What has been the association between relaxing restrictions on take-home methadone doses and the number of fatal overdoses involving methadone among different racial, ethnic, and sex groups?In this interrupted time series cohort study of 14 529 methadone-involved overdose deaths, the methadone take-home policy was associated with reduced deaths among Black and Hispanic men but did not affect deaths of Black or Hispanic women or White men or women.The urgency of the overdose crisis requires that national methadone policy debates and decisions address the heterogeneity of people in treatment; relaxing methadone restrictions may help some particularly at-risk groups. In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) permitted states to relax restrictions on take-home methadone doses for treatment-adherent patients to minimize COVID-19 exposures.To assess whether the methadone take-home policy change was associated with drug overdose deaths among different racial, ethnic, and sex groups.Interrupted time series analysis from January 1, 2018, to June 30, 2022. Data analysis was conducted from February 18, 2023, to February 28, 2023. In this population-based cohort study of drug overdose mortality including 14 529 methadone-involved deaths, monthly counts of methadone-involved drug overdose deaths were obtained for 6 demographic groups: Hispanic men and women, non-Hispanic Black men and women, and non-Hispanic White men and women.On March 16, 2020, in response to the first wave of the COVID-19 pandemic, SAMHSA issued an exemption to the states that permitted up to 28 days of take-home methadone for stable patients and 14 days for less stable patients.Monthly methadone-involved overdose deaths.From January 1, 2018, to June 30, 2022 (54 months), there were 14 529 methadone-involved deaths in the United States; 14 112 (97.1%) occurred in the study’s 6 demographic groups . Among Black men, there was a decrease in monthly methadone deaths associated with the March 2020 policy change . Hispanic men also experienced a decrease in monthly methadone deaths associated with the policy change . Among Black women, Hispanic women, White men, and White women, the policy change was not associated with a change in monthly methadone deaths .In this interrupted time series study of monthly methadone-involved overdose deaths, the take-home policy may have helped reduce deaths for Black and Hispanic men but had no association with deaths of Black or Hispanic women or White men or women. This cohort study investigates racial, ethnic, and sex differences in methadone-involved overdose deaths in the United States before and after a federal policy change expanding take-home methadone doses. On March 16, 2020, in response to the first wave of the pandemic, the Substance Abuse and Mental Health Services Administration (SAMHSA) issued an exemption that allowed OTPs, with state approval, to provide up to 28 days of take-home methadone for patients who were stable and 14 days for those who were less stable.2 When taken as prescribed, methadone is safe and effective; however, there is a substantial risk of overdose when more than the amount prescribed is taken or when illicit opioids, such as heroin or fentanyl, are used in addition to methadone.3For the past 50 years, outpatient methadone treatment for opioid use disorder has been tightly governed by federal statutes and regulations, which allow only federally certified opioid treatment programs (OTPs) to dispense methadone.12 A set of proposals that will permanently ease the take-home restrictions is now being considered by SAMHSA.13 To our knowledge, only 1 study has investigated the association between relaxing methadone restrictions and fatal overdoses among different racial, ethnic, or sex groups,14 although prior research suggests a strong possibility of demographic differences in outcomes. Research has shown the following: (1) Medication options available to persons with opioid use disorder differ by neighborhood, with OTPs dispensing methadone more often located in poor and minority neighborhoods, whereas less restrictive buprenorphine treatment services are more often located in higher-income areas with a higher percentage of White residents.16 (2) Access to OTP services differs by sex and race, with women and Black individuals spending more days on waiting lists to enter methadone treatment.17 (3) There are logistic impediments to retention in methadone treatment for women with children and family responsibilities.18 (4) There are lower methadone dosage regimens (“underdosing”) for Black patients and pregnant individuals from racial and ethnic minority groups.20The goal of the SAMHSA policy change was to protect public health by lowering the risk of COVID-19 infections among patients and health care clinicians . Results of research on the effects of the policy change are still emerging, but the weight of the evidence suggests that the policy change was associated with an increase in the number of patients receiving take-home doses and that it did not adversely affect treatment outcomes, including fatal overdoses.22Reducing barriers to methadone may have a disproportionately positive effect on these groups.In the present study, we compared methadone-involved overdose deaths before and after the March 2020 policy change among Black, Hispanic, and White male and female individuals. Collectively, the 6 groups experienced 14 112 of the 14 529 fatal methadone-involved drug overdoses (97.1%).23 Drug overdose deaths had International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes X40 to X44, X60 to X64, X85, and Y10 to Y14 for underlying cause of death; methadone-involved deaths had ICD-10 code T40.3. The cause-of-death determination is typically made by a coroner or medical examiner.24In this cohort study with interrupted time series analysis, we used US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research ; data are from the multiple cause of death files as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program.25We extracted monthly drug overdose deaths that involved methadone from January 1, 2018, to June 30, 2022, for 6 demographic groups: Hispanic men and women , non-Hispanic Black men and women, and non-Hispanic White men and women  to model trends in monthly drug overdose deaths for each demographic group28 we conducted a stratified analysis to control for the co-occurrence of synthetic opioids, mainly fentanyl and its analogs. Our aim was to determine whether the associations between the take-home policy and fatal methadone overdose were modified when separately estimated for (1) deaths that involved methadone but not fentanyl and (2) deaths that involved both methadone and fentanyl.Given the expanding role of fentanyl in the overdose crisis ,14We also assessed whether monthly nonmethadone overdose deaths could provide a secular trend comparison, which would help assess whether a change in the trend line of methadone-involved deaths was associated with the take-home policy change or could be attributed to other factors affecting trends in drug overdose deaths generally. Nonmethadone deaths satisfied the 2 a priori criteria for a secular trend variable: a theory-based association between methadone deaths  and the absence of a theory-based association with the policy change . A third criterion was strictly empirical: were methadone and nonmethadone overdose deaths closely or moderately correlated before the policy change? If not correlated in the preintervention period, then nonmethadone overdose deaths could not provide a basis for a postintervention comparison. Recent studies have used nonmethadone overdose deaths for secular trend purposes, but without providing empirical justification.STROBE) reporting guideline.Because this study used publicly available, deidentified data, the University of Pennsylvania institutional review board determined that approval and informed consent were not needed. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology  for data analysis. We conducted the data analysis from February 18, 2023, to February 23, 2023.We used totals and percentages to describe overdose mortality by demographic category and mean values to summarize observations per data point. We used the Stata module ITSA to estimate the preintervention and postintervention slopes, the change in mortality levels, and the change in slopes. To adjust for autocorrelation, we used the Akaike information criterion for the lag order selection. The ITSA specifies the maximum lag to be considered in the autocorrelation structure using Newey-West SEs.From January 1, 2018, to June 30, 2022, there were 406 484 drug overdose deaths in the US; 388 783 (95.6%) occurred in the study’s 6 demographic groups . During this period, methadone-involved overdose deaths totaled 14 529, or 3.6% of all drug overdose deaths. Of the methadone-involved deaths, 14 112 (97.1%) occurred in the study’s 6 demographic groups .Before April 2020, methadone-involved overdose deaths were decreasing . In April 2020, methadone-involved overdose deaths increased by 115.18 deaths , estimated by subtracting the end point of the preintervention trend line from the starting point of the postintervention trend line. Monthly methadone-involved overdose deaths continued to decrease after April 2020 . The difference between the slopes before and after April 2020 was –1.71 deaths per month  .Before April 2020, ITSA-estimated monthly methadone-involved overdose deaths were stable; that is, there was no significant monthly increase or decrease . In April 2020, methadone-involved overdose deaths increased by 15.41 deaths . Monthly methadone-involved overdose deaths decreased after April 2020 . The difference between the slopes before and after April 2020 was significant  .Before April 2020, methadone-involved overdose deaths were stable . In April 2020, methadone-involved overdose deaths increased by 6.58 deaths . Monthly methadone-involved overdose deaths remained stable after April 2020 . The before and after April 2020 slopes did not differ significantly  .Before April 2020, methadone-involved overdose deaths were stable . In April 2020, methadone-involved overdose deaths increased by 11.88 deaths . Monthly methadone-involved overdose deaths decreased after April 2020 . The before and after April 2020 slopes differed significantly  .Before April 2020, methadone-involved overdose deaths were decreasing slightly . In April 2020, methadone-involved overdose deaths increased by 10.04 deaths . Monthly methadone-involved overdose deaths were stable after April 2020 . The before and after April 2020 slopes did not differ significantly  .Before April 2020, methadone-involved overdose deaths were decreasing . In April 2020, methadone-involved overdose deaths increased by 46.46 deaths . Monthly methadone-involved overdose deaths continued to decrease after April 2020 . The before and after April 2020 slopes were similar  .Before April 2020, methadone-involved overdose deaths were stable . In April 2020, methadone-involved overdose deaths increased by 27.64 deaths . Monthly methadone-involved overdose deaths decreased after April 2020 . The before and after April 2020 slopes were similar  . The regThe results of the fentanyl stratification analysis are presented in the eTable, eFigure 1, and eAppendix 2 in r = 0.28, P = .15; Black women: r = 0.09, P = .66; Hispanic men: r = 0.09, P = .65; Hispanic women: r = –0.31, P = .11; White men: r = –0.25, P = .20; White women: r = 0.33, P = .09; and all persons: r = –0.13, P = .53).In the secular trend analysis, monthly nonmethadone overdose deaths were uncorrelated with monthly methadone overdose deaths during the preintervention period in each of the 6 demographic groups and overall .32 But this is piecemeal evidence. Constructing a precise denominator for a methadone treatment overdose rate  would require standardized national record keeping on the number of persons taking methadone for opioid use disorder and their duration of treatment.The overall decrease in methadone-involved drug deaths after the intervention does not appear to have been a function of fewer people taking methadone. In their study of buprenorphine and