Closing the gap between care recommended by evidence-based guidelines and care delivered in practice is an ongoing challenge across systems and delivery models. Clinical decision support systems (CDSSs) are widely deployed to augment clinicians in their complex decision-making processes. Despite published success stories, the poor usability of many CDSSs has contributed to fragmented workflows and alert fatigue.This study aimed to validate the application of a user-centered design (UCD) process in the development of a standards-based medication recommender for type 2 diabetes mellitus in a simulated setting. The prototype app was evaluated for effectiveness, efficiency, and user satisfaction.We conducted interviews with 8 clinical leaders with 8 rounds of iterative user testing with 2-8 prescribers in each round to inform app development. With the resulting prototype app, we conducted a validation study with 43 participants. The participants were assigned to one of two groups and completed a 2-hour remote user testing session. Both groups reviewed mock patient facts and ordered diabetes medications for the patients. The Traditional group used a mock electronic health record (EHR) for the review in Period 1 and used the prototype app in Period 2, while the Tool group used the prototype app during both time periods. The perceived cognitive load associated with task performance during each period was assessed with the National Aeronautics and Space Administration Task Load Index. Participants also completed the System Usability Scale (SUS) questionnaire and Kano Survey.P<.001) and between groups during Period 1 . Task completion times did not differ between groups (P=.23), but the Tool group completed medication ordering more quickly in Period 2 . Based on an adjusted α level owing to violation of the assumption of homogeneity of variance (Ps>.03), there was no effect on screens viewed and on perceived cognitive load .Average SUS scores from the questionnaire, taken at the end of 5 of the 8 user testing sessions, ranged from 68-86. The results of the validation study are as follows: percent adherence to evidence-based guidelines was greater with the use of the prototype app than with the EHR across time periods with the Traditional group (prototype app mean 96.2 vs EHR mean 72.0, Through deployment of the UCD process, a point-of-care medication recommender app holds promise of improving adherence to evidence-based guidelines; in this case, those from the American Diabetes Association. Task-time performance suggests that with practice the T2DM app may support a more efficient ordering process for providers, and SUS scores indicate provider satisfaction with the app. Diabetes affects roughly 34.2 million Americans, 90-95% of whom have type 2 diabetes mellitus (T2DM) . Another1c) values can prevent or delay diabetes-related complications and decrease direct medical costs [The high costs and suboptimal outcomes associated with T2DM may be associated at least in part with variability of care. For example, studies have shown that maintaining goal glycated hemoglobin  have emerged as one approach to close this gap. These systems can manifest as order sets, computerized alerts and reminders, digital guidelines, and clinical workflow tools designed to augment and support provider capabilities. Core functions of these software applications include summarizing patient facts, visualizing trends, supporting documentation, generating reminders, and making therapy recommendations to the provider ,6.1c levels—an indication of glycemic control [CDSSs generally support the provider by (1) pulling together relevant patient facts in a manner that is efficiently assessed, and (2) bringing up-to-date, evidence-based clinical guidelines to the point of care where clinical decisions are made. Sutton et al  identifi control -9.Measurable quality-of-care improvements are dependent on good CDSS design. Sim et al  developeThe aim of this study was to evaluate the application of a user-centered design (UCD) process toward the development of a prototype software that serves as a medication recommender for T2DM (the T2DM app). The prototype T2DM app is a standards-based CDS tool that provides evidence-based medication recommendations to health care providers with the aim of improving adherence to the latest evidence-based clinical guidance and reducing cognitive load for clinicians making prescribing decisions. The prototype T2DM app integrates into existing EHR systems that clinicians use as part of standard practice to review patient records, order tests and prescriptions, etc.The prototype app development consisted of two phases: (1) a predevelopment analytic phase to learn about user needs, the context of use, and specific workflow associated with reviewing patient facts and ordering medications; and (2) iterative user testing of the prototype app itself. The validation study with the final version of the prototype app addressed the following research questions: (1) is medication ordering with the T2DM app associated with more medication orders that align with American Diabetes Association (ADA) evidence–based guidelines compared to ordering medications with a typical EHR? (2) Is medication ordering with the T2DM app associated with faster overall task times compared to ordering medications with a typical EHR? (3) Is medication ordering with the T2DM app associated with lower perceived cognitive load  compared to ordering medications with a typical EHR?The analytic work that provided the foundation for the first interactive prototype entailed the review of ADA guidelines  to deterOnce the initial prototype was developed on the basis of findings from the analytic phase, 8 iterative rounds of user testing were carried out to get feedback on different parts of its evolving design. These were conducted remotely from May 4 to October 2, 2020, owing to COVID-19 restrictions, and each session was recorded. For each round of user feedback, a sample of prescribers were included in 1-hour, one-on-one test sessions with the prototype app. In total, 16 participants were recruited directly from a single large provider network, and the remaining participants were recruited via a national third-party recruitment service. The latter were compensated at the prevailing market rate for physicians, physician assistants, and nurse practitioners. In total, 25 MD physicians, 11 nurse practitioners, and 15 physician assistants participated in the user testing. We used a talk-aloud method for data collection while prescribers reviewed and ordered medications with the prototype.In addition, during 5 of the 8 rounds of user testing, participants completed the System Usability Scale (SUS) questionnaire at the end of their sessions . The SUS questionnaire is an industry standard for evaluating the usability of software applications consisting of 10 statements with 5 response options (ranging from “Strongly Disagree” to “Strongly Agree”) to each question. The statements are as follows:I think that I would like to use this system frequently.I found the system unnecessarily complex.I thought the system was easy to use.I think that I would need the support of a technical person to be able to use this system.I found the various functions in the system were well integrated.I thought there was too much inconsistency in this system.I would imagine that most people would learn to use this system very quickly.I found the system very cumbersome to use.I felt very confident using the system.I needed to learn a lot of things before I could get going with this system.The SUS survey yields a single number that represents a composite measure of the overall perceived usability of the system. SUS scores have a range of 0 to 100 and the score is a relative benchmark that is used against other iterations of the system. The SUS is a reliable and valid measure of system satisfaction. Sauro  reports In total, 43 participants completed the 2-hour remote evaluation study of the prototype T2DM app that was developed and refined through the user testing phase. Participants were recruited via a national third-party recruitment service. The study population included 21 MD and 22 non-MD physicians . To be included in the study, candidates were required to (1) have at least 1 year of experience treating T2DM, preferably in a family or internal medicine practice; (2) currently prescribe, prescribe on behalf of, or provide medication recommendations as part of their current role; and (3) currently interact with 15 or more patients per day. Participant compensation was set at the prevailing market rate for physician assistants, nurse practitioners, pharmacists, and nurses.Medical and legal review were conducted to ensure no aspect of clinical or legal regulations or ethical considerations were overlooked. Formal institutional review board or ethical review was not required in the study because no protected health information was included, and participation was limited to usability testing and providing feedback about the app. No private information about participants was collected or included in the analysis and study. All participants gave verbal consent and were reimbursed for their time.A Universal Design framework was followed for accessibility and to accommodate a wide range of people , and care was taken to convert typical in-person interaction to virtual to avoid exposure