The operation of a large-scale metro system creates problematic interior noise; the impact of this noise on passengers and drivers is a subject of increasing concern. To investigate the quantitative relationship between metro interior noise and passengers’ annoyance, this study analyzed questionnaires on passenger annoyance completed by 118 volunteers. The feedback from the questionnaire concerned eleven metro lines in Beijing. To test the interior noise levels, the volunteers were divided into two groups: A and B. The volunteers in group A took the same metro train as the testers, whereas those in group B took different trains. A total of 2080 noise annoyance samples from metro tunnel sections were collected and analyzed. Finally, the exposure-response relationship between interior noise and passenger annoyance was obtained by fitting these data with a logistic function. The results indicated that there was a significant positive correlation between the average subjective annoyance and the averaged equivalent sound pressure level. The fitting result was better for group A than for group B. For the mixed samples of two groups, the fitting result was greatly affected by the contribution of group A. To provide an acoustically comfortable environment, metro interior noise should not exceed 84–85 dB(A). Traffic-induced vibration and noise pollution are major contributors to environmental complaints in large cities; they also have negative impacts on human health and well-being. The health effects of exposure to noise include the sleep disorders with awakenings , learninOne type of this problem comprises train-induced building vibration and associate structure-borne noise, which have adverse effects on the sleep patterns of residents near railway lines. Elmenhorst et al.  comparedAnother type of the problem is the interior noise, which has the adverse effects on the train drivers and passengers . InvestiTo investigate and evaluate metro interior noise, East and Hardy  analyzedMeasures such as rail grinding and rail dampers are suggested to control interior noise. Zhao et al.  found thA-weighted SPL is commonly used to evaluate interior noise. However, this approach may underestimate the impacts of the low-frequency components of interior noise on passengers, especially regarding their interior acoustic comfort ,46. ReseThe above review shows that the characteristic analyses, test and evaluation and control measures of interior noise are widely studied. Although its negative effect on passengers has been recognized and widely investigated, few studies were conducted into the exposure-response relationship between metro interior noise and passenger annoyance. To address this problem, in the present study, passenger sound comfort was investigated with the help of 118 volunteers. Feedback was obtained from a questionnaire that was based on eleven metro lines in Beijing. Meanwhile, interior noise levels were also measured. Finally, the exposure-response relationship and corresponding mathematical expression were obtained by fitting a logistic function to the experimental samples.To obtain the exposure-response relationship between metro interior noise and passenger annoyance, both noise measurement and annoyance were measured. As individuals’ subjective perceptions to noise can vary greatly, evaluating noise annoyance results from a single passenger is of little reference value. Rather, it is more valuable to measure the percentage of passengers annoyed by interior noise.When analyzing the vibration and noise annoyance of residents near railway lines, statistics based on data from self-reported annoyance or questionnaire surveys can be used. However, this method is not applicable to analyzing metro interior noise annoyance. On the one hand, when metro trains run through different running tunnels and station sections, the interior noise is greatly affected by the train’s speed, the metro routine radius, the track type, and the rail wear state. Passengers cannot accurately recall their subjective experience of being annoyed by interior noises in the past, especially regarding their specific annoyance feelings for each running tunnel section. On the other hand, most passengers are not willing to cooperate with questionnaire surveys when traveling on a metro. Due to the generally short commuting times of passengers using metros, they have usually already arrived at their destination before they can be told the purpose of the investigation and the methods and rules for filling in the questionnaire. Moreover, the different destinations of each passenger greatly increase the difficulty of issuing and withdrawing questionnaires.To solve the problems above, 118 volunteers were employed to perform subjective annoyance assessments. The purpose and significance of the study, as well as the rules for completing the questionnaire, were clearly explained to each volunteer in advance. When they took the metro to work, back home, shopping, and traveling, they consciously paid attention to interior noise. They gave subjective scores for each running tunnel section and answered corresponding questions in the questionnaire.Due to the limitations of the numbers and time arrangements of the noise testers, as well as the time arrangements of the volunteers taking the subway, it was difficult to arrange for one tester to follow every volunteer taking the metro. Therefore, the volunteers were divided into two groups: A and B. The volunteers of group A traveled the metro with the testers. That is, the measured interior noise level was highly correlated with the volunteers’ annoyance feedback, as they were in the same train car. Testers did not follow the volunteers of group B when they took the metro. In the questionnaires, volunteers provided detailed information of the metro lines they took and the stations and sections through which they traveled. After obtaining this information, testers then tested the interior noise in the metro lines where the volunteers had traveled. As the volunteers and testers likely did not travel in the same train cars in group B, the correlation between subjective annoyance feedback and the measured noise level in this group was much lower than that in group A. The sample validity of group B was also tested in this study.ψ), and a short description on perception; details are listed in The noise annoyance questionnaire included three parts: passenger’s basic information, subjective rating of noise annoyance  for each section between two stations. The leaving from station and approaching station of each section were also filled by the volunteers. In the fourth column of this part ‘subjective rating’, they were told that scores TS 15666 , DELTA [TS 15666 , and ZouTS 15666 .For the item ‘Perception description’, volunteers were asked to provide some subjective description of the main effects of the interior noise if they rated a high subjective score.n = 72) males and 39% (n = 46) females; their ages ranged from 18 to 68 years old. Most volunteers were university students and office workers, and were between 20 and 30 years old. These volunteers commuted daily using the metro, and these groups represent the main sources of metro passengers. The volunteers’ age distribution is shown in A total of 118 volunteers were involved in the noise annoyance survey, with 61% (Two types of noise measurement equipment were used. One was an integrated circuits piezoelectric sound pressure sensor. It has a measurement range between 20 and 146 dB(A). In the frequency range between 20 and 20,000 Hz, its technical indices can meet the requirement of Class 1 according to the standards of IEC 61672-1 . The secConsidering the passengers’ seated positions, the microphones were located at a height of 1.2 m above the vehicle floor, following the suggestion of the national standard GB 14892  and the T = t2 − t1, the starting time, t1, corresponded to the moment when the doors were completely closed, and the train was leaving the previous station. Furthermore, the ending time, t2, corresponded to the moment when the train stopped completely but the door had not yet opened after reaching the next station.In the interior noise test, the discontinuous sampling mode was used. Each sampling included the whole process from the train leaving the previous station to it reaching the next station. Supposing that the train running time between two stations was To evaluate the interior noise, the A-weighted equivalent SPL was used as a main index.ψ ≥ 8), annoyed (ψ ≥ 5), and slightly annoyed (ψ ≥ 3) scores accounted for 14.1%, 49.2%, and 85.1% of all data, respectively. The 2080 subjective rating samples were from eleven metro lines, i.e., metro lines M1 (including its east extension), M2, M4, M6, M7, M8, M9, M10, M13, M16, and M27. The numbers of annoyance rating samples from the two groups were 1030 and 1050, respectively. A total of 2080 annoyance samples were obtained, and each volunteer took an average of 17.6 running tunnel sections. affecting conversation, irritating, and simulating eardrum.The main effects of interior noise on volunteer passengers were analyzed based on the third part of the questionnaire. As illustrated in The 1019 noise test samples were also from the eleven metro lines mentioned above. The measured SPL inside a vehicle may vary considerably depending on the location. However, even if the tester and the volunteer were in the same car , the microphones could not be placed immediately adjacent to the ears of the volunteers. That is, there was a difference between the noises that the volunteers heard and those that the microphones collected. This error was unavoidable in this study. Therefore, it was necessary to analyze the noise differences at different positions within a vehicle.To avoid the effect of passenger conversations on the test results, this error analysis was arranged in a special metro train without passengers. Six microphones were located in two adjacent vehicles (a motor car and a trailer). The microphones were arranged in the front, middle, and rear of each vehicle .In group B, the vehicles’ noise tests were conducted differently from the vehicles taken by passengers. Therefore, it was necessary to learn the noise difference inside different vehicles when they were running through the same running tunnel section. Then, the interior noises were repeatedly tested in 197 tunnel sections; a total of 1010 samples were collected. The dose-response curve is commonly used to describe the relationship between noise exposure and annoyance. This curve can be obtained by fitting the samples of noise tests and annoyance rating scores. To observe and describe the relationship between annoyance and SPL better, samples were averaged and fitted with the logistic function. First, the range of SPL values was divided into 19 sections with an interval of 1 dB(A). Both the annoyance