methadone supplies in the US, Chen and colleaguesIn a stratification analysis, we estimated whether the associations between the take-home policy and fatal methadone overdose were modified when separately estimated for (1) deaths that involved methadone but not fentanyl and (2) deaths that involved methadone and fentanyl. We found that only Black and Hispanic men had a significant change (decrease) in the slope of monthly overdose deaths under both conditions. Thus, the decrease in slope after the policy change among Black and Hispanic men cannot be attributed to fentanyl. We also found that the preintervention slopes of monthly methadone deaths were positive when fentanyl was involved and negative when it was not. Similarly, each of the postintervention slopes was more positive when fentanyl was involved compared with the stratum without fentanyl. This pattern suggests that fentanyl was associated with an increase in the number of methadone-involved deaths both before and after the policy change across all demographic groups, but it does not appreciably strengthen, mitigate, or make conditional the associations (or lack of associations) between the policy change and methadone-involved overdose deaths.8 using ITSA to model the percentage of all drug overdose deaths that involved methadone, found that the trend slopes were similar before and after March 2020 and concluded that the evidence was consistent with permanently expanding the take-home methadone policy. However, their study did not empirically justify the use of nonmethadone overdose deaths as a secular trend variable . Their study also did not stratify by demographic group, which effectively masked important differences in slope changes. In contrast to the results of Jones et al,8 Kleinman and Sanches14 reported that methadone-involved overdose deaths increased after the policy change, prompting the authors to warn against permanently relaxing the take-home regulations until the impact of the policy has been better clarified. In examining racial and ethnic differences in methadone-involved mortality, Kleinman and Sanches14 found that the number of individuals with methadone-involved deaths increased in each group  between the 12-month periods before and after March 2020, with the largest increases among Hispanic (70%) and non-Hispanic Black individuals (57%). However, when assessing trends, their year-over-year analysis did not control for the step increase in mortality level that occurred in the early spring of 2020. The authors assumed that the step increase could be attributed to the change in methadone regulations, yet the increase in level also has been found in drug overdose deaths that did not involve methadone35 and in related domains, such as alcohol use disorder–associated deaths.38 Disruptions related to COVID-19 provide a more intuitive and parsimonious explanation for the step increases.39The present study addressed several notable weaknesses in previous research. Jones et al,40In summary, we hypothesized that the policy change would not be associated with methadone-related overdose deaths. Although this was true for Black, Hispanic, and White women and for White men, we found fewer fatalities in Black and Hispanic men than expected. We did not expect to find differential associations based on demographic group and can only conjecture on the reason for these results: that having to daily report to an OTP is a distressing and demeaning experience for Black and Hispanic men who are already marginalized and continually exposed to systems of surveillance, stigma, alienation, and punishment. The additional take-home doses provided a sense of normalcy and dignity that was missing with frequent attendance at the OTP.41 As noted, the OTP take-home policy change happened in the context of concurrent trends , economic policy changes ,38 and other policy changes  that could have affected drug use and treatment for people with opioid use disorder. Second, analytic insight would be gained by relating the number of methadone-involved overdose deaths to the number of persons in methadone treatment each month by demographic group, but these data or reasonable proxies are not publicly available. Third, this study could not distinguish whether the individuals who died from methadone-involved overdoses received the methadone through OTPs , from pharmacy-dispensed prescriptions for pain (approximately 9%), or from other sources, including diverted methadone. Fourth, approximately 5% of death certificates do not list the specific drugs involved in the overdose.8 Fifth, the 2022 provisional mortality data may minimally underestimate overdose deaths because of delayed reporting.42This study has limitations. First, the lack of an external comparison, either a control group (persons taking methadone for opioid use disorder who were not exposed to the policy change) or a secular trend variable, precludes the drawing of causal inferences from the study data.In this interrupted time series cohort study of monthly methadone-involved overdose deaths, the take-home policy was associated with reduced deaths for Black and Hispanic men. However, no significant association was observed for Black or Hispanic women or White men or women. Regardless of the reason, the changes in slopes clearly display an association with race and ethnicity. The urgency of the drug overdose crisis requires that our national methadone policy debates and decisions attend to the heterogeneity of people in treatment.


Despite the high number of children living with neurodevelopmental disabilities in sub–Saharan Africa, access to early intervention is almost non-existent. It is therefore important to develop feasible, scalable early autism intervention that can be integrated into systems of care. While Naturalistic Developmental Behavioural Intervention (NDBI) has emerged as an evidence-based intervention approach, implementation gaps exist globally, and task-sharing approaches may address access gaps. In this South African proof-of-principle pilot study, we set out to answer two questions about a 12-session cascaded task-sharing NDBI—whether the approach could be delivered with fidelity, and whether we could identify signals of change in child and caregiver outcomes.We utilized a single-arm pre-post design. Fidelity , caregiver outcomes , and child outcomes  were measured at baseline (T1) and follow-up (T2). Ten caregiver-child dyads and four non-specialists participated. Pre-to-post summary statistics were presented alongside individual trajectories. Non-parametric Wilcoxon signed rank test for paired samples was used to compare group medians between T1 and T2.Caregiver implementation fidelity increased in 10/10 participants. Non-specialists demonstrated a significant increase in coaching fidelity (increases in 7/10 dyads). Significant gains were seen on two Griffiths-III subscales  and on the General Developmental Quotient (9/10 improved). Significant gains were also seen on two Vineland Adaptive Behaviour Scales (Third Edition) subscales  and in the Adaptive Behaviour Standard Score (9/10 improved). Caregiver sense of competence improved in 7/10 caregivers and caregiver stress in 6/10 caregivers.This proof-of-principle pilot study of the first cascaded task-sharing NDBI in Sub-Saharan Africa provided fidelity and intervention outcome data which supported the potential of such approaches in low-resource contexts. Larger studies are needed to expand on the evidence-base and answer questions on intervention effectiveness and implementation outcomes. Lancet Commission on future care in autism proposed the necessary coordination between healthcare and other sectors such as education to address the gap in access, and to promote programmes that can be personalized, taking into account the preferences, needs, and incurred costs  of families and their autistic children [Lack of services and supports for autistic individuals has been recognized by the World Health Organization as a global public health concern . In low-children . Furtherchildren . Early ichildren , 8. Currchildren , 10.Naturalistic Developmental Behavioural Intervention (NDBI) is a class of interventions delivered by trained therapists with active caregiver involvement, leverage the opportunity to support developmental growth of children at home and in their daily lives. Early childhood is a particularly sensitive stage of human development in which the brain undergoes rapid growth and maturation, offering a critical window for supportive intervention. Interventions that promote social and communication development during this period of rapid growth have been associated with a cascade of positive short- and long-term functional outcomes . The EarA high number of individuals with neurodevelopmental disabilities live in sub-Saharan Africa . This isMeeting the needs of families who care for young autistic children in LMIC is hampered by significant ongoing systemic challenges. Although 95% of the global population of children and adolescents reside in LMIC, only 10% of mental health research - and even less on neurodevelopmental conditions—has been conducted in these settings , 4, 6. APolicies that prioritize early childhood development (ECD) are emerging in sub-Saharan African countries, like South Africa . The enaAlthough South Africa is an upper-middle-income country, it remains an economy with one of the highest, persistent inequality rates globally . The imbThere are significant socioeconomic barriers that limit access to private health care services for much of the South African population, and racial variation in expressive language abilities at time of diagnosis has been reported in children accessing public health care services in the Western Cape Province of South Africa . In a 2-Lancet Commission report introduced the concept of a stepped care approach to service delivery as a framework for equitable resource distribution that supports improvement in outcomes for autistic individuals. This type of approach, where the least resource-intensive service such as low-intensity, non-specialist delivered interventions are offered first, may be particularly well suited to LMIC and other low resource settings [and non-specialist providers  may address the service gap impacting young autistic children and their families [While questions around the importance of cumulative intervention intensity are beginning to emerge, the vast majority of evidence-based early autism interventions are intensive and delivered by trained therapists , 24. Botsettings . In low-families . Task-shboth impact intervention outcomes and be impacted by the intervention be recognized [Task-sharing in autism intervention promotes active caregiver involvement via caregiver coaching. Caregiver-implemented intervention, where caregivers are coached in strategies to support their child’s social and communication growth during everyday activities, may be utilized to overcome some service access barriers . Increascognized . Furthercognized –31.Task-sharing the coaching role in caregiver-implemented intervention, from highly trained therapist to non-specialist provider, offers a parallel opportunity to increase access to services. In a meta-analysis of non-specialist delivered intervention, only two studies included autistic participants from LMIC . In thesIn intervention research, there is growing attention to the concepts of outcome proximity (whether outcomes mirror intervention targets or skills in domains directly targeted by the intervention) and boundedness (whether an outcome is measured in a context that differs from the intervention context) . In careOver the past eight years, the Center for Autism Research in Africa at the University of Cape Town has been studying various feasible approaches to early autism intervention  . EffortsBuilding on our formative work, in this proof-of-principle pilot study, we set out to answer two specific objectives about our cascaded task-sharing NDBI approach that required exploration. The first objective was to determine whether our approach impacted fidelity of implementation of both non-specialist coaches and caregivers. In our first objective we specifically aimed to: (i) assess whether coaching by non-specialist providers resulted in improvements in caregiver use of intervention strategies with their young autistic child, and (ii) whether coaches were able to adhere to coaching procedures as outlined in fidelity checklists. The second specific objective was to assess whether coaching impacted key short-term child and caregiver outcomes. In our second objective we specifically aimed to: (i) assess whether signals of change were detected in child social and communication abilities, and (ii) caregiver stress and sense of competence. These specific objectives were important to answer as without information on implementation fidelity and potential child and caregiver impact, larger-scale clinical trials may not be warranted.This proof-of-principle pilot study utilized a single-arm pre-post design to evaluate the fidelity of implementation by coaches  and caregivers, and to explore short-term caregiver and child outcomes of NDBI-informed caregiver coaching by non-specialist ECD practitioners employed by the Western Cape Education Department in Cape Town, South Africa.Partner schools in the Western Cape Education Department identified children who were on their waiting list for autism special education services to participate in the pilot study. Inclusion criteria for caregiver-child dyads were as follows: (i) child met DSM-5 criteria for autism spectrum disorder (ASD) , which wAutism schools in the Western Cape Education Department identified ECD practitioners to participate in caregiver coaching . InclusiThe ESDM Caregiver Fidelity Scale provides a method for assessing the fidelity with which a caregiver uses ESDM strategies in a joint activity routine with their young child . The 13-Griffiths Scales of Child Development, Third Edition  is a coThe Vineland Adaptive Behaviour Scales, Third Edition  is a meThe Parent Sense of Competence Scale  is a 16-item self-report questionnaire designed to measure the degree to which caregivers feel competent and confident in ‘parenting’ their children  and the quality of affect associated with ‘parenting’ . Items are rated on a 6-point Likert scale with high scores representing high degrees of satisfaction and efficacy. The Satisfaction subscale reflects ‘parenting’ frustration, anxiety, and motivation, whereas the Efficacy subscale assesses capability, problem-solving ability, and competence.The Parenting Stress Index-Short Form  is a 36n, percentage for categorical variables and range, median and inter-quartile range (IQR) for continuous and score variables) were computed separately for each participant group . Due to the limited sample size, pre-to-post summary statistics (median and IQR) were presented alongside participant trajectories to visually display individual-level data. Comparison of both group and individual change from baseline (T1) to follow-up assessment (T2) are visualized using box plots and connected dot-plots, respectively. Analysis was performed using R . Given n 4.1.1; .Given that this study was a collaboration between the Center for Autism Research in Africa at the University of Cape Town (UCT) and the Duke Centre for Autism and Brain Development at Duke University all study procedures were submitted and approved by both ethical review boards . Study procedures were reviewed with participants and informed consent was collected prior to data collection. The study protocol was registered on Clinical Trials.gov (NCT04068688). Study funding provided by the National Institute of Mental Health and the Fogarty International Center (R21 MH120696). As the study was funded by the National Institute of Mental Health all data has been submitted to ClinicalTrials.gov and the National Database for Autism Resarch (NDAR).The CONSORT flow chart in Fig. Child and caregiver baseline characteristics are outlined in Table The non-specialist ECD practitioner group (n = 12) consisted of three bilingual (English and Afrikaans) Coloured females, and one trilingual  Black female. One of the ECD practitioners had a Grade 12 education (completed secondary education) and the other three had post-Grade 12 Certificates.p = 0.009). Notably, fidelity of implementation improved in 9 out of 10 caregivers and remained the same for the 10th caregiver . At an individual level, coaching fidelity increased in 7/10 dyads coached, remained the same with 2 dyads and dropped in one  to follow-up assessment T2) in implementation fidelity of caregivers (n = 10) and ECD practitioners n = 4). Results are shown in Table  in imple. Resultsp = 0.557). Griffiths-III Gross Motor DQ improved in 5 out of 10 children and dropped in 5 , the Personal/Social-Emotional DQ improved in 8 out of 10 children, and dropped in 2 , with all 10 children demonstrating improved Foundations of Learning DQ scores . Language/Communication DQ improved in 9 out of 10 children and dropped in one . Eye and Hand Coordination DQ improved in 6 out of 10 children, 2 stayed the same, and 2 dropped . General Development DQ improved in 9 out of 10 children and dropped in 1 child . Notably, VABS-3 Communication Standard Scores improved in 9 out of 10 children and dropped in one . VABS-3 Socialization Standard Scores improved in 6 out of 10 children, 2 stayed the same, and 2 dropped . VABS-3 Daily Living Standard Scores improved in 7 out of 10 children, stayed the same in 1, and dropped in 2 . VABS-3 Adaptive Behaviour Standard Score improved in 9 out of 10 children and dropped in 1  T1 = 41 ; T2 = 50 ; see Fig. A. VABS-3p = 0.075). Sense of competence total scores improved in 7 out of 10 caregivers and dropped in 3 . Caregiver stress total scores increased in 6 out of 10 caregivers and dropped in 4 . The coaching was conducted by Early Childhood Development (ECD) practitioners in public schools in Cape Town, South Africa. Caregiver-child dyads were identified by partner schools, from their waitlist of young autistic children who were eligible for services, but not enrolled in in-person instruction. To our knowledge, this is the first study to evaluate a cascaded task-sharing NDBI caregiver coaching approach delivered by non-specialist ECD practitioners in any Sub-Saharan African country.All caregivers demonstrated improvements in fidelity scores across coaching sessions which suggests that non-specialist ECD practitioners were able to support growth in caregiver implementation of NDBI strategies. Increases in ECD practitioner coaching fidelity was also documented across coaching sessions which suggests that non-specialists increased their competency in coaching behaviours. Of note, ECD practitioners had only completed a 4-day in-person training prior to starting caregiver coaching sessions—and were otherwise naïve to both the coaching approach and NDBI strategies.Given the sample size and proof-of-principle nature of the study, results reported are exploratory in nature but were included to determine if key outcome measures changed in the desired direction and to identify outcome measures that may be more or less sensitive to change in a non-specialist led task-sharing intervention. The study was therefore ‘signal-seeking’ in terms of outcome measures. It was very encouraging that not only was growth in caregiver-implementation fidelity observed , but significant growth was also seen on two Griffiths-III subscales (Language/ Communication and Foundations of Learning) and on the General Development DQ. Significant growth was also seen on and two VABS-3 subscales  and the Adaptive Behaviour Standard Score. The Griffiths-III and the VABS-3 assess developmental and adaptive domains, which are not direct intervention targets such as caregiver positioning during caregiver-child interactions and following the child’s lead. The Griffiths-III and the VABS-3 are also measures that are administered in contexts different from the intervention suggesting generalization of child skills across interaction partners.While not statistically significant, an increase in caregiver sense of competence was observed in 7 out of 10 caregivers, suggesting increases in confidence in ‘parenting’ and ‘parenting’ satisfaction. In addition, although not statistically significant, an increase in total stress composite scores on the PSI-SF post-intervention were noted, suggesting increases in ‘parenting’ stress. However, given the sample size, this increase in ‘parenting’ stress appeared to be mostly driven by a large increase in a single participant’s score.both be impacted by the intervention and impact intervention outcomes, caregiver characteristics are particularly relevant to track [Perhaps a unique characteristic of this study was the profile of caregivers who completed coaching. Given primary caregivers critical role in caregiver-mediated interventions, and the transactional relationship of caregiver-coaching whereby caregivers can to track . Most cato track . In thisto track , 52. Furto track –31. All to track  At baselFirst, we acknowledge the importance of a mixed-method  intervention evaluation approach to provide a more comprehensive and nuanced understanding of research in novel contexts. The absence of any qualitative data to inform interpretation of these results was therefore a limitation of this study. We had in fact planned a qualitative component. However, this study was unexpectedly interrupted by the COVID-19 pandemic, which resulted in all study activities being suspended then pivoting to telehealth, and we were therefore not granted permission to complete qualitative interviews in a timely fashion . HoweverWhile limited by sample size and study design, the questions asked and answered in this proof-of-principle study are important as without information on caregiver and non-specialist coach implementation fidelity and potential child and caregiver impact, larger-scale clinical trials may not be warranted. Task-sharing caregiver coaching to non-specialist providers, who are integrated into existing systems of care, is a key implementation strategy that may support scale-up. Such an approach may be well suited to diverse, low-resource settings with limited supports and services for young autistic children. This approach will likely gain traction over time as stretched systems of care in low resource countries are tasked with supporting not only the physical health but also the developmental needs of all children, including those with developmental disabilities . As noteNow that there is proof-of-principle, larger scale studies are needed to expand on the evidence-base and answer the next set of key questions. It will be important that these studies include the perspectives of diverse stakeholders, including those with lived experience, in their design and implementation. This is an important way to decrease the research-to-practice gap and ensure that end-products are acceptable across stakeholder groups . Moving Lancet Commission for future care and clinical research in autism, this study is a small but critical step toward offering feasible and accessible services and supports, embedded within communities, drawing on local expertise to address the diverse needs of families [This was the first study, to our knowledge, to evaluate a non-specialist delivered cascaded caregiver coaching of an NDBI for autism in Sub-Saharan Africa. We set out to achieve  two specific objectives. The fIrst objective was to determine whether coaching impacted implementation fidelity of both caregivers and non-specialist coaches. All caregivers and non-specialist coaches demonstrated improvements in fidelity scores across coaching sessions. The second objective was to assess whether coaching impacted key short-term child and caregiver outcomes. Significant growth was seen in child social and communication abilities. While most caregivers demonstrated increases in their confidence in ‘parenting’ and ‘parenting satisfaction’, caregiver stress did not show a significant group-based decrease. This study provides a novel contribution to the literature by exploring a potentially scalable coaching intervention in Africa, utilizing a cascaded task-sharing approach delivered within an existing system of care. In keeping with the proposals set out in the families  This stufamilies , 15, 59.