to COVID-19.The prototype T2DM app  pulls daThe study was conducted between March 15 and 19, 2021, and because of continued COVID-19 social distancing restrictions, the test sessions were conducted remotely via a usability testing platform (Loop11) or via a web conference tool (Zoom or WebEx). One independent moderator was present with the participant throughout the session. Several sessions were observed by members of the product development team; two of the observing team members and the moderator asked participants clarifying questions during the session. The participants employed their own computers to display and interact with the apps. Although the environment with respect to seating, lighting, sound levels, temperature, and humidity varied, participants were most generally seated at a table or desk in a personal space within their home. In most cases, the participants shared their screens and interacted with the apps on their own desktops. In several cases, the moderator shared their screen and passed control of mouse and keyboard to the participant.The method of data capture depended on the platform employed in the session. The Loop11 platform captured videos, task time, and screen review data; the web conference tools captured video only. In all cases, a notetaker recorded participant responses, and medication orders were collected manually from screen shots taken during the time of the study and determined by video review.critical to quality characteristics, as defined by the voice of the customer [Must-Have: whatever the quality characteristic is, it must be present, such that if it is not, the customer will go elsewhere! (2) Linear or Performance: the better we are at meeting these needs, the happier the customer is. (3) Exciter or Delighter: those qualities that the customer was not expecting but received as a bonus.Participants also completed the Kano Model Survey. The Kano Model is a tool that can be used to prioritize the customer . The thrThe task data collected included “pass” or “fail” (medication order adheres or does not adhere to evidence-based recommendations), task time, subjective comments from the Kano Model Survey, and video recordings of the computer screen and audio.The study employed a 2 (Group) × 2 (Time Period) mixed model simulated-use design shown in . ParticiEach reviewing and ordering period was followed by administration of the NASA TLX to measure the perceived cognitive load associated with that performance period . The NASThe data were analyzed to test the hypothesis that providers would more frequently align their orders with the ADA evidence-based guidelines when using the T2DM app, and that the process would be more efficient and less taxing. The hypothesis predicts performance advantages for the Tool group during the first period, and a greater change in duration for Traditional group in Period 2.Each 2-hour session was conducted individually and began with guidance about the resolution of technical difficulties associated with the employed platforms and the informed consent process. The overall study process for both participant groups is shown in Orientation of participants to the EHR prototype. The moderator walked participants through the user interface and then participants completed 2 practice trials reviewing mock patient facts and ordering diabetes medications using traditional EHR methods. The purpose of the orientation was to ensure that participants understood the task. Both groups experienced the same protocol for this period.Orientation to the prototype T2DM app. The moderator walked participants through the user interface and then participants completed two practice trials reviewing mock patient facts and ordering diabetes medications using the prototype T2DM app. The Tool group experienced this protocol immediately before Period 1; the Traditional group experienced this protocol immediately before Period 2.Participants reviewed a set of 8 mock patients and ordered diabetes medications on the basis of each mock patient’s facts. Participants were instructed to complete each order within 5 minutes and to do so as though they were at work. Participants in the Traditional group employed the mock EHR during this period; participants in the Tool group employed the prototype T2DM app.Participants completed the NASA TLX survey aimed to measure perceived mental cognitive load for the tasks completed in Period 1.Participants reviewed another set of 8 mock patients and ordered diabetes medications on the basis of each mock patient’s facts. As in period 1, participants were instructed to complete each order within 5 minutes and to do so as though they were at work. Participants in both groups employed the prototype T2DM app.Participants completed the NASA TLX survey aimed to measure perceived cognitive load for the tasks completed in Period 2.P<.05.We analyzed data using SPSS . Dependent variables in the study  were all subjected to a 2 × 2 mixed model analysis of variance (ANOVA) with Period (Period 1 vs Period 2) as the within-subjects factor and Group  as the between-subjects factor. Statistical significance was accepted at a level of Each round of user testing focused on different elements of the prototype app while also iteratively reviewing changes that resulted from the previous round or rounds. Changes became smaller and more focused with each successive round of testing until the final version was reached after round 8. Comments made by user testing participants  were useThe SUS scores were “average” or “above average” on each of the rounds of user testing where measured . While tIn total, 14 of the validation study participants responded to the Kano Model Survey .pass if the participant ordered any medications that were on-guideline, discontinued any medications not aligned with guidelines  or if the guidelines recommended against medication changes, and fail if any ordered medication was off-guideline.Orders were scored as F1,41=8.99, P=.005, =0.18). As hypothesized, medication ordering by the Tool group was more frequently aligned with guidelines (mean 92.1) than it was by the Traditional group (mean 84.2). Furthermore, there was a main effect of Period on adherence to guidelines . Medication ordering in Period 2 was more frequently aligned with guidelines (mean 93.7) than it was during Period 1 (mean 82.6).The mean percentage adherence to ADA evidence-based guidelines is shown in F1,41=45.43, P<.001, =0.53). For the Traditional group, ordering was more aligned with guidelines during Period 2, when the T2DM Tool was first introduced (mean 96.2), than it was in Period 1 . For the Tool group, ordering was similarly aligned to guidelines during Period 1 (mean 92.6) and Period 2 .However, there was a significant Group × Period interaction .Of particular interest was a planned comparison between groups during Period 1. As hypothesized, medication ordering by the group using the prototype T2DM app was more frequently aligned to ADA evidence–based guidelines (mean 92.6) than medication ordering was by the group using the mock EHR , which resulted in extreme task times. Extreme task times were excluded based on a cutoff of 3 SD. Task time SDs were calculated using all available task time data. Task times greater than (and less than 3 SD) were excluded from the data analysis . The percentage of trials removed by the 3 SD trim was 1.8%. There were no task times 3 SD below the mean because that was a negative value.F1,41=1.46, P=.23, =0.03), but there was a main effect of Period . Medication ordering time was lower during Period 2 (mean 117.2) than it was in Period 1 (mean 133.4).The mean task time used for the completion of orders is shown in F1,41=5.23, P=.03, =0.11). The Tool group completed prescription orders more quickly during the second period (mean 107.7) than the first period . For the Traditional group, task time did not significantly differ between Periods 1 (mean 136.1) and Period 2 . Finally, Period 1 task times also did not significantly differ between the two groups .There was also a significant Group × Period interaction , and there was no main effect of Period . Because the variance was found to be unequal across groups (by Box M and Levene tests), to reduce the probability of type 1 error, the α level was adjusted accordingly to be increasingly conservative (α’=.001). Based on the adjusted α level, there was no Group × Period interaction effect .There was no main effect of Group on the number of screens reviewed , and there was no main effect of Period . There was no significant Group × Period interaction . Finally, the perceived workload associated with Period 1 did not significantly differ between the two groups .There was no main effect of Group on the NASA TLX score , and role × time interaction . Furthermore, there was no significant main effect of clinical role on test period , and role × time interaction . Provider type analysis was not conducted for other parts of the study, partly owing to the sample size and initial findings.As part of our analysis, we attempted to evaluate the effect of provider type on the studies using mixed ANOVAs with the clinical role (MD vs non-MD physicians) between subjects and test period (Period 1 and Period 2) within subjects. There was no significant main effect of clinical role on adherence to guidelines  app via a thorough UCD process and evaluate the design for effectiveness, efficiency, and