Documented deficiencies in adult sickle cell disease (SCD) care include poor access to knowledgeable providers and inadequate treatment in emergency departments (EDs).The aim of this study was to create patient-reported outcome measures of the quality of ambulatory and ED care for adults with SCD.We developed and pilot tested SCD quality of care questions consistent with Consumer Assessments of Healthcare Providers and Systems surveys. We applied psychometric methods to develop scores and evaluate reliability and validity.The participants of this study were adults with SCD (n = 556)—63% aged 18 to 34 years; 64% female; 64% SCD-SS—at 7 US sites.The measure used was Adult Sickle Cell Quality of Life Measurement information system Quality of Care survey.r = 0.32–0.83 correlations with global care ratings). Compared to general adult Consumer Assessments of Healthcare Providers and Systems scores, adults with SCD had worse care, adjusted for age, education, and general health.Most participants (90%) reported at least 1 severe pain episode  in the past year. Most (81%) chose to manage pain at home rather than the ED, citing negative ED experiences (83%). Using factor analysis, we identified Access, Provider Interaction, and ED Care composites with reliable scores (Cronbach α 0.70–0.83) and construct validity (Results were consistent with other research reflecting deficiencies in ED care for adults with SCD. The Adult Sickle Cell Quality of Life Measurement Quality of Care measure is a useful self-report measure for documenting and tracking disparities in quality of SCD care. Providers can be overly concerned about addiction, leading to failure to provide timely and adequate pain control when needed.,14–16 In turn, these negative health care experiences were related to many adults postponing seeking health care, managing pain episodes at home, and self-discharging from the hospital.–20Adults with SCD report stigmatization in the health care system NHLBI also sponsored the development of the Adult Sickle Cell Quality of life Measurement (ASCQ-Me—pronounced “Ask me”) information system,,23 a system designed to be complementary with the Patient-Reported Outcomes Measurement Information System (PROMIS). ASCQ-Me and PROMIS  use comparable methods for instrument development and validation to create state-of-the-science assessments for self-reported health.As a consequence of these shortcomings, the National Heart, Lung, and Blood Institute (NHLBI) launched a series of efforts aimed at improving adult SCD care, including the recent development of a set of evidence-based clinical practice guidelines for primary care providers.As part of the ASCQ-Me project, we concurrently developed and tested the ASCQ-Me Quality of Care (QOC) survey to be a patient-reported outcome designed to assess access and quality of adult sickle cell care. We used rigorous psychometric methods to evaluate the ASCQ-Me QOC survey with a cohort of adults with SCD, using a cross-sectional design. Our goal was to develop a measure that allows for comparison of results across care settings and over time, and to produce comprehensible information that has utility for both health care providers and patients served.Here we describe the development and psychometric properties of the ASCQ-Me QOC survey. We hypothesized that responses of adults with SCD to a series of questions about their health care experiences could be used to derive reliable and valid QOC scores. Moreover, we expected that the empirical evidence provided by these questions would reliably discriminate the care experience of patients with SCD from that of other populations.2All materials, methods, and procedures received approval from the Institutional Review Boards of the American Institutes for Research, Children's Hospital Oakland Research Institute, and the sponsoring hospitals.2.1,23 The sample size requirement for the QOC analysis was based on the number of respondents per question. Depending on the intercorrelations among items in the factors, recommendations can vary from 5 to 20 respondents per item in the factor analysis to support stable estimates—larger sample sizes are required when the intercorrelations are smaller. There were 12 questions hypothesized to address 4 composites in the field test version of the ASCQ-Me QOC; thus, a sample size of 240 would be ample. The targeted enrollment for the ASCQ-Me field test of 550 adults far exceeded that needed for the current study.Participants completed the ASCQ-Me QOC survey anonymously during the ASCQ-Me field test data collection, a larger study with methodology detailed elsewhere.Data were collected at 7 geographically and clinically  varied sites of care, with the goal of addressing potential sources of bias by enrolling a diverse sample of patients. Inclusion criteria were broad, as follows: any diagnosis of SCD and ages ≥18 years. Exclusion criteria were as follows: no diagnosis of SCD or diagnosis with sickle cell trait, younger than 18 years, and not able to read English. Participants answered screener questions when responding to recruitment materials in order to determine that they should not be excluded. Their sickle cell providers also referred participants to the study so they had a known diagnosis of SCD. Data were collected between October 2008 and May 2009.2.2Participants were volunteers responding to descriptions of the study at clinical care sites, SCD community-based organizations, and the Sickle Cell Disease Association of America website. At ASCQ-Me field test sites, site coordinators explained study procedures in detail to qualified adults who then signed informed consent forms. Site coordinators then entered minimal demographic data about the participants  and assisted them in logging into the ASCQ-Me data collection website. Participants proceeded to complete the survey on their own.2.3 and a literature review. Next, we conducted individual and focus group interviews involving 122 adults with SCD and 15 providers. We qualitatively analyzed participant responses to confirm and expand on initial themes related to QOC. Themes identified included the following:Lack of SCD knowledge on the part of providers in ambulatory and emergency department (ED) settings, leading to stigmatization of adults with SCD as drug seeking, as well as to inappropriate and ineffective careExtremely long waits before receiving care in the EDDisrespectful providers who did not consider information provided by the patient, leading to undermedication or overmedication for painPreference of adults to treat the symptoms of SCD outside of the health care setting, given the precedingWe generated preliminary themes about the experiences of adults with SCD, and then ASCQ-Me questions, from information from the NHLBI consumer working groups,28 CAHPS represents the most widely used method for capturing and reporting patients’ experiences of their care, covering literally millions of lives. CAHPS measures are used to assess the performance of health care entities including Medicare, Medicaid, private health plans, clinicians, and medical groups, among others.–33 We included questions that were similar or identical to CAHPS when questions were consistent with content suggested by the ASCQ-Me formative research, in order to enable comparisons across care experiences.These themes informed the construction of the ASCQ-Me QOC survey questions that were also modeled after the Consumer Assessments of Healthcare Providers and Systems (CAHPS) surveys. and consisted of 2 items, for example, “In the past 12 months, when you tried to make an appointment to see a provider, how often were you able to get one as soon as you wanted?” (rated Never to Always). The second domain mirrors the CAHPS “Provider Communication” composite and consisted of 4 items, for example, “In the past 12 months, how often did the doctor or nurse listen carefully to you?” (rated Never to Always). The third domain, “ED Care,” included 3 items regarding the patient's interaction with staff  during emergency visits along with an item asking the extent to which providers believed that the patient had severe pain. The fourth composite—ED Pain Treatment—included 2 items that asked how successfully pain was treated in the ED, and how long the patient had to wait to get treated.The ASCQ-Me QOC survey consists of 27 questions, but skip patterns allow respondents to complete the survey in as few as 5 questions, if they did not have any sickle cell–related pain in the past 12 months and never sought emergency or ambulatory care. Twelve ASCQ-Me QOC questions were hypothesized to be indicators of 4 domains of health care quality. The first domain mirrors the CAHPS “Access” compositeNever to Always) with their usual provider, and with the QOC received from their usual provider and the ED. Participants also provided an overall evaluation of all the care they received on a scale from 0 to 10 anchored from Worst to Best care possible. Separate scores were produced for each of the 4 global questions.Three questions addressed global evaluations of care for SCD by asking participants how often they were satisfied . Twelve QOC survey questions were hypothesized to form 4 composite scores: Access, Provider Communication, ED Care, and ED Pain Treatment. We evaluated the amount of systematic information provided by these 4 composites by determining their internal consistency reliability using Cronbach α. We examined the distribution of composite scores to see the percentage of patients who reported the highest (ceiling effect) and lowest (floor effect) quality. We evaluated the construct validity of the composites using the following: scaling success rate,37—to determine whether 100% of correlations between responses to questions and their composite score were stronger (correcting for overlap) than the correlation of those questions with other composite scores; confirmatory factor analysis (CFA),40—to determine whether the hypothesized relationships between indicators and underlying dimensions of QOC fit the data by requiring fit statistics >0.95 and the root mean square error of approximation (an indication of the amount of variance in the data not accounted for by specified relationships between questions and composites) <0.06; and examination of correlations of each composite measure score to the 4 overall ratings of care.Data analyses were conducted using Statistical Analysis Software . Once a final revised model was identified, the analyses were repeated on each of the 4 remaining sets of imputed values to evaluate the generalizability of the results. The analyses were then repeated using all 5 sets of imputed values combined into 1 data set. Results from these subsequent analyses are reported only if they differ from the results based on the single set of imputed values and if they suggest a poor fit for the revised structure. We expected QOC scores for adults living with SCD to be more similar to those for Medicaid, with lower quality scores compared with Medicare or private insurance.We also examined the validity of ASCQ-Me QOC scores by comparing the scores of those of “known groups”—comparable, publicly reported scores for people covered under private insurance, Medicare, and Medicaid.When the CFA did not support the hypothesized relationship of questions to composite measures, we conducted exploratory factor analysis (EFA) and examined the rotated factor loading pattern. We identified those items as belonging to a composite that had a factor loading >0.30, with differences between that primary loading and any secondary loadings on competing