In 2020, due to the COVID-19 pandemic, the European Centre for Disease Prevention and Control (ECDC) accelerated development of European-level severe acute respiratory infection (SARI) surveillance.We aimed to establish SARI surveillance in one Irish hospital as part of a European network E-SARI-NET.We used routine emergency department records to identify cases in one adult acute hospital. The SARI case definition was adapted from the ECDC clinical criteria for a possible COVID-19 case. Clinical data were collected using an online questionnaire. Cases were tested for SARS-CoV-2, influenza and respiratory syncytial virus (RSV), including whole genome sequencing (WGS) on SARS-CoV-2 RNA-positive samples and viral characterisation/sequencing on influenza RNA-positive samples. Descriptive analysis was conducted for SARI cases hospitalised between July 2021 and April 2022.Overall, we identified 437 SARI cases, the incidence ranged from two to 28 cases per week . Of 431 cases tested for SARS-CoV-2 RNA, 226 (52%) were positive. Of 349 (80%) cases tested for influenza and RSV RNA, 15 (4.3%) were positive for influenza and eight (2.3%) for RSV. Using WGS, we identified Delta- and Omicron-dominant periods. The resource-intensive nature of manual clinical data collection, specimen management and laboratory supply shortages for influenza and RSV testing were challenging.We successfully established SARI surveillance as part of E-SARI-NET. Expansion to additional sentinel sites is planned following formal evaluation of the existing system. SARI surveillance requires multidisciplinary collaboration, automated data collection where possible, and dedicated personnel resources, including for specimen management. What did you want to address in this study?In this study, we wanted to describe how we established sentinel surveillance of severe acute respiratory infection (SARI) in an Irish hospital, to outline the structures, processes and resources that are required for sustainable SARI surveillance, and to bring attention to the public health benefits of SARI surveillance data. We hope that our study helps to guide other countries to establish SARI surveillance.What have we learnt from this study?Implementing SARI surveillance is challenging. Multidisciplinary collaboration and communication, automating data collection and linkage of datasets where possible are important, as is ensuring that dedicated resources are in place for each step of the surveillance and sample management workflow.What are the implications of your findings for public health?Surveillance of SARI is important for public health in Ireland. The data are used at hospital and national level to assess the impact and burden of respiratory viruses, to inform public health services planning, and for pandemic preparedness and response. The data are included in a weekly national surveillance report, a weekly European surveillance report, and in European SARI, COVID-19 and influenza vaccine effectiveness monitoring.With the co-circulation of respiratory viruses, especially during winter, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and possibilities for new respiratory pathogens in the future, it is increasingly important to monitor severe acute respiratory infections (SARI) for preparedness and emergency response to national and cross-border public health threats. Population-level SARI surveillance has long been recommended by international agencies ,2 and inSetting up and maintaining a robust SARI surveillance system is challenging and requires multidisciplinary collaboration and considerable resourcing to collect information from various sources ,5. In 20Developing the pilot SARI surveillance system in Ireland was an iterative process; data sources were explored with hospital stakeholders, and data collection and management processes were continually streamlined.The study, initiated by the Health Service Executive (HSE) Health Protection Surveillance Centre (HPSC) in December 2020, was conducted in Saint Vincent’s University Hospital (SVUH), a 484-bed tertiary adult hospital in the Dublin metropolitan area, one of 48 public hospitals in Ireland. The emergency department is the major trauma centre for the South East Dublin region, the hospital catchment area covered 7.5% of the estimated population of Ireland for 2021 (based on the 2016 census of Ireland), a population of 304,145 persons aged 15 years and older. The study population was persons aged 15 years and older admitted to the emergency department.A multidisciplinary team was established, comprising teams from key hospital departments .To address resource challenges caused by high workloads and competing priorities during the COVID-19 pandemic, dedicated SARI surveillance personnel were recruited using funding provided by ECDC to support initial system development. Dedicated personnel included a research nurse for clinical data collection and an epidemiologist co-located between SVUH and HPSC to coordinate laboratory testing and data management.Guidance was provided to HPSC by ECDC and Epiconcept, who coordinated the European-level project. A specialist in public health medicine and a senior epidemiologist at HPSC coordinated and supervised the project in Ireland, and the pilot project was established by a fellow from the European Programme for Intervention Epidemiology Training (EPIET).Surveillance was undertaken in accordance with Article 9 of the General Data Protection Regulations (GDPR) 2018 , which pWe collected variables in line with the ECDC SARI protocol and included: age, sex, occupation, pregnancy, smoking, employment and healthcare worker status, obesity, COVID-19/influenza vaccination status, symptoms at/before admission, pre-existing chronic conditions, prior hospitalisation, prior SARS-CoV-2 test positivity, hospital and intensive care unit (ICU) admission and discharge dates, medications, respiratory support, complications, outcome, and laboratory test results for SARS-CoV-2, influenza and RSV.Symptoms, demographics, administrative and clinical data were captured in electronic information systems and/or physical medical charts and required manual data extraction. Hospital laboratory data were extracted in electronic reporting format. Molecular and whole genome sequencing (WGS) data were provided in electronic format by the National Virus Reference Laboratory (NVRL). Records of COVID-19 vaccination were available in electronic format from the National COVID-19 Vaccination System (COVAX) but required data linkage. Ireland does not have an electronic national immunisation system for all vaccines; influenza vaccine records were sourced from the HSE Primary Care Reimbursement Service (PCRS).Denominator data for the hospital catchment area, provided by the HSE Health Intelligence Unit, were based on geographical boundaries and 2021 population projections estimated by Ireland’s Central Statistics Office . The numActive surveillance and data collection commenced in July 2021, 7 months after initiation, during which time the system was designed and field tested. For the first 7 weeks of surveillance, we used the World Health Organization (WHO) SARI case definition to identify cases: a person who had an acute respiratory infection with a history of fever or measured fever of ≥ 38 °C and cough and onset within the last 10 days and who required hospitalisation . During Patients whose SARI symptoms were not evident in the emergency department, for example patients with hospital-acquired SARI or patients with SARI who were admitted to SVUH from other hospitals, were not captured in the surveillance system. Deaths recorded were all-cause in-hospital deaths.The surveillance workflow  was as fPatients admitted through the emergency department were screened on weekdays, with weekend admissions screened on Monday. We searched electronic triage notes for keywords; fever, cough, lower respiratory tract infection (LRTI), shortness of breath, pneumonia, COVID-19, influenza and RSV. Anosmia, ageusia and dysgeusia were not included. Those meeting the screening criteria were reviewed clinically.A daily COVID-19 inpatient list provided by SVUH to medical teams was checked for SARI cases potentially missed at screening. Daily inpatient lists for influenza and RSV were not available, but influenza-positive laboratory records were checked periodically.We assigned a unique identifying code to the identified cases and added them to a master log using Microsoft Excel software. The master log included the patient’s hospital medical record number (MRN) and was checked for prior SARI admissions to SVUH since the beginning of the study. Collected clinical data were manually entered into an online questionnaire using REDCap (Research Electronic Data Capture), a secure, web-based software platform ,12.Molecular investigation for SARS-CoV-2, influenza and RSV RNA was performed for SARI cases using nasopharyngeal samples collected within 48 h of admission, coordinated by the clinical team. Commercial assays were used, including the multiplex GeneXpert Xpress assay  for simultaneous SARS-CoV-2, influenza and RSV testing. Molecular results were linked to clinical data from the online questionnaire using Microsoft Access software.Specimens with a quantification cycle (Cq) value < 25 for SARS-CoV-2 RNA were referred weekly to the NVRL for WGS. Specimens PCR-positive for influenza were referred to the NVRL for confirmation and viral characterisation, those with Cq ≤ 30 were referred for influenza sequencing.Weekly reporting of disaggregate data to HPSC commenced in September 2021. SARI hospital records were linked to vaccination and molecular data from sources described previously. Deaths were validated using records of the General Register Office (GRO). As there was no unique patient identifier across all health datasets, we conducted linkage using personal data and matching algorithms. Linkage to COVID-19 vaccination data was established in December 2021 and was conducted retrospectively by the HSE Information Integrated Service Team and validated by HPSC. Data were transformed to the reporting format for The European Surveillance System (TESSy) using R statistical software . A weeklDescriptive analysis was conducted for SARI cases hospitalised between 5 July 2021 and 3 April 2022, which included a 6-month pilot period and 3 months post-pilot period. Data were extracted for analysis on 30 May 2022.Overall, 437 SARI cases were identified between 5 July 2021 and 3 April 2022, representing 3.7%  of all-cause admissions to the hospital, via the emergency department. The SARI case numbers ranged from two cases in week 27 of 2021 (week starting 5 July 2021)  to 28 cases in week 13 of 2022 (week starting 27 March 2022)  . Only onOverall, 229 (52%) cases were