scores and SPL values in each section were averaged, as illustrated in ψ is the annoyance response or the subjective rating score; u is the upper limit of ψ (ten in this study); k is the slope of the inverse logistic function, which is a constant to be fitted; Leq is the test equivalent SPL; and Lc is the value of Leq for a 50% annoyance response, which is the mean value of the normal distribution. By fitting the average values using Equation (3), the unknown parameters to be determined were obtained; they are listed in A logistic function is suggested as a method to describe average scores ,51; it iadj-R2 is the adjusted coefficient of determination, which was used to evaluate the goodness of fit. The coefficient of determination, R2, is defined as:RSS is the residual sum of squares; TSS is the total sum of squares; R2 value can be improved by increasing the number of samples. To eliminate this effect, the adjusted coefficient of determination, adj-R2, was introduced; this is defined as:n is the sample number, and p is the number of features.In R2 and adj-R2 are to one, the better the fitting effect is. The fitting result for group B only was unacceptable; it had an adj-R2 value of only 0.7523. This occurred because the subjective annoyance scoring and noise testing were carried out separately. The fitting result for group A was better (adj-R2 = 0.9789). It is interesting that the adj-R2 value for all samples of groups A and B was 0.9512, which was also acceptable. This reflects that the sample quality of group A was very good. In the mixed samples, the dominant sample from group A compensated for the deficiency of group B to a certain extent. When 50% of the samples from the two groups were mixed to fit, the effect fitting the group B samples was greatly improved.The closer the values of ψ% is the annoyance percentage; u is the upper limit of ψ% ; and the meanings of other variables are consistent with those defined in Equation (3).Based on analyzing all samples of the equivalent SPL and annoyance scores shown in adj-R2 showed that the fitting evaluation result was similar to that in The unknown parameters were obtained by fitting the average values using Equation (4), as listed in From adj-R2 values in group B. Therefore, if the conditions allow it, the method used for group A should be used as far as possible. If the conditions do not allow this, however, some samples of group B could be mixed with those of group A. However, the samples of group B cannot be used alone to obtain the exposure-response relationship, due to the large error results caused by the noise difference between different vehicles.The test errors were analyzed in LAmax) and sound exposure level (SEL) can also be used to describe noise. LAmax is usually used to describe the maximum value of SPL when a train is running between two stations. If the LAmax increases instantaneously and lasts for a very short time, the responses of different passengers will be different. Some volunteers will remember the maximum value and use it as a basis for rating a high annoyance score, but some volunteers will consider its short duration, and will still give the annoyance score according to the average noise level between two stations. Due to the randomness of LAmax and the different subjective cognitions of passengers regarding the maximum value, it was not suitable as an evaluation index in this study.Equivalent SPL, which was applied in this study, is widely used to evaluate interior noise. The maximum A-weighted SPL . This means that the effect of evaluating noise annoyance by SEL was very similar to that achieved by using SPL. However, if the samples from urban rail transit and suburban rail transit were both to be collected, there would be a significant difference in train running times between different stations. In this case, the SEL may be the better evaluation index. However, the samples collected in this study seldom involved suburban rail transit.Theoretically, SEL responds to the energy of the whole test time, which is more related to the subjective annoyance of passengers. In fact, however, due to the similar distances between metro stations in urban areas, the train running times between any two stations are relatively similar. Accordingly, the equivalent SPL and the SEL exhibit a high correlation. Another problem that needs to be addressed is that when using equivalent SPL, it is difficult to consider the influences of different noise frequencies on passengers’ annoyance fully. Volunteers’ subjective feedback suggested that high-frequency interior noise  caused by rail wear and other factors can probably cause high annoyance. However, low-frequency noise caused by laying floating slab tracks and other factors cannot easily annoy passengers, even though it has a high total SPL. However, despite the disadvantages mentioned above, the statistical study in this paper exhibits that the equivalent SPL is still a good index for evaluating passengers’ annoyance caused by interior noise.At present, there is no interior noise standard considering passengers’ annoyance in China. In the Chinese national standard GB 14892 , ‘Noise Unlike in the test environment in the above standard, in a regular operating metro train, there is not only broadcasting sound but also passenger conversation. This makes the interior noise during regular operation louder than that during the inspection. Therefore, based on the above specification limits, According to the above analysis, from the perspective of passengers’ acoustic comfort, the equivalent SPL of interior noise should not exceed 84–85 dB(A) when a metro train runs between two stations. If the test noises in one metro vehicle were to exceed this recommended value in several sections, it would be necessary to pay attention to the vehicle condition, such as door tightness, wheel out-of-round level, etc. If the test noises in several vehicles were to exceed this recommended value during the same section, it would be necessary to pay attention to the track condition in this section, such as abnormal rail corrugation.Analysis of all noise test samples revealed that 6.7 and 5.1% of samples exceeded 84 and 85 dB(A), respectively. Although these proportions are not high, interior noise is a problem for the Beijing metro, which is a huge system with a total mileage of nearly 700 km; it still needs to be addressed and solved.(1)There was a significant positive correlation between the average subjective annoyance and the average equivalent SPL.(2)The logistic function could accurately fit the relationship between interior noise and annoyance score/annoyance percentage.(3)The fitting result was best for samples from group A, and was worst for samples from group B. For the mixed samples of both groups, the fitting result was greatly affected by the contribution of group A.(4)To provide a comfortable acoustic environment, the metro interior noise should not exceed 84–85 dB(A).A research strategy was proposed to investigate the relationship between the metro interior noise and passengers’ annoyance based on interior noise tests and questionnaires completed by volunteers. The feedback from the questionnaire concerned eleven metro lines in Beijing. A total of 118 volunteers were divided into two groups: A and B. The volunteers of group A took the same metro train as the testers, whereas those of group B took different trains. The metro interior noises were tested, and a total of 2080 samples were collected and analyzed. The results indicated that:Finally, it should be highlighted that the results of this study and the obtained exposure-response relationship were only based on subjective evaluations on the noise of eleven metro lines in the Beijing urban area from 118 volunteers. There are two limitations of this study: one is the number of participants, which brings uncertainties in results; another is the results from group B, in which the separation of subjective annoyance scoring and noise testing induced an unacceptable fitting results. To analyze the influence of noise on passengers comprehensively, more noise test data are suggested to collect according to the model of group A, and more volunteers with different ages should be involved in the future, which would help to improve the research results.


As more people are surviving stroke, there is a growing need for services and programs that support the long-term needs of people living with the effects of stroke. Exercise has many benefits; however, most people with stroke do not have access to specialized exercise programs that meet their needs in their communities. To catalyze the implementation of these programs, our team developed the Stroke Recovery in Motion Implementation Planner, an evidence-informed implementation guide for teams planning a community-based exercise program for people with stroke.This study aimed to conduct a user evaluation to elicit user perceptions of the usefulness and acceptability of the Planner to inform revisions.This mixed methods study used a concurrent triangulation design. We used purposive sampling to enroll a diverse sample of end users  from three main groups: those who are currently planning a program, those who intend to plan a program in the future, and those who had previously planned a program. Participants reviewed the Planner and completed a questionnaire and interviews to identify positive features, areas of improvement, value, and feasibility. We used descriptive statistics for quantitative data and content analysis for qualitative data. We triangulated the data sources to identify Planner modifications.A total of 39 people participated in this study. Overall, the feedback was positive, highlighting the value of the Planner’s comprehensiveness, tools and templates, and real-world examples. The identified areas for improvement included clarifying the need for specific steps, refining navigation, and creating more action-oriented content. Most participants reported an increase in knowledge and confidence after reading the Planner and reported that using the resource would improve their planning approach.We used a rigorous and user-centered process to develop and evaluate the Planner. End users indicated that it is a valuable resource and identified specific changes for improvement. The Planner was subsequently updated and is now publicly available for community planning teams to use in the planning and delivery of evidence-informed, sustainable, community-based exercise programs for people with stroke. There are >13 million new cases of stroke per year worldwide . AdvanceAlthough many individuals see improvements during the acute rehabilitation phase after the stroke, many lose their initial gains when they return to the community, and their disability progresses over time . EvidencIn 2016, the Heart and Stroke Foundation’s Canadian Partnership for Stroke Recovery (CPSR)  