factors of ≥0.20.33.1A total of 561 adults with SCD at geographically dispersed sites were enrolled in ASCQ-Me with 556 completing the QOC survey. Participants were mostly female (64%) and most were between the ages of 18 and 34 years (63%), with 20% aged 35 to 44 years, and 18% aged 45 years and older. Most participants reported that they had the Hb-SS variation of SCD (64%), followed by Hb-SC (21%), and Hb-Sβ thalassemia (10%). Less than 1% of respondents (0.89%) had missing data on the QOC survey.3.2Almost all participants (90%) indicated that they had had a severe pain episode in the past 12 months, with 20% reporting a pain episode within the past week, and 9% reporting a pain episode at the time of the survey. Half reported ≥4 episodes and 9% reported no pain episodes in the past 12 months. The average severity rating for the last pain episode was 7.8 ± 2.3 on a word graphic rating scale, where 0 = no pain and 10 = worst pain imaginable. Most participants (67%) reported that the pain was severe enough to interfere with their lives, with 37% reporting that the pain was so severe that they could not take care of themselves and needed either some help or constant care. The duration of the most recent pain episode ranged from 1 day (68%) to >1 week (21%).3.3Seven questions on the ASCQ-Me QOC survey were not hypothesized to contribute to composite scores but were included to provide information to characterize health care experiences Table . The maj3.4The CFA fit statistics did not support the arrangement of the 12 questions into 4 composites, so we conducted EFA on the questions plus the question on bad experiences in the ED. The EFA pointed toward 3 composites that had fit indices exceeding the conservative cutoff criterion of 0.50 for loading on a single factor and no loadings on a secondary factor >0.25, with the exception of the question about ease of getting an appointment for ambulatory care (Table r = 0.65) and provider ratings overall (r = 0.83) compared with the other composites provided evidence of construct validity. Similarly, the ED Care composite was most strongly related to overall ratings of QOC in the ED. Interestingly, the Access composite was also most highly related to overall evaluations of ED care.Correlations between the composites and the CAHPS global ratings of QOC can be seen in Table Figure Figures   were comparable to reports of adults treated under Medicaid Fig. . Both gr4 Also consistent with this literature, the composite that most strongly related to overall evaluations of health care was ED Care.We propose our successfully developed measure, ASCQ-Me QOC, as a patient-reported outcome measure of QOC for adults with SCD. While the ASCQ-Me QOC survey was developed with 4 domains in mind—Access, Provider Communication, ED Care, and ED Pain Treatment—factor analytic results provided more support for a 3-composite structure in which subsets of questions hypothesized to belong to the ED Pain Treatment topic were found to be highly related to either Access or ED Care. Given the salient role that pain episodes play in most patients’ lives and in their interactions with the health care system, it makes sense that questions referring to SCD pain treatment would not be separable from other aspects of the patients’ interactions with the health care system. Our literature review and qualitative research indicates that the experience of SCD pain pervades all areas of the lives of adults with SCD.,47 Moreover, Fig. Results of our psychometric analyses supported the reliability and validity of the 3 composites—access to care, quality of provider communication, and QOC in the ED—for adults with SCD. All 3 composites showed good precision for discriminating among groups experiencing poor QOC, while the low ceiling effects for the Access and ED Care composites suggest that these measures will do a good job of discriminating among groups of individuals who experience higher QOC. The Provider Communication composite may not be as discriminating among groups of individuals who have positive experiences on this care dimension; however, ceiling effects of ≥44% are not unusual for items that ask patients to evaluate their providers.) was supported. These results not only support the validity of the ASCQ-Me QOC survey but are also consistent with studies showing that adults with SCD report greater race-based and disease-based discrimination in health care compared with other African Americans. In turn, negative provider attitudes influence patient–provider interactions and quality of SCD care provided.Our hypothesis that adults with SCD would report care experiences similar to those reported by patients treated under Medicaid (who have historically given the lowest ratings of care when compared to patients treated under Medicare or private insurance,20,22The majority of our volunteer sample of adults with SCD had reasonable access to ambulatory care, which is not surprising given our sampling strategy that was appropriate for conducting psychometric evaluation of the ASCQ-Me QOC survey and that was not intended to be representative of the population of adults with SCD. Our select group of adults with SCD reported that their outpatient providers were knowledgeable about SCD care and highly rated regarding communication, respect, and time spent. Nevertheless, our adults reported very poor QOC in the ED. The majority of adults with SCD in the United States do not have access to either adequate ambulatory or adequate ED care.,51 Given skip patterns, the fewest number of questions that an adult with SCD would have to answer would be 5, thus taking <2 minutes to complete. This brevity lends to the use of the ASCQ-Me QOC survey in day-to-day clinical practice.Because the ASCQ-Me QOC survey psychometrics were generated within the context of a larger field test including ASCQ-Me short forms and PROMIS measures, we did not time how long it took respondents to complete the QOC measure. Given its length, the time to complete the ASCQ-Me QOC survey is likely to be <10 minutes, according to previous research and practice, with quicker times expected if the survey is administered electronically. Deaths related to SCD due to patient refusal to seek needed health care have been documented. Severe painful vaso-occlusive episodes remain a marker for premature mortality in a modern cohort and the well-documented delays in treatment when adults with SCD present to the ED can be associated with preventable deaths, such as what can occur with the rapid progression of acute chest syndrome.,55 The research reported here suggests that the ASCQ-Me QOC survey could assist in efforts to improve the QOC delivered to adults with SCD by identifying deficiencies from the patient's perspective and enabling care delivery systems to implement quality improvement initiatives and evaluate their success in addressing these deficiencies.The needed improvement of adult health care for SCD is literally a matter of life and death. In our qualitative data analysis for ASCQ-Me, adults reported that they delayed or completely avoided going to the ED because of their past negative experiences, despite facing life-threatening complications.5Understanding patient experiences is a first step in improving the QOC delivery. Improving access to routine and emergency care, provider communication, and the quality of emergency care as measured by the patient-reported outcome measure, ASCQ-Me QOC, can potentially reduce health care costs as patients receive timely and appropriate care.


Transcatheter aortic valve implantation (TAVI) is currently indicated for patients with severe symptomatic aortic stenosis who are unfit for surgery or when the surgical risk is high. Thanks to the increasing experience of surgeons, better patient selection, and substantial improvements in device technology, the procedure is now being performed with excellent outcomes and a progressively lower rate of complications. As a result, the cut-off threshold to implant a transcatheter valve is gradually moving toward lower risk patients. However, this is not supported by strong evidence from rigorous large clinical trials. The PARTNER 2A and SAPIEN 3 trials were conducted to address this gap in our knowledge. With surgeons gaining more experience in both case selection and technical aspects of the procedure, and with the tremendous improvements in device technology, TAVI has become a safer procedure with more predictable and reproducible outcomes. The latest generation of commercially available valves can be delivered via sheaths as small as 14F. Greater than mild paravalvular leaks, an Achilles heal of the procedure, has now dropped to less than 3% in many series. The procedure itself is now being performed under conscious sedation in many centers around the world, and the overall length of hospital stay continues to decline steadily.Transcatheter aortic valve implantation (TAVI), also known as transcathter aortic valve replacement (TAVR), is currently indicated for patients with severe symptomatic aortic stenosis and a prohibitive risk for surgery, or in patients with high risk for surgical aortic valve replacement (SAVR). Since Alain Cribier performed the first successful implant in 2002,2–5 have led to a worldwide trend to use TAVI in low and/or intermediate risk patients. However, such practice is not supported by solid evidence from large clinical trials. The PARTNER 2A and SAPIEN 3 trials, two of the largest TAVI trials conducted to date, were conducted to address this knowledge gap using two different generations of valves that are currently being used in clinical practice – the Sapien XT and Sapien 3 respectively. Results of both trials were recently presented at the ACC.16 Scientific Sessions and were published simultaneously in the New England Journal of Medicine and The Lancet. 7These substantial advances, coupled with encouraging outcomes from small studiesPARTNER 2A was in fact two parallel prospective randomized multicenter trials using the same transcatheter valve . The study enrolled 2,032 patients with severe symptomatic aortic stenosis and with an intermediate risk for SAVR. Patients were considered to be intermediate risk based on a detailed assessment by a multidisciplinary heart team. Intermediate risk was defined as a Society of Thoracic Surgeons (STS) score of 4–8%. Patients with an STS score of less than 4% were also enrolled if they were judged by the heart team to be at a higher risk because of other conditions that are not represented in the STS risk model. Exclusion criteria included recent myocardial infarction, bicuspid (or unicuspid) aortic valves, predominant aortic regurgitation, preexisting artificial valve in any position, complex coronary disease (unprotected left main disease or Syntax score >32), left ventricular ejection fraction <20%, active upper GI bleeding within 90 days prior to the procedure, contraindication to anticoagulant therapy, native aortic annulus size <18mm or >27mm, severe renal insufficiency (creatinine >3 mg/dL) and/or renal replacement therapy, and patients with an estimated life expectancy <24 months due to other comorbidities.Eligible patients were stratified into two cohorts after evaluating the suitable access route , and were then randomly assigned in a 1:1 ratio to undergo either transcatheter or surgical aortic valve replacement. Among the 2,032 patients who underwent randomization, 1,011 were assigned to TAVI and 1,021 to SAVR. 1,550 patients (76.3%) were judged to be suitable for transfemoral TAVI. The mean STS score was 5.8% in both groups, with 6.7% of the patients having an STS score of less than 4%, and 12% having a score that was greater than 8%.The study’s primary endpoint was the composite of death from any cause or disabling stroke  at 2 years. Secondary endpoints included major vascular complications, life-threatening bleeding, acute kidney injury, new-onset atrial fibrillation, paravalvular regurgitation, and permanent pacemaker implantation. The study was powered to detect differences by both intention-to-treat and as-treated analyses.p = 0.25). This held true in both the intention-to-treat and as-treated analyses. The risk ratio at 2 years for the primary endpoint in the TAVI group was 0.92  compared to the SAVR group. This risk ratio met the prespecified criterion for noninferiority (p = 0.001). 