Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential Through Synergistic Antitumor Effects and Reduction of Systemic Toxicity.

Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than death, and high doses in patients elicit on-target dose-limiting neutropenia. Recent work from our group indicates that combination of p53-MDM2 inhibitors with the class-I HDAC inhibitor Entinostat (which itself has dose-limiting toxicity issues) has the potential to significantly augment cell death in p53 wild-type colorectal cancer cells. We investigated whether coencapsulation of RG7388 and Entinostat within polymeric nanoparticles (NPs) could overcome efficacy and toxicity limitations of this drug combination. Combinations of RG7388 and Entinostat across a range of different molar ratios resulted in synergistic increases in cell death when delivered in both free drug and nanoencapsulated formats in all colorectal cell lines tested. Importantly, we also explored the in vivo impact of the drug combination on murine blood leukocytes, showing that the leukopenia induced by the free drugs could be significantly mitigated by nanoencapsulation. Taken together, this study demonstrates that formulating these agents within a single nanoparticle delivery platform may provide clinical utility beyond use as nonencapsulated agents.

Analysis of SARS-CoV-2 antibody seroprevalence in Northern Ireland during 2020-2021.

Background: With the spread of SARS-CoV-2 impacting upon public health directly and socioeconomically, further information was required to inform policy decisions designed to limit virus spread during the pandemic. This study sought to contribute to serosurveillance work within Northern Ireland to track SARS-CoV-2 progression and guide health strategy. Methods: Sera/plasma samples from clinical biochemistry laboratories were analysed for anti-SARS-CoV-2 antibodies. Samples were assessed using an Elecsys anti-SARS-CoV-2 or anti-SARS-CoV-2 S ECLIA (Roche) on an automated cobas e 801 analyser. Samples were also assessed via an anti-SARS-CoV-2 ELISA (Euroimmun). A subset of samples assessed via the Elecsys anti-SARS-CoV-2 ECLIA were subsequently analysed in an ACE2 pseudoneutralisation assay using a V-PLEX SARS-CoV-2 Panel 7 for IgG and ACE2 (Meso Scale Diagnostics). Results: Across three testing rounds (June-July 2020, November-December 2020 and June-July 2021 (rounds 1-3 respectively)), 4844 residual sera/plasma specimens were assayed for anti-SARS-CoV-2 antibodies. Seropositivity rates increased across the study, peaking at 11.6 % (95 % CI 10.4 %-13.0 %) during round 3. Varying trends in SARS-CoV-2 seropositivity were noted based on demographic factors. For instance, highest rates of seropositivity shifted from older to younger demographics across the study period. In round 3, Alpha (B.1.1.7) variant neutralising antibodies were most frequently detected across age groups, with median concentration of anti-spike protein antibodies elevated in 50-69 year olds and anti-S1 RBD antibodies elevated in 70+ year olds, relative to other age groups. Conclusions: With seropositivity rates of <15 % across the assessment period, it can be concluded that the significant proportion of the Northern Ireland population had not yet naturally contracted the virus by mid-2021.

Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors.

PURPOSE: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. EXPERIMENTAL DESIGN: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction. RESULTS: Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. CONCLUSIONS: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.

Impact of the COVID-19 pandemic on early intervention utilization and need for referral after NICU discharge in VLBW infants.

OBJECTIVE: To examine the impact of COVID-19 pandemic on early intervention (EI) services in VLBW infants. STUDY DESIGN: 208 VLBW infants seen in NICU follow-up (FU) pre-COVID-19 were compared to 132 infants seen during COVID-19 at 4, 8 and 20 months corrected age (CA) in terms of enrollment in Child and Family Connections (CFC; intake agency for EI), EI therapies, need for CFC referral and Bayley scores. RESULTS: Infants seen during COVID-19 at 4, 8 and 20 months CA were 3.4 (OR, 95% CI 1.64, 6.98), 4.0 (1.77, 8.95) and 4.8 (2.10, 11.08) times more likely to need CFC referral at FU based on severity of developmental delay. Infants followed during COVID-19 had significantly lower mean Bayley cognitive and language scores at 20 months CA. CONCLUSIONS: VLBW infants seen during COVID-19 had significantly higher odds of needing EI and significantly lower cognitive and language scores at 20 months CA.

PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration.

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1ß, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

The role of texture summary statistics in material recognition from drawings and photographs.

Material depictions in artwork are useful tools for revealing image features that support material categorization. For example, artistic recipes for drawing specific materials make explicit the critical information leading to recognizable material properties (Di Cicco, Wjintjes, & Pont, 2020) and investigating the recognizability of material renderings as a function of their visual features supports conclusions about the vocabulary of material perception. Here, we examined how the recognition of materials from photographs and drawings was affected by the application of the Portilla-Simoncelli texture synthesis model. This manipulation allowed us to examine how categorization may be affected differently across materials and image formats when only summary statistic information about appearance was retained. Further, we compared human performance to the categorization accuracy obtained from a pretrained deep convolutional neural network to determine if observers' performance was reflected in the network. Although we found some similarities between human and network performance for photographic images, the results obtained from drawings differed substantially. Our results demonstrate that texture statistics play a variable role in material categorization across rendering formats and material categories and that the human perception of material drawings is not effectively captured by deep convolutional neural networks trained for object recognition.

Spatial Scene Memories Are Biased Towards a Fixed Amount of Semantic Information.

Scene memory has known spatial biases. Boundary extension is a well-known bias whereby observers remember visual information beyond an image's boundaries. While recent studies demonstrate that boundary contraction also reliably occurs based on intrinsic image properties, the specific properties that drive the effect are unknown. This study assesses the extent to which scene memory might have a fixed capacity for information. We assessed both visual and semantic information in a scene database using techniques from image processing and natural language processing, respectively. We then assessed how both types of information predicted memory errors for scene boundaries using a standard rapid serial visual presentation (RSVP) forced error paradigm. A linear regression model indicated that memories for scene boundaries were significantly predicted by semantic, but not visual, information and that this effect persisted when scene depth was considered. Boundary extension was observed for images with low semantic information, and contraction was observed for images with high semantic information. This suggests a cognitive process that normalizes the amount of semantic information held in memory.

Modular Chemical Construction of IgG-like Mono- and Bispecific Synthetic Antibodies (SynAbs).

In recent years there has been rising interest in the field of protein-protein conjugation, especially related to bispecific antibodies (bsAbs) and their therapeutic applications. These constructs contain two paratopes capable of binding two distinct epitopes on target molecules and are thus able to perform complex biological functions (mechanisms of action) not available to monospecific mAbs. Traditionally these bsAbs have been constructed through protein engineering, but recently chemical methods for their construction have started to (re)emerge. While these have been shown to offer increased modularity, speed, and for some methods even the inherent capacity for further functionalization (e.g., with small molecule cargo), most of these approaches lacked the ability to include a fragment crystallizable (Fc) modality. The Fc component of IgG antibodies offers effector function and increased half-life. Here we report a first-in-class disulfide rebridging and click-chemistry-based method for the generation of Fc-containing, IgG-like mono- and bispecific antibodies. These are in the FcZ-(FabX)-FabY format, i.e., two distinct Fabs and an Fc, potentially all from different antibodies, attached in a homogeneous and covalent manner. We have dubbed these molecules synthetic antibodies (SynAbs). We have constructed a T cell-engager (TCE) SynAb, FcCD20-(FabHER2)-FabCD3, and have confirmed that it exhibits the expected biological functions, including the ability to kill HER2+ target cells in a coculture assay with T cells.

ezPreemie study protocol: a randomised controlled factorial trial testing web-based parent training and coaching with parents of children born very preterm.

