Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Infants Born Extremely Preterm.

OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.

Preterm Infants off Positive Pressure Respiratory Support Have a Higher Incidence of Occult Cerebral Hypoxia.

OBJECTIVE: To use cerebral near-infrared spectroscopy (NIRS) to quantify occult cerebral hypoxia across respiratory support modes in preterm infants. STUDY DESIGN: In this prospective, longitudinal, observational study, infants ≤32 weeks gestation underwent serial pulse oximetry (oxygen saturation [SpO2]) and cerebral NIRS monitoring (4-6 hours per session) following a standardized recording schedule (daily for 2 weeks, every other day for 2 weeks, then weekly until 35 weeks corrected gestational age). Four calculations were made: median cerebral saturation, median cerebral hypoxia burden (proportion of NIRS samples below the hypoxia threshold [<67%]), median systemic saturation, and median systemic hypoxia burden (proportion of SpO2 samples below the desaturation threshold [<85%]). During each recording session, respiratory support mode was noted (room air, low-flow nasal cannula, high-flow nasal cannula, noninvasive positive pressure ventilation, continuous positive airway pressure, and invasive ventilation). RESULTS: There were 1013 recording sessions made from 174 infants with a median length of 6.9 hours. Although the systemic (SpO2) hypoxia burden was significantly greater for infants on the highest respiratory support (invasive and noninvasive positive pressure ventilation), the cerebral hypoxia burden was significantly greater during recording sessions made on the lowest respiratory support (8% for room air; 29% for low-flow nasal cannula). CONCLUSIONS: Premature infants on the highest levels of respiratory support have less cerebral hypoxia than those on lower respiratory support. These results raise concern about unrecognized cerebral hypoxia during lower acuity periods of neonatal intensive care unit hospitalization and adverse outcomes.

Variable Association of Physiologic Changes With Electrographic Seizure-Like Events in Infants Born Preterm.

OBJECTIVES: To determine the incidence of seizure-like events in a cohort of infants born preterm as well as the prevalence of associated vital sign changes (heart rate [HR], respiratory rate, and pulse oximetry [SpO2]). STUDY DESIGN: We performed prospective conventional video electroencephalogram monitoring on infants born at 23-30 weeks of gestational age during the first 4 postnatal days. For detected seizure-like events, simultaneously captured vital sign data were analyzed during the pre-event baseline and during the event. Significant vital sign changes were defined as HR or respiratory rate >±2 SD from the infant's own baseline physiologic mean, derived from a 10-minute interval before the seizure-like event. Significant change in SpO2 was defined as oxygen desaturation during the event with a mean SpO2 <88%. RESULTS: Our sample included 48 infants with median gestational age of 28 weeks (IQR 26-29) and birth weight of 1125 g (IQR 963-1265). Twelve (25%) infants had seizure-like discharges with a total of 201 events; 83% (10/12) of infants had vital sign changes during these events, and 50% (6/12) had significant vital sign changes during the majority of the seizure-like events. Concurrent HR changes occurred the most frequently. CONCLUSIONS: Individual infant variability was observed in the prevalence of concurrent vital sign changes with electroencephalographic seizure-like events. Physiologic changes associated with preterm electrographic seizure-like events should be investigated further as a potential biomarker to assess the clinical significance of such events in the preterm population.

Improving child health through Big Data and data science.

Child health is defined by a complex, dynamic network of genetic, cultural, nutritional, infectious, and environmental determinants at distinct, developmentally determined epochs from preconception to adolescence. This network shapes the future of children, susceptibilities to adult diseases, and individual child health outcomes. Evolution selects characteristics during fetal life, infancy, childhood, and adolescence that adapt to predictable and unpredictable exposures/stresses by creating alternative developmental phenotype trajectories. While child health has improved in the United States and globally over the past 30 years, continued improvement requires access to data that fully represent the complexity of these interactions and to new analytic methods. Big Data and innovative data science methods provide tools to integrate multiple data dimensions for description of best clinical, predictive, and preventive practices, for reducing racial disparities in child health outcomes, for inclusion of patient and family input in medical assessments, and for defining individual disease risk, mechanisms, and therapies. However, leveraging these resources will require new strategies that intentionally address institutional, ethical, regulatory, cultural, technical, and systemic barriers as well as developing partnerships with children and families from diverse backgrounds that acknowledge historical sources of mistrust. We highlight existing pediatric Big Data initiatives and identify areas of future research. IMPACT: Big Data and data science can improve child health. This review highlights the importance for child health of child-specific and life course-based Big Data and data science strategies. This review provides recommendations for future pediatric-specific Big Data and data science research.

Cardiorespiratory signature of neonatal sepsis: development and validation of prediction models in 3 NICUs.