18 patients (10 in the TAVI group and 8 in the SAVR group) died during the procedure or within 3 days afterwards. The incidence of the individual components of the primary endpoint were also similar between both groups .The composite primary endpoint of death from any cause or disabling stroke did not differ between both groups . However, there was no significant between-group difference in the transthoracic-access cohort . It is important to mention that the transfemoral and transthoracic cohorts were pre-specified but were not powered to detect differences in the primary endpoint between the TAVI and SAVR groups.In the transfemoral-access cohort, TAVI resulted in a borderline significant reduction in death from any cause or disabling stroke compared to SAVR . The incidence of greater-than-mild paravalvular regurgitation was also higher after TAVI . On the other hand, TAVI was associated with significantly less life threatening bleeding , acute kidney injury , and new-onset atrial fibrillation . The need for new permanent pacemakers within 30 days of the procedure did not differ between both groups . Furthermore, patients in the TAVI group had a significantly shorter index hospitalization compared to those in the SAVR group .With respect to key secondary endpoints, major vascular complications were more frequent in the TAVI group compared to the SAVR group . The results at one year were compared to the those in the surgical cohort of the PARTNER 2A trial using an innovative pre-specified propensity-score analysis to control for the different patient characteristics. The analysis incorporated 22 pre-specified baseline characteristics that were factored through a logistic regression model. Patients were stratified into 5 quintiles which allowed for cohort matching – rather than patient matching – which made it possible to capture all available data for the analysis, rather than end with a limited number of patients in each arm as the case usually is with conventional propensity matching. This design made it possible to evaluate clinical outcomes with the latest generation Sapien 3 valve – which only became available after the PARTNER 2A trial had started – in a comparative (but non-randomized) manner.Inclusion and exclusion criteria were identical to PARTNER 2A. The primary endpoint however was different; being the composite of death from any cause, all strokes, and incidence of moderate or severe aortic regurgitation in SAPIEN 3.Compared to the previous valve, the newer valve has a number of important design improvements including improved geometry of the trileaflet bovine pericardial valve; different cobalt alloy frame with more open cells on its aortic (outflow) portion to improve coronary blood flow; a second fine-adjustment wheel and enhanced flexion of the delivery system for more precise positioning; and perhaps most importantly, an external polyethylene terephthalate fabric skirt  sewn to the bottom portion of the frame to reduce paravalvular leaks. The valve also has a lower-profile delivery system which can be inserted through 14–16 French sheaths.p = 0.0004), lower left ventricular ejection fraction , and more frequent moderate or severe mitral regurgitation .Most baseline characteristics were similar between both groups. Patients in the SAPIEN 3 group had more frequent oxygen-dependent chronic obstructive lung disease. Patients in the PARTNER 2A surgery group had mildly higher mean STS scores . On the other hand, surgery was superior to TAVI with regards to moderate or severe aortic regurgitation .Compared to the surgical group, the TAVI group had a lower incidence of the composite primary endpoint of death from any cause, all strokes, and incidence of moderate or severe aortic regurgitation in each of the five quintiles (ranging from −14.5% in quintile 1 to −4.3% in quintile 5). The pooled difference in the incidence of the primary endpoint across all quintiles was significantly lower in the TAVI group . With regards to the individual components of the primary endpoint, mortality at one year and stroke were lower with TAVI compared to surgery  for TAVI is on the rise, PARTNER 2A and SAPIEN 3 both provide badly-needed data that helps close the gap between evidence and practice. Both studies provide reasonably reassuring evidence that TAVI can be offered to intermediate risk patients with outcomes that are at least comparable to surgery.While the non-randomized design of SAPIEN 3 carries inherent limitations and the risk of unmeasured confounders, the robust propensity matching methodology, identical inclusion and exclusion criteria, the same clinical event committee, near-identical clinical sites and operators as well as the same core echocardiography laboratory make it very unlikely for its key findings to be a “play of chance”. In addition, results from SAPIEN 3 emphasize earlier findings from smaller studies, showing an excellent safety profile of the newer generation valves with marked reduction in moderate or severe paravalvular leaks, dropping to only 2% in SAPIEN 3. Although the incidence of mild paravalvular leaks was high in both studies (approximately 40%), this did not have an effect on clinical outcomes. This is in contrast to findings from the original PARTNER trial where mild paravalvular regurgitation was associated with worse survival compared to none/trace regurgitation. The improved delivery profile of the newer valve (SAPIEN 3) also allowed for a transfemoral route in 88% of patients in SAPIEN 3 compared to 76% in PARTNER 2 with numerically less major vascular complications (6.1% vs. 7.9% respectively).Both studies continue to strengthen a culture that has been inherent to TAVI since its emergence; the Heart Team approach. This multidisciplinary approach continues to be an asset to and a major achievement of TAVI, and has been critical to the overall success of the procedure to date. Interestingly, results of both trials were presented by cardiac surgeons at the ACC scientific meeting.elderly patients; with a mean age of 82 years. Both trials excluded patients with bicuspid aortic valves (BAV), who may represent a substantial percentage of younger patients with severe aortic stenosis. While BAV per se is not an absolute contraindication to TAVI, and in fact many centers around the world are implanting transcatheter valves in this group of patients, the limitations of TAVI in this setting are well recognized.8–10 Paravalvular leaks in particular seem to be more common with BAV owing to a number of morphological features of the cusps, annulus and aortic root in addition to the pattern and extent of calcification.8It is important to understand the limitations of both studies in terms of the patient population enrolled. Both studies enrolled 11 as well as concerns about the long-term durability of the valve cusps and platform will also need to be addressed before TAVI becomes the treatment-of-choice for severe aortic stenosis in intermediate risk patients, particularly younger ones.Furthermore, accurate measurement of the annulus in patients with BAV, and hence selection of the appropriate valve size, can be challenging. Patients with complex coronary disease and those with severe left ventricular systolic dysfunction were also excluded from both trials. It is still unknown whether TAVI can be comparable to SAVR in these patient populations. Recent concerns about leaflet thrombosis and reduced mobility,Finally, with the current valve prices, it remains to be seen whether TAVI will be cost effective compared to surgery in patients with less surgical risk and fewer comorbidities.Results from PARTNER 2A and SAPIEN 3 strongly suggest that TAVI is a suitable alternative to SAVR in intermediate risk patients with severe symptomatic aortic stenosis. The results also suggest that transfemoral TAVI and the use of the third generation Sapien 3 valve is associated with better outcomes compared to SAVR. As the TAVI landscape moves toward younger patients with less comorbidities and longer life expectancy, it becomes crucial to evaluate the rate of valve degeneration over longer periods of time. These results also warrant further studies to evaluate the role of TAVI in low-risk patients, which represent more than 75% of patients undergoing aortic valve replacement. There are currently two ongoing trials in the United States alone that are investigating the outcomes of TAVI in this subset of patients.


Idiopathic adhesive capsulitis is a condition of uncertain etiology characterized by pain and decreased shoulder range of motion (ROM) that occurs without a known intrinsic disorder. Many treatments have been advocated, yet the best option remains unclear. The purpose of this study was to determine if arthrographic injection of the shoulder joint with steroid and local anesthetic results in decreased pain and increased shoulder function in a cohort of patients with idiopathic adhesive capsulitis.This is a retrospective case series of patients who were treated with an arthrographic steroid and local anesthetic injection for adhesive capsulitis. The injections were all given by the same musculoskeletal radiologist using image guidance, and the patients were all from the same surgeon's practice. Patients were evaluated with the Shoulder Pain and Disability Questionnaire (SPADI) and Constant Shoulder Score and their shoulder ROM was tested. Descriptive statistics in the form of counts, percentages, means and standard deviations were used, as well as parametric and non-parametric tests.Thirty-three shoulders in 25 patients were examined. The average length of follow-up was 17 months. Sixty-nine percent of the cohort continued to complain of some shoulder pain in the post-injection follow-up clinic, however, their pain had improved from 8.8/10 pre-injection to 2.2/10 post-injection (p=0.01). The average score of the SPADI Pain, SPADI Disability and Constant Score were 36, 31 and 64, respectively.All patients who received an arthrographic injection using steroid and local anesthetic reported improved pain and mobility. In addition, those who had tried other treatment modalities felt that the injection had been the most beneficial. The cet al. showed that 50% of patients treated non-operatively had continued mild pain or stiffness or both [Initially, frozen shoulder was felt by some to be a self-limiting condition with a favorable natural history , 7. Howe or both , 11.Many forms of treatment have been advocated for frozen shoulder including physiotherapy, injection with steroid, distension arthrogram, manipulation under anesthetic and arthoscopic releases , 12, 13.et al. randomly assigned patients diagnosed with adhesive capsulitis to receive either arthrographic joint distension with steroid and saline or a placebo consisting of simply the arthrogram. They found that patients receiving the distension