INTRODUCTION: Children born very preterm (VPT; gestational age <32 weeks) are twice as likely to demonstrate behaviour problems such as aggression, non-compliance, temper tantrums and irritability compared with their term-born peers. While behavioural parent training (BPT), also referred to as behaviour therapy is a gold standard for prevention and treatment of childhood problem behaviours, there are limited accessible and effective BPT interventions for families with children born VPT. The purpose of this paper is to describe a multicentre, randomised controlled protocol for a factorial design trial evaluating the independent and combined effects of the ezParent BPT intervention plus brief, weekly coaching calls on parent and child outcomes for families with toddlers born VPT. METHODS AND ANALYSIS: The study employs a 2×2 factorial randomised design. Parents (n=220) of children aged 20-30 months corrected age who were born VPT (<32 weeks) will be recruited from two large metropolitan Neonatal Intensive Care Units follow-up clinics and randomised to one of four conditions: (1) ezParent (2) ezParent +coach, (3) Active control or (4) Active Control +coach. Data on parenting and child behaviour outcomes will be obtained from all participants at baseline and 3, 6 and 12 months postbaseline. All analyses will use an intention-to-treat approach, independent of their actual dose of each intervention. ETHICS AND DISSEMINATION: The study protocol has been approved by The Ohio State University Institutional Review Board (IRB) using a single IRB. Study results will be disseminated through presentations at regional and national conferences, publications in peer-reviewed journals, and sharing research reports with participating families and recruiting sites. TRIAL REGISTRATION NUMBER: NCT05217615.

Neurodevelopmental Outcome in Very Low Birth Weight Infants Exposed to Donor Milk.

OBJECTIVE: This study was aimed to evaluate the impact of donor milk (DM) received in the first 28 days of life (DOL) on neurodevelopmental (ND) outcome at 20-months corrected age (CA) in very low birth weight (VLBW) infants. STUDY DESIGN: A total of 84 infants born in 2011 to 2012 who received only mother's own milk (MOM) and/or preterm formula (PF) was compared with 69 infants born in 2013 to 2014 who received MOM and/or DM. Daily enteral intake of MOM, DM, and PF was collected through 28 DOL. ND outcomes were assessed with the Bayley-III. Multiple regression analyses adjusted for the effect of social and neonatal risk factors alongside era of birth on ND outcome. RESULTS: Infants exposed to DM were born to older mothers (p < 0.01) and had higher incidence of severe brain injury (p = 0.013). Although DM group infants received first feed at earlier DOL (p < 0.001), there were no differences in MOM intake at DOL 14 or 28 between the two groups. In regression analyses, DM group did not predict 20-month ND outcome. CONCLUSION: There were no differences in ND outcome between infants born before and after the introduction of DM. This may have been due to the similar percent of MOM at DOL 14 and 28 in the two eras. KEY POINTS: · Donor milk use is increasing in VLBW infant. The impact of donor milk on neurodevelopment is unclear.. · Provision of mother's own milk was high at days of life 14 and 28 for both groups of infants.. · Donor milk was not associated with improved neurodevelopmental outcome..

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance.

The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours.

Enhanced target-specific delivery of docetaxel-loaded nanoparticles using engineered T cell receptors.

For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are attractive cancer targets as they can present peptides from tumour-selective proteins on the cell surface, which can be recognised by T cells via T cell receptors (TCRs). In this study, docetaxel-loaded polymeric NPs were conjugated to recombinant affinity-enhanced TCRs to target breast cancer cells presenting a tumour-selective peptide-HLA complex. The TCR-conjugated nanoparticles enabled enhanced delivery of docetaxel and induced cell death through tumour-specific peptide-HLA targeting. These in vitro data demonstrate the potential of targeting tumour-restricted peptide-HLA epitopes using high affinity TCR-conjugated nanoparticles, representing a novel treatment strategy to deliver therapeutic drugs specifically to cancer cells.