male, median age was 71 years (interquartile range (IQR): 53–82 years) . The mosOf 401 cases identified using our updated case definition (between 27 August 2021 and 3 April 2022), 55 (14%) did not have a cough, and 212 (53%) did not have a fever and did not meet the WHO SARI case definition. Most of those without cough  had SARS-CoV-2 RNA detected, four (7.3%) had influenza RNA detected, and none had RSV RNA detected. Ninety-four (44%) of those without fever had SARS-CoV-2 RNA detected, eight (3.8%) had influenza RNA detected, and four (1.9%) had RSV RNA detected.The vast majority  of the 437 cases had at least one pre-existing chronic condition; most commonly hypertension  and heart disease , while 91 (21%) developed pneumonia. Respiratory support was provided to 233 (53%) cases, 19 (4.3%) cases received invasive ventilation. Twenty-four (5.5%) cases had at least one ICU stay. At the time of data extraction, 336 (77%) cases had been discharged home or to other facilities , 55  cases were tested for SARS-CoV-2 RNA and six (1.4%) were not tested. Of those tested, 226 (52%) had SARS-CoV-2 RNA detected, 190 (44%) had not, and 15 (3.5%) were classified as low-level SARS-CoV-2 RNA detected (Cq ≥ 30). In total, 349 (80%) cases were tested for influenza and RSV RNA and 88 (20%) were not tested (for reasons outlined below). Of those tested, 15 (4.3%) had influenza A detected (13 were influenza A(H3) and two were not subtyped), influenza B was not detected in any specimen, and eight (2.3%) had RSV RNA detected.Two (0.6%) influenza-positive SARI cases were co-infected with SARS-CoV-2, and one (0.3%) RSV-positive case was co-infected with SARS-CoV-2. Of 349 cases tested for all three pathogens, 145 (42%) were negative for all three. Trends in laboratory results are shown in We conducted WGS for 130 (58%) SARI cases with SARS-CoV-2 RNA detected at an adequate viral load. Overall, 63 (48%) were Delta variants  designation B.1.617.2 and AY lineages) and 67 (52%) were Omicron variants (BA.1 and BA.2 lineages) .Twelve influenza A(H3)-positive samples were genetically characterised, all of which clustered in the A(H3) genetic clade subgroup 3C.2a1b.2a.2, represented by the A/Bangladesh/4005/2020 virus, the predominant subgroup circulating globally during the 2021/22 season. The A/Bangladesh viruses were antigenically diverse from the A(H3)/Cambodia/e0826360/2020 vaccine strain included in the northern hemisphere 2021/22 vaccine .There were multiple challenges in establishing SARI surveillance, these are outlined in the BoxClinical data collectionCollection of clinical data was resource-intensive because medical charts were located on restricted access COVID-19 wards or were in use by other hospital teams.Personnel resources were insufficient during peak periods including the beginning of the COVID-19 Omicron pandemic wave, which started in Ireland on 19 December 2021, and during periods of annual leave.Specimen collection and laboratory testingSARS-CoV-2:Specimens were not collected in hospital for a total of 21 (4.8%) SARI cases. Nine cases had a short hospital length of stay and were discharged before specimens could be collected, reasons why specimens were not collected were unknown for 12. Results of SARS-CoV-2 RNA testing carried out shortly before hospital admission were obtained for 15 of the 21.SARS-CoV-2 WGS could not be conducted for 96 (42%) of the 226 cases with SARS-CoV-2 RNA detected. The Cq values were too high for 52 (23%) and sequences could not be generated for a further four (1.8%).Fourteen (6.2%) specimens were disposed in error before WGS referral, and four (1.8%) were referred to the wrong laboratory.Other issues preventing WGS included the unavailability of specimens for cases investigated for SARS-CoV-2 RNA before hospital admission , and insufficient specimen volume sometimes relating to routine testing for variants of concern (VOC)  which ceased for all SARI specimens in September 2021.Influenza and RSV:Forty-one (9.4%) SARI cases hospitalised before the start of the 2021/22 influenza season, which started in Ireland on 4 October 2021, could not be tested for influenza and RSV because of laboratory supply issues for multiplex kits.For those admitted to SVUH under the COVID-19 care pathway, the request for influenza and RSV testing was not added at the time of sampling but was later added by the SARI team. The laboratory policy to dispose SARS-CoV-2 RNA-negative specimens after 1 week meant that specimens could not be retrieved at a later date for testing, this resulted in disposal of specimens for 19 (4.3%) cases before influenza and RSV testing could be conducted.Specimens for three (0.7%) cases were referred for SARS-CoV-2 WGS before influenza and RSV testing could be conducted.Influenza and RSV analytical quality control failures occurred for the specimens of four (0.9%) cases.Specimens were not collected for the remaining 21 (4.8%) cases as previously mentioned.Cq: quantification cycle; RSV: respiratory syncytial virus; SARI: severe acute respiratory infection; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; WGS: whole genome sequencing.We successfully established a SARI surveillance system in Ireland, using routine emergency department records to identify cases. Contributing factors included, but were not limited to, multidisciplinary collaboration, having a dedicated SARI epidemiologist co-located between the hospital site and HPSC, guidance provided by Epiconcept, which included development of a SARI protocol, and ECDC support including funding allocated to recruit dedicated personnel.Active daily screening and detailed review of clinical records was a strength of the surveillance system, in contrast to passive register-based surveillance in which there may be uncertainties around case classification and where laboratory diagnoses are frequently unavailable . Active The collected data demonstrate that syndromic SARI surveillance can be used to monitor SARI incidence and trends and to provide insights into the burden of respiratory disease arising from detected respiratory infections. We updated our case definition during the study, from the WHO SARI case definition that was developed in 2014 for influenza surveillance  to a casMost SARI cases were tested for SARS-CoV-2 and for influenza and RSV . Laboratory supply issues for influenza and RSV testing before the beginning of the influenza season highlighted the need for laboratories involved in SARI surveillance to have access to supplies through the health service central procurement process throughout the year, even when these pathogens are not widely circulating in the population.Surveillance of SARI provides a different measure of disease activity than national indicator-based and syndromic surveillance systems to monitor respiratory infections. All systems are fundamental to comprehensive surveillance of respiratory diseases, each have different goals and there are some overlaps. Influenza positivity among our SARI cases reflected low influenza activity overall during the 2021/22 influenza season in Ireland and an increase in influenza A virus circulation towards the end of the study period . The ratDevelopment of the surveillance system was not without challenges. Manual clinical data collection was resource-intensive and sensitive to elements beyond the control of the surveillance team, including difficulties obtaining medical charts. To reduce this burden, chart retrieval frequency was reduced to twice per case; once following admission and once following discharge, with variables relating to severity  collected after discharge only. A consequence of delayed data collection for indicators of severity was that they could not be included in trend analyses as they would not reflect the true situation. Resource challenges were heightened during peak periods of virus circulation, particularly the COVID-19 Omicron wave which began in Ireland in December 2021, requiring an additional resource to be recruited to assist with clinical data collection. To achieve sustainable surveillance, clinical data collection should be automated where possible. In Ireland, hospitals have different data infrastructures and methods for storing health data. Hospital information systems should be standardised nationally where possible in the future, and developments including electronic medical records should ensure capability for syndromic surveillance (not limited to SARI). Furthermore, the absence of a unique personal identifier across health datasets resulted in surveillance inefficiencies. Individual health identifiers are a fundamental enabler for such surveillance projects and should be prioritised in Ireland . SpecimeDespite the fact that SARI surveillance currently exists in only one sentinel hospital site, it has proved to be important to public health in Ireland. The SARI data are used at hospital level to assess the impact and burden of respiratory viruses, and at the national level to inform public messaging and planning for winter health services. A surveillance report is published weekly in Ireland , and disWe recommend expansion of SARI surveillance to additional sentinel sites in Ireland at the earliest opportunity, to benefit from the strengthened relationships that followed increased cross-sectoral and intra-sectoral work during the COVID-19 pandemic and from increased interest and perceived need expressed by clinicians in other hospitals for the SARI surveillance data. Benefits of SARI data to patient care could be explored to support integration of surveillance into clinical settings . Before The main limitation of our study was that SARI surveillance was limited to one adult hospital and was not nationally representative. Considerations for future SARI hospital site selection include a paediatric hospital and sentinel site hospitals in other regions. Viral respiratory infections are a frequent cause of hospitalisations in young children, with a considerable proportion caused by RSV and influenza each winter –30. OtheWe successfully established sentinel surveillance of SARI in an Irish hospital as part of a wider European network, with integrated testing for SARS-CoV-2, influenza and RSV RNA. The SARI surveillance data have proved to be important to public health in Ireland, and we recommend that surveillance be expanded to additional sentinel sites at the earliest opportunity, following formal evaluation of the existing system. We re-iterate the importance of unique health identifiers across all health datasets to enable data linkages and recommend implementation as a priority in Ireland. Future scale-up should ensure that SARI data collection be automated where possible and personnel resourcing requirements should not be underestimated, including for sample management.


Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive fatal disease characterized by accumulation of amyloid fibrils composed of misfolded transthyretin (TTR) protein in tissues, resulting in cardiomyopathy and heart failure. Approximately 50,000 people have hereditary ATTR amyloidosis, and up to 500,000 have wild-type ATTR amyloidosis globally, leading to poor quality of life and high morbidity, resulting in death within a median of 2 to 6 years after diagnosis. However, data on the prevalence of ATTR-CM is limited and poorly characterized. NTLA-2001, an in vivo gene-editing therapeutic agent designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum by knocking out the TTR gene, has been shown to be effective, presenting a new therapeutic strategy. However, the safety, tolerability, and pharmacodynamic response to IV NTLA-2001 administration has not been yet demonstrated.Study and results: The first-in-human in vivo CRISPR/Cas9 trial of TTR Gene editing by NTLA-2001 in patients with Transthyretin Amyloidosis and cardiomyopathy was designed to evaluate the safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic responses to IV NTLA-2001 administration and its effect on serum transthyretin (TTR) levels in patients with ATTR amyloidosis and cardiomyopathy. Twelve subjects received NTLA-2001 . Serum TTR levels were reduced from the baseline in all subjects (mean>90% after 28 days). Mean % reductions (+/-SEM) from baseline to day 28 were: NYHA I/II at 0.7 mg/kg = 92% (1%), at 1.0 mg/kg = 92% (2%), and for NYHA III at 0.7 mg/kg = 94% (1%) maintained through 4–6 months. Two of the 12 patients (16.7%) reported a transient infusion reaction. One patient experienced a grade 3 infusion-related reaction that resolved without any clinical sequelae.Lessons learned: This study showed a significant and consistent reduction in serum TTR protein levels after a single admission, while being generally well tolerated, representing a potential new option for the treatment and improvement of the prognosis of cardiac ATTR amyloidosis. Further research into the long-term safety and efficacy of NTLA-2001, particularly in higher-risk patients, including continued monitoring of whether knockout of the TTR gene results in sustained TTR reduction over the long term, is essential. Evaluation of the potential effects of markedly reduced TTR levels on patients’ clinical outcomes, with a focus on functional capacity, quality of life, and mortality benefits are essential. The analysis of the use of this technology for an array of other diseases is vital. Hereditary ATTR amyloidosis (hATTR), triggered by more than 100 different pathogenic mutations in TTR7, has a clinical phenotype dominated by amyloid polyneuropathy or cardiomyopathy, with most patients having a combination of the two5, 6, 8.Wild-type (acquired) ATTR amyloidosis (wATTR), the more common type of ATTR is an acquired condition with an unknown underlying cause that results commonly in cardiomyopathy and is an increasingly recognized cause of heart failure9, 10. Transthyretin amyloid cardiomyopathy (ATTR-CM) leads to poor quality of life, high morbidity, and results in death within a median of 2 to 6 years after diagnosis11. In the case of amyloid polyneuropathy in the absence of cardiomyopathy, life-expectancy increases to up to 17 years12.It is estimated that globally 50,000 persons have hereditary ATTR amyloidosis, and up to 500,000 have wild-type ATTR amyloidosis13, 14. However, data on the prevalence of ATTR-CM are limited and not well characterized15 due to missed and delayed diagnosis16 related to the heterogeneous clinical presentation17–25 and mainly because of a lack of sensitive diagnostic modality. Advancements in nuclear cardiac imaging with technetium pyrophosphate scan are leading to a more sensitive diagnosis of ATTR-CM, without cardiac biopsy26.Recent studies suggest that ATTR-CM is responsible for 20% of heart failure (HF) cases presenting with increased myocardial wall thickening ≥14 mm27. Wild-type ATTR is possibly related to the aging process as there is an absence of TTR mutation28 and the prevalence increases with older age28, 29.The TTR gene is present on chromosome 18. hATTR follows an autosomal dominant inheritance pattern; however, disease penetrance is more complicated and less understood. The age of onset of clinical disease in hATTR-CM varies widely and depends on the type of mutation, which has varied geographical distributionTTR gene and age-related changes in the structure of the TTR peptide can cause misfolding of the TTR protein, forming insoluble fibers and resulting in amyloid deposits that disrupt normal organ function and lead to progressive organ failure.Mutations in the In the heart, they occupy interstitial spaces in the myocardium, making it stiff and rigid. TTR deposition causes further myocardial fibrosis and eventually affects its mechanical function. Due to TTR deposition, the myocardium appears thickened and hypertrophied on cardiac imaging.30. Diastolic dysfunction causes an increase in left ventricular end-diastolic pressure and left atrial pressure. Persistently increased left atrial pressure and left atrial dilatation increases the likelihood of developing atrial arrhythmias. Myocardial infiltration also affects the electrical conduction system, resulting in conduction disorders31 as ventricular arrhythmias32.Compromise in ventricular compliance initially causes diastolic dysfunction. In advanced stages, myocardial dysfunction can result in globally reduced systolic function33, postpone progression, relieve symptoms, and prolong survival  and combined Cas9 (Cas9 endonuclease) system comprises a lipid nanoparticle (LNP) encapsulating mRNA for Cas9 protein and a single guide RNA targeting the TTR gene40. The CRISPR/Cas9 gene-editing technology41 allows the genome to be altered by causing a double-stranded DNA break42.Recently, clinical trials investigating chronic therapy with gene silencing agents targeting mRNA have shown that lowering TTR protein levels results in cardiac benefits. NTLA-2001 is an in vivo gene-editing therapeutic agent designed to treat ATTR amyloidosis by reducing the concentration of TTR in the serum by knocking out the 43.NTLA-2001, administered by a single intravenous infusion, is taken up by LDL receptors on hepatocytes, followed by endocytosis of the particle. The Cas9 mRNA is translated into the cytoplasm. The formed Cas9 protein subsequently interacts with the sgRNA targeting the TTR gene. This complex enters the nucleus, where the sgRNA binds to the complementary sequence of the DNA. Endogenous DNA repair subsequently leads to indels in the TTR gene that prevent the production of the TTR protein. Importantly, knock out of the gene coding the TTR protein minimally affects the normal physiological processes 43.40 providing clinical proof of concept for in vivo CRISPR-Cas9–mediated gene editing as a therapeutic strategy. However, the safety, tolerability, and pharmacodynamic response to IV NTLA-2001 administration to knock out the TTR gene and reduce serum TTR in subjects with ATTR amyloidosis with cardiomyopathy has not yet been demonstrated.In a small group of patients with hereditary ATTR amyloidosis and polyneuropathy, administration of NTLA-2001 led to decreases in serum TTR protein concentrations through targeted knockout of TTR with only mild adverse events45–47.This study presents the first-in-human in vivo CRISPR/Cas9 (phase 1) trial (NCT04601051) of TTR Gene editing by NTLA-2001 (Intellia/Regeneron) in patients with Transthyretin Amyloidosis and cardiomyopathyThe study is part of a two-part, open-label, multi-center Phase I randomized clinical trial designed to evaluate the safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic response to IV NTLA-2001 administration and its effect on serum transthyretin (TTR) levels in patients with ATTR amyloidosis with cardiomyopathy. The primary endpoints included adverse events, dose-limiting toxicities, and changes from baseline serum TTR levels at seven days to six months post-infusion.A total of 12 patients  were enrolled in the cardiomyopathy arm of the NTLA-2001 phase 1 study. Enrolled patients had either hereditary transthyretin amyloidosis with cardiomyopathy (hATTR-CM) or wild-type cardiomyopathy (wATTR-CM) and NYHA class I to III. All patients received a single dose of NTLA-2001 administered via intravenous infusion.Two doses (0.7 mg/kg and 1.0 mg/kg) were evaluated in subjects with NYHA Class I/II heart failure and one dose (0.7 mg/kg) in subjects with NYHA Class III heart failure.Circulating serum TTR was measured in samples collected at baseline, days 7, 14, and 28, and at pre-determined time points thereafter until study completion .Twelve subjects received NTLA-2001 .Serum TTR levels rapidly and profoundly reduced from baseline in all subjects (mean >90% at 28 days). Mean % reductions (+/-SEM) from baseline to day 28 were: NYHA Class I/II at 0.7 mg/kg = 92% (1%), at 1.0 mg/kg = 92% (2%), and for NYHA Class III at 0.7 mg/kg = 94% (1%) . This reTwo of the 12 (16.7%) patients reported transient infusion reactions, which were the only observed treatment-related adverse events. One patient with NYHA class III who received a dose of 0.7 mg/kg experienced a grade 3 infusion-related reaction, which resolved without any clinical sequelae. No other patients reported a treatment-related adverse event. No clinically significant laboratory abnormalities were observed at either dose level.In this first-ever human trial of gene editing in vivo, a single intravenous infusion of NTLA2001, the novel CRISPR/Cas9-based gene editing therapy, significantly reduced circulating transthyretin (TTR) protein levels in patients with ATTR amyloid cardiomyopathy. All patients achieved over 90% reduction in serum TTR levels by day 28, sustained through 4–6 months, regardless of baseline NYHA class, indicating consistent and durable TTR reduction at both 0.7 and 1.0 mg/kg doses of NTLA-2001.Moreover, NTLA-2001 gene editing therapy was generally well tolerated, with mild and transient infusion reactions being the only adverse events observed, with no clinically significant laboratory findings after infusion.40; however, there were no significant adverse events.Reductions in TTR levels over 90% in this trial were achieved with higher doses than those used in the previously reported polyneuropathy arm of the study48–50, which is a disadvantage compared to the single-dose admission of NTLA-2001.Recently, the APOLLO-B trial of patisiran in patients with ATTR amyloidosis with cardiomyopathy showed an average 87% serum TTR level reduction, but with the need for intravenous infusions every 3 weeks, life-long51, which has been addressed with a very rigorous process when selecting the guide RNA, targeting the specificity of the TTR gene. Furthermore, various studies using primary human hepatocytes found no evidence of off-target editing52, 53 at concentrations of NTLA-2001 that were threefold greater than the concentration used to knock down the protein by 90%54, indicating that the specificity of NTLA-2001 for the TTR gene seems to be absolute.One possible concern regarding the use of CRISPR technology in humans is the potential for off-target effects45, 46.The limitation to the interpretation of the current study is that it presents only the initial data of a Phase 1 dose escalation study in a small cohort of patients from which no dosing guidelines or long-term data can be deduced. Consequentially, the dose-expansion portion of the study (Part 2) which will inform the dose selection for subsequent pivotal studies is to be completed by the end of 2022Overall, the significant and consistent reductions in serum TTR protein levels observed in this study indicate that IV NTLA-2001 is a potential new treatment option that may stop disease progression in patients with ATTR amyloid cardiomyopathy and potentially improve prognosis and mortality.Further research into the role of CRISPR in ATTR therapy is crucial for establishing a permanent cure for this disease. Larger studies are needed to analyze the long-term safety and efficacy of NTLA-2001 admissions, particularly in high-risk patients, such as those in NYHA class III. Continued monitoring of whether knockout of the TTR gene results in sustained long-term TTR reduction is essential. In addition, the potential effects of markedly reduced TTR levels on patients’ clinical outcomes were evaluated, with a focus on functional capacity, quality of life, and mortality benefits.The data obtained in this study demonstrate promising perspectives for CRISPR and Cas9-based in vivo gene editing in humans. The use of this technology for an array of other diseases should be analyzed, not only to knock out the expression of harmful protein products, but also to insert genes to produce functional proteins where mutations cause pathologic deficiencies.This first-ever human trial with the investigational CRISPR/Cas9-based in vivo gene editing therapy NTLA-2001 showed a significant and consistent reduction in serum TTR protein levels after a single admission and was generally well tolerated, representing a potential new option for the treatment and improvement of prognosis of cardiac ATTR amyloidosis.Further research into the long-term safety and efficacy of NTLA-2001 is necessary, particularly in higher-risk patients, such as those in NYHA class III. Continued monitoring of whether knockout of the TTR gene results in sustained TTR reduction over the long term is required. Evaluation of the potential effects of markedly reduced TTR levels on patients’ clinical outcomes, with a focus on functional capacity, quality of life, and mortality benefits are essential.The data provided in this study demonstrates promising perspectives for CRISPR and Cas9-based in vivo gene editing in humans, and should inspire analysis of the use of this technology for an array of other diseases.