arthrogram with steroid and saline had significant improvements at 3 weeks in their SPADI, PET, overall pain, active abduction and internal rotation with their hand behind their back [One randomized control trial evaluated the use of an intra-articular corticosteroid injection in a diabetic population with adhesive capsulitis. The researchers found that those patients treated with the injection had less pain at 6 weeks, better function at 12 weeks, but no lasting differences when compared with the control group who did not receive an injection . Buchbineir back . A receneir back . As the The objective of this retrospective study was to determine if arthrographic injection of the shoulder joint with steroid in the mid tern resulted in decreased pain and increased shoulder function in a cohort of patients who presented with adhesive capsulitis.2This is a retrospective case series study of patients who had been treated with an image-guided arthrographic injection using steroid for adhesive capsulitis in one surgeon’s practice. The inclusion criteria comprised patients between 18-70 years of age with a diagnosis of primary adhesive capsulitis that was treated with an image-guided arthrographic injection using 40 mg of Triamcinilone and 5cc of 1% Lidocaine by the same musculoskeletal radiologist. The minimum follow-up was 3 months. The exclusion criteria included patients who developed adhesive capsulitis secondary to trauma or who had had a previous surgery on the affected shoulder.Patients were evaluated with questionnaires and their range of shoulder motion tested with a goniometer. Questionnaires included the SPADI (Shoulder Pain and Disability Index) and the Constant Score Shoulder questionnaire. The SPADI is a validated, self-report measure developed to evaluate patients with shoulder pathology. It contains two domains; one is a 5-item subscale that measures pain and the other an 8-item subscale that measures disability. The pain dimension has five questions regarding the severity of an individual’s pain and the functional activities dimension has eight questions designed to measure the degree of difficulty a patient has while carrying out the activities of daily living. The scores from both dimensions are averaged to derive a total score with 0 being the best outcome (less disability) and 100 the worst (greater disability) .The Constant Score is also a validated instrument used to assess pain and function of a diseased shoulder. It has a maximum score of 100: 15 points are allocated for a subjective assessment of pain, 20 points for shoulder function, 40 points for an objective measure of ROM and 25 points for shoulder strength. A higher score illustrates better function . SubjectStatistical analysis included descriptive statistics in the form of counts, percentages, means and standard deviations to summarize demographic and other study variables. Parametric and non-parametric tests were used to compare variables between sexes, as well as pre and post injection differences when possible. An alpha value <.05 was considered statistically significant.31) for a summary of patient characteristics.A total of 33 shoulders in 25 patients were enrolled in the study. Eighteen of the participants were female and 7 were male with an average age of 57 years and a range of 47-70 years. Twenty-six of the shoulders examined were right with 7 left and 83% of the cohort were right hand dominant. The average follow-up was 17 months post-injection with a range of 4-41 months. Multiple co-morbidities were identified in the cohort. The most common were diabetes, pulmonary disease and heart disease at 44%, 21% and 18% respectively. Please refer to , physiotherapy (67%), massage therapy (47%) and acupuncture (17%). For those who tried physiotherapy and massage, the average number of sessions were 27 and 5 respectively. The patients taking medications mostly took Tylenol or aspirin daily.Of the 6 patients that received 2 injections, 3 were men and 3 were women. All were right hand dominant expect 1. Half of these patients were diabetic and all were taking insulin; one was a smoker. They all reported taking weekly medication for the pain with minimal improvement. The one patient that had 3 injections was also diabetic and on insulin; was right hand dominant and was taking Tylenol for the pain with no relief. The average pain severity score of these 7 patients was 9.5Sixty-nine percent of the cohort continued to complain of some shoulder pain in the post-injection follow-up clinic, however, their pain had improved from a mean of 8.8/10 pre-injection to 2.2/10 post-injection (p=0.01). The average score of the SPADI Pain was 36/100 and the SPADI Disability was 31/100 for a total of 67/100. This is within the normative average of 61/100. The Constant Score total was 64/100 which is below the normal average of approximately 84 for this age group. Range of motion measures included forward flexion which was 130.5° (opposite=139.8), abduction was 120.2° (opposite=142.5), and based on the Constant scoring system of 0-10, external rotation was 8 and internal rotation was 4.3 for the index side (opposite= 9 on average for both). No patients reported any increased pain with the injection or within 24 hours post-injection and there were no other reported complications. Furthermore, there were no statistically significant differences on any measures between the men and women in our cohort.We found injections with steroid increased shoulder motion and function, and significantly decreased pain in our cohort, although not entirely. This same finding was reported in a recently published systematic review examining intra-articular steroid injection for frozen shoulder . The optet al. produced similar results finding that patients treated with intra-articular steroid injection had improved pain and function scores than those treated with a saline injection alone or in combination with supervised physiotherapy. They did however identify that those patients who received a combination of an intra-articular steroid injection and supervised physiotherapy program had the fastest improvement in their range of motion [et al. identified the short-term benefit of intra-articular steroid injection when compared with mobilization, ice and rest back in 1984 [et al. studied intra-articular steroid injection versus a course of oral steroid in the treatment of adhesive capsulitis [Carette f motion . These ff motion . These f in 1984 . Lookingpsulitis . They foThe strengths of this study include that all patients were recruited from the same surgeon’s practice and thus had the same evaluation, received the same recommendations and were offered the same treatment options. In addition, all of the arthrographic steroid injections were performed by the same experienced musculoskeletal radiologist who used a standard technique with each patient receiving 40 mg of Triamcinilone and 5cc of 1% Lidocaine. There were no complications in our cohort such as infection, facial flushing or increased pain post-injection. This is consistent with the literature as arthrographic injection using steroid is considered a relatively benign and inexpensive procedure with few inherent risks to the patient .This study had several limitations inherent to a retrospective study. The response rate was quite low; however, all patients were recruited from the same surgeon’s practice, which although limited our numbers, added to the consistency. The follow-up interval had a wide range from 4-41 months. Consequently, it would have been preferable to stratify the results but unfortunately, the small number of participants did not allow for this to be accomplished. In addition, the number of injections varied from 1-3 in the index shoulder of our participants, which could have influenced their response to the treatment. Finally, we did not have any pre-injection data for our subjects such as their range of motion, SPADI or Constant score. Subjectively, they all reported significant improvements in their level of pain, motion and functional abilities.Arthrographic injection with steroid is a safe treatment option for patients with adhesive capsulitis that appears beneficial in improving both pain and range of motion. Despite the limitations in our study, we feel arthrographic injection with steroid is a viable treatment option with very little downside. Thus, we continue to recommend it as a treatment option for patients with frozen shoulder.Future directions include a randomized control trial in which we will compare arthrographic injection with steroid, local anesthetic and saline to injection with local anesthetic and saline alone to determine whether steroid is actually of benefit to this patient population.


Cognitive impairment is common after acute ischemic stroke, affecting up to 75% of the patients. About half of the patients will show recovery, whereas the others will remain cognitively impaired or deteriorate. It is difficult to predict these different cognitive outcomes.The objective of this study is to investigate whether diffusion tensor imaging–based measures of brain connectivity predict cognitive recovery after 1 year, in addition to patient characteristics and stroke severity. A specific premise of the Prediction of Cognitive Recovery After Stroke (PROCRAS) study is that it is conducted in a daily practice setting.The PROCRAS study is a prospective, mono-center cohort study conducted in a large teaching hospital in the Netherlands. A total of 350 patients suffering from an ischemic stroke who screen positive for cognitive impairment on the Montreal Cognitive Assessment (MoCA<26) in the acute stage will undergo a 3Tesla-Magnetic Resonance Imaging (3T-MRI) with a diffusion-weighted sequence and a neuropsychological assessment. Patients will be classified as being unimpaired, as having a mild vascular cognitive disorder, or as having a major vascular cognitive disorder. One year after stroke, patients will undergo follow-up neuropsychological assessment. The primary endpoint is recovery of cognitive function 1 year after stroke in patients with a confirmed poststroke cognitive disorder. The secondary endpoint is deterioration of cognitive function in the first year after stroke.The study is already ongoing for 1.5 years, and thus far, 252 patients have provided written informed consent. Final results are expected in June 2019.The PROCRAS study will show the additional predictive value of diffusion tensor imaging-based measures of brain connectivity for cognitive outcome at 1 year in patients with a poststroke cognitive disorder in a daily clinical practice setting.RR1-10.2196/9431 Stroke has a high global incidence of 41-316 per 100,000 persons per year -5. In haPrediction of long-term cognitive outcome after ischemic stroke is, however, still inaccurate. Evidence is emerging on predictors of poor outcome, including demographic variables . BraiMeasures of brain connectivity are of particular interest in this context. Stroke not only affects local connectivity but can also cause remote brain changes, as shown by functional MRI and diffusion tensor imaging (DTI) studies . The valThe primary aim of the Prediction of Cognitive Recovery After Stroke (PROCRAS) study is to investigate whether DTI-based measures of brain connectivity predict cognitive recovery in the first year after stroke in patients with a confirmed poststroke cognitive disorder in addition to clinical, neuropsychological, and conventional imaging variables. Secondary aims are to assess the relation of DTI-based measures of brain connectivity with other outcomes. These