user satisfaction. The prototype T2DM app is considered For the primary research question of whether medication ordering with the prototype T2DM app would be more frequently aligned to ADA evidence–based guidelines than medication ordering without the app and using the mock EHR , the prototype T2DM app proved effective when measured within as well as between participants. Providers who ordered medications using the mock EHR first became more aligned to ADA guidelines when they switched to the prototype T2DM app. When comparing the method employed in the first period, the group of providers that used the T2DM app were more aligned to ADA guidelines than the group that used the mock EHR.For the primary research question of whether medication ordering with the prototype T2DM app would be accomplished more quickly than that without the app : medication ordering was accomplished more quickly in the second period, which can reasonably be expected owing to practice. When comparing methods employed in the first period, the group of providers that used the prototype T2DM app did not complete their medication ordering more quickly than the group that used the mock EHR. However, the group that used the prototype T2DM app in both time periods improved more during the second period than the group that switched from the mock EHR to the prototype T2DM app. This outcome suggests that providers may be more efficient when using the T2DM app, but not until they have become more familiarized with its display and features. The greater efficiency in the second period for the tool-only group compared to the EHR group is likely owing to the inherent design and features of the prototype app: it is fit-for-purpose, avoids navigation distractions in the chart, and pulls information from different parts of the EHR to prefill the clinical facts. There was also no significant effect of the difference in provider type in alignment to guidelines or task times.For the primary research question of whether medication ordering with the prototype T2DM app would be accomplished with lower perceived cognitive load than that without the app , NASA TLX scores were generally low. Although benchmarking is not possible with the TLX, a published analysis of 237 studies would place our overall mean of 42.5 at approximately the 35th percentile . Clearlyuser satisfaction throughout the iterative rounds of user testing. SUS scores throughout the iterative design process were at or above 68, which is considered average across industries. Round 6, the last iterative user testing during which the SUS was administered, had an average SUS score of 68. This was the lowest average SUS score obtained during the design process. The design evaluated in Round 6 went against several good user interface principles, and the prototype was not as interactive as the previous prototypes; hence, participants were not able to experience many of the previously identified valuable features. SUS scores for EHR systems have been shown to be lower than the average (68) from across different industries [Finally, the prototype T2DM app was evaluated for dustries . Melnickdustries  benchmarThe information from this prototype testing will contribute to the development of a real CDS-T2DM app, which will leverage SMART  on FHIR  technology. It is important to note that clinical decision support apps may be subject to FDA (Food and Drug Administration) review and approval. The scope of FDA oversight and compliance with any related regulatory requirements was beyond the scope of this study on the prototype app.We acknowledge some limitations of our study, including (1) a small sample size, (2) participant attrition in certain rounds of the study and NASA TLX assessment, and (3) difference in platforms for observation . Furthermore, owing to the limited sample size, we were neither able to reliably assess the effect of provider type (MD vs non-MD physicians) across the studies nor the impact of speed to adoption on task time. We believe that additional research is needed to further evaluate the effectiveness and efficiency of the T2DM app as it launches and becomes more widely used.T2DM and prediabetes affect millions of Americans, often resulting in harmful complications, additional chronic conditions, disability, premature death, and significant patient and system costs. Adherence to clinical treatment guidelines can improve patient health outcomes and reduce patient and system costs. Complexity of medical guidelines combined with limitations on providers’ time can impede guideline adherence. While CDSSs can help, lack of user involvement in their development can further impede progress and result in mistrust in technology solutions.Through deployment of the UCD process, we developed a prototype of a medication recommender app that promises to improve adherence to ADA evidence–based guidelines and support a more efficient and user-friendly ordering process for the provider in the management of T2DM. CDSSs offer promising solutions for closing the gap between provider behavior and evidence-based practice, and this study suggests that realizing their full promise may depend on greater attention to design from a user-centered perspective. Such a process could be beneficial in developing effective CDSSs for other conditions and tasks with associated improvement in quality and costs for patients, providers, and the health care system.


Control of visceral leishmaniasis (VL) on the Indian subcontinent has been highly successful. Control efforts such as indoor residual spraying and active case detection will be scaled down or even halted over the coming years. We explored how after scale-down, potential recurrence of VL cases may be predicted based on population-based surveys of antibody or antigenemia prevalence.Using a stochastic age-structured transmission model of VL, we predicted trends in case incidence and biomarker prevalence over time after scaling down control efforts when the target of 3 successive years without VL cases has been achieved. Next, we correlated biomarker prevalence with the occurrence of new VL cases within 10 years of scale-down.Occurrence of at least 1 new VL case in a population of 10 000 was highly correlated with the seroprevalence and antigenemia prevalence at the moment of scale-down, or 1 or 2 years afterward. Receiver operating characteristic curves indicated that biomarker prevalence in adults provided the most predictive information, and seroprevalence was a more informative predictor of new VL cases than antigenemia prevalence. Thresholds for biomarker prevalence to predict occurrence of new VL cases with high certainty were robust to variation in precontrol endemicity.The risk of recrudescence of VL after scaling down control efforts can be monitored and mitigated by means of population-based surveys. Our findings highlight that rapid point-of-care diagnostic tools to assess (preferably) seroprevalence or (otherwise) antigenemia in the general population could be a key ingredient of sustainable VL control. Visceral leishmaniasis (VL), also known as kala-azar, is a vector-borne infection that can lead to long-lasting fevers and death if left untreated, although most infected individuals will remain asymptomatic , 2. In tMany Indian subdistricts have entered or will be entering this validation phase in the coming years. The prospect of scaling down or even halting control measures without complete interruption of transmission poses a risk of recrudescence of infection. This highlights the need for continued monitoring of ongoing infection. In this study, we assessed the predictive power of population surveys that use serological tests  or antigen tests to predict the occurrence of new VL cases (reported or unreported) after scaling down control efforts. To this end, we developed a new stochastic age-structured VL transmission model that is based on an established deterministic VL transmission model .We used an established age-structured deterministic VL transmission model that describes the transmission of VL between humans and sand flies on the Indian subcontinent . To realModel parameters were previously calibrated based on age-structured data from approximately 21 000 individuals included in the KalaNet bednet trial in India and Nepal , 14, 15.pomp package (version 3.1.1.7); the model code is publicly accessible at https://gitlab.com/erasmusmc-public-health/vl-serosurveys. The Policy-Relevant Items for Reporting Models in Epidemiology of Neglected Tropical Diseases Summary is provided in The model was coded in R (version 4.0.2), using the With each version of the stochastic transmission model (E0 and E1), we performed 10 000 repeated simulations for a stable population of 10 000 people. Transmission conditions  were allowed to vary randomly between simulations such that the precontrol VL incidence ranged from 2 to 15 reported VL cases per 10 000 capita per year, as expected under the deterministic version of the model. During the precontrol phase, we assumed that only passive case detection was in place, leading to an average duration between the start of symptoms and the start of treatment of 60 days . To starTo see if the occurrence of at least 1 new VL case could be predicted based on prevalence of biomarkers in the population, we saved model-predicted trends in age-specific prevalence of DAT and antigenemia