convenedBuilding on this momentum, our team aimed to develop an evidence-informed resource  to guideThe well-established Knowledge-to-Action (KTA) cycle, which helps bring the results of health care research into effective changes in practice, provided the overarching framework for the planning process -26. It aThe “Planner development” phase  informedAs the prototype was developed, the research team engaged stroke advisors, including members from an existing group of Stroke Community Advisors through the CPSR. These stroke advisors  reviewed the Planner and provided feedback on the content and format to ensure that people with stroke, their families, and caregivers were reflected appropriately.ready for evaluation .On completing this rigorous initial Planner development process, the resource was deemed Characteristics of the planning approach:situated within the community and provided by organizations with a mandate for community service Intended for exercise programs Participant centered (putting people with stroke and caregivers at the center of decisions and seeing them as experts working with service providers to achieve the best outcomes) ) , qualitaThe user evaluation was a mixed methods study that used a concurrent triangulation design . We usedWe used purposeful sampling. All staff involved or interested in the planning and delivery of community-based exercise programs for people with stroke were eligible to participate in the user evaluation, including community and municipal program directors, managers and coordinators, regional health authority staff, fitness or exercise professionals, physiotherapists, and other consulting health partners. We identified potential participants through the professional networks of (1) study coinvestigators, many of whom have developed exercise programs; (2) individuals who previously participated in the Planner development process; and (3) participants enrolled in the study .In Canada, we aimed to identify participants from different geographical regions with various population densities. Using definitions from Statistics Canada , we creaWe started recruiting individuals to prospectively field test the Planner in December 2019. In March 2020, the COVID-19 pandemic caused significant challenges for recruitment as the pandemic resulted in many teams stopping community-based program planning. In May 2020, we amended our protocol to add 2 additional groups  to our scurrent program planners engaged in additional study activities as part of the field test component of the evaluation  was overwhelming and I went “oh my gosh I missed every single step”...But then I looked back and I saw that I did most of it, but just not necessarily with as much intention or thought. A lot of it [Planner content] is just kind of intuitive and I did it but it wasn’t as thoughtful.Rehabilitation health professional, ID37future and past program planners  indicated that they would likely use the Planner for future program planning. Similarly, most questionnaire participants  said they would likely recommend it to colleagues to support program planning, described by one participant as follows:Nearly all If I knew somebody was thinking of [planning a program], I think a resource such as this would be the exact one they should be using. If I were in a position where I was implementing or supporting or advising on the implementation of a program, I would definitely recommend the use of this resource at the planning stage in order to make sure that everything has been thought about.Rehabilitation health professional, ID21Most questionnaire participants  agreed that the Planner could be applied to planning programs that were not stroke specific, including exercise programs for people with other health conditions and nonexercise programs:I’m working on a different program and some of the concepts in the Planner have helped develop that program. It’s not an exercise program but the Planner has helped me think about other things when it comes to programming.Program manager or coordinator, ID12Although the most commonly reported first impression of the Planner was that it was long and possibly overwhelming, over three-quarters  of the questionnaire participants agreed that the Planner presented the right amount of information. Most participants indicated that after reading and digesting the information, they saw great value in all the presented materials and could not identify materials that could be removed. Participants recognized the need to strike a balance between making the Planner a comprehensive information source for people with various roles and experience levels while also ensuring that the material was not overly long or onerous to read:As far as usability, it’s trying to walk that fine line between providing too much information and not enough information. Because you get a variety of people, from those who have never implemented a community-based program, to those who are very used to that. Trying to make it work for both those groups, how do you do that as best as possible? That’s not an easy answer.Program manager or coordinator, ID13All questionnaire participants  agreed that the Planner was well organized, and nearly all agreed that it was easy to read and understand  and clearly presented the planning process . Participants were split on the format of the Planner: 56% (20/36) of participants would have preferred a web-based version over a paper-based version, and 28% (10/36) did not have a preference. Participants frequently desired access to both a web-based version for easy navigation and tool completion and a paper-based version for hard copy use.There were several recurring comments related to the Planner content, which cut across sections and tools that resulted in edits. For example, we observed a discordance in some participant settings between the Implementation Planning Roadmap and the “usual way things are done,” reflecting a difference in philosophy. To address this, we made the guiding principles and assumptions explicit at the beginning of the Planner to make the approach and values transparent and explain the rationale for the planning process . FurtherFor questions assessing specific Planner sections and tools, 70% (30/43) of the items were deemed “necessary—keep as is” by at least 75% of the questionnaire participants . Key conThe participants offered constructive comments on how to optimize the format and organization of the Planner, which resulted in several key changes .The study participants made some suggestions for Planner modifications that after careful consideration, we decided not to make. Here, we provide 2 key examples with the rationale.First, some participants requested that to facilitate use, the Planner should be separated into different sections to assign specific content to different roles on the planning team. However, the desire to distinguish between those “planning” and those “delivering” was not aligned with our guiding principle of using a participatory and inclusive approach. Planning teams are most effective when those delivering the program  and using the program  are engaged early in the planning process. In addition, team members’ roles may be fluid over time and in different contexts. Therefore, we left the Planner as one document designed for all team members, with the goal of encouraging awareness of and participation in the full planning process. The importance of an integrated planning team was supported by a study participant who regularly delivered community programming:I was really excited about having “boots on the ground” kind of people [on the planning team]. Because often times you don’t hear about these things until after others have made the decision and you’re like “oh if only you had talked to the people who actually implement these things. It would have been helpful.” Because the concept of policy can often vary greatly from the reality.Fitness or exercise professional, ID22Second, several participants commented on the level of repetition throughout the Planner and recommended making the document shorter and more concise. Although we carefully reviewed the Planner and eliminated unnecessary redundancies, some repetition was left in for pedagogical reasons . RepetitAll the participants provided positive feedback on the Planner and identified features that they found useful. We used this positive feedback to identify content and features to keep in the final version. We also identified ways of expanding upon and further enhancing these features where possible .Using the data reported in this study, we revised both the content and format of the Planner. Integrating this feedback involved extensive rewriting and editing by the core study team; contracting the graphic designer; and a final review by 16 coinvestigators, consultants, end users, and stroke advisors. The largest revision of the Planner involved improving the overall structure and navigation .The Stroke Recovery in Motion Implementation Planner is now hosted through March of Dimes Canada, a Canadian nonprofit organization offering services for people with disabilities, including the After Stroke program focused on stroke recovery in the community . The PlaThis paper provides a comprehensive description of how the Planner was developed, informing consumers of the rigorous process used. Our mixed methods user evaluation demonstrated that, overall, end users viewed the Planner positively and indicated that it was a useful and valuable resource. They reported that it would improve the planning process and help them make planning decisions informed by evidence. The participants’ constructive feedback on the content and organization was used to revise and strengthen the Planner.Our development process aligns with that used by others to develop implementation guides and toolkits in different settings, including selecting an underpinning theory or framework -48, searSome participants provided feedback consistent with findings reported in the literature; for example, perceptions that the implementation process could be overwhelming or the guide too long ,51, the The use of an implementation framework can contribute to more systematic planning, delivery, and evaluation of programs, thereby contributing to improved success and sustainability . HoweverThe Planner is based on the KTA, CAN-IMPLEMENT, and Implementation Roadmap frameworks ,25,27-29This study has some limitations that should be acknowledged. A key challenge was conducting the study during the COVID-19 pandemic. Although we successfully recruited 39 participants to review the Planner, the data collection period coincided with the pandemic, a time of high personal and professional stress. It is unknown how the stress of the pandemic may have influenced decisions to participate in the evaluation or how it influenced participants’ perspectives of the Planner. However, nearly