Clinical Milestone Research Articles

Incidence and Predictors of HBsAg Loss in Paediatric Patients With Chronic Hepatitis B Undergoing Antiviral Treatment.

Achieving HBsAg loss is a critical clinical milestone in the management of chronic hepatitis B (CHB) towards the eradication of hepatitis B. However, there are limited researches on the incidence and determinants of HBsAg loss in paediatric CHB patients undergoing antiviral treatment. Therefore, we aimed to analyse the incidence and potential determinants of HBsAg loss in children who suffered from CHB and received antiviral treatment. This retrospective cohort study was performed on paediatric patients with progressive CHB who initiated either monotherapy or combination therapy using interferon/peg-interferon and entecavir. We utilised Cox regression models to evaluate the relationships between HBsAg loss and various determining factors. In total of 306 subjects with an average age of 4.99 years (range 1-15) were identified in this study, of whom 200 (65.4%) were male. After a median follow-up of 26 months, HBsAg loss occurred in 135 participants. The accumulated rate of HBsAg loss was 67.8% at the end of the follow-up evaluation. Multivariate Cox regression analysis revealed that older age (HR = 0.84, 95% CI: 0.79-0.90), female sex (HR = 1.61, 95% CI: 1.13-2.30), baseline HBsAg levels (HR = 0.72, 95% CI: 0.62-0.84), HBsAb positivity (HR = 1.77, 95% CI: 1.20-2.59) and serum bilirubin levels (HR = 0.96, 95% CI: 0.92-0.99) were statistically significant predictors of HBsAg loss. The incidence of HBsAg loss continues to increase in paediatric patients with CHB after antiviral treatment. Age, sex, baseline HBsAg and bilirubin levels and HBsAb positivity are found to be associated with sustained HBsAg loss.

Decomposition of phenotypic heterogeneity in autism reveals distinct and coherent genetic programs.

Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory, and clinical manifestations of the many forms of the condition. Here, we leveraged broad phenotypic data from a large cohort with matched genetics to characterize classes of autism and their patterns of core, associated, and co-occurring traits, ultimately demonstrating that phenotypic patterns are associated with distinct genetic and molecular programs. We used a generative mixture modeling approach to identify robust, clinically-relevant classes of autism which we validate and replicate in a large independent cohort. We link the phenotypic findings to distinct patterns of de novo and inherited variation which emerge from the deconvolution of these genetic signals, and demonstrate that class-specific common variant scores strongly align with clinical outcomes. We further provide insights into the distinct biological pathways and processes disrupted by the sets of mutations in each class. Remarkably, we discover class-specific differences in the developmental timing of genes that are dysregulated, and these temporal patterns correspond to clinical milestone and outcome differences between the classes. These analyses embrace the phenotypic complexity of children with autism, unraveling genetic and molecular programs underlying their heterogeneity and suggesting specific biological dysregulation patterns and mechanistic hypotheses.

Clinical Milestone Recovery Pathway for Low-Risk Patients

Clinical Milestone Recovery Pathway for Low-Risk Patients

Access to athletic trainers and sex as modifiers of time to reach clinical milestones after sport-related concussion in collegiate athletes

ABSTRACT Objective Investigate whether an athlete's biological sex and exposure to a dedicated athletic trainer (AT) were related to clinical milestones after a sports-related concussion (SRC). Design Retrospective chart review. Methods Medical charts of collegiate athletes (n = 196 [70.9% female]) diagnosed with SRC were reviewed to extract: biological sex, dedicated AT exposure for their sport (yes/no), and time (days) to reaching clinical milestones (diagnosis, symptom resolution, unrestricted return to sport [RTS]). Mann–Whitney U tests were used to determine whether time to clinical milestones differed by sex, AT exposure, or their interaction. Proportions of same-day diagnoses and times to diagnosis, symptom resolution, and unrestricted RTS were evaluated with chi-squared and spearman’s rank correlations, respectively. Results There were no significant differences in times to reaching any clinical milestone by sex, AT exposure, or their interaction (ps > 0.05). Forty-three percent of participants were diagnosed on the day of their SRC. This did not differ by sex or AT exposure (ps > 0.29). Longer times to SRC diagnosis were associated with more days to symptom resolution (ρ = 0.236, p = 0.001) and unrestricted RTS (ρ = 0.223, p < 0.001). Conclusions Athlete sex and AT exposure were not associated with times to reach any clinical milestone; however, delayed diagnosis was associated with longer times to reach clinical recovery.