prevalence. Receiver operating characteristic (ROC) curves as well as positive and negative predictive values (PPV and NPV) of thresholds for biomarker prevalence were calculated for 3 time points: at the moment of scaling down control efforts, and 1 and 2 years after the scale-down. For the last 2 time points, we excluded simulations in which 1 or more VL cases were already detected before the time of the survey, assuming that this observation alone would already lead to policy action. For each survey, we assumed that a random subset of 500 individuals in the population is tested, simulating 100 random surveys for each time point in each simulation. Simulated surveys sampled either only preschool-age children (aged 0–4 years), school-age children (aged 5–14 years), or adults (aged ≥15 years). Threshold values were expressed in terms of the number of biomarker-positive individuals among this sample of 500 at or above which we expect recurrence of at least 1 VL case in the 10 years following scaling down of control efforts.Of the 10 000 repeated stochastic simulations that were performed with each model variant, in 8011 (model E1) and 4705 simulations (model E0) the target of 3 consecutive years of zero reported VL cases was achieved within 20 years of control, and control could be scaled down to passive case detection only. The probability of at least 1 new VL case occurring within 10 years after scaling down control was higher in model E0 (2936 of 4705 = 62.4%) than in model E1 (3028 of 8011 = 37.8%). If 1 or more new VL cases occurred, the first case typically occurred within the first year after scaling down (96.5% of simulations in model E1 and 69.3% in model E0) but with a very long right tail (up to 5 years for model E1 and 10 years for model E0) . The timIf a new VL case occurred after scaling down control, model E1 predicted that DAT prevalences were above 0% for at least 2 years after scale-down  after achieving 3 years of zero reported VL cases and scaling down control efforts is highly correlated with the seroprevalence (based on DAT) and antigenemia prevalence. Biomarker prevalence in adults (aged ≥15 years) provides the most predictive information on prospects of resurgence, and DAT prevalence appears to be a more informative predictor than antigenemia prevalence. Thresholds for biomarker prevalence to predict occurrence of new VL cases with high certainty were robust to variation in precontrol endemicity, allowing thresholds to be applied without exact knowledge of transmission conditions.For an area covering a population of 10 000 people, having no DAT-positive individuals in a sample of 500  at the moment of scale-down is a conservative approach to predicting whether or not new VL cases will occur. However, the predictive power of such a criterion does depend on whether or not asymptomatic individuals do  or do not contribute to transmission . In general, the predictive value could be further boosted by sampling more individuals (and adapting the threshold criterion accordingly) or by performing repeated surveys over time . Of course, as this is a modeling study and given that no monitoring program exists as suggested here, predictions should be validated based on field data, ideally longitudinal data of biomarker prevalence from areas that have implemented the control measures recommended by the WHO.A major strength of this study is that the calculated threshold values for the number of biomarker-positive cases in a sample of 500 individuals can be readily used for interpretation of field data (based on the same sample size) without the need for calculating confidence bounds around prevalence estimates. This is possible because stochastic as well as statistical uncertainty are captured in our calculations: stochastic uncertainty via many repeated simulations of the population dynamics over time, and statistical uncertainty via 100 repeated survey simulations within each transmission simulation. In addition, the methodology that we used can be easily adapted to other population sizes and survey sample sizes. However, for much larger population sizes, model predictions should ideally be based on a metapopulation model that accounts for the fact that individuals live in subpopulations and do not mix homogeneously. Such a model would also address the most important limitation of this study that we assume a closed population without the possibility of introduction of infection from outside. Recrudescence of VL transmission through introduction via human mobility is a real risk, unless the strategy is successfully rolled out on a very large scale. As such, the threshold for biomarker prevalence proposed here should be interpreted as an indicator of recurrence of VL transmission through local transmission. The metapopulation model that is needed to relax this assumption is currently being developed.Our finding that thresholds for biomarker prevalence were quite robust to variation in precontrol endemicity is extremely convenient for policy development and implementation of monitoring in field settings. This robustness is in stark contrast with, for example, thresholds for Ov16 seroprevalence to evaluate progress toward elimination of onchocerciasis, for which threshold values for a particular target predictive value strongly change with precontrol endemicity . This isAccording to our findings, measuring biomarker prevalence 1 or 2 years after scaling down control efforts (as long as no new VL cases have been detected in the meanwhile) increases the predictive power for absence of new VL cases , which was already very high when biomarker  prevalence was assessed at the moment of scale-down. This finding was mostly driven by the fact that if VL transmission resurged, it did so mostly within 1 year after scale-down. In other words, if no new VL cases were reported in the first year after scale-down, the probability of resurgence was very low to begin with, which drove up the NPV (and lowered the PPV). It is therefore important to note that the benefit of this higher NPV comes at the cost of delayed information, giving the infection more opportunity to be transmitted further throughout the population in case of resurgence. Given that in case of VL recurrence, this typically happened within 1 year of scaling down, we recommend that a biomarker survey be performed at the moment of scale-down or slightly before. However, if the biomarker survey is performed much earlier than the 3-year benchmark , threshold values for the number of positive cases would have to be adapted and might even depend more on precontrol endemicity.It is important to note that for the sake of illustrating the potential predictive value of biomarkers, in our simulations, we assumed that diagnostic tests for antibodies or antigens are 100% sensitive and specific at the individual level. However, in reality, false-positive and false-negative results should certainly be expected to occur, adding noise to observations and lowering the PPV and NPV of biomarker prevalence for recurrence of VL cases compared with what we estimate here. Also, it should be noted that our model predictions for DAT prevalence are quantified based on the diagnostic techniques and titer thresholds used to calibrate our model to data from the KalaNet study , 15. ForOur findings highlight the need for further operational research into effective monitoring to ensure sustained control of VL on the Indian subcontinent. First, given our finding that population-based surveys can be an extremely valuable monitoring tool when scaling down control, the questions arise, what geographical units such surveys should cover and how should surveys be implemented? For instance, how many communities and how many individuals should be selected per community? This would depend on the expected level of geographical clustering of VL transmission after prolonged control, which needs to be informed by field studies such as the recent KalaNet follow-up study . Second,We conclude that the risk of recrudescence of VL after scaling down control efforts can be monitored and mitigated by means of population-based surveys. We recommend that such surveys be based on biomarkers of current and recent infection, such as antibodies, as prevalences for such biomarkers are higher than antigen prevalences and thus provide more statistical information. Our findings highlight that rapid point-of-care diagnostic tools to assess (preferably) seroprevalence or (otherwise) antigenemia in the general population could be a key ingredient of sustainable VL control.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciab210_suppl_Supplementary-MaterialClick here for additional data file.


A 25-year-old gentleman with no past medical history presents with a 1-2 year complaint of intermittent episodes of a diffuse pruritic raised skin rash on his limbs and trunk (A). He reports this has happened to him 5-6 times in total and is typically associated with him awakening to find the room too warm. He brings up the issue for the first time because he also had angioedema of the lips that persisted for approximately 24 hours (B). There were no other identifiable food or environmental triggers, and he denied any headaches, dyspnea, nausea, vomiting. The patient was reassured that this is chronic urticaria, prescribed cetirizine as needed, and informed that this will likely resolve on its own in a few years.