half of the individuals approached to participate did so despite the burden of having to read the comprehensive Planner, complete a lengthy questionnaire, and participate in an interview. This suggests that those who participated were strongly committed to providing input on the Planner and provided thoughtful and detailed feedback.current program planning group, our primary contact was often the manager or coordinator or health partner. These planning leads had sometimes not yet identified the fitness professional team members and were unable to connect the research team with fitness professional study candidates. Furthermore, the pandemic led to the closure of community centers and fitness facilities, and therefore, many fitness professionals were not actively employed during this time. Despite these challenges, approximately 20% (8/39) of the study participants were fitness or exercise professionals who offered rich and thoughtful guidance on how to improve the Planner to meet their needs.Although our sample was diverse, we would have liked to have enrolled more fitness professionals, given their role in delivering exercise programs. There may be several reasons for their limited enrollment. For the Finally, the user evaluation involved the hard copy version of the Planner, and therefore, the findings may not reflect perceptions of a web-based format. Plans are underway to develop a web-based toolkit based on the hard copy version.current, future, and past) allowed us to collect data (and reach saturation) from a broad range of stakeholders in various geographical areas with differing experiences in community-based exercise programs for people with stroke. Our rigorous analysis process resulted in every comment being reviewed and carefully considered to inform the Planner revisions and facilitated improved relevance and feasibility of the Planner.A strength of the study was the mixed methods design, which facilitated assessing perceptions of the Planner through a comprehensive questionnaire with standard questions for all participants, followed by an interview for in-depth discussions on dimensions that were particularly important to each participant. We used multiple types of triangulation, including methods (questionnaires and interviews), sources (participants from diverse settings), and analysts (coding and interpretation by multiple researchers), all of which enhanced the quality and credibility of our findings . The tarWith the Planner finalized and freely and publicly available for use by community teams, we now have the opportunity to further evaluate its ongoing use and impact. Access and use will be monitored through website statistics and consumer inquiries. Working with key stakeholders, we also plan to augment the Planner to better address culturally tailored physical activity programs for racialized populations with stroke, as well as issues related to planning web-based programs for people with stroke. Finally, future work will involve developing products that distill the Planner information into alternate formats to meet diverse learning needs, including video vignettes, infographics, a condensed pocket guide, and a presentation slide deck.Community-based exercise programs are urgently required to address community reintegration and transitions for people living with the effects of stroke. The Stroke Recovery in Motion Implementation Planner  was desi


The results show that the Mg–Zn–Ce compound in both the as-cast and the homogeneous alloys is 12Ce. 12Ce phase formation depends on the content and the ratio of Zn and Ce elements in the initial residual melt of the eutectic reaction. The Zn/Ce mass ratios below 2.5 give the highest compound contents for different Zn contents, 5.262 wt.% and 7.040 wt.%, respectively. The increase in the amount of the 12Ce phase can significantly reduce the critical conditions for dynamic recrystallization formation. Both the critical strain and the stress decrease with increasing rare earth content. The reduction of the critical conditions and the particle-promoted nucleation mechanism work together to increase the amount of dynamic recrystallization. In addition, it was found that alloys with 6 wt.% Zn elements tend to undergo a dynamic recrystallization softening mechanism, while alloys with 3 wt.% Zn elements tend to undergo a dynamic reversion softening mechanism.The quantitative study of rare earth compounds is important for the improvement of existing magnesium alloy systems and the design of new magnesium alloys. In this paper, the effective separation of matrix and compound in Mg–Zn–Ce–Zr alloy was achieved by a low-temperature chemical phase separation technique. The mass fraction of the  Magnesium alloys have become one of the most promising lightweight structural materials today due to their low density, high specific strength, and specific stiffness ,2,3, and1−xZnx)11Ce and (Mg1−xZnx)12Ce are the key to playing a strengthening role. The organizational characteristics of Mg–Zn–Ce compounds, including morphology, distribution, and quantity, all influence their role in the alloy, among which the quantity of Mg–Zn–Ce compounds has been less studied. The quantitative study of the effect of the quantity of rare earth compounds on strengthening effect has become one of the important tasks of current research.The addition of Ce is expected to improve the strength and the heat resistance of Mg–Zn–Zr alloys due to its huge reserves in the earth’s crust and easy extraction, especially in the Mg–Zn–Zr system. According to the Mg–Ce binary phase diagram , the solSeveral methods have been used for the analysis of the content of rare earth compounds, among which the older point parameter method is more limited. Atomic probe chromatography (APT) ,20, alth12Ce phase and its content regulation method are the key elements in the study of Mg–Zn–Ce–Zr alloys. To this end, a novel chemical phase separation method was designed to investigate the mass fraction of the 12Ce phase in different composition alloys. In the Mg–Zn–Ce–Zr alloy, the Zn element can form the Zn–Zr phase before the eutectic reaction at the early stage of solidification, and it may form the Mg–Zn phase during the eutectic reaction. Therefore, in this study, it is assumed that all Zr forms Zn–Zr compounds, and the content of Zn and Ce in the solidified melt can be obtained by using the difference between the total amount of elements and the measured solid solution amount. Further, the effect of Zn and Ce content on the amount of Mg–Zn–Ce ternary compound formation is discussed in order to provide help for the design and the improvement of new high-strength alloys.In summary, the quantitative study of the −1, and a deformation of 50%. The deformed specimens were water-cooled immediately after deformation and used for deformation tissue observation.The Ce elements were added to the Mg–Zn–Zr alloy to form the alloy used for the experiments. The added Ce content was 0.5 wt.%, 1.0 wt.%, and 1.5 wt.%, respectively, and the Zn content was 3 wt.% and 6 wt.%. Pure magnesium and intermediate alloys  were melted under slag protection to prepare semi-continuous ingots of 210 mm. The actual chemical composition test results of the ingots are shown in The low-temperature phase separation of the alloy was performed by chemical methods. The solid solution phase in the alloy reacts with the solution and then decomposes and dissolves into the solution, while the compound phase remains in the solution in its original form. The phase separation solution uses methanol as the solvent, ammonium benzoate as the surface passivator of the compound, 2,2′-bipyridine as the complexing agent of Zn ions, salicylic acid as the inhibitor of hydrolysis products, and dioxane as the chemical corrosion inhibitor of the magnesium alloy. The reaction between the alloy and the separation solution was carried out at −20 °C with a reaction time of 2 h. After the reaction, the solid–liquid was separated by the centrifugation + membrane method. The liquid phase was used to determine the content of rare earths and Zn elements in the solid solution, and the solid phase was used for the physical identification and the morphological observation of the compounds.The HITACHI SU8220 scanning electron microscope (SEM) was used to observe the morphology of the metallographic sample and the separated solid phase of the alloy. The composition of the micro-area was analyzed by an energy dispersive spectrometer (EDS). The composition of the as-cast alloy and the solid phase separation was analyzed by D/Max 2500/PC X-ray diffraction (XRD). The X-ray diffractometer had a Cu-k target, and its working voltage was 40 kV and its current was 300 mA. The scanning speed was 1 degree per minute, and the scanning step was 0.02 degrees. The scanning angle range was 20–80 degrees. The transmission electron microscope (TEM) analysis sample of the as-cast experimental alloy was prepared by the ion thinning method. The phase morphology observation and the selected area diffraction analysis were carried out by the FEI Talos F200X transmission electron microscope. The electron acceleration voltage was 200 kV. 12Ce. A few Mg–Zn and Zn–Zr binary phases were detected in the fine bulk particles in the figure, corresponding to points B and D in 12Ce phase and the Mg21Zn25 phase. The Mg–Zn and the Zn–Zr phases may be too small and entrapped in a large number of particles to be effectively calibrated. Based on the relative intensities of the 12Ce phase diffraction peaks, it can be seen that the proportion of the 12Ce phase increases with the increase of Ce and Zn content. The position of the main peak of the 12Ce phase in the figure shows a small shift, which is caused by the change of Zn content in the Mg–Zn–Ce ternary phase.1−xZnx)12Ce, (Mg1−xZnx)10Ce, Mg7Zn12Ce, and Mg3Zn5Ce [12Ce phase, respectively. The TEM-EDS results show that the phases are all composed of Mg, Zn, and Ce. The atomic percentages of Mg, Zn, and Ce are 50.13%, 42.18%, and 7.7%, respectively, and the ratio of the sum of Mg and Zn atoms to Zn is 11.98:1. Therefore, the diffraction pattern calibration result is the 12Ce phase, which is consistent with the X-ray diffraction analysis result.The elements Mg, Zn, and Ce can form four major intermetallic compounds, including 12Ce phase in each alloy can be calculated from the Ce element content (the difference between the Ce element content and the solid solution amount), assuming that the 12Ce phase follows the stoichiometric ratios determined by SEM-EDS and TEM-EDS, and the results are shown in The Ce element in the alloy mainly exists as a solid solution and Mg–Zn–Ce ternary phases. Based on the determination of the rare earth compound phase as the 12Ce phase exists in the calibration results of the homogeneous alloy, which indicates that the 12Ce phase can exist stably at this homogenization temperature. As