Individualized predictions for clinical milestone in amyotrophic lateral sclerosis: A multialgorithmic approach.

The phenotypic heterogeneity and complex disease trajectory complicate the ability to predict specific clinical milestone for individual patients with amyotrophic lateral sclerosis (ALS). Here we developed individualized prediction models to estimate the time to the loss of autonomy in swallowing function. Utilizing the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we built three models of distinct time-to-event prediction algorithms: accelerated failure time (AFT), cox proportional hazard (COX) and random survival forest (RSF) for an individualized risk assessment of the swallowing milestone. The target variable was defined as the time to a decline in the ALSFRS-R swallowing item score to 1 or below, indicating a need for supplementary tube feeding. Internal cross-validation revealed the median concordance index (C-index) of 0.851 (IQR, 0.842-0.859) for AFT, 0.850 (0.841-0.859) for COX and 0.846 (0.839-0.854) for RSF, and all models demonstrated good distributional calibration with predicted and observed event probabilities closely matched across different time intervals. For external validation with a registry dataset with characteristics different from PRO-ACT, the discriminative power was replicated with comparable C-indices for all models, whereas the calibration revealed a left-skewed distribution suggesting a bias towards overestimation of event probabilities in real-world data. While all models were effective at stratifying patients, the results of RSF model, unlike AFT and COX, did not match well with the KM curves of the corresponding risk groups, supporting the importance of nuanced understanding of data structure and algorithmic properties. Our models are implemented into a web application which could be applied to individualized counselling, management and clinical trial design for gastrostomy intervention. Further studies for model optimization will advance personalized care in patients with ALS.

Predicting Time to Evaluation After Pediatric Concussion: Factors Affecting Specialty Concussion Care.

The timing of clinical evaluation after pediatric concussion represents an important and potentially modifiable clinical milestone for diagnosis, selection of appropriate treatment pathways, and recovery prognosis. Patient demographics, socioeconomic status, or medical history may affect the time to the initial evaluation and subsequently influence recovery outcomes. The purpose of this investigation was to evaluate the association of patient characteristics with the time to specialty evaluation after a concussion. It was hypothesized that patients with a history of concussion, a preexisting relationship with our specialty concussion program, or a higher ZIP code-based income estimate would present for care more quickly after a concussion than patients without these characteristics. Cross-sectional study; Level of evidence, 3. Included were patients with a concussion between 6 and 18 years old who were seen for care at a single sports medicine center between January 1 and December 31, 2019. Patient demographic, socioeconomic, injury, and clinical characteristics were collected through a retrospective review of the medical records. The primary outcome was the number of days between the date of the concussion and the patient's initial specialty evaluation. Overall, 220 patients (mean age, 14.4 ± 2.5 years; 46% female) were seen for care at a mean of 9.7 ± 5.6 days (range, 1-21 days) after concussion. A shorter time to specialty evaluation was associated with a history of concussion (β = -1.72 [95% CI, -3.24 to -0.20]; P = .03) and a prior clinical relationship with the treating clinical department (β = -1.85 [95% CI, -3.52 to -0.19]; P = .03). Referral by a primary care provider was associated with a longer time to evaluation (β = 3.86 [95% CI, 2.39-5.33]; P < .0001). A history of concussion and having a preexisting clinical relationship with the deparment were associated with a shorter time to evaluation after concussion. Referral from a primary care physician was associated with a longer time to evaluation. Issues may exist in the propensity to access care after an injury, resulting in delays for initiating early treatment.

Predictors of falls in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy: a retrospective study.