This cross-sectional regression discontinuity analysis compares deaths slightly younger and older than 65 years to examine the relationship between access to health insurance coverage and COVID-19 mortality. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology .We used a regression discontinuity design, a common method in health care research, to assess whether the death count changed sharply at age 65 years (Medicare eligibility age) between March and December 2020 and for the same span of months in 2015 to 2019 for comparison. We fit a model of the number of deaths by age in quarters with a dummy variable for deaths occurring to persons 65 years or older. The dummy variable captured discontinuities  in the death count associated with Medicare eligibility. A discontinuity at age 65 years in 2020, but not years prior, would suggest that Medicare eligibility affected COVID-19 mortality.P < .05. We also assessed the percent increase in deaths for 65- to 74-year-olds by calendar month in 2020 vs calendar month in 2015 to 2019 in the Datavant data and compared it with NCHS data. We reported the average percent increase during the pandemic period and plotted the percent increases by month. Data analyses were performed from December 14, 2020, to July 20, 2021, using Stata, version 16 (StataCorp LLC) and Python, version 3.8 (Python Software Foundation).Statistical analysis was conducted using 2-tailed tests with Huber-White robust SEs to assess statistical significance, defined as P = .85) nor during the 5 years prior  between March and December 2020. We did not find evidence of a discontinuity in the number of deaths at age 65 years during the 2020 study period  and did not include the cause of death nor the patient’s race or ethnicity. However, the excess death counts in the present study’s data were similar to those of other reliable sources. This cross-sectional regression discontinuity analysis found that entry into Medicare was not associated with the likelihood of death during the COVID-19 pandemic.


Various therapeutic strategies for angiogenesis are performed to improve symptoms in patients with critical limb ischemia (CLI). Pre-clinical studies have shown that low-intensity pulsed ultrasound (LIPUS) exposure induces angiogenesis. LIPUS may be a new stratergy for treatment of CLI. The purpose of this pilot trial was to evaluate outcomes in patients with CLI who were treated with LIPUS. Fourteen patients with CLI, who were not candidates for angioplasty or surgical revascularization, were enrolled in this study. Historical control data were obtained from the Hiroshima University PAD database. The primary endpoints were major amputation and death. The outcomes were compared in 16 lower limbs of the 14 patients with CLI who were treated with LIPUS and in 14 lower limbs of 14 patients with CLI as historical controls. All patients were followed for after 5 years after treatment with LIPUS. The mean duration of LIPUS exposure in the LIPUS group was 381± 283 days. During the 5-year follow-up periods, there were 3 major amputations and 7 deaths in the LIPUS group and there were 14 major amputations and 7 deaths in the historical control group. The overall amputation-free survival rate was significantly higher in patients who were treated with LIPUS than in historical controls. There was no significant difference between overall mortality-free survival rates in the LIPUS group and historical control group. LIPUS is a noninvasive option for therapeutic angiogenesis with the potential to reduce the incidence of major amputations in patients with CLI. Critical limb ischemia (CLI) has been considered as the end-spectrum of peripheral artery disease (PAD) and manifests as chronic >14 days) inadequate tissue perfusion with or without tissue loss. Patients with CLI are at a high risk for limb amputation, cardiovascular complications, and death 4 days in. A largeIt was reported that one third or more of patients with CLI were deemed “no-option” at the time of diagnosis and opted for limb amputation . There hPre-clinical studies have shown that LIPUS exposure induces angiogenesis –14. ThroThe present study was performed to evaluate 5-year outcomes in atherosclerotic PAD patients with CLI who were treated with LIPUS.Fourteen atherosclerotic PAD patients with CLI were diagnosed after they presented with severe rest pain with or without non-healing ulcers and were not candidates for angioplasty or surgical revascularization. These patients were enrolled for a LIPUS clinical trial from 2011 to 2015. For historical control analyses, data were obtained from the Hiroshima University PAD database. Rheumatoid factor, lupus anticoagulants, and serological investigations were assessed to rule out other vasculitis and hypercoagulable states. The diagnosis of arterial occlusion leading to ischemia was confirmed by angiography. CLI was classified according to the guidelines of the TransAtlantic Inter-Society Consensus II (TASC II) [This pilot trial was a retrospective, observational study to determine the 5-year outcomes of LIPUS in CLI patients, and data were obtained for determining the overall survival and major amputation-free survival rates of the patients was obtained. Reports of 3-point major adverse cardiovascular events (MACE)  and any causes of deaths in patients after 5 years of follow-up were also acquired. Amputation-free survival rates and overall survival rates for patients with CLI who were treated with LIPUS were compared to those of historical controls. The UMIN-CTR Clinical Trial ID is UMNI000004901.Historical control data were obtained from the Hiroshima University Hospital PAD database. These atherosclerotic PAD patients with CLI were previously treated according to the standard practice in Hiroshima University Hospital between 2011 to 2015 and had limbs (“no-option”) that were deemed unsalvageable and/or deemed for amputation during a 5-year follow-up period.2, beam nonuniformity ratio of 5 ± 2, pulse duration of 200 μ ± 5%, pulse repetition frequency of 1 kHz ± 5%, pulse duty of 20% ± 5% and output duration of 20 minutes per probe. Ultrasound exposure was applied over the skin of the calf region of the symptomatic limb for 20 min per day and the subject could be either in a supine or seated position. The gap between the transducer and the skin was filled with ultrasonic gel. Eight transducer probes were attached to the symptomatic lower limb. The LIPUS device is portable and was used by patients at home with recorded log data [The LIPUS device  with a transducer element (Nippon Sigmax Co. Ltd.) emits ultrasound frequency of 2 MHz ± 10%, ultrasound output power of 30 mW/cmlog data  Fig 1)..2, beam P<0.05 were considered significant. Continuous variables were compared by using ANOVA for multiple groups and the t-test between two groups. Categorical variables were compared by means of the chi-squared test or Fisher’s exact test. Time-to-event end-point analyses were performed by using the Kaplan-Meier method. The log-rank test was used to compare amputation-free survival and overall survival rates in the groups. Data were processed using JMP version 13.0 software .Results are presented as frequencies for categorical variables and means±SD. All reported probability values were 2-tailed. Values of Baseline clinical characteristics in the LIPUS group and the historical control group are summarized in The mean duration of LIPUS exposure was 381± 283 days and the follow-up period was for 5 years after LIPUS exposure. After 5 years of follow-up, there were 3 major amputations in the LIPUS treatment group and 14 major amputations in the historical group. Kaplan-Meier analysis revealed the overall amputation-free survival rate was significantly higher in patients who were treated with LIPUS than in historical controls .After 5 years of follow-up, there were 7 deaths in the LIPUS treatment group and 7 deaths in the historical group. There was no significant difference between the overall survival rates in the two groups . There wDuring the 5-year of follow-up period, 2 subjects died from cardiovascular causes, 1 had stroke, and 1 had hospitalization for heart failure in the LIPUS group and 3 subjects died from cardiovascular causes, 2 had myocardial infarction and 1 had stroke in the historical control group. There was no significant difference in 3-point MACE between patients with CLI who were treated with LIPUS and the historical group up to 5 years after LIPUS exposure.There were no adverse effects and no severe acute adverse effects in patients with CLI who were treated with LIPUS.In the present study, we demonstrated that patients who were treated with LIPUS had significantly better limb survival than that of historical controls for limbs that were deemed unsalvageable and/or deemed for amputation during a 5-year follow-up period. LIPUS did not alter the survival rate of those patients compared to that of historical controls in a similar period of time. There was no report of serious acute adverse effects within the study period.It is clinically important to focus on the microvasculature and nonvascular tissue such as skeletal muscle and skin as well as re-establishing macrovascular blood flow in the management of CLI –20. DegrIn general practice, about one third of patients with CLI were not suitable for conventional intervention at the time of presentation . The eff2 synthesis along with Ca2+ release to induce angiogenesis. Expression levels of VEGF, FGF2, angiopoietin 1 and transcriptional factor of PPAR gamma coactivator-1α (PGC-1α) were significantly increased in mesenchymal stroma/stem cells after LIPUS exposure. PGC-1α is known to play a role in the regulation of cellular energy metabolism. PGC-1α induced VEGF independently of the transcription factor hypoxia-induced factor pathway. LIPUS-induced angiogenesis may be due to mechanisms similar to those of exercise-induced angiogenesis through paracrine and metabolic effects [It has been shown that LIPUS induces endothelial cell proliferation, migration and sprouting with increased capillary density and increased blood flow in LIPUS-treated ischemic hind-limb models –16. The  effects . LIPUS a effects –14. LIPUThis study has a number of limitations. It was performed in a single center with a small number of patients and is not a prospectively randomized trial. However, in the present study, we found a significant difference between major amputation rates in the LIPUS group and historical control group in a 5-year follow-up period. LIPUS exposure in patients with CLI was performed according to inclusion and exclusion criteria based on the registered clinical trial as mentioned in the method section, whereas data for historical controls were collected with no inclusion or exclusion criteria. The patients enrolled in this study and those in the historical control group were referred to the University Hospital Vascular Unit with severe disease at different times and were deemed unsuitable for conventional limb salvage treatments with multiple comorbidities. Future studies are needed to include more patients and to analyze the outcomes in different clinical settings and approaches.LIPUS is a noninvasive option for therapeutic angiogenesis with the potential to improve ischemic limb conditions in patients with CLI. Modulating the treatment approach to include several therapies for PAD including exercise, pharmacologic medication, inflow and outflow macrovascular interventions, and microvascular regeneration through cell and gene therapies along with LIPUS may improve overall outcomes in patients with PAD including CLI.