Non-functioning pituitary adenomas (NFPAs) may present with hypopituitarism, and patients may develop or continue to exhibit hypopituitarism following surgery or radiotherapy to treat NFPAs. Panhypopituitarism is characterised as a deficiency in most or all pituitary hormones. Prediction of post-intervention hypopituitarism is currently limited, with no accurate models existing for medium- to long-term prognosis. The aim of this study was to develop machine learning (ML) models towards improving prediction of hypopituitarism up to 15 years following surgical intervention for NFPAs. Pre-operative hormone levels were shown to be the best predictor of panhypopituitarism up to 1 year post-operatively. Endocrine tests performed up to 1 year post-operatively were shown to support strong predictive models for assessing the probability of panhypopituitarism at 5 and 10 years post-operatively.Post-operative endocrine outcomes in patients with non-functioning pituitary adenoma (NFPA) are variable. The aim of this study was to use machine learning (ML) models to better predict medium- and long-term post-operative hypopituitarism in patients with NFPAs. We included data from 383 patients who underwent surgery with or without radiotherapy for NFPAs, with a follow-up period between 6 months and 15 years. ML models, including k-nearest neighbour (KNN), support vector machine (SVM), and decision tree models, showed a superior ability to predict panhypopituitarism compared with non-parametric statistical modelling , with SVM achieving the highest performance . Pre-operative endocrine function was the strongest feature for predicting panhypopituitarism within 1 year post-operatively, while endocrine outcomes at 1 year post-operatively supported strong predictions of panhypopituitarism at 5 and 10 years post-operatively. Other features found to contribute to panhypopituitarism prediction were age, volume of tumour, and the use of radiotherapy. In conclusion, our study demonstrates that ML models show potential in predicting post-operative panhypopituitarism in the medium and long term in patients with NFPM. Future work will include incorporating additional, more granular data, including imaging and operative video data, across multiple centres. Non-functioning pituitary adenomas (NFPAs) are well-differentiated tumours arising from adenohypophysis of the pituitary gland, accounting for up to 54% of all pituitary adenomas . ClinicaHypopituitarism is defined as a deficiency of one or more pituitary hormones. A substantial number of patients with NFPAs develop a degree of hypopituitarism due to mechanical compression of the pituitary gland and reduction of pituitary portal circulation ,5. In adPrevious studies have demonstrated the application of machine learning (ML) models in predicting individual pituitary hormone deficiencies immediately following transsphenoidal surgery for NFPAs . The aimEthics approval to conduct this study was obtained from Westminster Research Ethics Committee on 7 April 2020. The Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Statement was used in the preparation of this manuscript . This stPatients with severe growth hormone (GH) deficiency on dynamic testing (peak GH response < 3 µg/dL) or those on GH-replacement therapy were defined as GH-deficient . PatientData were collected in Microsoft Excel before being imported into a series of Python scripts for analysis and visualisation (Python 3.9.7 64-bit|Windows 10). Key libraries used were pandas (v1.3.4), numpy (v1.20.3), sklearn (v1.1.2), and matplotlib (v3.4.3), and seaborn (v0.11.2) for visualisation. Conversion of text, numbers, and dates took place to ISO standard data types where possible.For initial analysis, connections between surgeries and hormone deficiencies were investigated to draw broad connections between tumour behaviour following intervention and endocrine outcomes. Due to the established impact of radiotherapy on hormone deficiencies , an effeIn preparation for the application of ML algorithms, more sophisticated timelines were created for each patient for endocrine and radiological outcomes. These timelines were necessary in order to provide a chronology of endocrine and radiological findings granular enough to provide clinical insight and standardised for analysis across the full patient population. An example of the logic used is shown in For the application of ML algorithms, the endocrine and radiological outcome timelines were then filtered to focus the analysis. To maximise clinical relevance, hormone periods were restricted to the first 5 years following the first surgery. ML algorithms were applied to each subsequent radiological period, up to a maximum of 15 years. All hormone deficiencies were investigated, including the compound conditions for panhypopituitarism, and panhypopituitarism combined with AVP deficiency. Again, for clinical purposes, radiological outcomes were filtered to remove secondary outcomes . Finally, supplementary features within the source data then had the option of being added to the ML dataset, normalising where appropriate . Any features with only two possible values , were reduced to a single Boolean feature. Features with multiple results , were converted to two features for each possible result . This ensured that potential missing data points , did not add bias in the ML models, allowing the developed algorithms to select for both the existence of a result and the absence of the same result in determining the best predictive model.ML classification algorithms were applied with the aim of predicting post-operative panhypopituitarism up to 15 years following first surgery. Algorithms tested were simple logistic regression, k-nearest neighbour (KNN), support vector machine (SVM), and decision trees. These algorithms were selected due to their comparative strength in classification models over small datasets . Due to To account for potential model instability, each algorithm was run 20 times, varying the random seed each time, with all associated metrics assessed as the mean and standard deviation of the resulting output. Results of the algorithms were assessed against the best predictive capability for panhypopituitarism at 6 months, 1 year, 5 years and 10 years post-operatively. For the decision tree algorithm, results were captured for feature importance, using the GINI index, allowing extraction of the most influential features for each outcome period.Simple population statistics for the patient cohort are shown in p = 0.001) and older patients (p = 0.005).Pre-operatively, 235 patients (61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men , and rose to 55 patients in the period immediately following surgery (14.4% of the population). This figure decreased marginally over the period 6–24 months after surgery, to a minimum of 49 patients, before steadily rising to 57 patients 10 years after initial surgery. ML models showed strong performance in predictions of panhypopituitarism up to 15 years following initial surgery, with the strongest-performing models being SVM  and decision tree . Both SVM and decision tree models exhibited stronger predictive capability than standard logistic regression .The decision tree model showed strong performance in predicting panhypopituitarism up to 1 year following initial surgery, based upon endocrine profiles taken pre-operatively. On analysis of feature importance within the model, only pre-operative presentation of panhypopituitarism showed a strong contribution , with weaker contributions from patient age and tumour volume. The same model showed strong performance in the prediction of panhypopituitarism at 5 and 10 years following initial surgery, based upon endocrine profiles taken 1 year post-operatively. For these periods, only the prior presentation of panhypopituitarism (with or without AVP deficiency) contributed strongly to the model , with weak contribution from follow-up intervention with radiotherapy.A recent study by Fang et al. , the onlML models have been shown to provide stronger predictive performance than standard statistical methods when assessing patients’ prognosis for hypopituitarism following surgical intervention to treat NFPAs. Investigation of a feature-rich patient dataset (383 cases), including population demographics, endocrine assessment, treatment modalities and results, and radiology scan results, indicated prior presentation of panhypopituitarism as the strongest predictor of post-operative panhypopituitarism. Minor influence was observed from the patient’s age, tumour volume, and post-operative treatment with radiotherapy. ML models can be employed to predict endocrine outcomes in pituitary adenomas as demonstrated in this study. Further research is needed to develop accurate and reliable ML algorithms to aid in identifying prognostic markers in pituitary adenomas. Patients with pre-operative pituitary impairment in NFPAs are at a higher risk of persistent hypopituitarism following surgery or in combination with radiotherapy. This cohort of patients requires long-term endocrine monitoring to optimise hormone replacement and overall outcome.


