Low-value use of screening colonoscopy is wasteful and potentially harmful to patients. Decreasing low-value colonoscopy prevents procedural complications, saves patient time and reduces patient discomfort, and can improve access by reducing procedural demand. The objective of this study was to develop and validate an electronic measure of screening colonoscopy overuse using ICD-10 codes and then apply this measure to estimate facility-level overuse to target quality improvement initiatives to reduce overuse in a large integrated healthcare system.Retrospective national observational study of US Veterans undergoing screening colonoscopy at 119 Veterans Health Administration (VHA) endoscopy facilities in 2017. A measure of screening colonoscopy overuse was specified by an expert workgroup, and electronic approximation of the measure numerator and denominator was performed (“electronic measure”). The electronic measure was then validated via manual record review (n=511). Reliability statistics (n=100) were calculated along with diagnostic test characteristics of the electronic measure. The measure was then applied to estimate overall rates of overuse and facility-level variation in overuse among all eligible patients.The electronic measure had high specificity (99%) and moderate sensitivity (46%). Adjusted PPV and NPV were 33% and 95%, respectively. Inter-rater reliability testing revealed near perfect agreement between raters (k=0.81). 269,572 colonoscopies were performed in VHA in 2017 . Applying the measure to these 88,143 screening colonoscopies, 24.5% were identified as potential overuse. Median facility-level overuse was 22.5%, with substantial variability across facilities (IQR 19.1%–27.0%).An ICD-10-based electronic measure of screening colonoscopy overuse has high specificity and improved sensitivity compared to a previous ICD-9-based measure. Despite increased focus on reducing low-value care and improving access, a quarter of VHA screening colonoscopies in 2017 were identified as potential low-value procedures, with substantial facility-level variability. Low-value care is particularly problematic in large integrated healthcare systems such the Veterans Health Administration (VHA), where reduced access may lead to longer-than-acceptable wait times and impair VHA’s ability to meet its central mission to ensure that United States military veterans are able to access the care they need in a timely manner. Indeed, VHA has previously been scrutinized for prolonged wait times for routine medical care, including elective outpatient procedures such as colonoscopy.9Low-value use of colonoscopy for screening and other preventive indications is a common and well-documented problem across healthcare systems.9 Prior to 2014, our team developed an International Classification of Diseases, Ninth Edition (ICD-9)-based electronic measure to identify potential low-value use of screening colonoscopy in VA endoscopy facilities.3 However, interim adoption of International Classification of Diseases, Tenth Edition, Clinical Modification  rendered the ICD-9-based measure unusable to monitor overuse as the health system sought to improve access to care.In 2014, VHA was investigated for prolonged wait times for routine medical care including elective outpatient colonoscopies at the Phoenix VA and other sites.10 We also hypothesized that our ICD-10-based measure would have similar specificity but enhanced sensitivity compared to the previously developed ICD-9-based measure due to the addition of more specific codes for non-screening indications in ICD-10.In this study, we sought to develop and validate an ICD-10-based electronic measure of screening colonoscopy overuse. We then applied this measure to estimate facility-level variation in colonoscopy overuse in VHA for purposes of targeting quality improvement initiatives to reduce overuse. We hypothesized that there would be substantial potential overuse of screening colonoscopy in VHA given inherent challenges in reducing use of low-value services and the lack of specific programs or interventions focused on this topic.This was a retrospective observational study using VHA administrative, clinical, and laboratory data available in the Corporate Data Warehouse (CDW). Because this work was performed under an operations Memorandum of Understanding with the VA Office of Reporting Analytics, Performance, Improvement and Deployment (RAPID), approval by the Ann Arbor VA Institutional Review Board was not required. VHA is the largest integrated healthcare system in the United States. The study population included Veterans undergoing a screening colonoscopy at one of 119 VHA endoscopy facilities in 2017. For patients who had 2 or more colonoscopies within the 2017 study period, we included only the first (index) procedure because our primary focus was on identifying overuse of routine, ambulatory screening colonoscopies. A small proportion of patients undergo multiple colonoscopies in a short period of time, but in most instances those colonoscopies repeated in the short-term  are appropriate .The study proceeded in 3 steps: (1) measure specification and electronic approximation of the measure using ICD-10-era administrative codes; (2) measure validation via manual record review using a national random sample of colonoscopy cases, with oversampling to ensure adequate numbers of screening colonoscopies; and (3) application of the ICD-10-based electronic measure to all eligible patients undergoing colonoscopy to calculate 2017 VHA screening colonoscopy overuse rates, facility-level variation in overuse, and potential explanatory factors.3 Prior to the initial workgroup meeting, members were provided with relevant literature to review, including U.S. Preventive Services Task Force (USPSTF) guidelines for colorectal cancer screening and Veterans Health Administration (VHA) Colorectal Cancer Screening Directives in effect at the time of measure development. While there were interim updates to USPSTF guidelines between 2013 and 2017,11 these updates did not impact the measure specifications . Workgroup members were charged with developing a measure that: (1) was based on high-quality evidence ; (2) maximized specificity at the expense of sensitivity; and (3) could be implemented electronically.Measure specifications were initially defined by an expert workgroup comprising VA experts in colorectal cancer screening and in performance measurement.The workgroup began by broadly defining overuse as a screening colonoscopy performed at an inappropriately short interval  or in a patient for whom the benefit of screening is low . The workgroup was then asked to more clearly specify the data elements that comprised the measure denominator  consisted of all index colonoscopies performed in FY2017 in patients who had not had a colonoscopy within the preceding 12 months. To approximate the measure denominator , we firs14 First, we excluded patients who had an ICD-10 code for specific gastrointestinal symptoms or for colorectal neoplasia within 12 months of the FY17 colonoscopy , we were able to ensure that roughly 50% of colonoscopies in our validation sample were screening colonoscopies.The electronic, ICD-10-based measure was validated against the gold standard of manual record review using a national random sample of colonoscopy cases  , Table 515 Therefore, we initially pulled a sample of 1,000 patients – 500 who had a colonoscopy in a VA facility and 500 who had a colonoscopy through VA community care per administrative data. While the initial sample size for the VA measure validation was 500, 11 of the patients who were identified as having their colonoscopy through VA community care were found to have received their procedure at a VA facility on further review. Therefore, these 11 patients were included in our validation of the measure using VA data. Thus, the final validation sample for this study was 511. Validation of the new ICD-10 measure included review of fewer charts than the validation of the previous ICD-9-based measure ,3 because the ICD-10-based measure was an update of the previous measure and the same core data elements used in the original 2012 abstraction were used in the 2017 abstraction, with minor changes in how reviewers were instructed to document several of these data elements.In parallel with the present study, we also validated the measure in VA community care data . VA has recently expanded the ability of VA-enrolled Veterans to receive care in non-VA facilities at VA expense.Manual record review was performed by Quality Insights, a professional chart abstraction group that performs large-scale, national chart reviews for the VA performance measurement program  on an ongoing basis. EPRP uses quality control processes to maximize the consistency and completeness of data collected from VA records. These processes include: (1) internal quality control (IQC) question and mnemonic level analysis; and (2) inter-rater reliability (IRR) assessment.3 A 78-question abstraction algorithm  abstraction algorithm to identify overuse measure elements in manual record review, using a progress similar to that used for the ICD-9-based colorectal cancer screening overuse measure.lgorithm  was devePrior to beginning chart abstraction, Quality Insights staff provided education to the abstractors via webinar and PowerPoint presentation. This included introducing each step of the abstraction algorithm and clarifying relevant medical terminology. Abstractors were blinded to the electronic measure determination. During the abstraction process, a log of questions from the abstractors was compiled, and these questions were reviewed and resolved by members of the study team on an ongoing basis . A total of 6 trained abstractors , utilized the final algorithm/abstraction instrument  to revieInter-rater reliability (IRR) testing of the final instrument was performed using Cohen’s kappa and Gwet’s AC as measures of agreement. Since the abstraction of all medical records in the validation sample was impractical, IRR testing was performed on a weighted sample of 100 records drawn from the 511-record validation sample .These 100 records included 25 non-screening, 25 screening/non-overuse cases, and 50 screening/overuse cases, randomly sampled from the full 511-record validation sample. With this sample size, we had >80% power to detect a kappa of 0.61 (moderate agreement) or greater. The two IRR reviewers were Registered Nurses and held the Registered Health Information Administrator credential, with extensive medical record review experience.The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the electronic measure were assessed. Because we oversampled for screening procedures in the validation sample using the Z12.11 code , direct calculations of PPV and NPV would be inaccurate. We therefore used bootstrapping to calculate the PPV and NPV of the electronic measure in resampled subsets of the 511-record validation sample with the same proportion of screening procedures as in the national/overall sample.Following measure validation, we applied the electronic measure to all eligible patients in 2017 to calculate facility-level overuse, and variation in facility-level overuse of screening colonoscopy to identify facilities with high-levels of overuse as candidates for closer inquiry and potential targets of quality improvement efforts. Rates of overuse were reported as a composite of “possible” and “probable” overuse as specified by the expert workgroup .We also used negative binomial regression to model the proportion of overused screening colonoscopies per facility, with the number of overused screening colonoscopies as the outcome and total number of screening colonoscopies as the offset. Facility-level predictors examined included the following: (1) proportion of screening-eligible patients up to date for screening per current guidelines as assessed by chart review via VA’s ongoing EPRP, (2) median number of weeks between a positive FOBT and colonoscopy (“FOBT wait time”), (3) VA facility complexity score  to 3 (lowest complexity)), (4) academic affiliation (obtained from the VA Office of Academic Affiliations), (5) annual colonoscopy volume , and (6) proportion of colonoscopies outsourced to non-VA facilities ; (7) proportion of colonoscopies performed on Black patients (extracted from CDW), and (8) proportion of colonoscopies performed on Hispanic or Latino patients (extracted from CDW). Risk ratios (RR) and 95% confidence intervals (CI) were calculated. All data management and analyses were performed using SAS, Version 9.4, of the SAS Enterprise Guide for LINUX .Based on independent duplicate manual review (n=100), the kappa of the final instrument was 0.81 (95% CI 0.69–0.93) and the Gwet’s AC was 0.83 (95% CI 0.72–0.94), indicating “near perfect” and “very good” agreement, respectively. Both reviewers identified 35 of 100 cases as screening colonoscopy overuse, and 56 of 100 cases as appropriate colonoscopies. Reviewers disagreed in 9 of 100 cases. In 7 of 9 cases of disagreement, reviewers disagreed regarding whether the procedure was a screening procedure, rather than on whether that screening procedure was overuse. In the other 2 cases of disagreement, the reviewers agreed that the procedure was a screening colonoscopy but disagreed regarding whether that screening colonoscopy was appropriate vs. overuse.3 The electronic ICD-10-based measure was also accurate in estimating overuse compared to manual record review (19% ICD-10-based measure overuse (95% CI 15–24%) vs. 23% manual record review overuse (95% CI 19–28%)). The adjusted PPV of the electronic measure was 33% (95% CI 21%–42%) and the adjusted NPV was 95% (95% CI 93%–97%).Compared to manual record review (n=511), the ICD-10-based electronic measure had high specificity  and improved sensitivity  compared to the prior ICD-9 based measure (which had a sensitivity of 20% and a specificity of 97%).16 = 0), with a median age of 62 (interquartile range (IQR) 54–68). . After applying exclusion criteria, 88,143 screening colonoscopy encounters remained. Patients were predominantly male (91.6%) and healthy (median Charlson-Deyo comorbidity index score 54–68).  FacilitiApplying the electronic measure to all eligible patients in 2017, 24.5%  of VA screening colonoscopy encounters in 2017 met the definition for probable  or possible  overuse. Of the 21,600 colonoscopies meeting a consensus definition of overuse, the top two reasons for overuse were screening colonoscopy performed <9 years after a previous colonoscopy (45% in 2017) and screening colonoscopy performed <6 months after a negative FOBT (23% in 2017).  Median fExamining the association between screening colonoscopy overuse and facility characteristics, none of the facility-level factors examined were found to be associated with screening colonoscopy overuse except academic affiliation . 3 The new ICD-10-based measure could be used to track facility-level screening colonoscopy overuse over time in the ICD-10 era with little to no burden to clinicians or patients. Such information can be used to limit low-value colonoscopies, thus resulting in both improved quality and expanded capacity for high-value colonoscopies. This is particularly important in systems where access to colonoscopy is limited. Decreasing screening colonoscopy overuse also saves patient time and the anxiety, stress and discomfort associated with undergoing an invasive procedure. Despite increased focus on reducing low value care and enhancing access, approximately 24% of screening colonoscopies in VHA in 2017 were identified as potential low-value procedures with substantial facility-level variability. The ICD-10-based measure was substantially more sensitive in identifying overuse than the previous ICD-9-based measure,3 meaning that it detects more potential cases of overuse. While drawing direct comparisons between 2013 and 2017 data has limitations given differences in ICD-9 and ICD-10 measure characteristics, it is worth noting that screening colonoscopy overuse rates did not meaningfully change between 2013 (as measured by an ICD-9 based measure) and 2017 (as measured by an ICD-10 based measure).3 This rate of potential overuse is within the credible range found in non-VA health systems in the ICD-9 era in a recent systematic review.17In this study, we developed and validated a new ICD-10 based measure of screening colonoscopy overuse and demonstrated that it measures overuse with robust specificity and markedly better sensitivity than a previous ICD-9-based measure.High-rates of potential low-value screening colonoscopy across VHA medical centers  may result in part from the absence of assessment of colonoscopy overuse in VHA’s centralized performance measurement and improvement infrastructure. However, in response to high-profile access challenges, there has been increased focus by VHA leadership since 2017 on proposing innovative solutions to address these access challenges, including a focus on reducing procedural overuse. For example, in response to ongoing specialty care backlogs, the VHA Office of Veterans Access to Care (OVAC) convened a VA GI Access Meeting in Washington, DC in September 2018 focused specifically on development and implementation of a coordinated, multi-component access strategy to reduce wait times. This included development and implementation of guidelines and strategies to address overuse, including facility-level monitoring over periods of time  with targeted interventions for sites with relatively high levels of overuse. This work remains ongoing at the national VHA level in conjunction with the VA Office of Reporting, Analytics, Performance, Improvement and Deployment and other operational offices, with continued efforts focused on implementing this ICD-10-based measure into national reporting systems and development of facility-specific reports that can be utilized to communicate performance