a result, the Mg–Zn phase was not calibrated, indicating that the non-equilibrium phase such as Mg–Zn was fully decomposed in the homogenization process. As only the 12Ce phase in the homogeneous alloy compound contains the Ce element, the mass fraction of the 12Ce phase in the alloy can be calculated according to the Ce content in the compound (the difference between the Ce addition amount and the solid solution amount), and the results are shown in 12Ce phase, SEM images of the as-cast and the homogenized states were analyzed in the study by using image analysis software, and the results are shown in 12Ce phase is shown on the left axis (black) and the area percentage of the 12Ce phase is shown on the right axis (red), which shows similar values and the same trend of 12Ce phase content with alloy composition.To verify the accuracy of the quantitative analysis results of the 12Ce phase distributed along the grain boundary and large extruded grains. In the high-power SEM image, besides the second phase broken during extrusion, a large number of dynamically recrystallized grains are distributed at the grain boundary, and the dynamically recrystallized grains are concentrated around the broken 12Ce phase. The above results show that a large number of initial grains remain during hot deformation, so that complete dynamic recrystallization is impossible, and a large number of dynamic recrystallization grains can be formed in the 12Ce phase.The stress–strain curves of the experimental alloy are shown in 2) and area ratio of recrystallized grains , average area 12Ce phase by using the alloy components in the residual liquid phase.The generalized phase diagram generally describes the condition that the system is in thermodynamic equilibrium. In fact, the diffusion coefficient of solute in the solid phase is very small, so equilibrium solidification is extremely difficult to achieve. The actual solidification process is usually closer to the Scheil–Gulliver cooling condition, that is, there is no diffusion in the solid phase, the liquid phase is uniformly mixed, and the solid–liquid interface is in a local equilibrium state ,22. The 12Ce phase, and the change trend of compounds is similar, while the number of compounds formed in the alloy with 6 wt.% Zn content is obviously greater. It shows that the conditions for increasing the number of compounds are increasing the content of Zn and Ce in the remaining melt and decreasing the mass ratio of Zn/Ce.The Zn and Ce contents in the remaining melt are shown in 12Ce phases increases, the critical stress for dynamic recrystallization decreases and the corresponding critical strain decreases, indicating that the alloy is more likely to start dynamic recrystallization during thermal deformation.The critical condition of dynamic recrystallization (DRX) is an important parameter to study the evolution of dynamic recrystallization, and the work hardening rate method is often used to judge the condition of dynamic recrystallization of magnesium alloys . The cri12Ce phases reduces the size of the recrystallized grains, while increasing the area fraction of recrystallized grains in the alloy, which is consistent with the results in previous reports.The second phase during thermal deformation can act as a nucleation point for recrystallized particles, i.e., play a particle stimulated nucleation (PSN) mechanism, and what role the particles play depends on the size, spacing, and fraction of the particles . The intθ value in the work hardening curve of the alloy decreases to 0. In the flow stress curve of ZCⅢ alloy, the stress tends to be stable after reaching the peak stress, and it does not show typical DRX softening characteristics. At this time, the dynamic softening mechanism is dominated by the dynamic recovery mechanism (DRV). However, during the subsequent strain increase, the softening effect of DRX gradually increases, and DRX grains appear at the grain boundaries of the alloy. The flow stress curve of ZCIV alloy shows obvious DRX softening characteristics. The flow stress gradually decreases after reaching the peak stress, and the dynamic softening mechanism is dominated by DRX. The above analysis shows that the content of the Zn element will affect the dynamic softening mechanism of the alloy. The dynamic softening mechanism of low Zn alloy is mainly DRV, while that of high Zn alloy is mainly DRX, and the effect of DRX is stronger in the alloy with a high content of the 12Ce phase.12Ce phases in the experimental alloy. With the increase of compound content in alloys with different Zn content, the peak stress increases, and the changing trend is consistent. However, it can be seen that the peak stress is obviously lower in 6 wt.% Zn alloy with a higher number of compounds, which is attributed to the role of the 12Ce phase in the process of thermal deformation. The increase in the number of 12Ce phases reduces the critical conditions for dynamic recrystallization and greatly advances the dynamic softening effect in the alloy. In the corresponding stress–strain curves, ZCIV, ZCV, and ZCVI alloys show peak stress at small strain. In addition, the increase in the number of 12Ce phases also strengthens the PSN mechanism, provides conditions for the nucleation of recrystallized particles, and inhibits their growth, which corresponds to the stress reduction stage in the stress–strain curve. The above analysis results show that controlling the amount of the 12Ce phase can not only predict the properties of the alloy during the current deformation process but also adjust the trend of the stress–strain curve to obtain ideal mechanical properties.12Ce phase in the alloy was obtained based on a chemical phase separation method. The effects of Zn and of Ce contents in the remaining liquid phase on the 12Ce phase content were analyzed in combination with the quantitative analysis results, revealing the effects of the 12Ce phase content on the mechanical properties, and the main conclusions can be summarized as follows.In this study, the mass fraction of the 12Ce phase, and the Zn and Ce content will affect the amount of the compound formed in the alloy. With the increase of Zn and Ce content, the 12Ce content increased from the lowest 3.586 wt.% to the highest 7.040 wt.%. Additionally, the 12Ce phase can be stable in the homogenization treatment due to its higher thermal stability.The Mg–Zn–Ce compound in the as-cast alloy is only the 12Ce phase is formed in the liquid phase remaining after the solidification of the α-Mg phase is completed. Therefore, the formation of the 12Ce phase was more accurately analyzed using the content of each element in the remaining liquid phase. The maximum compound content for different Zn contents can be obtained by controlling the Zn/Ce mass ratio in the remaining melt to below 2.5 in the composition designed for the study.The 12Ce phase can reduce the critical strain and the critical stress of dynamic recrystallization and promote the dynamic recrystallization process together with the PSN nucleation mechanism of the 12Ce phase. In addition, the work-hardening curves indicate that alloys with 6 wt.% Zn elements tend to undergo a DRX mechanism, while alloys with 3 wt.% Zn elements tend to undergo a DRV mechanism.The increase in the amount of the At present, we have studied Mg–Zn–Zr alloys with different types of rare earths added using chemical phase separation methods, all of which can achieve the expected results. However, this method is currently limited to Mg–Zn-based magnesium alloys and a few Mg-Al-based magnesium alloys. Due to differences in the physical and the chemical properties of the elements in the alloys, the adjustment of the reagents used in the separation solution can expand the application area of the phase separation method.


Dear Editor,BCR::ABL1 fusion gene resulting from translocation of the 3′ region of ABL1 oncogene from its normal position on chromosome 9q34 to the 5′ region of the BCR gene, located on chromosome 22q11.2. The characteristic t translocation occurs in ~90% of CML cases, and the derivative 22 from this translocation is recognized as the Ph1 chromosome. Most of the remaining CML cases (8–10%) represent complex 9;22 translocation with a third or fourth chromosome involved; [BCR::ABL1 fusion [BCR::ABL1 fusion transcript typically translates to the corresponding P210 (e13a2/e14a2) fusion protein with molecular weight of 210 kDa with a minority displaying other similarly oncogenic isoforms, including P190 (e1a2) and P230 (e19a2), as a result of different BCR breakpoints [BCR::ABL1 is the most frequent fusion transcript in Ph1-positive ALL [BCR::ABL1 isoforms [BCR::ABL1 oncoprotein is causally linked to both chronic myeloid leukemia (CML) and Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) and is the product of the BCR::ABL1 e1a2 (P190) transcripts, in terms of overall survival, risk of blast transformation, and response patterns to TKI therapy, thus expanding upon our previous report that included only two patients with CP-CML [Two relatively large studies have provided prevalence estimates for P190 CML , 7. One BCR::ABL1. Conventional criteria were used for diagnosis and disease classification as CP vs AP vs BP CML [BCR::ABL1/ABL1 transcript <1%, on the International Scale (IS)-like approach regarding measurement thresholds, as is currently applied for monitoring P210 BCR::ABL1 transcripts. Major molecular response (MMR) entailed a ratio of BCR::ABL1/ABL1 transcript ≤0.1%, and further considered as deep molecular response for a ratio of ≤0.01% (MR4.0), based on IS-like approach as mentioned above. Response assignments were double-checked in an independent fashion to assure accuracy. Date of last follow up or death was updated through January 2022. Overall survival indicated the interval between diagnosis and death or last follow up. Statistical analysis was based on conventional procedures using JMP Pro 16.0.0 software .After approval by the Mayo Clinic instituitional review board, study patients were retrospectively recruited from the Mayo Clinic institutional database, based on documentation of CML diagnosis associated with P190/e1a2 s BP CML . Hematols BP CML . CompletBCR::ABL1 transcripts , AP disease at time of diagnosis (n = 1), and concomitant diagnosis of JAK2 V617F mutation (n = 1). The latter patient presented with constitutional symptoms and splenomegaly and his P190 BCR::ABL1 and JAK2V617F allele burdens at diagnosis were both below 1% and karyotype showed only 2 of 20 metaphases with Ph1; patient was treated with imatinib during which time his e1a2 clone was suppressed but JAK2V617F allele burden increased with progression to overt primary myelofibrosis, subsequently treated with allogeneic hematopoietic stem cell transplant (AHSCT); serial post-transplant mutation screening revealed disappearance of both BCR::ABL1 e1a2 and JAK2V617F clones. The patient with AP-CML was treated with IFN-α initially with no response and subsequently with imatinib and achieved CCyR. At last documented follow-up, patient was alive at 12 years from diagnosis on varying doses of imatinib and going in and out of CCyR.A general CML database search for documentation of P190 (e1a2) produced 14 cases. Four of these 14 cases were excluded from the core study because of concomitant presence of P210 BCR::ABL1  with CP-CML and harboring sole e1a2 (P190) ABL kinase domain mutation studies were not consistently performed but a G250E ABL kinase domain mutation was documented in patient 6 , two (18%) deaths were reported, both from causes unrelated to CML. In addition, there were no instances of disease transformation into AP-CML or BP-CML or AHSCT. Figure –16, two BCR::ABL1 transcripts. None of our 10 CP-CML patients progressed into BP-CML, after a median follow-up of 6 years; by contrast, 9 (36%) of 25 MDACC patients with either CP-CML (n = 23) or AP-CML (n = 2) were previously reported to have experienced blast transformation, after a median follow-up of 7.5 years [Observations from the current study paint a relatively better picture, than previously suggested , on the .5 years . Additio.5 years  but not