Recurrent falling is a major clinical milestone in Parkinsonian syndromes. It has a detrimental impact on quality of life, further prognosis, and life expectancy. To improve fall management and prevention, we aimed at identifying clinical parameters predicting fall frequency. To this end, we retrospectively analysed records of fall events of patients with Parkinson's disease (PD), or progressive supranuclear palsy (PSP), or multiple system atrophy (MSA), during their two-week inpatient stay at the Parkinson-Klinik Ortenau, Wolfach, Germany. This data served as an objective proxy for patients' fall frequency and allowed us to estimate the impact of several demographic and clinical variables on the occurrence of falling. Of 2,111 patients admitted to our hospital, 1,810 presented with PD, 191 with PSP, and 110 with MSA. We employed a multiple (quasi-) poisson regression analysis to model the fall frequency as a function of various demographic variables (age at diagnosis, gender) and clinical variables (disease duration and sub-type, motor and cognitive impairment, autonomic dysfunction). Statistically significant predictors for falls in PD were cognitive impairment, motor impairment, and autonomic dysfunction. In PSP, significant predictors for falls were motor and autonomic dysfunction, while in MSA only disease duration predicted falls, but with only marginal statistical significance. Our results stress the importance of different factors in predicting falls in the different types of Parkinsonian syndrome. Preventive interventions should address these disease-specific targets for optimal success.

β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.

Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, β-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the β-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, β3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). In wild type hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with wild type, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the β3AR-agonist, BRL-37344, increased myocyte BDNF content, while β3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the β1AR blocker, metoprolol, via upregulated β3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac β3AR stimulation, or β-blockers (via upregulated β3AR), is another BDNF-based means to fend off chronic postischemic heart failure.

Predicting the risk of a clinical event using longitudinal data: the generalized landmark analysis

BackgroundIn the development of prediction models for a clinical event, it is common to use the static prediction modeling (SPM), a regression model that relates baseline predictors to the time to event. In many situations, the data used in training and validation are from longitudinal studies, where predictor variables are time-varying and measured at clinical visits. But these data are not used in SPM. The landmark analysis (LA), previously proposed for dynamic prediction with longitudinal data, has interpretational difficulty when the baseline is not a risk-changing clinical milestone, as is often the case in observational studies of chronic disease without intervention.MethodsThis paper studies the generalized landmark analysis (GLA), a statistical framework to develop prediction models for longitudinal data. The GLA includes the LA as a special case, and generalizes it to situations where the baseline is not a risk-changing clinical milestone with a more useful interpretation. Unlike the LA, the landmark variable does not have to be time since baseline in the GLA, but can be any time-varying prognostic variable. The GLA can also be viewed as a longitudinal generalization of localized prediction, which has been studied in the context of low-dimensional cross-sectional data. We studied the GLA using data from the Chronic Renal Insufficiency Cohort (CRIC) Study and the Wisconsin Allograft Replacement Database (WisARD) and compared the prediction performance of SPM and GLA.ResultsIn various validation populations from longitudinal data, the GLA generally had similarly or better predictive performance than SPM, with notable improvement being seen when the validation population deviated from the baseline population. The GLA also demonstrated similar or better predictive performance than LA, due to its more general model specification.ConclusionsGLA is a generalization of the LA such that the landmark variable does not have to be the time since baseline. It has better interpretation when the baseline is not a risk-changing clinical milestone. The GLA is more adaptive to the validation population than SPM and is more flexible than LA, which may help produce more accurate prediction.

PhoreMost Achieves Target Discovery Milestone with Boehringer Ingelheim

GEN EdgeVol. 5, No. 1 TopicsPhoreMost Achieves Target Discovery Milestone with Boehringer IngelheimUsing the targets found by PhoreMost, Boehringer Ingelheim will now develop potential new treatments, which could result in additional success-based pre-clinical, clinical, and commercial milestone paymentsJonathan D GrinsteinJonathan D GrinsteinSearch for more papers by this authorPublished Online:6 Jan 2023https://doi.org/10.1089/genedge.5.1.05AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 5Issue 1Jan 2023 Information© 2023 by GEN PublishingTo cite this article:Jonathan D Grinstein.PhoreMost Achieves Target Discovery Milestone with Boehringer Ingelheim.GEN Edge.Jan 2023.21-23.http://doi.org/10.1089/genedge.5.1.05Published in Volume: 5 Issue 1: January 6, 2023PDF download

Development of Clinical Milestones in Parkinson’s Disease After Bilateral Subthalamic Deep Brain Stimulation