data to sites and explicitly highlight the link between reducing low-value colonoscopy and improving overall endoscopy access. Thus, there is reason for optimism regarding VHA’s ability to achieve a meaningful reduction in low-value screening colonoscopy in the future. To our knowledge, other well-regarded integrated healthcare systems, including the Kaiser Permanente integrated managed care consortium, do not presently employ a screening colonoscopy overuse monitoring program. Our updated colonoscopy overuse measure could easily be adopted in these non-VHA settings to improve access and enhance overall performance. In addition, non-integrated healthcare systems, such as academic medical centers, community practices, and others could benefit from monitoring of screening colonoscopy overuse, particularly as healthcare reimbursement systems shift to value-based payment/alternative payment models.19 For example, sites may have varying levels of available resources to carefully triage colonoscopy consults to detect low-value procedures, differences in leadership support and stakeholder engagement to support these efforts, and varying levels of recognition of the strong link between minimizing low-value care  and improving overall endoscopy access. Because overuse is a complex problem, accomplishing meaningful and sustainable improvements in facility-level performance will require not only rigorous performance measurement and performance feedback, but also collaboration with willing leaders and frontline providers and patients to facilitate necessary changes to organizational culture.20The substantial variability in performance across VHA’s 119 endoscopy facilities may be reflective of cultural or other unmeasured facility-level characteristics that enhance or impede efforts to reduce low-value care at those sites. Indeed, substantial variability in use of other low-value diagnostic testing has been demonstrated across facilities in other studies.21 The markedly improved sensitivity of our updated colonoscopy overuse measure was largely due to significant improvement in the sensitivity of the underlying electronic measure for screening indication due to the addition of more specific codes for non-screening indications in ICD-10. Specifically, the sensitivity of the ICD-9-based electronic measure for screening indication was only 36%,3 as compared to 79% for the ICD-10-based measure. Examples of cases that might still be missed by the ICD-10-based measure include situations in which an overuse screening colonoscopy is misclassified as non-screening  platforms such as Epic or Cerner, and used in clinical decision support  to flag a potential low-value procedure or used for quality monitoring and improvement efforts such as what is being considered in VHA. While this measure is currently not included in national performance programs such as the Merit-Based Incentive Payment System (MIPS) or other pay-for-performance programs, which have tended to favor more typical underuse measures, widespread adoption of a screening colonoscopy overuse or other low-value care measure in this manner could aid in dissemination across practice settings and enhance its potential impact.Applying such a measure at the health system level can be particularly effective, because health systems can leverage efficiencies of scale to apply such metrics across a large number of affiliated clinicians, use such measures to track performance over time, and develop and disseminate new programs or technologies  to improve system-wide care delivery and change organizational culture to value stewardship of healthcare resources.24We acknowledge that varying incentives  may influence the degree of motivation present in these various practice settings to adopt such low-value care measures into routine performance monitoring programs. However, adoption of alternative payment models that modify these organizational incentives could be effective at reducing low-value care, as suggested by a recent study of variation in use of low-value services in provider organizations.Several study limitations also are worthy of mention. First, our measure relies on accurate coding of colonoscopy indication in administrative data, which is difficult to verify. However, comparing our measure to medical record abstraction did show high levels of accuracy. Further, facility-level variation in screening colonoscopy overuse rates may have been confounded by unmeasured factors including the potential for systematic differences in coding of procedural indication across sites and existing implementation of facility-specific interventions designed to curb screening colonoscopy overuse. The potential for coding differences across sites is mitigated, however, by use of automated endoscopy reporting software across VA endoscopy sites that auto-populates ICD/CPT codes into the reports. It also is important to acknowledge that our measure is a composite measure that combines cases of “possible” and “probable” overuse. However, prioritization of measure elements is possible  and is being discussed as part of our efforts to use this measure for quality improvement within the VHA. Additionally, some reasons for overuse  are arguably more important to target than others. Finally, we acknowledge that there can never be perfect adherence to guidelines, both because guidelines themselves are not perfect and because guidelines must be applied in the context of the individual patient. While the “acceptable” level of overuse has not been precisely defined, this measure can aid in identifying outlier facilities whose practices should be more closely scrutinized.With respect to our analysis of facility-level predictors of screening colonoscopy overuse, we acknowledge that, because some of the confidence intervals are wide and the point estimates substantial, there could be associations between overuse rates and facility-level predictors other than academic-affiliation that were not detected in our analysis. However, it is not possible to increase the power of our study because the number of VHA endoscopy facilities is fixed.15 and its predecessors. However, we were able to capture these cases in our manual record review. We also separately validated our measure using VHA community care data, suggesting the measure could be applied to data and sites outside of VHA. Finally, emerging changes in screening colonoscopy guidelines, including a newly updated USPSTF recommendation (released May 2021) to begin colorectal cancer screening at age 45 (rather than 50) in average risk patients, may require refinement of overuse criteria in the future to ensure that the measure does not penalize appropriate care.12 However, it is important to note that only a small proportion (12%) of potential overuse was due to performance of a screening colonoscopy in patients 45–49 years of age.Therefore, while this component of our analysis may leave some unanswered questions, we believe the findings still add substantially to the literature and presenting our results is valuable to the field. Certainly, as the largest integrated healthcare delivery system in the United States, VHA is an optimal setting in which to conduct this type of analysis. It is also important to recognize that, while our study demonstrates variation in facility-level overuse, the drivers of overuse among individual low-performing facilities may be quite different, such that tailored strategies to reduce low-value use of screening colonoscopy will likely be needed rather than a uniform approach. We also could have underestimated the true rate of screening colonoscopy overuse among VA-enrolled Veterans by not capturing use of non-VA care, which is increasingly prevalent given legislative initiatives such as the VA Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act of 2018Our updated ICD-10 based measure reliably measures screening colonoscopy overuse with similar specificity but markedly better sensitivity than a previous ICD-9-based measure, allowing VHA to track facility-level performance over time and target sites with higher rates of low-value procedures for improvement. Despite increased focus on reducing low value care and enhancing access, levels of screening colonoscopy overuse in VHA were substantial in 2017, with significant facility-level variability. None of the facility-level factors examined were found to be associated with screening colonoscopy overuse, except for academic affiliation. However, recent systematic efforts to address specialty care access barriers, including through reducing procedural overuse, reflect increasing recognition of the impacts of overuse on overall procedural access and hold promise for reducing overuse of procedural services such as low-value screening colonoscopies in the future.Supp1Appendix 1. Additional details regarding electronic approximation of measure denominator and measure numerator.Supp2Appendix 2. Abstraction instrument for manual record review.