BACKGROUND: Heart rate characteristics aid early detection of late-onset sepsis (LOS), but respiratory data contain additional signatures of illness due to infection. Predictive models using cardiorespiratory data may improve early sepsis detection. We hypothesized that heart rate (HR) and oxygenation (SpO2) data contain signatures that improve sepsis risk prediction over HR or demographics alone. METHODS: We analyzed cardiorespiratory data from very low birth weight (VLBW, <1500 g) infants admitted to three NICUs. We developed and externally validated four machine learning models to predict LOS using features calculated every 10 m: mean, standard deviation, skewness, kurtosis of HR and SpO2, and cross-correlation. We compared feature importance, discrimination, calibration, and dynamic prediction across models and cohorts. We built models of demographics and HR or SpO2 features alone for comparison with HR-SpO2 models. RESULTS: Performance, feature importance, and calibration were similar among modeling methods. All models had favorable external validation performance. The HR-SpO2 model performed better than models using either HR or SpO2 alone. Demographics improved the discrimination of all physiologic data models but dampened dynamic performance. CONCLUSIONS: Cardiorespiratory signatures detect LOS in VLBW infants at 3 NICUs. Demographics risk-stratify, but predictive modeling with both HR and SpO2 features provides the best dynamic risk prediction. IMPACT: Heart rate characteristics aid early detection of late-onset sepsis, but respiratory data contain signatures of illness due to infection. Predictive models using both heart rate and respiratory data may improve early sepsis detection. A cardiorespiratory early warning score, analyzing heart rate from electrocardiogram or pulse oximetry with SpO2, predicts late-onset sepsis within 24 h across multiple NICUs and detects sepsis better than heart rate characteristics or demographics alone. Demographics risk-stratify, but predictive modeling with both HR and SpO2 features provides the best dynamic risk prediction. The results increase understanding of physiologic signatures of neonatal sepsis.

Early Vital Sign Differences in Very Low Birth Weight Infants with Severe Intraventricular Hemorrhage.

OBJECTIVE: Severe intraventricular hemorrhage (sIVH, grades 3 and 4) is a serious complication for very low birth weight (VLBW) infants and is often clinically silent requiring screening cranial ultrasound (cUS) for detection. Abnormal vital sign (VS) patterns might serve as biomarkers to identify risk or occurrence of sIVH. STUDY DESIGN: This retrospective study was conducted in VLBW infants admitted to two level-IV neonatal intensive care units (NICUs) between January 2009 and December 2018. Inclusion criteria were: birth weight <1.5 kg and gestational age (GA) <32 weeks, at least 12 hours of systemic oxygen saturation from pulse oximetry (SpO2) data over the first 24 hours and cUS imaging. Infants were categorized as early sIVH (sIVH identified in the first 48 hours), late sIVH (sIVH identified after 48 hours and normal imaging in the first 48 hours), and no IVH. Infants with grades 1 and 2 or unknown timing IVH were excluded. Mean heart rate (HR), SpO2, mean arterial blood pressure (MABP), number of episodes of bradycardia (HR < 100 bpm), and desaturation (SpO2 < 80%) were compared. RESULTS: A total of 639 infants (mean: 27 weeks' gestation) were included (567 no IVH, 34 early sIVH, and 37 late sIVH). In the first 48 hours, those with sIVH had significantly higher HR compared with those with no IVH. Infants with sIVH also had lower mean SpO2 and MABP and more desaturations <80%. No significant differences in VS patterns were identified in early versus late sIVH. Logistic regression identified higher HR and greater number of desaturations <80% as independently associated with sIVH. CONCLUSION: VLBW infants who develop sIVH demonstrate VS differences with significantly lower SpO2 and higher mean HR over the first 48 hours after birth compared with VLBW infants with no IVH. Abnormalities in early VS patterns may be a useful biomarker for sIVH. Whether VS abnormalities predict or simply reflect sIVH remains to be determined. KEY POINTS: · A higher HR in the first 48 hours is seen in infants with severe IVH.. · Infants with sIVH have lower blood pressure in the first 48 hours.. · Infants with sIVH have more oxygen desaturations in the first 48 hours..

Seizure burden in preterm infants and smaller brain volume at term-equivalent age.

BACKGROUND: Seizures are underrecognized in preterm infants, and little is known about their impact on brain growth. We aimed to define the association between early seizures and subsequent brain growth. METHODS: Infants <30 weeks gestation underwent 72 h of prospective amplitude-integrated electroencephalography (aEEG) monitoring, term-equivalent age (TEA) magnetic resonance imaging (MRI), and 2-year neurodevelopmental testing. Seizures were defined as trains of sharp waves >10 s, evolving in frequency/amplitude/morphology, and identified using automated algorithms with manual review. Using T2-weighted images, cortical surface area (CSA) and gyrification index (GI) were calculated and volumes were segmented into five tissue classes: cerebrospinal fluid, gray matter, white matter (WM), deep nuclear gray matter, and cerebellum. Correlations between total seizure burden and tissue-specific volumes were evaluated, controlling for clinical variables of interest. RESULTS: Ninety-nine infants underwent aEEG/MRI assessments (mean GA = 26.3 weeks, birthweight = 899 g). Seizure incidence was 55% with a median of two events; median length = 66 s and mean burden = 285 s. Greater seizure burden was associated with smaller CSA and volumes across all tissue types, most prominently in WM (R2 = -0.603, p < 0.01), even after controlling for confounders. There was no association with GI. CONCLUSIONS: Seizures in preterm infants are common and associated with smaller TEA brain volumes. This relationship was strongest for WM and independent of clinical factors. IMPACT: Seizures in preterm infants are common. Little is known about the association between early seizures and later brain growth. Greater seizure burden is linked with smaller volumes of all brain tissue types, most prominently the WM. This relationship is true even controlling for other factors. Additional study is needed to identify the optimal EEG monitoring and seizure treatment strategy for improved brain growth and neurodevelopmental outcomes.

