Heart rate characteristics predict risk of mortality in preterm infants in low and high target oxygen saturation ranges.

Background: The Neonatal Oxygenation Prospective Meta-analysis found that in infants <28 weeks gestational age, targeting an oxygen saturation (S pO2 ) range of 85-89% versus 91-95% resulted in lower rates of retinopathy of prematurity but increased mortality. We aimed to evaluate the accuracy of the heart rate characteristics index (HRCi) in assessing the dynamic risk of mortality among infants managed with low and high target S pO2 ranges. Methods: We linked the SUPPORT and HRCi datasets from one centre in which the randomised controlled trials overlapped. We examined the maximum daily HRCi (MaxHRCi24) to predict mortality among patients randomised to the lower and higher target S pO2 groups by generating predictiveness curves and calculating model performance metrics, including area under the receiver operating characteristics curve (AUROC) at prediction windows from 1-60 days. Cox proportional hazards models tested whether MaxHRCi24 was an independent predictor of mortality. We also conducted a moderation analysis. Results: There were 84 infants in the merged dataset. MaxHRCi24 predicted mortality in infants randomised to the lower target S pO2 (AUROC of 0.79-0.89 depending upon the prediction window) and higher target S pO2 (AUROC 0.82-0.91). MaxHRCi24 was an important additional predictor of mortality in multivariable modelling. In moderation analysis, in a model that also included demographic predictor variables, the individual terms and the interaction term between MaxHRCi24 and target S pO2 range all predicted mortality. Conclusions: Associations between HRCi and mortality, at low and high S pO2 target ranges, suggest that future research may find HRCi metrics helpful to individually optimise target oxygen saturation ranges for hospitalised preterm infants.

Impact of race on heart rate characteristics monitoring in very low birth weight infants.

BACKGROUND: A multicenter RCT showed that displaying a heart rate characteristics index (HRCi) predicting late-onset sepsis reduced mortality for VLBW infants. We aimed to assess whether HRCi display had a differential impact for Black versus White infants. METHODS: We performed secondary data analysis of Black and White infants enrolled in the HeRO RCT. We evaluated the predictive performance of the HRCi for infants with Black or White maternal race. Using models adjusted for birth weight, we assessed outcomes and interventions for a race × randomization interaction. RESULTS: Among 2607 infants, Black infants had lower birth weight, gestational age, length of stay, and ventilator days, while sepsis and mortality were similar. The HRCi performed equally for sepsis prediction in Black and White infants. We found no differential effect of randomization by race on sepsis, mortality, antibiotic days, length of stay, or ventilator days. However, there was a differential randomization effect by race for blood cultures per patient: White RR 1.11 (95% CrI 1.04-1.18), Black RR 1.00 (0.93-1.07). CONCLUSIONS: The HRCi performed similarly for sepsis prediction in Black and White infants. Randomization to HRCi display increased blood cultures in White but not in Black infants, while the impact on other outcomes or interventions was similar. IMPACT: Predictive analytics, such as heart rate characteristics (HRC) monitoring for late-onset neonatal sepsis, should have equal impact among patients of different race. Infants with Black or White maternal race randomized to HRC display had similar outcomes, but randomization to the study arm increased a related clinical intervention, blood cultures, in White but not in Black infants. This study provides evidence of a differential effect of predictive models on clinical care by race. The work will promote consideration and analysis of equity in the implementation of predictive analytics.

Near-field electrospinning of polydioxanone small diameter vascular graft scaffolds.