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. Currechildren –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. Bothsettings . 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 sets of critical questions about our cascaded task-sharing NDBI approach that required exploration. First, we wanted to determine whether our approach impacted fidelity of implementation of both non-specialist coaches and caregivers. Specifically, whether coaching by non-specialist providers resulted in improvements in caregiver use of intervention strategies with their young autistic child and whether coaches were able to adhere to coaching procedures as outlined in fidelity checklists. Second, we wanted to assess whether coaching impacted key short-term child and caregiver outcomes. Specifically, whether signals of change were detected in child social and communication abilities and caregiver stress and sense of competence. These questions 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 PSOC;  is a 16-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; .ClinicalTrials.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).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 The CONSORT flow chart in Child and caregiver baseline characteristics are outlined in The non-specialist ECD practitioner group (n = 4) 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 (see p = 0.042). 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 iver see . Similar one see .p = 0.557). Griffiths-III Gross Motor DQ improved in 5 out of 10 children and dropped in 5 (see p = 0.084), the Personal/Social-Emotional DQ improved in 8 out of 10 children, and dropped in 2 (see p = 0.002), with all 10 children demonstrating improved Foundations of Learning DQ scores (see p = 0.004). Language/Communication DQ improved in 9 out of 10 children and dropped in one (see p = 0.27). Eye and Hand Coordination DQ improved in 6 out of 10 children, 2 stayed the same, and 2 dropped (see p = 0.02). 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 (see p = 0.042). VABS-3 Socialization Standard Scores improved in 6 out of 10 children, 2 stayed the same, and 2 dropped (see p = 0.086). VABS-3 Daily Living Standard Scores improved in 7 out of 10 children, stayed the same in 1, and dropped in 2 (see p = 0.009). VABS-3 Adaptive Behaviour Standard Score improved in 9 out of 10 children and dropped in 1 (see The VABS-3 Communication Standard Scores increased significantly between T1 and T2 (median (IQR) T1 = 41 ; T2 = 50 ;  one see . VABS-3 pped see . VABS-3 in 2 see . Finallyin 1 see .p = 0.075). Sense of competence total scores improved in 7 out of 10 caregivers and dropped in 3 (see p = 0.332). 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 naive 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 and are 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. Furtto 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. 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.


Granulocyte colony-stimulating factors such as filgrastim are used to decrease the incidence of febrile neutropenia (FN) among patients with nonmyeloid cancers undergoing chemotherapy treatment. Although the biosimilar filgrastim-sndz has been approved in the United States since 2015, limited real-world comparisons of filgrastim-sndz versus reference filgrastim (filgrastim-ref) have been conducted.To compare FN incidence and assess overall FN-related health care resource utilization and medical costs among U.S. patients with non-myeloid cancer who received filgrastim-sndz or filgrastim-ref during their first chemotherapy cycle.This was a retrospective claims analysis of patients with non-myeloid cancer who were enrolled in commercial or Medicare Advantage insurance plans from March 2015 through June 2016 and received filgrastim-sndz or filgrastim-ref during their first observed chemotherapy cycle. Patients with evidence of hematopoietic stem cell transplantation or pregnancy and those with missing demographic information were excluded. FN was defined on the basis of diagnosis codes for neutropenia and fever (N/F); neutropenia and infection (N/I); and neutropenia, infection, and fever (N/I/F). Cohorts were adjusted for differences in baseline patient characteristics using the inverse probability of treatment weighting (IPTW) method, and equivalence testing was used to compare the proportion of patients who developed FN between weighted cohorts. On the basis of the range of neutropenic fever incidence found in the PIONEER clinical trial, FN incidence was considered equivalent if 90% CIs for between-cohort differences were within ± 6%. Mean FN-related health care resource utilization and total FN-related medical costs were calculated for the overall study population.A total of 3,542 patients were included in the study . After IPTW, there were 162 patients in the filgrastim-sndz cohort and 3,297 in the filgrastim-ref cohort (mean age 64.5 years for both). FN incidence in the weighted filgrastim-sndz versus filgrastim-ref cohorts, respectively, was 1.4% versus 0.9% for N/F, 2.3% versus 1.7% for N/I, and 0.0% versus 0.3% for N/I/F; FN incidence was statistically equivalent between treatment cohorts. Among patients in either treatment cohort who developed FN, the proportion with FN-related inpatient stays during the first chemotherapy cycle ranged from 35.0% for N/I to 70.0% for N/I/F. Mean (SD) FN-related total medical costs across all patients who developed FN were $11,977  for N/F, $8,040  for N/I, and $21,733  for N/I/F, in 2015 U.S. dollars. For all 3 definitions of FN, the largest proportions (73.5%-93.4%) of medical costs were inpatient related.In this real-world study of patients with nonmyeloid cancers undergoing chemotherapy, the incidence of FN was statistically equivalent between individuals treated with filgrastim-sndz versus filgrastim-ref during their first chemotherapy cycle. FN-related health care resource utilization and medical costs among patients who developed FN were substantial. What is already known about this subjectFebrile neutropenia (FN), a common side effect of myelosup-pressive chemotherapy, is associated with increased morbidity, mortality, and health care costs and can compromise the delivery of optimal chemotherapy regimens by necessitating treatment delays or reductions in chemotherapy dose intensity.Prophylaxis with granulocyte colony-stimulating factors such as filgrastim can reduce the risk of hospitalization, death, and chemotherapy dose intensity reduction among patients whose chemotherapy regimens are associated with high risk of FN.Previous studies have shown that clinical and safety outcomes among patients treated with the biosimilar filgrastim-sndz are similar to those reported historically for reference filgrastim (filgrastim-ref).What this study addsThe incidence of FN among patients with nonmyeloid cancers undergoing chemotherapy was statistically equivalent between those treated with filgrastim-sndz versus filgrastim-ref during their first chemotherapy cycle, based on real-world data.Among patients who developed FN, hospitalization was common and mean total medical costs ranged from $8,040 to $21,733, depending on the FN definition used.1 predisposes patients to infection and often requires hospitalization and treatment with broad-spectrum antibiotics.4 Most common in the first cycle of chemotherapy,5 FN is associated with increased morbidity and mortality and carries a heavy economic burden8; moreover, its development can compromise the delivery of optimal chemotherapy regimens by necessitating treatment delays or reductions in chemotherapy dose intensity.10Febrile neutropenia (FN), a common and potentially life-threatening side effect of myelosuppressive chemotherapy,13 These biologic drugs promote the growth and differentiation of neutrophils to accelerate neutrophil recovery after chemotherapy.14 G-CSF prophylaxis may also be considered for patients on chemotherapy regimens with intermediate FN risk (10%-20%), depending on the presence of patient-related risk factors such as age, disease stage, comorbidities, and previous history of FN.13Practice guidelines in the United States and Europe recommend prophylaxis with granulocyte colony-stimulating factors (G-CSFs) for patients whose chemotherapy regimens are associated with high (≥ 20%) risk of FN.15 These outcomes are associated with substantial economic benefit: It is estimated that in 2014, G-CSF treatment and prophylaxis of patients with cancer resulted in a total social value