Treatment for Hodgkin lymphoma (HL) has evolved considerably from the time it was originally described in the 19th century with many patients now being cured with frontline therapy. Despite these advances, upwards of 10% of patients experience progressive disease after initial therapy with an even higher percentage relapsing. Until recently there had been limited therapeutic options for relapsed and/or refractory HL outside of highly intensive chemotherapy with stem cell rescue. Improved understanding of the pathophysiology of HL, coupled with the emergence of more targeted therapeutics, has reshaped how we view the treatment of relapsed/refractory HL and its prognosis. With this, there has been an increased focus on immunotherapies that can reprogram the immune system to better overcome the immunosuppressive milieu found in HL for improved cancer cell killing. In particular, chimeric antigen receptor (CAR) T cells are emerging as a valuable therapeutic tool in this area. Building on the success of antibody-drug conjugates directed against CD30, CAR T cells engineered to recognize the same antigen are now reaching patients. Though still in its infancy, CAR T therapy for relapsed/refractory HL has shown exceptional promise in early-stage clinical trials with the potential for durable responses even in patients who had progressed through multiple lines of prior therapy. Here we will review currently available data on the use of CAR T cells in HL, strategies to optimize their effectiveness, and how this therapy may fit into the treatment paradigm of HL going forward. Hodgkin lymphoma (HL) is a B cell malignancy that affects ~8000 people yearly of all ages with the highest incidence in young adults. Phenotypically, it is characterized by the co-expression of CD15 and CD30 on malignant Hodgkin and Reed–Sternberg (HRS) cells, though it can also be identified by a particular gene signature . DespiteA key feature of HL, particularly classical HL (cHL) that we will focus on in this review, is a relatively sparse number of malignant cells interspersed in a heavily immune infiltrated background . In cHL,For years, the mainstay of treatment for r/r HL has been high dose chemotherapy followed by ASCT after this was shown to be a viable therapeutic strategy in the early 1990s , with trAs mentioned above, a hallmark of cHL is the presence of malignant HRS cells scattered about a large contingent of immune cells which distort the typical lymph node architecture. This supports tumor growth in HL through varied mechanisms. The inflammatory TME fuels the generation of pro-tumorigenic immune and stromal support cells, which modulate the angiogenic, metabolic, and signaling pathways in the tumor environment to promote cancer cell proliferation and survival. The unique chemokine and cytokine milieu here also favors both regulatory T cell formation and recruitment , leadingWhile the incorporation of immune checkpoint inhibitors has certainly led to improved outcomes, it only addresses one mechanism by which cancer cells escape immune surveillance in cHL. In other hematologic malignancies, especially non-Hodgkin lymphomas (NHL), adoptive T cell therapy has shown the potential for not only high response rates but also durable responses in multiply relapsed and refractory patients. In particular, multiple trials with CAR T cells have repeatedly demonstrated the applicability of this platform for treatment ,30,31. CEarly studies demonstrating a potential role for adoptive T cell therapies in the treatment of HL took advantage of the fact that 30–40% of cHL cases are also Epstein–Barr Virus (EBV) positive, with HRS cells expressing EBV antigens . This le7 up to 2.1 × 107 cells/kg. Peak levels of CAR T cells were detected 3 to 9 days after infusion with levels returning to nearly undetectable at 8 weeks. There was however evidence of CAR T cells reaching the tumor microenvironment based on IHC staining of tumor specimens suggesting T cells likely persist here longer than those in circulation. The treatment was well tolerated with no episodes of Grade 3 or 4 cytokine release syndrome (CRS) or neurotoxicity. All patients experienced Grade 1 or 2 febrile syndrome (maybe CRS), around the time of infusion that quickly resolved without intervention. Low levels of CRS seen in this study and subsequent trials are in contrast to what has been seen to date with other CAR T cell-based approaches, particularly anti-CD19 based CAR therapies. The reason for this is likely multifactorial, including but not limited to inherent differences in the target antigen and disease burden, especially when considering the relatively low numbers of HRS cells in HL.The success of BV in r/r HL also provided a nidus to use CD30 as the target for CAR in HL. CD30 has the added advantage of being highly expressed on malignant HRS cells and minimally expressed on other cells and tissues, thereby limiting the potential for toxicity. Wang and colleagues were the first to publish on the feasibility and tolerability of anti-CD30 CAR T cells for the treatment of r/r HL , where t8 CAR T cells/m2. The CAR construct in this study differed from that previously used by the group in China as it was delivered to T cells using a gammaretrovirus and with a CD28 co-stimulatory domain. Additionally, although no lymphodepletion was used ahead of CAR T cell delivery, secondary endpoint analysis showed an ORR of 33% (including durable responses) highlighting the direct effect of CAR T cells. Similar to the results of Wang et al., peak levels of CAR T cells were seen one week after infusion, and by 6 weeks, the CAR signal was minimally detectable in blood. There was also no appreciable toxicity from the CAR T cells, including no CRS.The safety of anti-CD30 CAR T cells was further demonstrated in another Phase I trial conducted by Ramos and colleagues . Here, n8 cells/m2) with the most common adverse effect being cytopenias primarily related to lymphodepletion (grade 3/4 thrombocytopenia in 24% of patients and grade 3/4 neutropenia in 10%). CRS was limited to grade 1 and did not require intervention, and similar to prior studies, there was no neurotoxicity observed. ORR of those evaluable for a disease response was 72% with ~60% of these patients demonstrating a complete response. The one-year PFS and overall survival rates were 41% and 94%, respectively. Moreover, more than a third of the patients showed durable responses to the treatment with five patients remaining in a CR more than a year out from infusion. Based on these results, a multi-center phase 2 pivotal trial of CD30 CAR T cells for relapsed/refractory HL is currently ongoing (NCT04268706).Based on these results, our group, in conjunction with the Center for Cell and Gene Therapy (Baylor College of Medicine), initiated parallel Phase I/II trials further investigating the efficacy of anti-CD30 CAR T cells in r/r HL . A totalThe above results highlight the potential of CAR T treatment in even the most resistant HL patients. Building on these early clinical studies, there are now upwards of 20 clinical trials in progress further investigating the role of CAR T cells in the treatment of relapsed/refractory HL (recently reviewed in ). As the18F-FDG PET imaging based on the maximum standardized uptake value, we noted a direct correlation between MTV ahead of CAR T treatment and PFS. Patients with higher MTV (greater than 60 mL) prior to lymphodepletion and cell infusion had a significantly lower 1-year PFS (14%) as compared to those with a low MTV (58%). Patients who responded to bridging therapy with a decrease in MTV from high to low ahead of CAR T cell infusion also had an improved 1-year PFS (40%) compared to those who showed no reduction in tumor burden with bridging therapy (1-year PFS 0%). That being said, bridging therapy in itself was not associated with a statistical difference in PFS. Surprisingly, the degree of expansion and/or persistence of anti-CD30 CAR T cells did not lead to differences in PFS in this cohort. Similarly, there was no difference seen among the MTV groups in pre-CAR T cytokine levels or peak cytokine levels after cell infusion. The percentage of circulating PD-1+ T cells was not predictive of response to treatment, though the study was unable to characterize the extent to which PD-1+CAR T cells specifically were present.A recent study by our group evaluated factors that were associated with response to anti-CD30 CAR T cells in an attempt to develop a predictive model of responders . LookingThe above results indicate that MTV may be a useful parameter to risk stratify potential CAR T candidates in HL and that bridging therapy to lower MTV ahead of lymphodepletion might lead to improved outcomes. Given the limited number of