other outcomes include deterioration of cognitive function, cognitive complaints, quality of life, participation, global health, and functional outcome. PROCRAS will also assess the feasibility of an extensive work-up including cognitive assessment and DTI in daily clinical practice.The PROCRAS study is a longitudinal, prospective, mono-center cohort study of cognition in patients with acute ischemic stroke, who will be followed for 1 year using 5 assessments.Patients will be recruited from the stroke unit of the Elisabeth-Tweesteden Hospital Tilburg, the Netherlands. This is a hospital with an admission rate of approximately 700 patients per year for the diagnosis of acute ischemic stroke. Additionally, 60 patients with a MoCA score of 26 or higher (screen negative) will be included as a reference group, matched for age and gender to the screen-positive patients (frequency matching). For this reference group, the other inclusion and exclusion criteria and study procedures are identical to the screen-positive patients.Clinical diagnosis of ischemic strokeAge ≥50 yearsMontreal Cognitive Assessment (MoCA) <26 (MoCA≥26 for the reference group)Prestroke dementia: Known diagnosis of dementia or Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) ≥3.6Life expectancy <1 yearSevere stroke expected to require long-term nursing care facilitiesHistory of major neurological disease interfering with cognitive functioningPrestroke dependence in activities of daily living (Barthel Index<18)Insufficient command of the Dutch language to participate and understand questionnairesImpossibility to participate in a neuropsychological assessmentAn absolute contraindication to undergo an magnetic resonance imaging MRI-scan of the brainIt is expected that the inclusion target will be reached in 1.5 years. Patients are treated the same way as patients that do not participate in this study. This study does not interfere with treatment choices or rehabilitation therapy. To account for any confounding, it will be registered whether patients received rehabilitation therapy and what kind of therapy was provided. Moreover, basic demographic data will be collected on the source population to understand what patient population participates in the PROCRAS.After informed consent, baseline characteristics will be assessed during hospital admission (T1). The second assessment takes places in an outpatient clinic 3-6 weeks after stroke (T2); the third assessment is a telephone interview 3 months after stroke (T3); the fourth assessment is another telephone interview 6 months after stroke (T4); and the fifth assessment is performed in an outpatient clinic 1 year after stroke T5; see . The PROThe neuropsychological assessment will be performed at T2 and T5. It is designed using the “60-minute protocol” as proposed in the vascular cognitive impairment harmonization standards . PatientUnimpaired Mild VCD (performance on ≥1 domains is ≥1 SD but <2 SDs below appropriate norms)Major VCD (performance on ≥1 domains is ≥2 SDs below appropriate norms).The raw score for each test will be converted into a T-score corrected for age, gender, and level of education, when possible. The score for a domain is calculated by averaging the T-scores of the tests constituting that domain. The T-score is standard score with a mean of 50 and a SD of 10. For example, a T-score of 30 translates to 2 SDs below the mean, and a T-score of 60 corresponds to 1 SD above the mean.Only for the bells test, no normative data are available. An abnormal score on this test will be defined based on a cutoff score of a difference of 5 or more omissions between columns 1-3 and columns 5-7 .MRI data will be acquired on a Philips 3 Tesla scanner  for each patient at T2 using a standardized scanning protocol. The protocol consists of a sagittal 3D T1-weighted, an axial T2-weighted, an axial fluid attenuated inversion recovery, an axial diffusion-weighted imaging, and a DTI sequence. Brain tissue volumes and white matter hyperintensity volumes will be automatically determined by brain segmentation, and infarct volumes will be determined by manual segmentation ,43.Attention and processing speedReaction time test, Vienna Test System, S1, S2Symbol Digit Modalities TestTrailmaking test A(Working) memory and learningWechsler Adult Intelligence Scale (WAIS) Digit Span forward and backwardThe Rey Auditory Verbal Learning TestFrontal-executive functionsControlled Oral Word Association TestHayling testReaction time test Vienna Test System S3Trailmaking test BLanguageBoston naming testSemantic fluencyVisuospatialBells testSocial cognitionFacial Expressions Emotions Stimuli TestDTI data will be analyzed and processed in ExploreDTI , as descAt T1, demographic factors will be ascertained, apolipoprotein E (APOE) genotyping will be performed, stroke severity will be assessed using the National Institutes of Health Stroke Scale , comorbiAt T3 and T5, self-efficacy will be assessed using the Self-Efficacy for Symptom Management Scale ; cognitiThe primary aim of this study is to investigate whether DTI-based measures of brain connectivity predict cognitive recovery after 1 year, in addition to other determinants including patient characteristics and stroke severity. The main DTI marker that will be used is global network efficiency. This measure reflects the integration as well as the microstructural integrity of the white matter.The primary outcome measure is recovery of cognitive function in the first year after stroke. This measure will be dichotomized into cognitive recovery and no cognitive recovery . Cognitive recovery is operationalized as a transition from a mild VCD at 3-6 weeks  to no disorder at 1 year , or a transition from a major VCD at T2 to a mild or no VCD at T5. Hence, only patients with a confirmed VCD at T2 will be considered for this outcome. Patients that dropout will not be considered in the primary analyses. Their outcomes, obtained by telephone interview where possible, will be reported.The secondary outcome measure is deterioration of cognitive function, operationalized as a transition from a mild VCD at T2 to a major VCD at T5 or a transition from no VCD at T2 to a mild or a major VCD at T5. For this outcome, only patients with no or a mild VCD at T2 will be considered.In secondary analyses, we will also address change in cognitive performance as a continuous measure, using domain T-scores. For neuropsychological tests that require writing or drawing, we will take motor functioning into account as a covariate in the analysis.A secondary aim is to assess the relation of DTI-based measures of brain connectivity with patient-reported outcomes and functional outcome. For this aim, the main DTI marker that will be used is, again, global network efficiency.The outcome measures are cognitive complaints, quality of life, participation, global health, and functional outcome. The first 4 outcome measures will be assessed with questionnaires at 3 months after stroke  and 1 year after stroke . The questionnaires are repeated at T5 to assess whether a change in one of these measures occurs. Functional outcome is defined by the score on the modified Rankin Scale as assessed with a telephonic interview by a trained researcher at T1, T3, T4, and T5. All patients with completed follow-up until at least T3 will be considered for this analysis. Moreover, each of the outcome measures will be compared between the cognitive impaired group and the reference group.Another secondary aim is to assess the feasibility of an extensive work-up including cognitive assessment and DTI in daily clinical practice.The outcome measure will be the proportion of patients that underwent an MRI scan and neuropsychological assessment within the timeframe of 3-6 weeks at T2.On the basis of available literature, we estimate an area under the receiver operating characteristic (ROC) curve of 0.7 for the prediction model using clinical, neuropsychological, and conventional imaging parameters, and that approximately half of the patients with a confirmed cognitive disorder will recover ,6,62. WhFirst, descriptive statistics will be used. Second, to assess the additional value of DTI-based measures of brain connectivity, the 6 strongest predictors from clinical and conventional imaging parameters will be selected using univariable logistic regression with cognitive recovery as a dichotomous outcome measure. The predictive value of the multivariate model including the strongest predictors from clinical parameters and conventional imaging markers will be assessed. ROC analyses will be used to assess whether this predictive value can be improved by adding network metrics achieved from DTI. The same procedure will be performed in the prediction of the outcome measures related to the secondary aim. In the model, we will take the interval between the stroke and the assessment at T2 as covariate.The study will be conducted according to the principles of the Declaration of Helsinki  and in accordance with the Medical Research Involving Human Subjects Act (WMO).The PROCRAS study was approved by the medical ethics committee of Brabant, based in Tilburg, the Netherlands. Written informed consent will be obtained from all participants.At time of acceptance of this paper for publication, this study has been ongoing for 20 months. Thus far, 252 patients have provided written informed consent. Final results are expected in June 2019.The PROCRAS study investigates whether DTI-based measures of brain connectivity predict cognitive recovery in a large stroke cohort in daily clinical practice in addition to known predictors of cognitive outcome. It adds to the existing literature because of several reasons.First, it specifically focuses on cognitive recovery, using a selection of relevant determinants of cognitive outcome after stroke. As the mechanisms of cognitive recovery or deterioration after stroke are complex and involve multiple factors, a prediction model should incorporate each of the most important factors to provide reliable results. Moreover, by combining many of the known determinants in a large patient sample, the coherence between each of these factors can be better understood.Second, this study combines the knowledge of different disciplines working in the stroke field, such as cognitive neuroscience, neuropsychology, and cognitive rehabilitation. Approaching VCDs from different angles may help us better understand how VCDs develop and how they continue to exist. Moreover, fundamental findings in cognitive neuroscience are not often translated in clinical practice . If the The study design has several limitations. First, the study focuses on a relatively specific patient group, because of several exclusion criteria. For example, patients that cannot undergo a neuropsychological examination due to severe aphasia are excluded. We have chosen to exclude patients with risk factors for a major VCI, as these patients have a low potential to show cognitive recovery. This would lower the sensitivity to find an effect. Second, this is a single-center study, which can affect generalizability of the results. Third, the timeframe of 3 weeks at T2 is rather broad. This might result in more patient variation, as patients show most recovery in the first weeks after stroke -66. HoweIn summary, the results of the PROCRAS study will support individualized PROCRAS. The results of this study may help in the psychoeducation of patients, they may add value to rehabilitation programs in setting realistic and attainable therapeutic goals, and they may help to anticipate the need for support.