Responders to natalizumab showed higher concentration of serum IgM-PC b.t than those who did not respond to it (p = 0.019). The 73.3% of patients with the highest level of serum IgM-PC b.t responded to natalizumab. IgM-PC level decreased a.t in both cases, non-responders and responders to natalizumab. IgM-PC levels a.t did not decrease in non-responders to interferon-β, but in responders to it the IgM-PC level decreased (p = 0.007). Serum IgM-PC could be a biomarker of response to natalizumab or interferon-β treatment. Further studies would be necessary to validate these results.We developed an ELISA assay demonstrating the high prevalence of serum IgM to phosphatidylcholine (IgM-PC) in the first stages of multiple sclerosis (MS). We aimed to analyze the role of serum IgM-PC as a biomarker of response to treatment. Paired serum samples from 95 MS patients were obtained before (b.t) and after (a.t) treatment with disease modifying therapies. Patients were classified as non-responders or responders to treatment, according to classical criteria. Serum IgM-PC concentration was analyzed using our house ELISA assay. The level of serum IgM-PC b.t was higher in patients treated later with natalizumab than in those treated with Copaxone ( Moreover, IgM-PC in cerebrospinal fluid is associated with a more aggressive disease form of MS, characterized by more frequent relapses, faster progression of the EDSS, and rapid evolution to the progressive phase of the disease2. Recently, we detected IgM on axons and oligodendrocytes in MS brain samples, co-localizing with activation complement factors3. Moreover IgM co-localizes with markers of cellular and axonal damage4.Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS). Lipids are the main component of myelin, and antibodies to sulfatide, ganglioside GM4, galactocerebroside and cholesterol5. Recently, we developed a sensitive assay, which detected serum IgM-PC in almost 90% of MS patients during the initial phases of the disease1. These and additional data suggest a role of antibodies as potential biomarkers in MS.The analysis of the peripheral compartment has also demonstrated the presence of antibodies to lipids in MS. Serum IgG antibodies to lactosylceramide are associated with cerebral tissue damage in these patients7, and most available treatments show limited efficacy in the progressive phase of disease8. Moreover, side effects, such as cardiomyopathy, leukemia, progressive multifocal leukoencephalopathy, bradyarrhythmia, macular edema, herpes zoster virus infections, autoimmune thyroiditis, thrombocytopenia and glomerulonephritis are associated to immunosuppressive therapies9. Thus, it is important to characterize biomarkers of treatment response to develop personalized therapies, improving their effectiveness while minimizing their side effects. With this goal in mind, we evaluated the role of serum IgM-PC as a biomarker of response to MS treatment.Treatments delay MS progression, but do not cure it. In addition, 40% patients do not respond to first-line treatments10. The analytical assay (ELISA to quantify the IgM-PC levels) and the clinical data collection were developed by different researchers in a double-blind study.This is a Class II criteria study with retrospective sample and clinical data collection from MS patientsA total of 95 MS patients were included in this study. All the protocols were approved by the Bioethics Committee of Hospital Clínico San Carlos  and Committee of Bioethics of Hospital Universitario Quirónsalud .All the patients gave verbal and written informed consent for sample collection.11.All methods were carried out in accordance with relevant guidelines and regulations Paired samples were obtained before treatment and 6 months after starting it, and were aliquoted and stored at -80º C until analyzed.12, considering the progression of the disease and the number of relapses. To assert progression, we considered the following criteria: (1) increase ≥ 1.5 points at 24-months visit, if pre-treatment EDSS = 0; (2) increase ≥ 1 point at 24-months visit, if pre-treatment EDSS was ≥ 1 and ≤ 5; (3) increase ≥ 0.5 points at 24-months visit, if pre-treatment EDSS was ≥ 5.5. Relapses were uttered as a worsening of neurological impairment or a new neurologic dysfunction affecting a different area of the central nervous system, with a duration of more than 24 h and preceded by stability of at least 1 month. Based on these criteria, we stated the clinical response to treatment (defined as an absence of relapses and disability progression) and the therapeutic failure (≥ 2 relapses and/or disability progression) after two years of follow-up.Patients were classified depending on the response to treatmentThe demographic and clinical data, treatment, and response of all patients analyzed are summarized in Table 1. Briefly, 96-well plates were coated with PC . After washing three times with phosphate-buffered saline, the wells were blocked. Serum samples were diluted (1/50) in blocking solution and pipetted by triplicate into the wells. IgM antibodies were detected with anti-human IgM biotin , followed by streptavidin–horse peroxidase (Sigma- Aldrich). Finally, we used TMB-one (Thermofisher Scientific Inc) as substrate. Plates were read at 450 nm using a Varioscan Flash spectrophotometer (Thermofisher Scientific). The level of antibodies was described as optic density (O.D). To determine variations in the level of IgM-PC before (b.t) and after (a.t) the treatment, we used this equation: ((O.Da.t-O.Db.t)/O.Db.t) × 100. We asserted variations when the value was ± 5%.To detect IgM antibodies to PC, we used a method we published previouslyp values < 0.05 were considered statistically significant. Mann Whitney test was used to compare IgM-PC levels in patients treated with different drugs, and in non-responders and responders. We used the Wilcoxon test to compare the IgM-PC concentration in serum samples before and after treatment. To analyze the percentage of non-responders and responders in the quartiles of IgM-PC concentration or the percentage of patients showing decrease, no changes or increase in IgM-PC levels after the treatment we used the χ2 test.Statistical analyses were performed with GraphPad Prism (version 6.0) and IBM SPSS 24 statistical packages; 1.To assert the role of IgM-PC as a biomarker of response to treatment, we analyzed the IgM-PC levels in serum samples obtained before the administration of the different disease modifying therapies (IgM-PC.b.t) by using the highly sensitive technique developed in our laboratoryIgM-PC.b.t was neither related to sex, age, nor disease duration.p = 0.010) or IFN-β (interferon-β) . No significant differences were detected between patients treated with Copaxone or interferon-β  than in those treated with Copaxone   compared with those who did not respond  than those who did   to Q4 (higher IgM-PC.b.t levels) and then, we analyzed the probability of responding to treatment for each one.p = 0.006)  of patients in Q4 responded to natalizumab, but only 26.3% (5/19) in Q1-Q3 responded to this drug (p = 0.010)  in paired samples from MS patients Table .Table 2Ip = 0.007) in responders to this drug (− 26.63 ± 8.95)  and responders (− 40.29% ± 7.29%) Fig. A. On theTo assess the role of IgM-PC levels as a prognosis biomarker, we aimed to determine the probability of response to treatment in those patients showing decreased IgM-PC levels. We established three groups of patients: without variation in serum IgM-PC antibody levels, and with increased or decreased serum IgM-PC levels, in clinical responders and non-responders.p = 0.017) ; we did not detect differences between responders and non-responders. In patients treated with Copaxone, we did not find differences in IgM-PC variation in clinical responders nor in non-responders. In contrast, 76.5% of responders to interferon-β showed a decreased serum IgM-PC and only 29.4% of non-responders had a diminution of these immunoglobulins  responded to natalizumab. In this line, previous results indicate that the decrease of IgM in the cerebrospinal fluid is a biomarker of response to natalizumab19. Our results draw attention to the role of serum IgM-PC level as a biomarker of response to natalizumab.We could observe that patients treated with natalizumab showed higher basal IgM-PC levels than patients receiving Copaxone or interferon-β. This treatment is indicated when first-line drugs are not efficient and patients have a high number of relapses and a rapid EDSS progression20 after treatment with this humanized antibody, because 80% of the circulating IgM consists of “natural antibodies” synthetized by B1 lymphocytes14. VLA-4 mediates the homing of B lymphocytes to peripheral lymph nodes21, splenic white pulp22, mesenteric lymph nodes, and Peyer’s patches22. Therefore, the administration of natalizumab increases the number of B cells in the blood more than other cells23. Different studies reported that the subpopulations affected are pre-B23, memory and marginal zone-like cells24. Unfortunately, there are not experimental evidences describing the effect of natalizumab on B1 lymphocytes. We hypothesize that anti-VLA inhibits the activation of B1 lymphocytes25, or their homing to lymphoid organs, where they have their niches and differentiate to plasmablasts26, main effectors in MS27.In addition, most patients treated with natalizumab showed a significant decrease in the levels of IgM-PC despite of they responded or not to the treatment. These results are consistent with those demonstrating reduced levels of both, IgG and IgM in serum1, and the characteristics of patients treated with this monoclonal