of $8.5 billion, including $770 million due to fewer FN-related hospitalizations, $2.65 billion due to fewer FN-related deaths, and $230 million due to reduced indirect costs.15Use of G-CSF among patients with solid tumors or nonmyeloid malignancies has been shown to reduce the risk of hospitalization, death, and chemotherapy dose intensity reduction while improving chemotherapy-related quality of life.16 It is well accepted that prophylaxis with filgrastim  effectively decreases both FN risk and the severity of FN episodes.18The G-CSF filgrastim (Neupogen) has been approved in the United States since 1991 for decreasing the incidence of FN among patients with nonmyeloid malignancies who are undergoing chemotherapy associated with a substantial risk of neutropenic complications.19 Designed to encourage innovation and promote the introduction of lower-cost biosimilars, the BPCIA established an abbreviated approval pathway for biologics shown to be highly similar to or interchangeable with a reference drug already approved by the U.S. Food and Drug Administration.20 Approval of filgrastim-sndz was based on a comprehensive package of analytical, preclinical, and clinical data,19 including results from the PIONEER randomized controlled trial, which demonstrated that there were no clinically meaningful differences in safety or efficacy between the biosimilar and the reference drug (filgrastim-ref) for neutropenia prevention among patients with breast cancer receiving myelosuppressive chemotherapy.21Expiration of the filgrastim basic patent paved the way for the development of biosimilars such as filgrastim-sndz (Zarxio), which became available in the United States in 2015 as the first biosimilar approved after passage of the Biologics Price Competition and Innovation Act (BPCIA).22 but limited real-world comparisons of filgrastim-sndz versus filgrastim-ref have been conducted in the United States or globally.Given that patient characteristics and treatment patterns often differ substantially between clinical practice and clinical trial settings, the current evidence supporting the biosimilarity of filgrastim-sndz and filgrastim-ref would be bolstered by real-world comparative studies. A recent European multi-center prospective observational study (MONITOR-GCSF) demonstrated that clinical and safety outcomes among patients treated with filgrastim-sndz (Zarzio) were similar to historically reported data for filgrastim-ref,To help address this evidence gap, we performed a retrospective observational study to compare FN incidence among filgrastim-sndz–treated versus filgrastim-ref–treated patients undergoing chemotherapy treatment for nonmyeloid malignancies in U.S. clinical practice. FN-related health care resource utilization and costs were also assessed across all study patients to enhance understanding of the real-world impact of this condition.This was a retrospective claims analysis conducted during a study period of September 1, 2014, through July 31, 2016, using data from the Optum Research Database (ORD), a proprietary U.S. health insurance database that contains fully de-identified medical and pharmacy claims and enrollment information for commercial and Medicare Advantage health plan members. The ORD is geographically diverse across the United States and covers 60 million lives from 1993 to the present.International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-CM); Current Procedural Terminology (CPT) or Healthcare Common Procedure Coding System (HCPCS) codes; and other information. Outpatient pharmacy claims included National Drug Code (NDC) numbers for dispensed medications, quantity dispensed, dose, and number of days supply.Medical claims included diagnosis and procedure codes from the For individuals aged ≥ 18 years, data in the ORD are also linked to dates of death (month and year) from the Social Security Administration death master file. Institutional review board approval or waiver of authorization was not required for this study, as no identifiable protected health information was extracted or accessed.5 Selected patients were required to have at least 1 claim for chemotherapy in the 30 days before the first qualifying receipt of filgrastim-sndz or filgrastim-ref (first chemotherapy date was the index date), at least 1 claim with a diagnosis code for nonmyeloid malignancy (codes are available from the authors upon request) during the study period ([index date minus 180 days] through the end of the follow-up period), and continuous health plan enrollment with medical and pharmacy benefits for 6 months before the index date (baseline period) and at least 1 month after the index date. This time frame was chosen to increase the chance of capturing at least 1 complete chemotherapy cycle for each patient. The end of the follow-up period was defined as the end of continuous enrollment, death, or July 31, 2016, whichever came earliest. At least 1 month of follow-up continuous enrollment was required.The study population comprised adult patients (aged ≥ 18 years) with at least 1 claim for filgrastim-sndz or filgrastim-ref during the patient identification period  in the first observed cycle of a chemotherapy treatment regimen; the first cycle was chosen for analysis because it is the time of greatest FN risk.Patients were excluded if they had evidence of radiation or surgery on or within 5 days after the index date, any claim for hematopoietic cell transplantation during the study period, evidence of chemotherapy > 30 days before the first qualifying receipt of filgrastim-sndz or filgrastim-ref, evidence of pregnancy during the 6-month baseline period, or missing demographic information, or had switched G-CSF drugs during the observed chemotherapy cycle. Cohort assignments (filgrastim-sndz or filgrastim-ref) were based on the first qualifying claim for G-CSF.24 The initial regimen in the LOT comprised all agents filled or infused within the first 6 days. The end of the LOT was identified as the earliest of the following: (a) initiation of a new agent or receipt of radiation or surgery after the first 6 days of the cycle; (b) a gap in therapy of > 60 days after the run-out date of all agents in the chemotherapy regimen; (c) death; or (d) health plan disenrollment or the end of the study period. The first observed chemotherapy cycle began on the first day of the first observed LOT and continued until the earlier of the next fill/infusion of cancer therapy occurring on or after day 8 of the LOT, or the end of the LOT. Chemotherapy cycles that ended due to censoring  were considered to be incomplete and excluded from the equivalence testing analysis but were included in the analysis of health care resource utilization and medical costs.This analysis used the first observed chemotherapy course  for each patient. The first observed LOT began on the index date and included all HCPCS codes for injectable drugs and NDC numbers observed in the claims, as per First Databank and Facts & Comparisons.25 number of colony-stimulating factor (CSF) doses, length of the first observed chemotherapy cycle, use of CSF prophylaxis, and certain diagnoses and procedures . As FN rarely occurs within the first 5 days of chemotherapy, use of filgrastim-sndz or filgrastim-ref was categorized as prophylactic if it had been initiated on or before day 5 of a chemotherapy cycle26; later uses were categorized as treatment.Demographic and clinical characteristics assessed during the baseline period included age, sex, geographic region, insurance type, Quan-Charlson comorbidity index score,27FN was defined on the basis of claims with a combination of diagnosis codes for neutropenia (ICD-9-CM 288.0 or ICD-10-CM D70*), fever (ICD-9-CM 780.61 or ICD-10-CM R50.81), or bacterial or fungal infection (codes are available from the authors upon request) in the first or second position, starting after the last dose of filgrastim-sndz or filgrastim-ref in the first observed chemotherapy cycle or the fifth day after the index date, whichever was earlier to the end of the cycle. Outcomes were assessed using 3 definitions of FN: neutropenia + fever (N/F), neutropenia + infection , and neutropenia + infection  + fever (N/I/F). Use of these definitions to identify patients with FN from administrative claims data was verified previously.28 For FN-related inpatient stays, all costs generated during the stay were considered attributable to FN.Mean FN-related health care resource utilization and FN-related medical costs were calculated for the full study