Objective Deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson’s disease (PD) patients does not halt disease progression, as these patients will progress and develop disabling non-levodopa responsive symptoms. These features may act as milestones that represent the overall functionality of patients after DBS. The objective of this study was to investigate the development of clinical milestones in advanced PD patients who underwent bilateral STN-DBS.Methods The study evaluated PD patients who underwent STN-DBS at baseline up to their last follow-up using the Unified Parkinson’s Disease Rating Scale and Hoehn and Yahr scale. The symptoms of hallucinations, dysarthria, dysphagia, frequent falls, difficulty walking, cognitive impairment and the loss of autonomy were chosen as the clinical milestones.Results A total of 106 patients with a mean age of 47.21 ± 10.52 years at disease onset, a mean age of 58.72 ± 8.74 years at surgery and a mean disease duration of 11.51 ± 4.4 years before surgery were included. Initial improvement of motor symptoms was seen after the surgery with the appearance of clinical milestones over time. Using the moderately disabling criteria, 81 patients (76.41%) developed at least one clinical milestone, while 48 patients (45.28%) developed a milestone when using the severely disabling criteria.Conclusion STN-DBS has a limited effect on axial and nonmotor symptoms of the PD patients, in contrast to the effect on motor symptoms. These symptoms may serve as clinical milestones that can convey the status of PD patients and its impact on the patients and their caregivers. Therefore, advanced PD patients, even those treated with bilateral STN-DBS, will still require assistance and cannot live independently in the long run.

High preoperative gait variability is a prognostic predictor of gait and balance in Parkinson disease patients with deep brain stimulation

IntroductionThe objective biomarker for prediction of gait and balance in the long-term follow-up of Parkinson's disease(PD) patients with subthalamic nucleus deep brain stimulation(STN-DBS) has not yet been elucidated. We investigated the value of pre-operative quantitative gait parameters for the prediction of long-term prognosis of gait in PD patients with DBS. MethodsWe retrospectively collected gait videos(both medication ON/OFF states) of PD patients recorded as preoperative evaluation before STN DBS. We enrolled patients who were followed-up for more than 5 years after the surgery from 2006 to 2014. We derived objective gait parameters from video-based gait analysis algorithm. We defined the clinical milestones of frequent falling, impaired walking, and loss of autonomy based on the Unified Parkinson's disease rating scale and Hoehn and Yahr stage, which were regularly followed up to 156 months after surgery. We calculated hazard ratios(HRs) of baseline gait parameters for predicting the clinical milestones. ResultsA total of 96 gait videos from 63 PD patients were analyzed. The mean follow-up duration(standard deviation) was 88.0(34.2) months after surgery. Relatively high (>mean + 1 standard deviation) variability for step length, step time and stride time (HR = 2.92[1.02–8.33], 3.91[1.38–11.11] and 7.16[2.09–24.52],respectively) in medication-ON state significantly predicted reaching any of the three clinical milestones of frequent falling, impaired walking and loss of autonomy. Gait parameters from the medication-OFF state did not predict any clinical milestone. ConclusionsHigh preoperative gait variability from the medication-ON state predicts long-term outcomes for gait and balance in PD patients with STN DBS.

Parkinson’s disease clinical milestones and mortality

Identification of factors predicting and driving mortality in PD is important for patient information, disease management, and design of future clinical trials. This study included newly diagnosed PD patients and normal controls (NC) from a population-based study with repeated assessments over a 10-year period. We used the Kaplan–Meier method to estimate survival, Cox proportional hazards regression models to identify baseline risk factors of mortality, and Cox regression models with time-dependent covariates to evaluate the impact of four clinical milestones of advanced PD (visual hallucinations, recurrent falls, dementia, and nursing home placement) on mortality risk. During the 10-year study, 65 (34.2%) of 190 patients and 25 (12.3%) of 203 NC died, with an unadjusted hazard ratio (HR) of 2.85 (95% CI 1.80–4.52) and a HR of 2.48 (95% CI 1.55–3.95) when adjusted for confounders, including comorbidities. Higher age, more severe motor impairment, and postural instability-gait difficulty (PIGD) phenotype were independent baseline predictors of mortality. Each clinical milestone alone more than doubled the risk of death and had a cumulative effect on mortality, with a HR of 10.83 (95% CI 4.39–26.73) in those experiencing all four milestones. PD patients have an increased mortality risk that is disease-related and becomes evident early during the course of the disease. While motor severity and PIGD phenotype were early risk factors of mortality, clinical milestones signaled a substantially increased risk of death later during the disease course, highlighting their potential significance in clinical disease staging and prognosis.