malignant HRS cells in the TME that is characteristic of cHL, the authors speculated that the uptake seen in PET imaging may be more reflective of the immunosuppressive niche supporting cancer growth. Consistent with this, a recent report demonstrated that cells from the myeloid lineage take up the most glucose in the TME . This isAn alternative way to target the TME in HL patients was tested by Svoboda and colleagues, who used CAR T cells directed against CD19 in an attempt to deplete potentially immunosuppressive B cells from the TME in HL . B cellsThe above results highlight what has been studied to date in terms of targeting the TME in HL, though it represents only a subset of the immunosuppressive cells known to be found here. More research is needed to clarify the impact of targeting other pro-tumorigenic cells in the TME, such as cancer-associated fibroblasts, regulatory T cells, or MDSCs, among others. MDSCs are particularly intriguing as the degree to which circulating MDSCs are found in HL correlate negatively with clinical outcome , and MDSThe issue of persistence of CAR T cells is of paramount importance to their efficacy and in order to achieve durable responses in patients. To date, the clinical trials using anti-CD30 CAR T cells have shown detectable levels of circulating CAR T cells up to 8 weeks post-infusion (in rare patients they are detected months out), though they may exist for longer in the TME and tissues ,38,39. Iscm) cells, have the highest antitumor potential [scm-like cells had superior anti-tumor activity in a mouse xenograft model of HL compared to cell products lacking Tscm cells. Further, Tscm-like cells were resistant to exhaustion in the presence of repeated antigen stimulation, and they were capable of preventing tumor growth in a re-challenge model. Strategies aimed at increasing the population of Tscm cells could provide a therapeutic advantage over traditional CAR platforms, though it remains unclear how best to generate these cells.One approach that has been applied to CAR T development for HL has been the use of an infused product that is enriched for memory stem CAR T cells. Because of the gene manipulation required for CAR expression, most CAR T cells consist of a population predominately made up of terminally differentiated effector cells. While these cells have excellent in vitro anti-tumor properties, they are often not as effective in vivo  owing tootential ,55,56. Totential . They shA potential mechanism for increasing the memory pool of these cells may lie in the design of the CAR T cell. When evaluating the impact of co-stimulatory domains in CAR T cells on their phenotype, it was noted that those that express 4-1BB CD137) were more likely to be skewed towards central memory cells . This wa were morThe choice of agent used for lymphodepletion may also play a role in CAR T memory cell development. Studies have shown that fludarabine can lead to increased memory formation in both CD4 and CD8 T cell compartments . In our 5 copies/µg of DNA) compared to the peripheral blood (4.3 × 105 copies/µg of DNA). This suggests that with the proper modifications, CAR T cells in HL can be further refined to improve their efficacy and potentially, the durability of their response.Another way to improve the efficacy of CAR T cells in HL is to increase their trafficking to the TME. One barrier to CAR T cells gaining access to the malignant HRS cells in HL is the immunosuppressive chemokine and cytokine milieu that they encounter. CCL17/TARC represents one of the key chemokines here, which is important for recruiting Th2 and regulatory T cells that express the cognate receptor CCR4, which further fuels the immunotolerant background. Cytotoxic T cells do not express CCR4 and, therefore, are not readily recruited to the TME in HL. Pre-clinical work demonstrated that forced expression of CCR4 on adoptively transferred T cells improved their activity and tumor-killing potential . This haAmong the multiple mechanisms to evade the immune system employed by HRS cells, CD58 downregulation represents a common feature in HL patients who relapse . CD58 isThis therapy has since been moved to Phase 1 clinical trials at MD Anderson (NCT04074746) with preliminary results presented at AACR in 2021, showing a 100% response rate in r/r HL in the four patients evaluable at the time of presentation. The other advantage of this therapy is that theoretically, the NK cells can be isolated from healthy donors for an “off-the-shelf” product. In this way, it could be delivered to patients without the same wait time usually required for manufacturing autologous products or the concern about prior therapies impairing immune cell function. However, a potential limitation lies in the relative fragility of NK cells and the challenges that could come with freezing and thawing these products from a viability standpoint. The possibility of using other immune cells outside of T cells as the backbone for cellular therapy opens the door to novel approaches for improving these treatments for patients with HL. In line with this, CAR NK cells have been shown to be effective in the treatment of non-Hodgkin lymphomas (NHL), and potentially with a more favorable side effect profile .Interestingly, there has been no evidence of CD30 antigen loss in HL patients who relapse after CAR T therapy . This isOne wonders, though, whether an upfront combination of checkpoint inhibition and CAR T cell infusion may prove to be a more effective strategy, as is currently being explored in solid tumors . In factWhile the role of adoptive T cell treatments is becoming clearer in relapsed/refractory HL patients who are transplant-ineligible or relapse after transplant , it remaThis has yet to be explored in HL, though is being investigated in cases of B-cell acute lymphoblastic leukemia (B-ALL). In a study of B-ALL patients who had undergone allogeneic transplant, outcomes for those patients who had received CAR T cells as a bridge to transplant compared similarly to those receiving chemotherapy when looking at NRMrates, leukemia-free survival, and overall survival . PatientAnother use of CAR T cells in the context of transplant could be as a maintenance or consolidation strategy post-transplant in r/r HL. This is currently under investigation at our institution (NCT04083495) where high-risk patients  received an infusion of CD30 CAR T cells after ASCT . A totalThere have been questions regarding the safety of CAR T therapy after both autologous and allogeneic transplants with concerns regarding an increased incidence of immune-related adverse events. This has, however, not been appreciated to date with studies largely demonstrating the long-term safety of CAR T cells even after transplant . This daThe success of CAR T therapy in hematologic malignancies has also called into question whether this treatment option could replace stem cell transplant as the standard of care in the future for relapsed or refractory disease . In an iThough the majority of patients diagnosed with HL will respond to frontline therapy and be cured, a sizeable fraction (up to 30%) may relapse and a number of patients may have refractory disease. Treatment options in the relapsed and/or refractory setting have changed dramatically since the turn of the century with a number of novel agents revolutionizing our approach to treatment. CAR T cells have now joined the armamentarium for treatment of r/r HL and demonstrate exceptional promise with high response rates in this population, along with the potential for durable responses. How this therapy fits with the current treatment paradigm in r/r HL is the key question going forward. The fact that there has been limited toxicity observed with anti-CD30 CAR T cells to date is especially encouraging and may cause us to rethink how we view the timing and role of transplant for r/r HL in the future. That being said, much work remains to determine how best to optimize this therapy and whether or not the durable responses we have seen thus far truly translate to a ‘cure’ for these patients. Further clarification of the optimal target for CAR T cell design in HL is also needed, especially when considering that the majority of cells encountered are not malignant HRS cells, but rather immunosuppressive cells of the adaptive and innate immune systems. Combinatorial treatment approaches that address both of these populations may be needed to fully eradicate the tumor. The success of this will ultimately dictate the degree to which CAR T cells can be relied upon for treatment in r/r HL. The results from early-phase clinical trials to date would suggest that the future here is bright and that even the most refractory patients could see long-term disease control.