population. Claims with a diagnosis code for fever, bacterial or fungal infection, or neutropenia in the first or second position were defined as FN related. The number of ambulatory, emergency room, and inpatient visits and the length of inpatient stays were captured to reflect health care resource utilization. In order for an inpatient stay to be categorized as FN related, an FN diagnosis code was required to be on the facility claim. Total FN-related medical costs were calculated as combined health plan-paid and patient-paid amounts adjusted to 2015 U.S. dollars using the annual medical care component of the Consumer Price Index and were also subcategorized as ambulatory, inpatient, emergency room, or other medical.29 All statistical analyses were performed using SAS software package 9.4 .Baseline characteristics, health care resource utilization, and medical costs were analyzed descriptively. Results were presented by treatment cohort; numbers and percentages were provided for dichotomous and polychotomous variables, and means and standard deviations (SDs) were provided for continuous variables. Standardized differences were calculated to compare characteristics between cohorts, with values < 10% considered to indicate high similarity.29 IPTW uses weights based on propensity scores to create a synthetic sample in which the distribution of baseline covariates is independent of treatment assignment; each subject’s weight is equal to the inverse probability of receiving the treatment that the subject actually received. The covariates used to calculate propensity scores  were age, sex, geographic region, insurance type, Quan-Charlson index score, number of CSF doses, length of chemotherapy cycle 1, use of G-CSF prophylaxis, cancer type, metastatic cancer in general and specific to bone, infection, radiation, surgery, renal or hepatic dysfunction, and prior use of CSF agents. Weighted comparisons were made using the Rao-Scott test for categorical variables and regression with Taylor series variance estimation  for continuous variables.For the equivalence analysis, weighted cohorts were created using inverse probability of treatment weighting (IPTW) to control for possible confounding of the relationship between the outcome (development of FN) and the independent variable of interest (G-CSF agent received).21 90% CIs within ± 6% were considered to denote statistical equivalence between cohorts.30FN incidence was calculated among the weighted cohorts for all 3 definitions of FN. Bootstrap methods were used to calculate 90% confidence intervals (CIs) of the difference in FN prevalence between groups. On the basis of the range of neutropenic fever incidence reported in the PIONEER trial,Of the 8,022 commercial and Medicare enrollees with medical and pharmacy benefits who received 1 of the study drugs during the patient identification period, 3,542 met the remaining study criteria and were included in the unweighted treatment cohorts  ages for the unweighted filgrastim-sndz and filgrastim-ref cohorts were 62.1 (13.4) years and 64.7 (12.9) years, respectively . Mean agFN incidence between the weighted treatment cohorts was statistically equivalent  for N/I to 62.5% (20/32) for N/F, and the proportion with FN-related inpatient stays ranged from 35.0% (21/60) for N/I to 70.0% (7/10) for N/I/F . Mean S. The lar21 Moreover, our results expand on those of the MONITOR-GCSF study, which concluded that the safety and efficacy of biosimilar filgrastim prophylaxis in clinical practice were within the ranges previously reported for filgrastim-ref.22The present analysis is one of the first to confirm the equivalence of filgrastim-sndz with filgrastim-ref by directly comparing FN incidence among real-world patients treated with these drugs. Among patients undergoing chemotherapy for nonmyeloid cancers, the proportion that developed FN during their first observed chemotherapy cycle was statistically equivalent between those treated with filgrastim-sndz versus filgrastim-ref. Our findings are congruent with results of the PIONEER randomized controlled trial, which demonstrated that there were no clinically meaningful differences in FN incidence or FN-related hospitalization between patients treated with the biosimilar versus the reference drug.8 with the mean cost of a single FN-related inpatient stay surpassing $22,000.8This demonstration of real-world equivalence between filgrastim-sndz and filgrastim-ref has important implications for improving access to G-CSF treatment in clinical practice. FN is a costly condition, both economically and in terms of patient morbidity and mortality. It frequently requires hospitalization—indeed, 7 of 10 patients in the present study who met the strictest definition of FN (N/I/F) had an inpatient stay—and patients hospitalized for FN have considerable risk of death as well as large health care expenditures,31 However, only about 17% of such patients actually receive prophylaxis, and a substantial additional proportion receive treatment that is inconsistent with guidelines .33 This phenomenon was also observed in our study, as patients in both treatment cohorts received approximately 2 G-CSF doses only, on average. The consequences of this widespread G-CSF under-utilization are clear: In a recent retrospective claims analysis of patients whose chemotherapy regimens and other characteristics warranted CSF prophylaxis, half of all FN episodes occurred among those who had received either no prophylaxis or prophylaxis that was guideline noncompliant and associated with poorer clinical outcomes.34In light of these data, it is perhaps unsurprising that G-CSF prophylaxis may be cost saving among patients for whom it is guideline recommended.35 Given that filgrastim-sndz is less costly than filgrastim-ref—15% less expensive at the time of its 2015 U.S. launch36—increasing use of the biosimilar has the potential to promote guideline compliance by improving drug access. This scenario has already been borne out in Europe, where burgeoning acceptance of biosimilar filgrastim since its 2008 approval has led to more widespread use of prophylaxis, suggesting that health care providers are more able and/or willing to follow clinical guidelines now that the biosimilar is available.37It is thus apparent that increased use of G-CSF has the potential to reduce FN incidence among patients receiving chemotherapy. However, G-CSFs, like many biologics, are expensive drugs, and evidence suggests that cost is a barrier to treatment access for some patients.39 with recent analyses concluding that prophylaxis with filgrastim-sndz is cost-efficient in routine clinical practice relative to both filgrastim-ref and pegfilgrastim,40 and that widespread use of the biosimilar in place of filgrastim-ref would yield cost savings sufficient to treat thousands of additional patients on a budget-neutral basis.41Notably, European studies demonstrating that biosimilar filgrastim is the most cost-efficient approach for preventing FN among patients undergoing myelosuppressive chemotherapy are being replicated in the United States,43In the present study, the prevalence of FN ranged from 0.0% to 2.3% in the filgrastim-sndz group and from 0.3% to 1.7% in the filgrastim-ref group (depending on the FN definition used) and the overall rate of FN-related hospitalization ranged from 0.28% to 0.59% (depending on FN definition). These findings suggest a rate of FN that is lower than the 1.3%-3.5% observed in previous administrative claims analyses assessing the incidence of neutropenic complications  among filgrastim-treated cancer patients undergoing chemotherapy.44 In addition, previous analyses identified FN based on the presence of a diagnosis code for neutropenia, whereas our more restrictive definition required at least the presence of codes for neutropenia plus fever or infection. As the stricter definition  has been shown to have higher positive predictive value and sensitivity,27 our study may provide a more accurate reflection of FN incidence among chemotherapy-treated patients in real-world clinical practice.This discrepancy is likely due in part to the fact that earlier analyses included data prior to a 2006 revision of the American Society of Clinical Oncology guidelines, which changed the FN risk cutoff for prophylaxis from 40% to 20%.8 In accordance with existing evidence that hospitalization is a major driver of expense in this patient population,8 73.5%-93.4% of total FN-related medical costs in the present study were associated with inpatient