CAR T cells reach clinical milestone in prostate cancer.

CAR T cells reach clinical milestone in prostate cancer.

Effect of tactile–kinesthetic stimulation on growth, neurobehavior and development among preterm neonates

BackgroundPreterm neonates are at risk of delayed growth and development. Hence, early tactile–kinesthetic stimulation (TKS) is required to improve their growth and development. ObjectiveTo evaluate the effect of TKS on growth, neurobehavior and development among preterm neonates. MethodAn interventional study was conducted from August 2015 to July 2017 in the neonatal unit of Dr. Cipto Mangunkusumo Hospital. Preterm neonates were recruited via random sampling and divided into two groups (the intervention group and control group). TKS was performed for 15 min, three times a day, for 10 days. The anthropometric measurements, neurobehavior (Dubowitz score) and development (Capute Scale score) of neonates in both groups were assessed. ResultsThere were 126 preterm neonates (n = 63 in each group). During the 10-day TKS period, the intervention group had a significant increment in weight and length compared to the control group (p < 0.05) at 11–14 days, at term and 3 months. Moreover, increased tone, reflexes, and improvement in behavior based on the Dubowitz score were observed during monitoring. However, the result did not differ significantly (p > 0.05). There was no significant difference in terms of cognitive and language development in both groups (Developmental Quotient of Clinical Linguistic Adaptive Milestone Scale, Developmental Quotient of Clinical Adaptive Test and Full Scale Developmental Quotient scores, p > 0.05). ConclusionTKS was significantly effective in promoting growth, particularly weight and length, among preterm neonates. However, it did not significantly influence neurobehavior and development at 3 months of chronological age.

Achievement of maturational milestones among very low birth weight infants.

Very low birth weight (VLBW) infants must achieve several maturational milestones to be discharged home from the NICU. Describe the timing of maturational milestones in VLBW infants and the impact of clinical variables and milestone achievement on postmenstrual age (PMA) at discharge. For VLBW infants without severe lung disease discharged home from a level IV NICU, we assessed PMA at the achievement of thermoregulation, cardiorespiratory stability, feeding, and discharge. In 400 infants (median GA 28.4 weeks), lower birth weight, white race, and having multiple comorbidities of prematurity predicted later discharge PMA. The most common milestone sequence was CPAP discontinuation, caffeine discontinuation, thermoregulation, apnea resolution, and full oral feeds. PMA at apnea resolution and full oral feeds correlated highly with discharge PMA. In a single-center VLBW cohort, comorbidities of prematurity impacted the timing of NICU discharge through delay in oral feeding and cardiorespiratory stability.

Perioperative Precedex: Whole New Ball Game or Whole New Ball of Wax?

Perioperative Precedex: Whole New Ball Game or Whole New Ball of Wax?

Milestone Learning Trajectories of Residents at Five Anesthesiology Residency Programs