Outside of a clinical setting, oscillometric devices make remote monitoring of blood pressure and virtual care more convenient and feasible. HeartBeat Technologies Ltd developed a novel approach to measuring blood pressure remotely after an initial blood pressure reading by a nurse using the conventional measurement method. Using a finger pulse oximeter, a photoplethysmogram wave is transmitted by Bluetooth to a smartphone or tablet. A smartphone app (MediBeat) transmits the photoplethysmogram to a server for analysis by a proprietary algorithm—the person’s current blood pressure is sent back to the smartphone and to the individual’s health care provider.This study sought to determine whether the HeartBeat algorithm calculates blood pressure as accurately as required by the European Society of Hypertension International Protocol revision 2010 (ESH-IP2) for validation of blood pressure measuring devices.ESH-IP2 requirements, modified to conform to a more recent international consensus statement, were followed. The ESH-IP2 establishes strict guidelines for the conduct and reporting of any validation of any device to measure blood pressure, including using the standard manual blood pressure instrument as a comparator and specific required accuracy levels for low, medium, and high ranges of blood pressure readings. The consensus statement requires a greater number of study participants for each of the blood pressure ranges. The validation of the accuracy of the algorithm was conducted with a Contec CMS50EW pulse oximeter and a Samsung Galaxy XCover 4 smartphone.The differences between the HeartBeat-calculated and the manually measured blood pressures of 62 study participants did not meet the ESH-IP2 standards for accuracy for either systolic or diastolic blood pressure measurements. There was no discernible pattern in the inaccuracies of the HeartBeat-calculated measurements.The October 4, 2019 version of the HeartBeat algorithm, implemented in combination with the MediBeat app, a pulse oximeter, and an Android smartphone, was not sufficiently accurate for use in a general adult population.ClinicalTrials.gov NCT04082819; http://clinicaltrials.gov/ct2/show/NCT04082819 Accurately assessing blood pressure is necessary for the proper diagnosis of hypertension, implementing treatments and monitoring whether those treatments are working ,2. To meA novel approach to measuring blood pressure remotely has been developed . The measurement is taken after an initial blood pressure reading using the conventional measurement method, supplemented by specific characteristics of a person  to establish a baseline for the person. Unlike other devices -9, this The purpose of this study was to test whether the accuracy of the HeartBeat algorithm, available as of October 4, 2019 and for a general adult population (ages 25 years and older), was sufficient to seek regulatory approval when compared with a standard aneroid sphygmomanometer with stethoscope for measuring blood pressure.The European Society of Hypertension International Protocol revision (ESH-IP2) for the validation of blood pressure measuring devices in adults  was follAn international consensus statement group  reviewedThe pulse oximeter  used toPotential participants were recruited by mass email and offline posters at a single-site multistory office building in Markham, Ontario, Canada, where they worked; participants provided informed consent  and wereThree registered nurses who had training and expertise in blood pressure measurement carried out the measurements required for this study between October 4, 2019 to November 22, 2019. One nurse was the supervisor, and two nurses were the observers throughout the duration of the study. The nurses were trained as per ESH-IP2 directives and were instructed on how to follow the protocol guidelines for data collection. Blood pressure measurements were recorded to the nearest 2 mmHg.Two new sphygmomanometers , whose The observers were instructed that, in the event that an abnormal blood pressure reading was detected , they were to remeasure the blood pressure using conventional means to determine if the abnormal reading was accurate. If the abnormal blood pressure measurement was accurate, the nurse supervisor was to act according professional standards. The abnormal blood pressure measurement should also be recorded on ESH-IP2 Form 2.2 (oxygen saturation) values. (4) Once the values were displayed, the supervisor initiated a new session on the smartphone to connect the phone to the Contec device via Bluetooth. This connection started the 1-minute calibration process, at which point each participant was asked to remain still until the calibration had been completed successfully.Participants’ blood pressure measurements were taken in a room that was a comfortable temperature, without any noises or other influences that would have caused disturbances, such as telephones. The temperature in the room was the same as that throughout the building—20 °C to 24 °C. All participants participated in the study between the working hours of 9 AM and 4:30 PM. The pulse oximeter and the supervisor’s smartphone were charged and tested each day prior to interactions with participants. The MediBeat app was calibrated for each participant as follows: (1) Reference data for the individual  were entered. (2) The participant rested for 10 minutes while seated comfortably with their legs uncrossed, back supported, and arm resting on the table at heart level. (3) The supervisor attached the finger pulse oximeter to the participant’s index finger  and waited for a few seconds until a stable signal was received and the device displayed both the participant’s pulse and SpOpass (an acceptable level of accuracy) if it meets 4 pass criteria.Overseen by an independent supervisor, measurements were recorded by the two observers who were blinded from both the other observer’s readings and from the reading calculated by the HeartBeat algorithm. Each participant’s blood pressure was measured as illustrated in The study was reviewed and approved by the Southlake Regional Health Centre Research Ethics Board, Newmarket, Ontario, Canada (007-1920).A total of 105 individuals volunteered and were screened for the study, of whom 62 participants met the ESH-IP2 criteria, and 43 were excluded . As requy-axis) and the average of the 2 measurements (x-axis). r=0.04, P=.53; diastolic blood pressure: r=.04, P=.54). This indicates that the HeartBeat-calculated blood pressure measurements are not sufficiently accurate. There was no discernible pattern in the inaccuracies in the HeartBeat-calculated measures; therefore, the source of the inaccuracies is not known.The Bland-Altman plots show that the October 4, 2019 version of the HeartBeat algorithm, used in conjunction with a Contec CMS50EW pulse oximeter, MediBeat app, and a Samsung Galaxy XCover 4 smartphone, was not sufficiently accurate to meet ESH-IP2 standards for measuring the blood pressure of adults in the general population; therefore, as per the protocol, it is not recommended for personal or clinical use in this configuration.