antibody. Natalizumab inhibits mainly the egression of CD4 + cells and B cells19 from blood to the CNS28. In addition, natalizumab reduces the intrathecal synthesis of IgG and IgM, but do not eliminate the presence of oligoclonal IgG or IgM bands completely19. We observed plasma cells and IgM deposits4 in chronic demyelinating lesions from MS patients with a long evolution. Moreover, it was detected lymphoid follicle-like structures in the meninges, associated with the damage of the nervous system29. Therefore, natalizumab can not avoid the presence of resident B and plasma cells producers of antibodies against self-antigens of the central nervous system. In this sense, depletion of B-lymphocytes in these patients does not eliminate the presence of oligoclonal bands in the CSF30.It seems contradictory that different evidences support the role of IgM to lipids as a main pathological mechanism, but patients who did not respond to natalizumab showed reduced serum levels of these antibodies after treatment. This is the reflection of the existence of two different compartments, CNS and peripheral system17 in patients with a poor evolution. The main mechanism of action of first-line drugs, such as Copaxone or interferons, is to inhibit the activity of T-lymphocytes31. These evidences support that in these cases immunosuppressive therapies do not regulate this population, which also plays a main role in the disease32. Moreover, it was suggested that intrinsic neurodegenerative mechanisms could be involved, especially in patients in the progressive phase33, explaining the inefficiency of immunosuppressive therapies in these individuals8.As described above, this is a second-line treatment, administered in those cases in which first-line drugs have failed34, and prevents the response of T lymphocytes to MBP, a major protein of the myelin. The inhibition of CD4 T lymphocytes could explain the suppression of experimental allergic encephalomyelitis by this polymer35. Patients treated with this drug showed increased levels of IL-10, IL-4 in serum, an anti-inflammatory profile36 that promotes the skewing towards TH2 responses. Regarding these, Copaxone reduces the number total number of B cells, plasmablast and memory B cells38. Probably, the affected subpopulation are the B2-lymphocytes, because B cells obtained from patients treated with the copolymer did not proliferate in response to CD40L39, the pathway used by T lymphocytes to activate this B2 subpopulation. However, B1 lymphocytes, the minority B subset in blood, are T independent14.IgM-PC.b.t levels did not predict the response to Copaxone. Interestingly, this therapy did not drop the IgM-PC levels, neither in non-responders nor in responders. These were expected results, because its main mechanism of action is to inhibit autoreactive T lymphocytes. This copolymer binds to many MHC molecules, inhibiting the response to different antigens40, IFN-ɣ, TNF-α41 IL-242, TRAIL41 and CXCL1340, and the response to interferon-β. Another possible biomarker of response to treatment is the quantification of neurofilament heavy and light chains, a marker of axonal damage40. Nevertheless, they are not used in daily clinical practice. On the other hand, the detection of IgM-PC as a biomarker of prognosis has large advantages, the technique is cheap and standardizable, the interpretation of results is easy, and serum samples are used. In summary, this assay could be used routinely in most clinical laboratories. Moreover, the diminution of IgM-PC concentration in patients who do not experience relapses or increased disability after treatment could demonstrate that these immunoglobulins are a major pathologic mechanism in MS. These data are in line with other previously published, since interferon-β decreases the number of memory and activated B cells43. This could be mediated by the activation of the FAS-FASL pathway, inducing apoptosis of B cells44. However, the physiology and regulation of B lymphocytes producers of antibodies to lipids, and the effect of the disease modifying therapies in this subpopulation remains unknown. Our results support that interferon-β regulates this subpopulation. This could be of great relevance to characterize new therapeutic targets and also for the basic knowledge of the functioning of the immune system. In the future, it would be of great interest to study the functioning of these cells in patients who respond and do not respond to the treatment, in order to offer more personalized therapies and obtain greater effectiveness in the disease treatment.The levels of IgM-PC did not decrease in patients who did not respond to interferon-β. However, the immunoglobulin concentration dropped in patients who responded to this treatment. A decrease in these antibodies was observed in almost 80% of the responding patients. These data demonstrate that the study of IgM-PC could be a biomarker of response to treatment with interferon-β. It was described the relation between the concentration of different inflammatory molecules, such as, IL-17AIn summary, these data could have a significant impact at the clinical level, but further studies are necessary to validate these results in larger cohorts of patients.


The COVID-19 Pandemic forced many health and community organizations to suspend some previously offered services and supports for older adults. This created heightened concerns about negative impacts of isolation and loneliness on already vulnerable older adults. In response, the Western Reserve Area Agency on Aging (WRAAA) began the TeleCare Program, providing weekly telephone reassurance calls to home and congregate meal clients to maintain contact and identify unmet service needs. Because of its success, the TeleCare Program has continued as a regularly offered service, but the WRAAA sought to improve the Program by integrating it with BRI Care ConsultationTM, an evidence-based program of the Benjamin Rose Institute on Aging (BRIA). This poster reports on initial results of a randomized controlled trial to test the efficacy and feasibility of a new protocol for delivering telephone reassurance calls. The new protocol is modeled after the Initial Assessment in BRI Care Consultation, which is a semi-structured, telephone conversation covering a comprehensive range of potentials problems. The protocol also connects high-risk clients to existing available home- and community-based services. Results demonstrate that components of proven evidence-based interventions are feasible to integrate into existing programs and services. This includes adapting a model for problem-identification and assessment based on a consumer-driven conceptual framework, a record keeping system to enhance consistency and fidelity of program delivery, and establishing a formal referral protocol to more seamlessly link clients to other available services.


Antibody-based strategies have been attempted to antagonize early cytokines of sepsis, but not yet been tried to target inducible late-acting mediators. Here, we report that the expression and secretion of procathepsin-L (pCTS-L) was induced by serum amyloid A (SAA) in innate immune cells, contributing to its late and systemic accumulation in experimental and clinical sepsis. Recombinant pCTS-L induced interleukin-6 (IL-6), IL-8, GRO-α/KC, GRO-β/MIP-2, and MCP-1 release in innate immune cells and moderately correlated with blood concentrations of these cytokines/chemokines in clinical sepsis. Mechanistically, pCTS-L interacted with Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) to induce cytokines/chemokines. Pharmacological suppression of pCTS-L with neutralizing polyclonal and monoclonal antibodies attenuated pCTS-L–mediated inflammation by impairing its interaction with TLR4 and RAGE receptors, and consequently rescued animals from lethal sepsis. Our findings have suggested a possibility of developing antibody strategies to prevent dysregulated immune responses mediated by late-acting cytokines. An antibody strategy is developed to attenuate pCTS-L-mediated dysregulated inflammation in sepsis. Microbial infections and resultant sepsis syndromes are the most common causes of death in intensive care units, accounting for approximately 20% of total deaths worldwide   also induce proinflammatory mediators such as serum amyloid A (SAA) in hepatocytes (Cathepsin L (CTS-L) is a papain-like lysosomal enzyme responsible for degrading endocytosed proteins to generate immunogenic antigens for adaptive immunities. Although human and murine proCTS-L (pCTS-L) share nearly 86% of sequence homology, they exhibit only 59% homology to the counterpart pCTS-L of a distantly related liver fluke parasite   to survey the mRNA expression profiles of several  animals . In linere (CLP) . In a shd spleen , suggestnfection , a time To evaluate its clinical relevance, we used various immunoassays to characterize the dynamic changes of circulating pCTS-L in parallel with several surrogate markers of clinical sepsis. Although pCTS-L was not detected in the plasma of normal healthy controls “H”; . In patiKd) = 20.2 ± 3.5 nM; Kd = 3.5 ± 2.6 nM; Kd = 64.4 nM; Kd = 3.0 nM; In light of the TLR4 dependence of a distantly related liver fluke pCTS-L (fig. S3A) in activating dendritic cells  and chemokines  except for MIP-2/GRO-β and KC/GRO-α , two neuExcessive inflammation is often accompanied by a parallel up-regulation and activation of Casp-11/4/5, which triggers dysregulated inflammasome activation, pyroptosis, and passive DAMP release . SimilarTo elucidate the role of pCTS-L in sepsis, we intraperitoneally injected mice with recombinant pCTS-L at suprapathological doses and found that pCTS-L caused marked injuries to the liver . Administration of pCTS-L markedly up-regulated several genes involved in the acute-phase response  and coagulation  in the liver  and bactCtsl+/− KO mice. Unfortunately, female Ctsl−/− KO mice were found infertile, because CTS-L was still needed for the normal degradation of the follicle wall to release mature oocytes during the process of ovulation  and pCTS-L–deficient (Ctsl−/−) mice. The genotypes of WT littermates and Ctsl KO mice were confirmed by genotyping  in rabbits (fig. S6) and tested their pharmacological effects on the lethal outcomes of sepsis. The epitope profiles of anti–pCTS-L rabbit serum were determined by dot blotting with 24 synthetic peptides corresponding to different region of murine or human pCTS-L proteins , which revealed the presence of pAbs recognizing two homologous peptides corresponding to residues 175 to 193 (“P12”) and residues 194 to 214 (“P13”) of murine and human pCTS-L (figs. S6B and S7A). Anti-murine pCTS-L total immunoglobulin Gs (IgGs) (pAbs) conferred a dose-dependent and significant protection against lethal sepsis in both male and female mice when the first dose was given at 2 hours after CLP  as well To develop potential therapies for