The ideal "off the shelf" tissue engineering, small-diameter (SD) vascular graft hinges on designing a scaffold to act as a template that facilitates transmural ingrowth of capillaries to regenerate an endothelized neointimal surface. Towards this goal, we explored two types of near-field electrospun (NFES) polydioxanone (PDO) architectures, as SD vascular graft scaffolds. The first architecture type consisted of a 200 × 200 µm and 500 × 500 µm grid geometry with random fiber infill, while the second architecture consisted of aligned fibers written in a 45°/45° and 20°/70° offset from the long axis written, both on a 4 mm diameter cylindrical mandrel. These vascular graft scaffolds were evaluated for their effective pore size, mechanical properties, and platelet-material interactions compared to traditionally electrospun (TES) scaffolds and Gore-Tex® vascular grafts. It was found that effective pore size, given by 9.9 and 97 µm microsphere filtration through the scaffold wall for NFES scaffolds, was significantly more permeable compared to TES scaffolds and Gore-Tex® vascular grafts. Furthermore, ultimate tensile strength, percent elongation, suture retention, burst pressure, and Young's modulus were all tailorable compared to TES scaffold characterization. Lastly, platelet adhesion was attenuated on NFES scaffolds compared to TES scaffold which approximates the low level of platelet adhesion measured on Gore-Tex®, with all samples showing minimal platelet activation given by P-selectin surface expression. Together, these results suggest a highly tailorable process for the creation of the next generation of small-diameter vascular grafts.

Methods for Quantifying Neutrophil Extracellular Traps on Biomaterials.

Neutrophils rapidly accumulate at sites of inflammation, including biomaterial implantation sites, where they can modulate the microenvironment toward repair through a variety of functions, including superoxide generation, granule release, and extrusion of neutrophil extracellular traps (NETs). NETs are becoming increasing implicated as a central player in the host response to a biomaterial, and as such, there is a need for reliable in vitro methods to evaluate the relative degree of NETs and quantify NETs on the surface of biomaterials. Such methods should be relatively high throughput and minimize sampling bias. In this chapter, we describe two procedures, (1) fluorescent image analysis and (2) a NETs-based ELISA, both of which have been specifically optimized to quantify NETs generated from human neutrophils on electrospun polydioxanone templates. Both methods are valid and also compatible with tissue culture plastic, but have a variety of advantages and disadvantages. Therefore, both methods can be used to concomitantly study NETs on the surface of a biomaterial. Finally, while these methods were developed for electrospun templates in a 96-well cell culture plate, they may be easily adapted to a large scale and for other biomaterials, including but not limited to metallics, ceramics, and natural and synthetic polymers.

Cost-effectiveness analysis of heart rate characteristics monitoring to improve survival for very low birth weight infants.

Introduction: Over 50,000 very low birth weight (VLBW) infants are born each year in the United States. Despite advances in care, these premature babies are subjected to long stays in a neonatal intensive care unit (NICU), and experience high rates of morbidity and mortality. In a large randomized controlled trial (RCT), heart rate characteristics (HRC) monitoring in addition to standard monitoring decreased all-cause mortality among VLBW infants by 22%. We sought to understand the cost-effectiveness of HRC monitoring to improve survival among VLBW infants. Methods: We performed a secondary analysis of cost-effectiveness of heart rate characteristics (HRC) monitoring to improve survival from birth to NICU discharge, up to 120 days using data and outcomes from an RCT of 3,003 VLBW patients. We estimated each patient's cost from a third-party perspective in 2021 USD using the resource utilization data gathered during the RCT (NCT00307333) during their initial stay in the NICU and applied to specific per diem rates. We computed the incremental cost-effectiveness ratio and used non-parametric boot-strapping to evaluate uncertainty. Results: The incremental cost-effectiveness ratio of HRC-monitoring was $34,720 per life saved. The 95th percentile of cost to save one additional life through HRC-monitoring was $449,291. Conclusion: HRC-monitoring appears cost-effective for increasing survival among VLBW infants.

Multivariable Predictive Models of Death or Neurodevelopmental Impairment Among Extremely Low Birth Weight Infants Using Heart Rate Characteristics.

