prior reports that self-efficacy scores at baseline correlate with the cardiovascular risk profile. Indeed in our population, patients with low self-efficacy scores were found to have a higher predicted cardiovascular risk by Framingham Risk Score in addition to less healthy cardiovascular behaviors . Given tPrior studies assessing the impact of self-efficacy on adherence to behavior change have frequently been limited to a single behavioral dimension such as nutrition , Timlin, Nothwe, Cha, 2 or exercEmploying an empowerment intervention early in the sequence of events in a heart-healthy program provides a mechanism for increased patient self-efficacy. Our findings validate numerous studies showing that interventions that aim to empower patients are valuable in promoting patient well-being, decision-making and self-management of chronic disease .The results of the current study appear to be generalizable to other locations and institutions. This group of patients at risk for CVD mirrors the population at large with regard to demographic profile and comorbid illnesses. The intervention that was provided does not require special equipment or resources and is therefore scalable and could be duplicated in other centers targeting CVD prevention.The current study has limitations. Because the intervention aimed at multiple dimensions of healthy CV behaviors, it is not possible to determine which aspects of the empowerment intervention were most effective. Likewise, with the current study design it is not possible to determine whether or not there was a synergistic impact from improvement in one behavior that helped stimulate improvements in other behaviors. A second limitation is the use of measurement tools that rely on self-report. While these tools are validated instruments to measure the behaviors for which they were targeted, the use of objective measures would give more robust information and therefore be more convincing. Unfortunately, objective measures are complex (nutrition measures), unwieldy (actigraphy for exercise and sleep), or do not readily exist (stress management).In summary, the results of this study support the idea that a lifestyle behavioral change program aimed at providing an early boost to self-efficacy is feasible and can yield positive results. These findings are particularly significant in high-risk patients who are vulnerable to CVD and may be in a position to make critical behavioral lifestyle modifications to lower their risk of overt disease. Further study is warranted to measure the impact that such behavior changes have on prevention of CVD events.