It has been suggested that orthographic transparency and age changes may affect the relationship between visual attention span (VAS) deficit and reading difficulty. The present study explored the developmental trend of VAS in children with developmental dyslexia (DD) in Chinese, a logographic language with a deep orthography. Fifty-seven Chinese children with DD and fifty-four age-matched normal readers participated. The visual 1-back task was adopted to examine VAS. Phonological and morphological awareness tests, and reading tests in single-character and sentence levels were used for reading skill measurements. Results showed that only high graders with dyslexia exhibited lower accuracy than the controls in the VAS task, revealing an increased VAS deficit with development in the dyslexics. Moreover, the developmental trajectory analyses demonstrated that the dyslexics seemed to exhibit an atypical but not delayed pattern in their VAS development as compared to the controls. A correlation analysis indicated that VAS was only associated with morphological awareness for dyslexic readers in high grades. Further regression analysis showed that VAS skills and morphological awareness made separate and significant contributions to single-character reading for high grader with dyslexia. These findings suggested a developmental increasing trend in the relationship between VAS skills and reading (dis)ability in Chinese. It has been suggested that DD is caused by multiple genetic, cognitive, and environmental risk factors2. Based on the relevant literature in the context of different languages4, two major frameworks have always been presented for the possible mechanism of reading disability: the linguistic and non-linguistic framework hypotheses. First, the linguistic framework hypothesis postulates that individuals with dyslexia usually exhibit core deficits in phonological processing, orthographic awareness, semantic analysis, and their interactions 5. Although the above impairments were consistently reported by research on different languages6, it has been suggested that deficits in accessing and manipulating phonological information were more remarkable for dyslexic readers of alphabetic languages5, and difficulty with morphological awareness may contribute more greatly to reading disability in Chinese7. Second, the non-linguistic framework hypothesis proposes that dysfunction at the linguistic level may stem from more fundamental deficits in basic cognitive processing, including perception8, working memory9, and visual attention10.Developmental dyslexia (DD) is a specific impairment in learning how to read accurately, fluently and in gaining reading comprehension, which is not accounted for by problems in general intelligence, learning opportunities, general motivation, or sensory acuity” for “” in Chinese reading) and exhibit visual confusion  when they are trying to read11, and reading begins with visual processing, some researchers have thus indicated that the exploration of dyslexia should be traced back to the basic visual-spatial processing underlying the language skills. Some relevant studies have focused on the visual attention span (VAS) of dyslexics10. VAS refers to the amount of distinct visual elements that can be processed in parallel in a multi-element array12. Previous studies typically adopted whole/partial report tasks and relevant modified paradigms to measure the VAS ability10. According to the visual attention span deficit hypothesis proposed by Bosse et al.8, VAS impairment might contribute to poor reading outcomes in dyslexics independent of their phonological disorders.Given that dyslexic readers often tend to transpose letters or characters  through whole/partial report tasks in both French and Portuguese children with dyslexia as compared to their age-matched controls19, in which the orthographic depths of French and Portuguese were deep and intermediate, respectively21. Neuroimaging findings revealed that French children and adults with dyslexia both exhibited lower brain activation in their parietal region  functioning in the visual attention span, with multiple-element paradigms being modified on the basis of the whole/partial report tasks, such as a visual categorization task20. Moreover, high frequency repetitive transcranial magnetic stimulation over the bilateral parietal regions of the dyslexic adults improved accuracy of their non-word reading22. A case study of a VAS intervention on a French girl with dyslexia reported that the training resulted in the faster identification of words, improved text reading, and increased activation in her bilateral superior parietal cortices and bilateral precuneus15. These findings provided evidence for the causal link between the visual attention span deficit and reading disability.In the context of alphabetic languages, several studies reported VAS dysfunction in some dyslexic readers from both behavioral and neural aspects25, in which the dyslexic readers did not differ from the non-impaired readers in the VAS-related tasks25. Hawelka and Wimmer found that German adults with dyslexia showed similar reaction times as normal readers in a partial report task24. Yeari et al.’s study reported that there were no significant differences in the recognition sensitivity between dyslexic adults in Hebrew and the age-matched skilled readers in either whole or partial report tasks25. Because it has been suggested that a potential modulation of the visual attention span on reading depends on orthographic transparency26, the above inconsistencies in the existing literature might thus be associated with differences in orthographic depth. Studies reporting VAS impairments in the dyslexic individuals were usually in the context of languages with deep/intermediate orthography , while studies that found an absence of VAS deficit in dyslexics were mostly in languages with shallow orthography . Orthographic transparency may exert an influence on the nature of reading strategies27. In transparent orthographies , readers prompt sub-lexical decoding strategies based on the rules of grapheme-to-phoneme correspondence (GPC), with the characterization of small orthographic units during reading. By contrast, in opaque languages , the availability of larger orthographic units is more regular than smaller ones, which encourages readers to use whole-word reading strategies through the lexical route28. Accordingly, it could be suggested that the VAS skills may be influenced by the orthographic depth. Namely, the visual attention span might contribute more to reading in languages with deep orthographies. A recent cross-language study provided support for the above inference to some extent26. Awadh et al. recruited Arabic, French and Spanish adults, and they found that the visual attention span of French adults was correlated with their scores on an oral reading fluency test, in which the orthographic depth of French was deeper than that of both Spanish and Arabic. This finding revealed that the visual attention span might exhibit a more significant relation to reading skills in languages with deep orthography26. The VAS ability might be better for languages with deep orthography, in which reading is usually involved in processing a larger orthographic unit, compared to that in languages with shallow orthography. Consequently, the VAS impairment of dyslexic readers might be more obviously exhibited in processing languages with deep orthography. Whereas, the VAS may be small for both dyslexics and normal readers in languages with shallow orthography, and group differences may not be markedly presented.However, some other studies failed to replicate the VAS deficit in dyslexics29. The visual attention span may contribute more to a global coarse-grain strategy than a sub-lexical small-grain strategy30, and thus it could be inferred that VAS skills might play a more important role during the later stages of reading development, as supported by the findings in the relevant literature31. A developmental study by Bosse et al. found that the independent contribution of phonological skills to reading was much greater in the 1st grade than in later grades, revealing a developmental decrease, while there seemed to be a developmental increasing trend in the unique contribution of VAS to reading 31. Would the VAS ability of dyslexic readers then vary with their reading development? According to the developmental pattern of the relationship between the visual attention span and reading in the normal readers mentioned above, is it possible that the visual attention span deficit of dyslexics might be more obviously exhibited during the later stages of development, in which a larger visual attention span is required for reading processes ? These issues need to be addressed in further studies.Particularly for languages with deep orthography, another aspect that should be carefully considered is the understanding of age-related changes in the relationship between the visual attention span and reading. With reading development, there is a transition from relying on the sub-lexical decoding strategies of letter-by-letter spelling to depending on a strategy through the whole lexical-word route32. With increased reading experience, the direct connections between the visual forms and the corresponding meanings of Chinese characters would be well established, and the utilization of Pinyin in reading procedures would be gradually diminished33. That is, the developmental pattern is a decrease in the influence of phonological skills and a developmental increase in the involvement of morphological processing32. Considering that visual words/characters in Chinese directly and globally map onto relevant speech sounds primarily through an addressed route that greatly differs from that in alphabetic languages (an assembled way based on GPC rules)34, it is interesting to explore the development of the relationship between the visual attention span and Chinese reading (disability). Is the developmental pattern of the visual attention span in Chinese individuals with dyslexia similar to the prediction based on alphabetic languages with deep orthography? Alternatively, would there be a language specificity for this relationship in Chinese? That is, the VAS of Chinese dyslexic readers would have a relationship to the addressed mapping between whole visual forms of characters and whole syllables during the early stages of Chinese reading development , considering that the visual-spatial attention has been suggested to be essential in creating the visual images of spoken stimuli35. To our knowledge, there has been no relevant developmental study. Reports exploring the relationship between the visual attention span and Chinese reading (disability) are also scarce, and the relevant findings are inconsistent. Mi et al.36 adopted whole and partial report tasks with verbal responses to measure the visual attention span, in which the target stimuli were five Chinese characters with high frequency. Their results showed that there were no significant differences in the visual attention span between Chinese dyslexic children and age-matched normal readers. However, the participants in their study were selected from the 2nd to 5th grades. The large range of participant ages might be implicated with the additional influence of developmental changes in the visual attention span and its relation to reading in Chinese. Additionally, a recent study37 found that Chinese adults exhibited a close relationship between their visual attention span and silent reading fluency, suggesting that the visual attention span might play an important role in Chinese reading even for skilled readers.As a logographic writing system, Chinese lacks strict GPC rules and has a deep orthography. In the early stage of reading development in Chinese, beginning readers are taught Chinese primarily through Pinyin, which expresses spoken Chinese using the Roman alphabet and plays a special role in bridging the gap between speech and the written form of Chinese characters12 generally used a letter-report task. This task requires a verbal response and the use of verbal stimuli, and it thus may additionally tap into linguistic processing  besides visual rapid simultaneous processing. To separate these two processes, the visual 1-back task designed by Lallier et al.38 was adopted to measure the visual attention span with nonverbal stimuli and no verbal report. The visual attention span ability in each position was analyzed to examine the influence of the spatial location on the VAS. Moreover, Chinese dyslexic children from different age groups were recruited to explore the developmental changes in the relationship between their visual attention span and reading disability.The present study investigated the