OBJECTIVE: We hypothesized that a cumulative heart rate characteristics (HRC) index in real-time throughout the neonatal intensive care unit (NICU) hospitalization, alone or combined with birth demographics and clinical characteristics, can predict a composite outcome of death or neurodevelopmental impairment (NDI). STUDY DESIGN: We performed a retrospective analysis using data from extremely low birth weight infants who were monitored for HRC during neonatal intensive care. Surviving infants were assessed for NDI at 18-22 months of age. Multivariable predictive modeling of subsequent death or NDI using logistic regression, cross-validation with repeats, and step-wise feature elimination was performed each postnatal day through day 60. RESULTS: Among the 598 study participants, infants with the composite outcome of death or moderate-to-severe NDI had higher mean HRC scores during their stay in the NICU (3.1 ± 1.8 vs 1.3 ± 0.8; P < .001). Predictive models for subsequent death or NDI were consistently higher when the cumulative mean HRC score was included as a predictor variable. A parsimonious model including birth weight, sex, ventilatory status, and cumulative mean HRC score had a cross-validated receiver-operator characteristic curve as high as 0.84 on days 4, 5, 6, and 8 and as low as 0.78 on days 50-52 and 56-58 to predict subsequent death or NDI. CONCLUSIONS: In extremely low birth weight infants, higher mean HRC scores throughout their stay in the NICU were associated with a higher risk of the composite outcome of death or NDI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00307333.

Mechanical characterization and neutrophil NETs response of a novel hybrid geometry polydioxanone near-field electrospun scaffold.

Near-field electrospinning (NFES) is a direct fiber writing sub-technique derived from traditional electrospinning (TES) by reducing the air gap distance to the magnitude of millimeters. In this paper, we demonstrate a NFES device designed from a commercial 3D printer to semi-stably write polydioxanone (PDO) microfibers. The print head was then programmed to translate in a stacking grid pattern, which resulted in a scaffold with highly aligned grid fibers that were intercalated with low density, random fibers. As the switching process can be considered random, increasing the grid size results in both a lower density of fibers in the center of each grid cell as well as a lower density of 'rebar-like' stacked fibers. These scaffolds resulted in tailorable as well as greater surface pore sizes as given by scanning electron micrographs and 3D permeability as indicated by fluorescent microsphere filtration compared to TES scaffolds of the same fiber diameter. Furthermore, ultimate tensile strength, percent elongation, yield stress, yield elongation, and Young's modulus were all tailorable compared to the static TES scaffold characterization. Lastly, the innate immune response of neutrophil extracellular traps was attenuated on NFES scaffolds compared to TES scaffolds. These results suggest that this novel NFES scaffold architecture of PDO can be highly tailored as a function of programming for a variety of biomedical and tissue engineering applications.

Heart rate characteristics monitoring and reduction in mortality or neurodevelopmental impairment in extremely low birthweight infants with sepsis.

We questioned whether a heart rate characteristics (HRC) sepsis risk score displayed to clinicians would modify 18-22 month neurodevelopmental outcomes for extremely low birthweight infants who develop sepsis. Infants allocated to HRC display with sepsis had a 12% absolute reduction in the composite outcome of death or neurodevelopmental impairment. TRIAL REGISTRATION: NCT00307333.

Near-Field Electrospinning and Melt Electrowriting of Biomedical Polymers-Progress and Limitations.

Near-field electrospinning (NFES) and melt electrowriting (MEW) are the process of extruding a fiber due to the force exerted by an electric field and collecting the fiber before bending instabilities occur. When paired with precise relative motion between the polymer source and the collector, a fiber can be directly written as dictated by preprogrammed geometry. As a result, this precise fiber control results in another dimension of scaffold tailorability for biomedical applications. In this review, biomedically relevant polymers that to date have manufactured fibers by NFES/MEW are explored and the present limitations in direct fiber writing of standardization in published setup details, fiber write throughput, and increased ease in the creation of complex scaffold geometries are discussed.

Predicting extubation outcomes using the Heart Rate Characteristics index in preterm infants: a cohort study.