stays.Our results also underscore the substantial economic burden of FN among patients undergoing chemotherapy. Mean FN-related inpatient costs for the most stringent definition of FN were $21,733, aligning closely with the $18,880-$22,086 range indicated by earlier analyses with similar study populations.Our findings should be interpreted in light of certain limitations. Because this study was conducted in a managed care population among patients who met the study criteria, its results may not be generalizable to other populations . In addition, the number of eligible patients with a claim for filgrastim-sndz during the identification period was low, as the study was conducted within the first 2 years of the drug’s U.S. approval. The effect of small sample size on the equivalence analysis was mitigated by adjusting for covariates using a weighting method (IPTW using propensity scores) rather than a matching method, which allowed us to retain as many patients as possible in the final study cohort. However, the limited sample size precluded meaningful comparison of FN-related health care resource utilization and costs for filgrastim-sndz versus filgrastim-ref.Finally, because causality was not examined in this analysis, differences in study outcomes cannot be definitively attributed to the G-CSF agent received. Moreover, it is possible that the minimal exposure of patients to either G-CSF during the study period (due to the low mean number of doses received) may have masked any potential differences in efficacy.This study is also subject to limitations inherent to administrative claims analyses. Administrative claims data are collected for the purpose of billing, not research; therefore, the presence of a diagnosis code on a medical claim does not prove the presence of disease, as diagnoses may be coded incorrectly or included as rule-out criteria. Although the diagnosis codes used to identify patients with FN in this study were chosen on the basis of literature review and applied within a limited time frame after chemotherapy administration, any coding errors or inconsistencies could lead to misidentification of patients with the outcome of interest.It should be noted, however, that such errors were expected to be infrequent because proper claims documentation is a prerequisite for optimal reimbursement for provided health care services. Moreover, we did not foresee any systematic differences in the occurrence of errors between treatment cohorts in this study, or between our study and those in the existing literature.In this real-world study of patients with nonmyeloid cancers undergoing chemotherapy, the incidence of FN was statistically equivalent between individuals treated with filgrastim-sndz versus filgrastim-ref during their first chemotherapy cycle. Availability of biosimilar filgrastim as a treatment option has the potential to improve patient access to G-CSF treatment and promote physician compliance with prophylaxis guidelines.


Discriminating between virus-induced fever from superimposed bacterial infections is a common challenge in intensive care units. Superimposed bacterial infections can be detected in severe SARS-CoV2-infected patients, suggesting the important role of the bacteria in COVID-19 evolution. However, indicators of patients’ immune status may be of help in the management of critically ill subjects.Monocyte CD169 is a type I interferon-inducible receptor that is up-regulated during viral infections, including COVID-19. Monocyte HLA-DR expression is an immunologic status marker, that decreases during immune exhaustion. This condition is an unfavorable prognostic biomarker in septic patients. Neutrophil CD64 upregulation is an established indicator of sepsis.In this study, we evaluated by flow cytometry the expression of cellular markers monocyte CD169, neutrophil CD64, and monocyte HLA-DR in 36 hospitalized patients with severe COVID-19, as possible indicators of ongoing progression of disease and of patients’ immune status. Blood testings started at ICU admission and were carried on throughout the ICU stay and extended in case of transfer to other units, when applicable.The marker expression in mean fluorescence intensity (MFI) and their kinetics with time were correlated to the clinical outcome.p= 0.04) and than patients who died . In most cases, the recovery of the SARS-CoV2 infection-related signs was associated with the downregulation of monocyte CD169 within 17 days from disease onset. However in three surviving long hospital stay patients, a persistent upregulation of monocyte CD169 was observed. An increased neutrophil CD64 expression was found in two cases with a superimposed bacterial sepsis.Patients with short hospital stay (≤15 days) and good outcome showed higher values of monocyte HLA-DR  than long hospital stay patients (>15 days, median 9590 MFI, Monocyte CD169, neutrophil CD64, and monocyte HLA-DR expression can be used as predictive biomarkers of SARS-CoV2 outcome in acutely infected patients. The combined analysis of these indicators can offer a real-time evaluation of patients’ immune status and of viral disease progression versus superimposed bacterial infections. This approach allows to better define the patients’ clinical status and outcome and may be useful to guide clinicians’ decisions. Our study focused on the discrimination between the activity of viral and bacterial infections and on the detection of the development of anergic states that may correlate with an unfavorable prognosis. CD169  is a type I interferon-inducible receptor, and as reported by several studies, its expression is upregulated on the surface of monocytes and dendritic cells during viral infections . CD169 imoCD169) is increased upon the release of antiviral molecules, such as Interferon Type I [CD169 monocyte expression  expression is an immunologic status marker, correlating with an efficient antigen-presenting function [Monocytes/macrophages play a key role in the immune control of infections. Namely, monocyte HLA-DR  is promptly upregulated upon stimulation by bacteria and their soluble products, thus being considered a sensitive and specific marker of severe bacterial infections and sepsis [During prolonged stays in ICU for COVID-19, a common clinical problem is the discrimination between virus-induced findings and superimposed bacterial infections, which tend to occur in a later phase. The ordinary clinical parameters, i.e., fever, acute-phase reactant levels, lactate, blood, and respiratory tract cultures, do not always provide clues of the necessary sensitivity and specificity , 16. It d sepsis , 17. Sepd sepsis . The inid sepsis , 21. In d sepsis , 23.The aim of our study was therefore to evaluate by a quick, real-time flow cytometric assay if the combined expression of moCD169, moHLA-DR, and neCD64 in ICU patients with severe COVID-19 could allow a better definition of patients’ clinical status and outcome, to guide clinicians’ decisions. Our study focused on the discrimination between the activity of viral and bacterial infections and in the detection of developing anergic states, which may correlate with an unfavorable prognosis. The kinetics of moCD169, moHLA-DR, and neCD64 during the clinical course was also prospectively evaluated in some representative patients.Thirty-six hospitalized patients from December 2020 to April 2021 with severe COVID-19 were included in the study. Twenty-two patients (61%) were admitted to ICU and overall 6/36 (16.6%) died within a median of 44 days from admission. The characteristics of patients are reported in Table Ground-glass opacities at chest x-ray were present at admission in 64% of cases and in 8 patients pulmonary embolism was subsequently evidenced. In 33/36 cases, steroid treatment was undertaken in the early phase, along with support therapy. Blood testings started at hospital admission and were carried on throughout the ICU unit transfer and stay. In 15 subjects (42%), the prospective evaluation of moCD169, neCD64, and moHLA-DR during the clinical course was carried out, for a median of 12 days after the first analysis.In addition, 10 age-matched healthy donors were included as the normal control group (NC).The approval of this observational study was obtained from the local scientific committee, within the extended informed consent procedures activated during the early COVID-19 epidemic. The immunophenotypic testings were performed using the leftovers of routine full blood counts, and the study results were not used to undertake any