human sepsis, we generated mAbs against both murine and human pCTS-L and explored their therapeutic potential by administering the first dose of mAb to septic animals in a delayed fashion—starting at 24 hours after CLP, a time point when circulating pCTS-L approached plateau concentrations and some septic animals started to succumb to death. Most of the mAbs cross-reacted with two homologous peptides corresponding to residues 175 to 193 (P12) or residues 194 to 214 (P13) of murine and human pCTS-L , suggestTo further elucidate the protective mechanisms of pCTS-L–specific mAbs, we examined their effects on pCTS-L–induced production of cytokines/chemokines in primary human PBMCs. Recombinant pCTS-L time dependently induced several cytokines  and chemokines  in human PBMCs  and not Kd for TLR4 and RAGE, respectively  and chemokines  have been characterized as surrogate markers of experimental  We have not yet obtained sufficient number of critically ill patients who died of severe sepsis, so we do not know whether blood pCTS-L concentrations could be used as a surrogate marker or predictor of lethal outcomes of sepsis. (ii) We do not know whether anti–pCTS-L mAbs are protective in other infectious diseases such as coronavirus disease 2019 (COVID-19), although a single-cell meta-analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry genes across tissues revealed a possible role of CTS-L up-regulation in the regulation of SARS-CoV-2 entry into host cells , recombinant human SAA , HMGB1, or pCTS-L. The intracellular and extracellular concentrations of pCTS-L or various other cytokines/chemokines were determined by Western blotting analysis, cytokine antibody arrays, or enzyme-linked immunosorbent assay (ELISA) as previously described  at 3 days after intraperitoneal injection of 2 ml of thioglycolate broth (4%) as previously described , and the corresponding 40-kDa band was subjected to matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF) MS analysis as previously described , which simultaneously detect 62 cytokines on one membrane, were used to measure relative cytokine concentrations in macrophage-conditioned culture medium or murine serum as described previously .We used the Nicoya Life Science gold nanoparticle–based OpenSPR technology  to characterize protein-protein interactions following the manufacturer’s instructions. For instance, highly purified recombinant pCTS-L, human TLR4 , or extracellular domain of human RAGE  was respectively immobilized on nitrilotriacetic acid (NTA) sensor chip , and TLR4, RAGE, or pCTS-L was applied as analyte at different concentrations. To determine the binding affinities of mAbs to human or murine pCTS-L, highly purified human or murine pCTS-L was immobilized on the NTA sensor chip , and various mAbs were applied at various concentrations. The response units were recorded over time, and the binding affinity was estimated as the equilibrium dissociation constant https://cluspro.org)  of the Feinstein Institutes for Medical Research (FIMR). To evaluate the role of pCTS-L in lethal sepsis, Balb/C mice  were subjected to lethal endotoxemia or sepsis by intraperitoneal administration of bacterial endotoxins  or by a surgical procedure termed as CLP as previously described .This study was conducted in accordance with policies of the National Institutes of Health (NIH) Ctsb , Ctse , Ctsl , Ctss , and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene  to quantify the mRNA expression levels of respective genes using an ABI 7900HT Fast Real-time PCR system. The relative abundance of various Cts mRNA expression in control group was normalized by GAPDH.Male Balb/C mice were subjected to lethal sepsis by CLP, and animals were sacrificed at 24 hours after CLP. Total RNAs were isolated from various tissues using a TRIzol reagent kit and reversely transcribed into the first-strand cDNA. Following reverse transcription, quantitative PCR was performed with TaqMan Master Mix (Thermo Fisher Scientific) for murine Ctsl KO [NOD.129P2(B6)-CtsltmCptr/Rcl J] mice from The Jackson Laboratory  and bred heterozygous Ctsl+/− females with heterozygous Ctsl+/− males to produce homozygous Ctsl KO as well as WT littermates for the proposed animal studies. To verify the genotypes of WT and Ctsl KO mice, tail biopsies were digested in Direct PCR Lysis Reagent  containing proteinase K , and lysate containing genomic DNA was amplified by PCR using the following primers: WT Ctsl: 5′-GGAGGAGAGCGATATGGG-3′ (forward) and 5′-AGCCATTCACCACCTGCC-3′ (reverse); mutant Ctsl: 5′-AATTCGCCAATGACAAGACG-3′ (forward) under the following conditions: 95°C for 3 min, followed by 37 cycles of 95°C for 15 s, 60°C for 15 s, and 72°C for 15 s. The PCR products were resolved on a 2% agarose gel and visualized by ethidium bromide staining. We subjected the genetic background-, age-, and sex-matched WT littermate (Ctsl+/+) and pCTS-L–deficient (Ctsl−/−) mice to lethal sepsis and compared sepsis-induced liver injuries between WT and Ctsl-deficient mice at 24 hours after CLP.We obtained a few breeding pairs of heterozygous The liver and intestine samples were harvested at 24 hours after CLP or pCTS-L intraperitoneal administration and fixed in 10% buffered formalin before being embedded in paraffin. Paraffin-embedded tissues were cut into 5-μm sections, stained with hematoxylin and eosin, and examined under light microscopy. As previously described (https://string-db.org/cgi/input.pl). Differential expression analysis was performed using the Wald test (DESeq2) to generate P values and log2 fold changes. Genes with an adjusted P value of <0.05 and absolute log fold change of >2 were defined as differentially expressed.To elucidate the mechanisms underlying pCTS-L–mediated pathogenesis, normal healthy Balb/C mice were intraperitoneally given recombinant pCTS-L (20 mg/kg), and various tissues were harvested 24 hours later to isolate total RNA to characterize the expression profile of a full catalog of transcripts by RNA-seq . Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to analyze the differentially expressed genes by using String online tools  of the FIMR (IRB protocols #18-0184 and #18-0700) and endorsed by written informed consent from all participants providing blood samples. The inclusion criteria for septic patients were (i) acute diagnosis (within 24 hours) of sepsis with suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infections, (ii) receiving vasopressor , (iii) scheduled blood sampling, and (iv) have an indwelling arterial of central venous catheter for blood drawing. The exclusion criteria for septic patients were (i) significant underlying immunodeficiency or known autoimmune disease, (ii) recent (within 1 month) administration of any immunomodulating drugs including glucocorticoids or drugs used for treatment of autoimmune diseases, (iii) diagnosis of sepsis >24 hours before recruitment, (iv) inability to obtain consent, (v) member of a protected population , and (6) patients for whom parents or legal guardians did not wish to give consent.MyBioSource.com) with reference to purified recombinant human pCTS-L at various dilutions.Blood samples (5.0 ml) were collected from 8 healthy control subjects and 10 septic patients recruited to North Shore University Hospital and the Long Island Jewish Medical Center between 2018 and 2019 (listed as “P1-P10” in data file S1). Patients were diagnosed with sepsis or septic shock by the Sepsis-3 criteria , followed by the Fisher least significant difference test. For comparison among multiple groups with nonnormal (skewed) distribution, the statistical differences were evaluated with the nonparametric Kruskal-Wallis ANOVA test. For survival studies, the Kaplan-Meier method was used to compare the differences in mortality rates between groups with the nonparametric log-rank post hoc test. The Spearman rank or the Pearson correlation coefficient test was used to evaluate associations between two quantitative variables that exhibit nonnormal or normal distribution, respectively. A P value of <0.05 was considered statistically significant.All data were assessed for normality by the Shapiro-Wilk test before conducting appropriate statistical tests among groups. The comparison of two independent samples was assessed by Student’s


In this paper, we provide a complete proof for a bound on the growth of multi-recurrences which are defined over a number field. The proven bound was already stated by van der Poorten and Schlickewei 40 years ago. K. It is well known that any linear recurrence sequence has an explicit representation of the formK,  the so-called Binet formula. It is also well known (see [n,  we haveA linear recurrence sequence is a sequence entclass1pt{minimaentclass1pt{minimas and k are positive integers, s variables, and G is defined over a field K if the coefficients and the bases K. If G is defined over K,  then it takes values in K. For more information about recurrence sequences, we refer to [There is a natural generalization of linear recurrence sequences. If we allow more than one parameter, we can generalize  to\documrefer to . Van derrefer to  a similaentclass1pt{minimaentclass1pt{minimaG as defined above. Our main result is the following theorem:In the sequel, we shall use the abbreviationK be a number field and s a positive integer. Consider the polynomial-exponential functionLet The condition concerning tated in . Indeed,K in the proven lower bound instead of the standard absolute value.We emphasize that the same statement as in Theorem B cannot be given explicitly since it depends, among others, on the ineffective constant given by Theorem The bound in Theorem We are only able to prove the result for number fields. To the knowledge of the authors, it is still open to find and prove an analogous result in the function field case, i.e., a version of [K in K and by K:In our proof, we will need the following result of Evertse. The reader will find it as [t be a non-negative integer and S a finite set of places in K,  containing all infinite places. Then for every C exists,  depending only on T of S and every vector Let Moreover, the next lemma is used in the proof of our theorem. It is an analogous version of , Lemma 1K be a number field of degree D,  let m and let T be a non-empty set of places in K. Then there exists a positive constant c,  depending only on K, f,  such that for all Let Obviously we have D infinite places. Hence there is a positive constant f and are independent of c. There are at most Before we start with proving Theorem G are algebraic integers, we can find a non-zero integer z such that S as a finite set of places in K containing all infinite places as well as all places such that S-units. Let Since the bases We may assume that for the index z is a fixed integer and that the S-units, we getm denote the maximum of the absolute degrees of the polynomials Thus we can apply Theorem