developmental pattern of the visual attention span in Chinese children with developmental dyslexia. The aforementioned studies on VASA visual control task on single-figure recognition was adopted to examine whether the participants had sufficient efficiency in identifying an individual figure. A two-way ANOVA was submitted to analyze the correct reaction times, accuracy, and d-prime values in the visual control task, with the group (dyslexics vs. controls) and grade  as the two between-subject factors. First, one-sample Kolmogorov-Smirnov tests were conducted to examine whether the dependent variables of accuracy, correct reaction time, and d-prime values showed normal distributions or not. The results showed no significant effects (ps > 0.1), revealing that the test distributions were (nearly) normal. Levene’s tests of homogeneity of variance were then conducted, and the relevant results showed that the variance in accuracy, correct reaction time, and d-prime values were separately equal (ps > 0.1).The results of the two-way ANOVAs on any of the three dependent variables showed no significant effects or interactions ps > 0.1). Table . Table 1Correct reaction times longer than three standard deviations away from the mean were excluded . The remaining data were submitted to further analysis. A three-way mixed ANOVA was submitted to analyze the reaction times, accuracy and d-prime values in the visual 1-back task, with the group (dyslexics vs. controls) and grades  as the between-subject factors and the position  as the within-subject factor. The results of one-sample Kolmogorov-Smirnov tests exhibited no significant effects (ps > 0.1), suggesting a normal distribution for all the dependent variables. The results of Levene’s test for the homogeneity of variance showed that the variances were equal for accuracy, correct reaction time, and d-prime values under every condition (ps > 0.1). The sphericity assumption was accepted in ANOVA for correct reaction times, while the sphericity assumption was violated in ANOVA for accuracy and d-prime values, in which the Greenhouse-Gasser correction was applied. Post hoc analyses were conducted in which the relevant p-values were corrected by Bonferroni adjustment.2 = 0.20]. Post hoc analyses showed that children in the low grade responded more slowly than the children in middle and high grades (ps < 0.05), and children from the middle grade exhibited longer reaction times than the ones in the high grades . There was no any other significant effect or interaction (ps > 0.1).The ANOVA results for the correct reaction times showed that the main effect of the grade was significant . Post hoc analyses indicated that the accuracy when targets were presented in the middle position of a string  was higher than that in the other four positions (ps < 0.001), and there was no significant difference in the accuracy across the other four positions within a string (ps > 0.1).The relevant results for accuracy showed that the main effect of the position was significant . Simple effect analyses showed that the position effect was significant for all three grades . Post hoc analyses demonstrated that for the children in the low grades, the accuracy when the target was presented in the 3rd position within a string was higher than that in the other four positions (ps < 0.05), and there was no significant difference in accuracy across the other four position conditions (ps > 0.1). For the students from the middle grade, the accuracy for the 3rd position within a string was higher than that of the 2nd, 4th and 5th positions (ps < 0.01), and the accuracy when the target was presented in the 1st position within a string did not differ from the other four positions (p > 0.1). For the children in high grades, there were no significant differences in the accuracy across the 1st, 2nd, and 3rd positions (ps > 0.1), or between the 4th and 5th positions within a string (p = 0.99); the accuracy when the target was presented in any of the 1st, 2nd, and 3rd positions was higher than that in both of the 4th and 5th positions (ps < 0.1). The grade effect was only significant when targets were presented in the 1st, 2nd, 3rd positions of a string. Post hoc analyses showed that children from the low grade showed higher accuracy than the children in the other two grades (ps < 0.05) under the condition of the 3rd position within a string. The grade effects of the 1st and 2nd positions were similar to one another, in which the children in low grades exhibited lower accuracy than those in the high grades (ps < 0.5), while any other comparisons were not significant (ps > 0.1).The position × grade interaction was significant . Simple effect analyses showed that the group effect was only significant in the high grade  but not in the low or middle grades . In detail, the dyslexic children in the high grade made more errors in the visual 1-back task than the age-matched normal readers  = 1.08, p = 0.35, η2 = 0.04] readers.Moreover, the group × grade interaction was marginally significant . Post hoc analyses showed that the d-prime values in the 3rd position of a string was higher than that in the other four positions (ps < 0.1), and the d-prime values in the 2nd position was higher than that in the 4th and 5th positions (ps < 0.05), and there was no any other significant comparisons (ps > 0.1).The results of the ANOVA for d-prime values showed that the main effect of the position was significant , and morphological awareness .The dyslexics exhibited lower accuracy than the age-matched controls did in tests of phonological awareness [low grade: t38, the visual 1-back paradigm was adopted here to measure the visual attention span skills with non-verbal stimuli and no verbal response. The test-retest reliability was 0.81. The stimuli in this test were 15 figures (Fig. et al.37. In each trial (Fig. 58. All the participants were tested individually in a quiet room. At the beginning of the experiment, the experimenter explained the procedure in detail from a standard script. The test trials were preceded by 10 practice trials.Referring to relevant studiesres Fig. . A list ial Fig. , a 500-mA recognition task using a single figure Fig.  was desiThe data in the current study are available upon request.


This review surveys the literature regarding the development of catalytic versions of the Wittig and aza-Wittig reactions. The first section summarizes how arsenic and tellurium-based catalytic Wittig-type reaction systems were developed first due to the relatively easy reduction of the oxides involved. This is followed by a presentation of the current state of the art regarding phosphine-catalyzed Wittig reactions. The second section covers the field of related catalytic aza-Wittig reactions that are catalyzed by both phosphine oxides and phosphines. As was the case in the previous work described above, both aromatic and aliphatic aldehydes 6 were suitable substrates in this reaction system to form products 7.Quite a few years later Yong Tang and co-workers, also of the Shanghai Institute of Organic Chemistry, carried on with this research and extended it by using a combination of Pheactions  11]. In. In3As  as the catalyst in related reactions , polymethylhydrosiloxane was used as the reductant, and 14 could be recovered and reused efficiently in numerous reaction cycles without loss of catalytic activity.Most recently the Tang research group has reported the use of polymer-supported arsine eactions  12]. In. In14 (03 (2Te (15) could function similarly as a catalyst in such Wittig-type reactions due to the relatively weak tellurium–oxygen bond of dialkyl telluroxides, such as Bu2Te=O (16)  and acetonitrile as a co-solvent. However, product yields and stereoselectivities were slightly improved when 15 was used at the same loading level  and with a similar set of aldehyde 6 substrates.At about the time that Huang and co-workers reported their catalytic reactions using 3 , they ale=O (16)  13]. Al. Al3 . Unfortunately, despite the fact that 19 could be easily reduced to 18 using triphenylphosphite or sodium bisulfite, and simply removed from the desired alkene products, recovered 18 had a much lower activity when attempts to reuse it were made. Nevertheless, the use of 18 with sodium bisulfite as the reducing reagent allowed for very simple product isolation, and reaction yields and stereoselectivities were similar to when 15 was used as the catalyst.Tang’s research group also followed up this tellurium-based research many years later and published several papers describing the use of polymer-supported tellurides, such as atalysts  14–16].–16.18, a20 (prepared from 15) decomposed in the presence of water to form 21. This compound could be used as a pre-catalyst in Wittig-type reactions because it is reduced to 15 by triphenylphosphite in the presence of potassium carbonate , which was reduced in situ with diphenylsilane (Ph2SiH2) to phosphine 23, which served as the actual catalyst in their Wittig reactions  instead of diphenylsilane . Th. Th22]. ne oxide –24, and  heating .31) as the starting material to form products 32 catalyzed by tributylphosphine    26]. In. In31) aeduction .36 to generate products 37 using 22 as the pre-catalyst with triethylamine as the base, phenylsilane as the reducing reagent, and 4-nitrobenzoic acid as an acidic additive. It should be noted that the role of the base in these reactions is unclear and not directly commented on. According to the proposed mechanism for the formation of the required ylide intermediate, a base is not necessary, but the authors reported that when it was omitted from a control reaction, no reaction occurred.At about the same time as the penultimate report by Werner and co-workers appeared, Wenwei Lin and a co-worker published conceptually similar catalytic Wittig reactions that were based on their previous research regarding related non-catalytic phosphine-mediated base-free Wittig reactions  28]. Th. Th28]. 38 as a catalyst for phosphine oxide reduction and have incorporated it into Wittig reactions catalyzed by 1  catalyst, and the other using a phosphorous(III) catalyst that is regenerated in the catalytic cycle. These strategies are the topic of this section of the review.Aza-Wittig reactions are similar to Wittig reactions in that they also involve the reaction of a phosphonium ylide, in this case an iminophosphorane (or phosphinimide) such as uch as 2 . The dif39 for an aza-Wittig reaction, it is regenerated as a byproduct, and thus can participate directly in another reaction cycle. More than 25 years before Huang’s research group made their first report regarding arsine catalysis . Su. Su61 an Marsden . In thei1 to catalyze intramolecular reactions that converted aryl azides 68 into 4(3H)-quinazolinones 69 via intermediate iminophosphoranes 70, using the combination of titanium tetraisopropoxide and tetramethyldisiloxane (TMDS) for the in situ reduction of byproduct 2 -ones 75.This group has more recently studied catalytic aza-Wittig reactions using carboxylic acid anhydrides as the starting materials  37]. Fo. Fo37]. 76 (from the reduction of 44) was the catalyst that transformed diazo group containing starting materials 77 into pyridazine derivatives 78. In these reactions 44 was actually added to the reaction mixtures as the pre-catalyst that was reduced using diphenylsilane.Lastly, the research group of Piet Herdewijn extended this general concept and reported catalytic diaza-Wittig reactions  38]. In. In38]. It is readily evident from the above examples that regardless of whether phosphine or phosphine oxides were used as the catalyst, catalytic aza-Wittig reactions have emerged to become powerful tools in the synthesis of collections of various heterocyclic compounds since it seems that the required isocyanate or azide group containing precursors are readily synthesized from simple starting materials.While great advances have been reported regarding the development of catalytic Wittig and aza-Wittig reactions, it remains to be seen how widely these methods will be adopted. Evidence that the former reactions are being described in the literature with increasing frequency are the very recent reports by Saleh and Voituriez , and Wen