clinical decision. In our institution, healthy blood donors sign informed consent for research studies on their routine samples, which are used to represent normal reference values in a variety of laboratory testings, including cell phenotyping.Fifty microliters of EDTA-whole blood samples were taken from the fresh routine tubes ordered for the full blood count. Aliquots were mixed with 10 μl IOTest Myeloid Activation antibody cocktail , containing anti-CD169-PE , anti-CD64-PB , and anti-HLA-DR-APC  and incubated for 20 min at room temperature in the dark. The samples were processed with a lyse-no-wash technique using ammonium chloride and no fixation. Flow cytometric analysis was immediately performed on a FACS Lyric , daily calibrated using BD CS&T beads according to the recommended Euroflow procedures , with a Data from 100,000 total white cell events were acquired. Monocytes were identified with a Side Scatter (SSC)/CD64 dot plot. Granulocytes and lymphocytes were gated based on the respective SSC, CD64, and forward scatter (FSC) features  ratio. The MFI ratio is calculated by dividing the geometric mean of the positive fluorescence peak of the relevant population  by the geometric mean of the negative control or reference population  that is not expressing that marker.Monocyte CD169 expression levels were calculated as the ratio between CD169 geometric mean fluorescence intensity (MFI) units on monocytes and MFI units on lymphocytes, which acted as the internal negative reference population.CD64 expression level on granulocytes was similarly calculated as the ratio between CD64 MFI geometric mean units on granulocytes and CD64 MFI units on lymphocytes, which acted as the internal negative reference population.MoHLA-DR expression level was calculated as plain geometric mean MFI, since no internal purely HLA-DR-negative reference cell populations can be found. Patient moHLA-DR is displayed in comparison to normal control subjects, as depicted in the examples in Fig. t-test. Statistically significant differences were established by a p value < 0.05 in both cases.The distributions of surface antigen expression levels and ratios were checked for normality using the Kolmogorov-Smirnov test. In the case of non-normally distributed variates, statistical comparisons were performed using the non-parametric Mann-Whitney test. Comparisons between groups with normally distributed variates were performed using the Student t-test was used for comparisons.The moCD169 MFI ratios and neCD64 MFI ratios were not normally distributed, as assessed with the Kolmogorov-Smirnov test. The Mann-Whitney test was therefore used for comparisons. MoHLA-DR expression levels showed a normal distribution both in patients and normal controls (NC), and Student’s p= 0.00084).SARS-CoV2-infected patients invariably expressed a strongly upregulated moCD169 during the early disease phase Figs.   . During the early SARS-CoV2 infection, no significant differences of moHLA-DR expression were found between the six patients who died and those surviving in ICU   and than patients who died within 44 days . No significant differences in moCD169 MFI ratios were found between long and short hospital stay patients.Patients with short hospital stay  and good outcome showed higher values of moHLA-DR  than long hospital stay patients . However, in three surviving long hospital stay patients (median 56 days), a persistent upregulation of moCD169 was observed Fig. , with a A total of twenty-two patients were admitted to ICU. Nine surviving patients had short hospital stay (<15 days), and 21 surviving patients had long hospital stay (mean 47 days). Six subjects died within 44 days from ICU admission.p= 0.01). In two cases, a superimposed bacterial sepsis was diagnosed during the hospital follow-up. In one case with neCD64 MFI ratio = 15.7 an overt sepsis was defined with positive blood cultures for Serratia marcescens. In the other case with neCD64 MFI ratio = 11.5 and a severely downregulated moHLA-DR MFI, averaging 327, an overt sepsis supported by positive blood cultures for Staphylococcus capitis was diagnosed, shortly before the patient’s death . On the other hand, in another ICU patient, the progressive recovery of moHLA-DR was associated to an improving clinical condition that allowed his discharge after 63 days.The aim of our study was to evaluate retrospectively the changes in the expression of moCD169, moHLA-DR, and neCD64 by flow cytometry in 36 hospitalized patients with severe COVID-19. The marker expression findings with time were correlated to the clinical outcome and the length of hospital stay. In 15 cases, the prospective analysis of these markers with time during the clinical course was also evaluated.Several studies reported that the presence of risk factors such as obesity, hypertension, cardiovascular, or pulmonary disease might lead to a more severe outcome of SARS-CoV2 infection , 26. In On the other hand and in accordance with other recent studies , 28, we Patients admitted to ICU showed significantly lower values of moHLA-DR than subjects admitted to other clinical units, indicating that a dysfunctional immune response may contribute to the development of acute respiratory failure .In general, COVID-19 patients in ICU display a more critical and dynamic clinical picture that often gets complicated with time. For this reason, reliable biological indicators that may enable the quick interpretation of the different ongoing signs and symptoms are needed. The flow cytometric monitoring of the combined expression of moCD169, moHLA-DR, and neCD64 seems fitting the purpose.In a report on a group of 110 patients admitted to the surgical ICU , those wWe found that patients with short hospital stay  and good outcome showed higher values of moHLA-DR than long hospital stay patients , and than patients who died within 44 days. To our knowledge, these observations were not reported before in patients with SARS-CoV2 infection. The definition of “long hospital stay” was set after 15 days taking into account the changes in viral load. As reported by Doehn et al.  between In 33/36 cases, steroid treatment was undertaken along with support therapy in both short hospital stay patients and in ICU long stay patients. The blood testings were performed during the steroid treatment. The steroid administration did not seem however to influence the moHLA-DR expression. As reported by Boomer et al., no significant difference was seen in cytokine production in septic patients treated or not treated with corticosteroids .In the study by Spinetti et al. , low moHIt was also reported that moCD169 expression is increased in early SARS-CoV2 infection  and retuAs reported by other authors we found that in most cases, the clearance of the SARS-CoV2 infection was associated with the downregulation of moCD169 within 17 days from disease onset . TherefoTherefore, the kinetics of moCD169, moHLA-DR, and neCD64 expression may be useful to discriminate febrile events and to stratify patients according to their risk of complications and length of hospital stay. The quick and real-time characteristic of this flow cytometric assay makes it suitable for on-demand orders with a very short turn-around time (less than 60 min).Superimposed bacterial infections are the commonest complications in ICU patients. An upregulated neCD64 expression has long been demonstrated as a reliable indicator of severe bacterial infections and sepsis . In our Our study has several limitations: the small patient cohort, the initial flow cytometric monitoring not strictly performed at regular intervals during the early phase of the study, and the lost to follow-up of some patients due to their transfer to external ICUs or medical wards during the early SARS-CoV2 epidemic.The monocyte CD169 and HLA-DR expression can be used as predictive biomarkers of SARS-CoV2 outcome in acutely infected patients, since they can reliably indicate the status of viral persistence or clearance and the occurrence of superimposed biological phenomena that negatively affect the immune response. The simultaneous assessment of neCD64 expression is of help in discriminating virus-induced fever from severe bacterial infections and sepsis. This real-time flow cytometric assay can be performed on demand, with a short turnaround time (1 h). We believe that the prospective combined monitoring of moCD169, moHLA-DR, and neCD64 can be useful for the management of COVID-19 patients and possibly also for other critical infectious diseases and sepsis.