Dynamic Electrode-to-Image (DETI) mapping reveals the human brain's spatiotemporal code of visual information.

A number of neuroimaging techniques have been employed to understand how visual information is transformed along the visual pathway. Although each technique has spatial and temporal limitations, they can each provide important insights into the visual code. While the BOLD signal of fMRI can be quite informative, the visual code is not static and this can be obscured by fMRI's poor temporal resolution. In this study, we leveraged the high temporal resolution of EEG to develop an encoding technique based on the distribution of responses generated by a population of real-world scenes. This approach maps neural signals to each pixel within a given image and reveals location-specific transformations of the visual code, providing a spatiotemporal signature for the image at each electrode. Our analyses of the mapping results revealed that scenes undergo a series of nonuniform transformations that prioritize different spatial frequencies at different regions of scenes over time. This mapping technique offers a potential avenue for future studies to explore how dynamic feedforward and recurrent processes inform and refine high-level representations of our visual world.

A Role for Somatostatin-Positive Interneurons in Neuro-Oscillatory and Information Processing Deficits in Schizophrenia.

Alterations in neocortical GABAergic interneurons (INs) have been affiliated with neuropsychiatric diseases, including schizophrenia (SZ). Significant progress has been made linking the function of a specific subtype of GABAergic cells, parvalbumin (PV) positive INs, to altered gamma-band oscillations, which, in turn, underlie perceptual and feedforward information processing in cortical circuits. Here, we review a smaller but growing volume of literature focusing on a separate subtype of neocortical GABAergic INs, somatostatin (SST) positive INs. Despite sharing similar neurodevelopmental origins, SSTs exhibit distinct morphology and physiology from PVs. Like PVs, SSTs are altered in postmortem brain samples from multiple neocortical regions in SZ, although basic and translational research into consequences of SST dysfunction has been relatively sparse. We highlight a growing body of work in rodents, which now indicates that SSTs may also underlie specific aspects of cortical circuit function, namely low-frequency oscillations, disinhibition, and mediation of cortico-cortical feedback. SSTs may thereby support the coordination of local cortical information processing with more global spatial, temporal, and behavioral context, including predictive coding and working memory. These functions are notably deficient in some cases of SZ, as well as other neuropsychiatric disorders, emphasizing the importance of focusing on SSTs in future translational studies. Finally, we highlight the challenges that remain, including subtypes within the SST class.

Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer.

BACKGROUND: Antibody-drug conjugate (ADC) construction poses numerous challenges that limit clinical progress. In particular, common bioconjugation methods afford minimal control over the site of drug coupling to antibodies. Here, such difficulties are overcome through re-bridging of the inter-chain disulfides of cetuximab (CTX) with auristatin-bearing pyridazinediones, to yield a highly refined anti-epidermal growth factor receptor (EGFR) ADC. METHODS: In vitro and in vivo assessment of ADC activity was performed in KRAS mutant pancreatic cancer (PaCa) models with known resistance to CTX therapy. Computational modelling was employed for quantitative prediction of tumour response to various ADC dosing regimens. RESULTS: Site-selective coupling of an auristatin to CTX yielded an ADC with an average drug:antibody ratio (DAR) of 3.9, which elicited concentration- and EGFR-dependent cytotoxicity at sub-nanomolar potency in vitro. In human xenografts, the ADC inhibited tumour growth and prolonged survival, with no overt signs of toxicity. Key insights into factors governing ADC efficacy were obtained through a robust mathematical framework, including target-mediated dispositional effects relating to antigen density on tumour cells. CONCLUSIONS: Together, our findings offer renewed hope for CTX in PaCa therapy, demonstrating that it may be reformatted as a next-generation ADC and combined with a predictive modelling tool to guide successful translation.

Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature.