The recently implemented mARC-rotation-technique is capable to deliver high dose rate bursts. For the case of hypopharynx cancer plans we evaluate whether the mARC can achieve an advantage in treatment time in comparison to IMRT. These plans consider two arcs with flat and flattening filter free (FFF) beam energies.For 8 hypopharynx-cancer patients step-and-shoot-IMRT and mARC plans were created retrospectively using flat and FFF beam energy. The comparison of the plan scenarios considered measures of quality for PTV coverage and sparing of organs at risk. All plans were irradiated on an anthromorphic phantom equipped with thermoluminescent dosimeters to measure scattered dose and treatment times.A visual comparison of the dose distribution did not show a marked preference for either technique or energy. The statistical evaluation yielded significant differences in favor of the mARC technique and the FFF energy. Scattered dose could be decreased markedly by the use of the mARC technique. Treatment times could be reduced up to 3 minutes with the use of mARC in comparison to IMRT. The high dose rate energy results in another time advantage of about 1 minute.All four plan scenarios yielded equally good quality plans. A combination of the mARC technique with FFF 7 MV high dose rate resulted in a decrease of treatment times from about 9 minutes to 5–6 minutes in comparison to 6 MV IMRT. Modern radiotherapy offers highly conformal treatment by using rotational techniques with the possibility to decrease treatment times due to continuous gantry rotation and MLC movement. There is a large body of literature evaluating VMAT (volumetric modulated arc therapy) and RapidArc for Elekta and Varian machines regarding plan quality and treatment times . The anaAlthough first mARC applications have already been presented –4, only For comparatively simple target volumes, as it is in the case of the prostate without lymphatics, a single arc (one full gantry rotation) will yield good quality plans . HoweverIn this planning study we therefore focus on a relatively complex target volume, hypopharyngeal carcinoma, to evaluate if the mARC technique can yield equally good quality plans. Moreover we analyse if there is an advantage in treatment time in comparison to IMRT although two full gantry rotations are needed. As the mARC can, but need not, be combined with a FFF beam energy, we include both a flat 6 MV and a FFF 7 MV photon beam in the analysis.The mARC technique as a Siemens analogue to VMAT and RapidArc offers rotational hybrid IMRT irradiation in burst mode , 9. WherBy using a flattening filter free (FFF) mode, it is possible to irradiate with high dose-rate burst up to 2000 monitor units (MU) per minute. The beam profiles show the characteristic cone-shaped dose fall-off from the central axes in contrast to the uniform beam profiles of flat beams. To compensate for the spectral softening beam energy for the FFF mode is slightly decreased to 7 MV resulting in similar depth dose curves, energy spectrum and surface dose in comparison with flat 6 MV beams . The mARThe present study is based on planning CT´s of 8 head and neck-cancer patients  treated at our department. The patients, treated between October 2010 and September 2012, were selected from a previous planning study . For thePlanning target volume (PTV)-contours were drawn by a senior radiation oncologist for hypopharynx tumor sites. The PTV includes bilateral cervical and supraclavicular lymph nodes (level II-V). No boost-contours are included in this study because of greater individual variability; besides, the most extended and complex volume for planning is the PTV, which is therefore exclusively considered here. A total dose of 50 Gy (fraction dose 2 Gy) was prescribed so that 95% of the PTV received 95% of the prescribed dose.At our department, one of the three available linear accelerators (linac), a Siemens Artiste machine, is equipped with the mARC technique and flat 6 MV as well as flattening filter free 7 MV beam energies. The MLC consists of 160 leafs with a width of 5 mm at isocenter distance.Both energies show very similar depth dose characteristics, as the FFF 7 MV beam compensates for the spectral softening caused by the removal of the flattening filter . TherefoFor IMRT plans 11 beams were used with about 5 segments per beam with the step-and-shoot-technique and 2 collimator orientations, based on the approach of a previous study  for hypoThe same previous study showed that high quality IMRT plans could be achieved using 50–60 segments, which we consequently use as the “gold-standard” for head-and-neck IMRT planning at our institution. In individual cases, the segment number is reduced for the sake of decreasing treatment time if good plan quality can be maintained. Although many literature studies about IMRT planning rely on a smaller number of beams , the auto-sequencing option of the Artiste linac allows relatively fast irradiation because the gantry rotates automatically between the beams, so that employing 11 beams with a total of 55 segments is feasible in the clinical routine. Therefore, this plan scenario is taken as the baseline for comparison regarding plan quality of mARC plans.The mARC plans involve two complete (360°) gantry rotations with optimization points every 8° and arclet length of 4° (88 control points). Hence, the mARC plans offer more degrees of freedom for the optimizer (45 optimization points per arc); however, we chose not to increase the number of segments for the IMRT plans, since plans with 90 segments are never used at our department due to the long treatment time. Moreover, hardly any improvement in plan quality is normally observed for plans exceeding 50–60 segments .So for this study we evaluate four plan scenarios, two mARC plans with flat 6 MV and FFF 7 MV and the same for the IMRT technique.Planning is performed in the Eclipse treatment planning system (TPS) V13.5  on a 2.5 mm dose grid using an anisotropic-analytic-algorithm based on planning CT data from a Brilliance BigBore CT .Using a similar set of inversion objectives for both techniques, the optimization can be carried out interactively by adjusting the dose-volume-histogram (DVH) objectives given in  and weigMaximum objectives for the organs at risk were scaled down since this planning study disregarded subsequent boost irradiation up to a total of 76 Gy. Although the maximum dose to the spinal cord and extended spinal cord are given as objectives, the final assessment of the plans relies on the dose to a small volume (ca. 1%) rather than the point maximum.All plans (DVHs and dose distributions) were reviewed by a senior radiation oncologist and a visual comparison of the plan qualities for the four scenarios  was conducted.TV denotes the volume of the PTV, PIV is the volume of the prescribed isodose (95%) and TVPIV is the volume of the PTV covered by the prescribed isodose (95%);PTV(X%) is the dose received by X% of the PTV volume.For the statistical evaluation, we consider the quality indices for PTV conformity (CI)  and homoSparing of organs at risk is assessed by DVH-objectives for the parotid glands (V(20%) and mean) and the spinal cord (D(1%) and D(2%)).All plans were exported to the machine for treatment and irradiated on an anthromorphic Alderson phantom to record treatment times. The phantom was equipped with thermoluminescent dosimeters  at the left breast (about 25 cm distance to the isocenter) to measure scattered out-of-field dose. Three TLDs were placed in close proximity and the readings were averaged. Readout was performed using a Harshaw TLD 5500 Automatic Reader.The statistical analysis was performed using a two-way ANOVA with repeated measures and interactions. Plans were compared pairwise with the Holm-Bonferroni test for mARC vs. IMRT and for 6 MV vs. FFF 7 MV energies, considering the measures of quality defined above, monitor units (MU), treatment times and scattered dose.Based on an inspection of the dose distributions and DVHs, the radiation oncologist approved all plans acceptable for treatment  covers 95% of the PTV, the coverage is obviously identical in all plans. In addition, The statistical evaluation of OAR sparing mostly shows no significant differences . In those cases where a statistically significance is found, it is always in favor of the mARC technique and the FFF 7 MV energy .The use of the FFF 7 MV beam energy results in considerably more monitor units than the flat 6 MV. For 7 MV, IMRT and mARC require almost the same amount of MUs, the IMRT FFF 7 MV plans need about 779 MU in comparison to 758 MU for the corresponding 7 MV mARC plans. 6 MV IMRT require 598 MUs on average, whereas mARC 6 MV required the fewest MUs, with an average of about 406.Treatment times could be markedly decreased by the use of the high dose rate and the mARC technique Tables  and 5. IScattered dose was considerably lower 25% - 26%) for the mARC as compared to IMRT Tables  and 5. T% - 26% fThe statistical evaluation confirms the results of the visual inspection of DVH and dose distributions. All four scenarios  lead to comparatively good quality plans. If there are significant differences related to homogeneity or conformity, the absolute values of CI and HI show little differences, resulting in reduced clinical relevance. These findings are similar to the results obtained in Mynampati DK et al.  comparinThe sparing of organs at risk also shows no significant differences in most cases. Looking at the few cases where significant differences exist, they are always in favor of the mARC-technique and the FFF 7 MV energy. However, in these cases as well, absolute differences are so small to lack clinical relevance.Monitor units differ significantly between 6 MV and FFF 7 MV. This is plausible because of the large PTV in head and neck cases. The dose intensity of FFF beams decreases with distance from the central axis, so with a large PTV more MUs are needed to add dose far from the central axis. This does not occur for the flat energy, because the dose profile does not peak and can cover a larger part of the PTV uniformly with less MUs. These findings were also observed in the study by Dzierma et al. .In spite of this, flattening-filter-free beam energies result in a reduction of treatment time. Therefore, the most efficient way to reduce treatment times is to combine the mARC technique with the high dose-rate FFF 7 MV energy, with a time advantage up to factor 2 in comparison to IMRT 6 MV.a priori clear which effect will be dominant. Although the number of monitor units is markedly elevated, our study shows that scattered dose at the breast is still decreased with the use of FFF 7 MV.The absence of the flattening filter physically leads to a reduction in scattered dose per MU. This has also been observed in other studies , 16–20. The reduction in scattered dose for mARC in comparison to IMRT is supposed to be caused by the fact that Y jaws were completely opened for IMRT within the Eclipse TPS. In contrast to that the TPS adapts the Y jaws to the maximum opening of the treatment field for mARC, leading to less leakage radiation. Similar findings occurred for the previous study regarding prostate planning .in vitro [in vivo. As mARC and IMRT are modulated techniques, treatment times remain of the order of a few minutes and the delivered dose per fraction is much smaller in comparison to stereotactic treatment, so the relevance of potential biological effects of the high dose rate may be questionable.The biological aspects of the high dose rate are discussed controversially. While in most studies no effects of the instantaneous dose rate on cell survival is observed in vitro –23, one in vitro . HoweverKainz et al.  have beeIn previous studies ,6, mARC Regarding VMAT, treatment times differ between different linacs and planning approaches. Several planning studies for head and neck cancer result in about 3–4 min for two complete gantry rotations using a flattening filter , 8, 26. In the context of a scientific cooperation, we were able to use the Eclipse TPS only for a limited period of time for the evaluation of the mARC planning option. Consequently the number of cases presented here is rather small. Moreover, the use of a simultaneous integrated boost (SIB) concept for head and neck treatment is presently considered , 29, whiFor all modalities  it was possible to create highly conformal treatment plans. In those cases where significant differences exist, they are mostly in favor of the mARC technique and the FFF 7 MV energy. Monitor units and hence integral dose are considerably higher for the FFF 7 MV than the flat 6 MV energy; they are reduced by the use of mARC.Although two full gantry rotations are needed for hypopharynx treatment, it is possible to reduce treatment times by up to three minutes by using the mARC technique instead of IMRT. The use of the high dose rate energy results in another time advantage of about one minute.Consequently, with a combination of the mARC technique with FFF 7 MV high dose rate, treatment times could be reduced from about 9 minutes to 5–6 minutes in comparison to 6 MV IMRT for hypopharynx treatment, while scattered dose was reduced and plan quality remained comparable, or even better.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(TIF)Click here for additional data file.S8 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.