Construct: Every six months, residency programs report their trainees’ Milestones Level achievement to the Accreditation Council for Graduate Medical Education (ACGME). Milestones should enable the learner and training program to know an individual’s competency development trajectory. Background: Milestone Level ratings for residents grouped by specialty (e.g., Internal Medicine and Emergency Medicine) show that, in aggregate, senior residents receive higher ratings than junior residents. Anesthesiology Milestones, as assessed by both residents and faculty, also have a positive linear relationship with postgraduate year. However, these studies have been cross-sectional rather than longitudinal cohort studies, and studies of how individual residents progress during the course of training are needed. Longitudinal data analysis of performance assessment trajectories addresses a relevant validity question for the Next Accreditation System. We explored the application of learning analytics to longitudinal Milestones data to: 1) measure the frequency of “straight-lining”; 2) assess the proportion of residents that reach “Level 4” (ready for unsupervised practice) by graduation for each subcompetency; 3) identify variability among programs and individual residents in their baseline Milestone Level and rates of improvement; and 4) determine how hypothetically constructed growth curve models fit to the Milestones data reported to ACGME. Approach: De-identified Milestone Level ratings in each of the 25 subcompetencies submitted semiannually to the ACGME from July 1, 2014 to June 30, 2017 were retrospectively analyzed for graduating residents (n = 67) from a convenience sample of five anesthesia residency programs. The data reflected longitudinal resident Milestone progression from the beginning of the first year to the end of the third and final year of clinical anesthesiology training. The frequency of straight-lining, defined as the resident receiving the same exact Milestone Level rating for all 25 subcompetencies on a given 6-month report, was calculated for each program. Every resident was evaluated six times during training with the possibility of six straight-lined ratings. Findings: The number of residents in each program ranged from 5-21 (Median 13, range 16). Mean Milestone Level ratings for subcompetencies were significantly different at each six-month assessment (p < 0.001). Frequency of straight-lining varied significantly by program from 9% − 57% (Median 22%). Depending on the program, 53%-100% (median 86%) of residents reached the graduation target Level 4 or higher in all 25 anesthesiology subcompetencies. Nine to 18% of residents did not achieve a Level 4 rating for at least one subcompetency at any time during their residency. Across programs, significant variability was found in first-year clinical anesthesia training Milestone Levels, as well in the rate of improvement for five of the six core competencies. Conclusions: Anesthesia residents’ Milestone Level growth trajectories as reported to the ACGME vary significantly across individual residents as well as by program. The present study offers a case example that raises concerns regarding the validity of the Next Accreditation System as it is currently used by some residency programs.

SMA – THERAPY: P.261 Long-term follow-up of onasemnogene abeparvovec gene therapy in spinal muscular atrophy type 1 (SMA1)

Onasemnogene abeparvovec (formerly AVXS-101) is designed to address the genetic root cause of SMA1. In the phase 1 trial (START; NCT02122952), patients who received a one time high-dose (proposed therapeutic dose) infusion (n=12) demonstrated significantly improved outcomes versus untreated natural history. START patients could electively enrol into long-term follow-up (LTFU; NCT03421977). Primary objective: long-term safety. Patients have annual visits (5 years) followed by annual phone contact (additional 10 years). Assessments include medical history/record review, physical examination, clinical laboratory evaluation, pulmonary assessments, and milestone maintenance. As of 31 Dec 2019, 13 patients (low dose, n=3; therapeutic dose, n=10) were enrolled. The oldest patients were aged 6.2 (low dose) and 5.6 (therapeutic dose) years. Serious adverse events (AEs) were reported in 8/13 patients; no new treatment-related AEs have emerged, supporting a favorable risk:benefit profile. All patients who received the therapeutic dose have survived and are free of permanent ventilation (mean [range] age at last datacut: 4.8 [4.3–5.6] years; mean [range] time since dosing: 4.5 [4.1–5.2] years). These patients have either maintained all previously attained milestones or gained new milestones; 2 patients have newly achieved standing with assistance while not receiving concomitant survival motor neuron 2 protein (SMN2) upregulating therapy at any point. Of the 10 enrolled patients who received therapeutic dose, 6 did not require regular, daily respiratory support more than 4 years after dosing. Additionally, 6 have never received concomitant SMN2 upregulating therapy. Data suggest that onasemnogene abeparvovec shows a favorable risk:benefit profile, and continues to demonstrate efficacy with new milestone developments.

DMD & BMD – CLINICAL: P.55 Prognostic factors for loss of ability to rise from supine in Duchenne muscular dystrophy (DMD)

Loss of ability to rise from supine is an important early clinical milestone in DMD. We investigated prognostic factors for time to loss of rise ability in 316 ambulatory boys (median age = 7.9 years, range 4.4-19.4 years; 64% on deflazacort, 36% on prednisone) with DMD drawn from four natural history databases (UZ Leuven, PRO-DMD-01 data provided by CureDuchenne, iMDEX, and ImagingDMD). Patients’ inability to rise was either explicitly recorded, or inferred based on having a recorded rise from supine completion time greater than 30 seconds.