A strategy of early extubation to noninvasive respiratory support in preterm infants could be boosted by the availability of a decision support tool for clinicians. Using the Heart Rate Characteristics index (HRCi) with clinical parameters, we derived and validated predictive models for extubation readiness and success.Peri-extubation demographic, clinical and HRCi data for up to 96 h were collected from mechanically ventilated infants in the control arm of a randomised trial involving eight neonatal centres, where clinicians were blinded to the HRCi scores. The data were used to produce a multivariable regression model for the probability of subsequent re-intubation. Additionally, a survival model was produced to estimate the probability of re-intubation in the period after extubation.Of the 577 eligible infants, data from 397 infants (69%) were used to derive the pre-extubation model and 180 infants (31%) for validation. The model was also fitted and validated using all combinations of training (five centres) and test (three centres) centres. The estimated probability for the validation episodes showed discrimination with high statistical significance, with an area under the curve of 0.72 (95% CI 0.71-0.74; p<0.001). Data from all infants were used to derive models of the predictive instantaneous hazard of re-intubation adjusted for clinical parameters.Predictive models of extubation readiness and success in real-time can be derived using physiological and clinical variables. The models from our analyses can be accessed using an online tool available at www.heroscore.com/extubation, and have the potential to inform and supplement the confidence of the clinician considering extubation in preterm infants.

Characterization of Polydioxanone in Near-Field Electrospinning.

Electrospinning is a popular method for creating random, non-woven fibrous templates for biomedical applications, and a subtype technique termed near-field electrospinning (NFES) was devised by reducing the air gap distance to millimeters. This decreased working distance paired with precise translational motion between the fiber source and collector allows for the direct writing of fibers. We demonstrate a near-field electrospinning device designed from a MakerFarm Prusa i3v three-dimensional (3D) printer to write polydioxanone (PDO) microfibers. PDO fiber diameters were characterized over the processing parameters: Air gap, polymer concentration, translational velocity, needle gauge, and applied voltage. Fiber crystallinity and individual fiber uniformity were evaluated for the polymer concentration and translational fiber deposition velocity. Fiber stacking was evaluated for the creation of 3D templates to guide the alignment of human gingival fibroblasts. The fiber diameters correlated positively with polymer concentration, applied voltage, and needle gauge; and inversely correlated with translational velocity and air gap distance. Individual fiber diameter variability decreases, and crystallinity increases with increasing translational fiber deposition velocity. These data resulted in the creation of tailored PDO 3D templates, which guided the alignment of primary human fibroblast cells. Together, these results suggest that NFES of PDO can be scaled to create precise geometries with tailored fiber diameters for biomedical applications.

Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring.

OBJECTIVE: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT). STUDY DESIGN: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring. RESULTS: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance. CONCLUSIONS: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00307333.

Identification of c-kit-positive cells in the mouse ureter: the interstitial cells of Cajal of the urinary tract.

The existence of a pacemaker system in the urinary tract capable of orchestrating the movement of filtrated urine from the ureteral pelvis to the distal ureter and lower urinary tract seems intuitive. The coordinated activity necessary for such movement or "peristalsis" would likely require an intricate network of cells with pacemaker-like activity, as is the case with the interstitial cells of Cajal (ICC) of the gut. We investigated whether these putative pacemaker cells of the urinary tract are antigenically similar to ICC of the gut by using immunofluorescence staining for c-kit, a cell-surface marker specific for ICC. Ureteral, urinary bladder, and urethral tissues were harvested from female mice of the WBB6F1 strain, and fixed sections were prepared and stained for c-kit. Cell networks composed of stellate-appearing, c-kit-positive, ICC-like cells were found in the lamina propria and at the interface of the inner longitudinal and outer circular muscle layers of the ureteral pelvis but not in the urinary bladder or urethra. Thus, like in the gut, c-kit-positive, ICC-like cells are present in the urinary tract but appear to be restricted to the proximal ureter of this murine species.