Approximately 32,000 cases are diagnosed each year, and 150,000 people are living with MM in the United States.4 Unfortunately, most patients eventually relapse; patients with relapsed or refractory MM (RRMM) often cycle through different combinations of available agents. When a patient’s disease is no longer responding to agents in each of these classes, the disease is referred to as “triple-class refractory” MM (TCRMM).4 Response rates to existing, later-line therapies are relatively low, underscoring the need for new treatment options in this heavily pretreated population.Current treatment of MM typically includes 3 general classes of drugs: immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies.The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of 3 new treatments targeting the B-cell maturation antigen (BCMA) for heavily pretreated patients with RRMM. BCMA is preferentially expressed on plasma cells, making it an attractive therapeutic target for MM. Belantamab mafodotin blmf  is an antibody drug conjugate, with a monoclonal antibody to BCMA linked to a cytotoxic drug. Belantamab was studied in patients with heavily pretreated (6-7 previous lines of therapy) TCRMM . Idecabtagene vicleucel  and ciltacabtagene autoleucel  are chimeric antigen receptor (CAR) T-cell therapies, involving engineering a patient’s own T cells to target BCMA.Ide-cel and cilta-cel were studied in patients who were mostly TCRMM (majority triple- or quad-refractory patients). Belantamab was approved by the US Food and Drug Administration (FDA) for RRMM in August 2020; idecel was approved in March 2021; and cilta-cel was granted fast track designation and has a Prescription Drug User Fee Act (PDUFA) target action date of November 29, 2021.https://icer.org/assessment/multiple-myeloma-2021/. In this review, we present the summary of our findings and highlights of the policy discussion with key stakeholders held at a public meeting of the Midwest Comparative Effectiveness Public Advisory Council on April 16, 2021. In addition, new data for cilta-cel has become available since that meeting and is highlighted here.Complete details of ICER’s systematic literature search and protocol, as well as the methodology and model structure for the economic evaluation, are available on ICER’s website at 6 Our review also evaluated information from conference abstracts, regulatory documents, and data submitted by the manufacturers.The systematic literature review identified only 2 open-label, single arm phase 1/2 studies of the CAR-Ts (one each for ide-cel and cilta-cel) and 1 open-label phase 2 study of belantamab, making indirect comparisons of relative effectiveness impossible. At the time of the review, only the pivotal trials of ide-cel and belantamab had been published.5 The pivotal trial of belantamab included patients who were older, had undergone more pretreatment, and were more likely to have high-risk cytogenetics compared with the patient populations in the CAR-T trials.6 A key difference between the pivotal CAR-T therapy trials and the belantamab trial was the approach for inclusion in the outcomes analysis. The CAR-T trials only included patients who were infused in the analysis in an “as-treated” approach, whereas the belantamab trial reports on the full intention-to-treat (ITT) population. At the time of this publication, only interim, unpublished data on cilta-cel was available.6The pivotal trials of ide-cel and cilta-cel included similar distributions of baseline characteristics (such as age and previous lines of therapy); however, the ide-cel trial included more patients with extramedullary disease (a marker of more aggressive disease) and high-risk cytogenetics.7In the pivotal trial of ide-cel, with a median follow-up of 13.3 months, as-treated median progression-free survival (PFS) and overall survival (OS) were 8.8 months and 19.4 months, respectively. Using an ITT approach, 94 of 149 enrolled patients (63%) achieved an overall response to treatment . Twelve-8 With a median follow-up of 18 months, median PFS and OS had not been reached. Ninety-five of 126 enrolled patients (75%) achieved an overall response  were 2.8 and 13.7 months, respectively. Thirty-one of 97 enrolled patients (32%) achieved an overall response . Twelve-10 The median duration of CRS symptoms was 4 to 5 days and were most likely to be managed with tocilizumab or corticosteroids. In the pivotal ide-cel trial, 3 deaths (2%) were treatment related  within 8 weeks of infusion, and an additional death from pneumonia was reported within 6 months of infusion. In the pivotal cilta-cel trial, 6 deaths (6%) were related to treatment .In the pivotal trials of ide-cel and cilta-cel, the most important adverse events (AEs) included cytokine release syndrome (CRS), neurotoxicity, and thrombocytopenia. CRS of any grade was reported by 84% and 95% of patients in the ide-cel and cilta-cel trials, respectively.6In the pivotal trial of belantamab, AEs were reported by 98% of patients, of which 88% were related to treatment. Nine patients (10%) discontinued due to AEs. The most important treatment-related AE was keratopathy (a disease of the cornea), reported by 72% of patients; however, at 13 months follow-up, the majority had recovered. A decline in vision in their better-seeing eye to 20/50 or worse was reported by 18%, but no patients had permanent vision loss. One death (1%) was treatment related (due to sepsis).The primary limitations in the clinical evidence include the lack of data from randomized controlled trials and limited follow-up time. The lack of head-to-head comparative data near the time of launch is not unexpected but makes even indirect comparisons needed to guide judgments of relative effectiveness highly uncertain.Differences in study populations between the single arm trials and in assessing and reporting outcomes further complicate the comparability of the trial results. Although outcomes of ide-cel and cilta-cel show response rates that are better than currently available treatments, there continues to be considerable uncertainty about their long-term efficacy and concerns about potential safety issues. One potential advantage of the CAR-T therapies is the ability for patients to be off treatment for extended periods; however, long-term data are needed to confirm if this holds true over time. The pivotal trial of ide-cel included retreatment, but it is unclear if standard of care for CAR-Ts will include retreatment. For belantamab, the trial data suggest similar response rates to existing therapies, but its use is associated with potentially serious ocular side effects.12 Belantamab, cilta-cel, and ide-cel were compared with a triple- or quad-refractory MM comparator market basket that was derived from a contemporaneous observational study of similar patient populations.13 For the CAR-T therapies, an initial decision tree was used to calculate the costs and consequences from treatment initiation  to T-cell infusion.We developed a de novo decision analytic model for the evaluation of treatments for heavily pretreated MM patients. Our model was informed by key clinical trials, previous relevant economic models, as well as by stakeholder input.https://icer.org/wp-content/uploads/2020/10/ICER_Multiple-Myeloma_Final-Report_Update_070921.pdf.Outcomes of interest included total life-years (LYs) gained, quality-adjusted life-years (QALYs) gained, equal value life-years gained (evLYG), time spent in progression free state/responding to treatment, and total costs for each intervention over a lifetime time horizon discounted at 3% per annum. Full details on ICER’s cost-effectiveness analysis and model are available on ICER’s website at The base-case findings suggest that CAR-T therapies provide clinical benefit for this population, with gains in both QALYs and OS over current treatment options. Model findings across all interventions were sensitive to the cost of comparators, PFS and OS estimates, quality of life related to PFS (on and off treatment), and overall health care costs for MM patients.The incremental cost-effectiveness ratios for ide-cel vs the MM comparator market basket were approximately $319,000 per QALY gained, $250,000 per LY gained, $280,000 per evLYG gained, and $35,000 per additional PFS month gained. Incremental cost-effectiveness ratios for cilta-cel vs the MM comparator market basket were updated with newly released 18-month trial data and found approximately $253,000 per QALY gained, $207,000 per LY gained, and $228,000 per evLYG gained.Base-case findings for belantamab suggest that current list pricing is within commonly cited cost-effectiveness thresholds when compared with a triple-, quad-, or penta-refractory MM market basket. However, small changes in any of the key model inputs changed the belantamab model findings to a significant extent, so our results should be viewed with caution. https://icer.org/wp-content/uploads/2020/10/ICER_Multiple-Myeloma_Final-Report_Update_070921.pdf.The ICER health benefit price benchmark (HBPB) is a suggested price range based on cost-effectiveness thresholds at the $100,000 and $150,000 per QALY and per evLYG. The annual HBPB for ide-cel ranged from $192,000 to $265,000. The annual HBPB for cilta cel ranged from $230,000 to $312,000. The HBPB for belantamab ranged from $8,300 to $9,500 per vial. Full results are available on ICER’s website at Considering that evidence was abstracted from single-arm studies, it was difficult to obtain data for a suitable comparator, and significant uncertainty remains regarding how these treatments would compare head-to-head to current best usual care. Furthermore, given that the treatment landscape changes dramatically over short time periods in RRMM and the lack of a quantitative indirect treatment comparison to inform these analyses, caution should be used when interpreting cost-effectiveness estimates, particularly for the cilta-cel results.The Midwest Comparative Effectiveness Public Advisory Council (CEPAC) is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical and cost-effectiveness of health care interventions. The Midwest CEPAC is composed of medical evidence experts, including practicing clinicians, methodologists, and leaders in patient engagement and advocacy. Their deliberation includes input from clinical experts and patient representatives specific to the condition under review, as well as formal comment from manufacturers and the public. A policy roundtable concludes each meeting during which representatives from insurers and manufacturers join clinical experts and patient representatives to discuss how best to apply the findings of the evidence to clinical practice, insurance coverage, and pricing negotiations.not adequate to demonstrate that the net health benefit of belantamab mafodotin is superior to that provided by usual care; (2) the panel voted 15-0 that the evidence was adequate to demonstrate that the net health benefit of ide-cel is superior to usual care; (3) the panel voted 13-2 that the evidence was adequate to demonstrate that the net health benefit of cilta-cel is superior to usual care; and (4) the panel voted 15-0 that the evidence was not adequate to distinguish the net health benefit of ide-cel from cilta-cel.The ICER report on treatments for heavily pretreated RRMM was the subject of a Midwest CEPAC meeting on April 16, 2021. Following the discussion, the Midwest CEPAC panel members deliberated on key questions raised by ICER’s report. The results of their votes on the clinical evidence were as follows: (1) the panel voted 10-5 that the evidence was The CEPAC panel also voted on “other potential benefits” and “contextual considerations” as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money not adequately captured in analyses of clinical and/or cost-effectiveness. The results of these votes are shown in https://icer.org/wp-content/uploads/2020/10/ICER_Multiple-Myeloma_Final-Report_Update_070921.pdf. Several key policy recommendations follow:Following its deliberation on the evidence, the Midwest CEPAC panel engaged in a moderated discussion with a policy roundtable about how best to apply the evidence on CAR-T therapies and belantamab for TCRMM to policy and practice. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website: Manufacturers should engage with a variety of people from diverse communities to help inform the design and implementation of clinical trials and to ensure that people of color and those from less advantaged backgrounds are adequately represented in the trials. In addition, manufacturers should moderate new treatment pricing. Even with insurance coverage, cost is a tremendous driver of health inequities.Payers should recognize that, in addition to often steep out-of-pocket costs for the treatments, there are often ancillary costs that can become real barriers to care and exacerbate inequities. Payers should develop coverage that creates a broader package of benefits so that patients who face financial or logistical hurdles can have equal access to specialized care at Centers of Excellence, if desired.Clinicians and clinical societies should conduct (or continue to conduct) active outreach and education to underserved communities and the general oncologists and other members of the health care team serving those communities to get new, effective treatments to those patients who would benefit most.All stakeholders have a responsibility and an important role to play in ensuring that effective new treatment options for patients with MM are introduced in a way that will help reduce health inequities.The clinical research community should move rapidly to address key gaps in evidence for treatments for MM. These gaps include whether patients can stop therapy while in response (which could decrease side effects for patients and decrease costs for payers), how well the clinical trial populations reflect the target populations for treatment, data on preferences and patient-reported outcomes in historically disadvantaged populations, and the clinical characteristics of the disease and its affected populations that may be predictive of response.Manufacturers should seek to set prices that will foster affordability and good access for all patients by aligning prices with the patient-centered therapeutic value of their treatments. In the setting of these new interventions for MM, while there is considerable hope associated with the promise of the therapies, there also remains substantial uncertainty regarding their longer-term safety and effectiveness, and the platform on which they are based has been funded in part with taxpayer money. Manufacturer pricing should also reflect these considerations in moderating launch pricing.Payers should use the FDA label as the guide to coverage policy and engage clinical experts and diverse patient representatives in considering how to address coverage issues for which there is limited or no evidence at the current time.