Whilst there is an extensive body of preclinical nanomedicine research, translation to clinical settings has been slow. Here we present a novel approach to the targeted nanoparticle (NP) concept: utilizing both a novel targeting ligand, VNAR (Variable New Antigen Receptor), a shark-derived single chain binding domain, and an under-investigated target in delta-like ligand 4 (DLL4). We describe the development of an anti-DLL4 VNAR and the site-specific conjugation of this to poly(lactic-co-glycolic) acid PEGylated NPs using surface maleimide functional groups. These nanoconjugates were shown to specifically bind DLL4 with high affinity and were preferentially internalized by DLL4-expressing pancreatic cancer cell lines and endothelial cells. Furthermore, a distinct anti-angiogenic effect endowed by the anti-DLL4 VNAR was evident in in vitro tubulogenic assays. Taken together these findings highlight the potential of anti-DLL4 targeted polymeric NPs as a novel therapeutic approach in pancreatic cancer.

DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models.

Pancreatic cancer is usually advanced and drug resistant at diagnosis. A potential therapeutic approach outlined here uses nanoparticle (NP)-based drug carriers, which have unique properties that enhance intra-tumor drug exposure and reduce systemic toxicity of encapsulated drugs. Here we report that patients whose pancreatic cancers express elevated levels of Death Receptor 5 (DR5) and its downstream regulators/effectors FLIP, Caspase-8, and FADD had particularly poor prognoses. To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655). Binding and clustering of the DR5 is a prerequisite for efficient apoptosis initiation, and the αDR5-NPs were indeed found to activate apoptosis in multiple pancreatic cancer models, whereas the free antibody did not. The extent of apoptosis induced by αDR5-NPs was enhanced by down-regulating FLIP, a key modulator of death receptor-mediated activation of caspase-8. Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs. CPT-loaded αDR5-NPs significantly increased apoptosis and decreased cell viability in vitro in a caspase-8- and FADD-dependent manner consistent with their expected mechanism-of-action. Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer.

Adaptation and Acceptability of a Digitally Delivered Intervention for Parents of Very Low Birth Weight Infants.

BACKGROUND: Very low birth weight (VLBW) infants are at elevated risk for behavioral problems as early as the second year of life. The purpose of this feasibility study was to evaluate the adaptation and acceptability of an existing digitally delivered behavioral parent training program-the ezParent program, with the addition of weekly coaching calls-for parents of former VLBW infants in their second year of life. OBJECTIVES: To assess the adaptation of ezParent for this population, we assessed parent access and use of ezParent and coaching calls, parent learning of strategies from ezParent, and changes in parenting practices or child behavior after using ezParent plus coaching calls. For acceptability, we assessed if parents viewed ezParent content as applicable to their experiences of parenting a former VLBW infant and how parents viewed coaching calls. METHODS: Ten parents of VLBW infants (20 months of age adjusted for prematurity) were recruited from a neonatal intensive care follow-up clinic. Parents completed the six modules of ezParent plus weekly coaching calls over 10-week intervention period. ezParent usage data were electronically uploaded to secure servers. Completion and timing of coaching calls were monitored using a tracking log. Parents completed child behavior and parenting belief and practice questionnaires pre- and postintervention. Calls were recorded and transcribed to assess for learning of parenting strategies, acceptability with the VLBW population, and acceptability of coaching calls. RESULTS: On average, parents completed 85% of the ezParent modules and 89% of the scheduled coaching calls, respectively. Parents spontaneously introduced 44% of the ezParent strategies during their coaching calls. Modest within-group effect sizes were detected for improvement in parenting self-efficacy and child externalizing behavior. Parents felt the ezParent content applied to their experiences parenting a preterm infant and had high satisfaction with coaching calls as a method of reinforcing program content and assessing knowledge and supporting accountability for program participation. DISCUSSION: ezParent with coaching calls is a feasible method of delivering behavioral parent training to parents of former VLBW infants in their second year of life. Coaching calls have high potential to be a low-cost, time-efficient component of digitally delivered programs that would allow for rapid integration into clinical practice.