The Impact of Dexmedetomidine Initiation on Cardiovascular Status and Oxygenation in Critically ill Neonates.

Dexmedetomidine is being increasingly used as a primary or adjunctive sedative agent in neonates. There are a paucity of high-quality, high-resolution physiologic data during administration, despite significant potential cardiorespiratory effects. Term and preterm infants admitted between January 2018 and July 2020 were screened for dexmedetomidine exposure. Prospectively recorded vital signs (heart rate, oxygenation, arterial blood pressure) were cross-matched with pharmacy records to identify infants with data available 24 h before and 48 h after drug initiation. Vital sign data were processed via a standardized pipeline to (a) remove missing data, (b) obtain baseline averages of vital signs for 24 h preceding dexmedetomidine, and (c) calculate the hourly mean deviation from the baseline for the 48 h following initiation of dexmedetomidine. Infants were clustered by postmenstrual age (preterm ≤ 35 weeks; term > 35 weeks). 72 infants were identified with mean gestational age of 32 weeks and mean ± SD birth weight of 1976 ± 1341 g. Although both groups of infants experienced bradycardia, heart rate in term infants dropped faster and reached a nadir 5 beats per minute lower, before converging at a common deviation of - 10 beats per minute. No hypo- or hypertension was noted in either group. Unexpected instability of oxygenation occurred in a subset of preterm infants, requiring escalation of respiratory support. Administration of dexmedetomidine results in differential timing and magnitude of bradycardia in term and preterm infants, no major impact on blood pressure, and a surprising instability of oxygenation in preterm infants, requiring increased ventilatory support. Further investigation is warranted.

The hidden consequence of intraventricular hemorrhage: persistent cerebral desaturation after IVH in preterm infants.

BACKGROUND: Previous studies describe a short-term decrease in cerebral oxygen saturation (StO2) after intraventricular hemorrhage (IVH) in premature infants; little is known about long-term implications. METHODS: Infants born <30 weeks gestational age (GA) were included. Clinical characteristics, hemoglobin measurements, the highest grade of IVH, and white matter injury (WMI) were noted. NIRS monitoring occurred daily or every other day for 4 weeks; weekly through 36 weeks GA. Recordings were error-corrected before calculation of mean StO2 and fractional tissue oxygen extraction (FTOE). Mean StO2 and FTOE were plotted by postnatal age and injury group (IVH/no IVH; WMI/no WMI). Non-linear regression by locally estimated scatterplot smoothing was used to generate the best-fit line and CI. RESULTS: A total of 1237 recordings from 185 infants were included; mean length = 6.5 h; mean GA = 26.3 w; mean BW = 951 g; overall/severe IVH incidence was 29/8%, WMI incidence was 16%. IVH was independently associated with an acute drop in StO2, which remained lower for 68 d. Severe IVH was associated with lower StO2 values than mild IVH. WMI was associated with early and persistent elevation of FTOE. CONCLUSION: IVH of any grade is associated with a prolonged cerebral desaturation and WMI is associated with prolonged elevation of FTOE. This finding is exacerbated for infants with severe IVH. IMPACT: The longitudinal impact of IVH on cerebral oxygenation has not been previously studied. IVH is associated with persistent cerebral desaturation, months in length, and is independent of anemia. More severe IVH is associated with worsened cerebral hypoxia. Infants later diagnosed with white matter injury have an early and persistent elevation of cerebral oxygen extraction (cFTOE). This cerebral desaturation, below previously identified normative ranges, may provide insight into the mechanistic link between IVH and white matter injury.

Vital sign metrics of VLBW infants in three NICUs: implications for predictive algorithms.

BACKGROUND: Continuous heart rate (HR) and oxygenation (SpO2) metrics can be useful for predicting adverse events in very low birth weight (VLBW) infants. To optimize the utility of these tools, inter-site variability must be taken into account. METHODS: For VLBW infants at three neonatal intensive care units (NICUs), we analyzed the mean, standard deviation, skewness, kurtosis, and cross-correlation of electrocardiogram HR, pulse oximeter pulse rate, and SpO2. The number and durations of bradycardia and desaturation events were also measured. Twenty-two metrics were calculated hourly, and mean daily values were compared between sites. RESULTS: We analyzed data from 1168 VLBW infants from birth through day 42 (35,238 infant-days). HR and SpO2 metrics were similar at the three NICUs, with mean HR rising by ~10 beats/min over the first 2 weeks and mean SpO2 remaining stable ~94% over time. The number of bradycardia events was higher at one site, and the duration of desaturations was longer at another site. CONCLUSIONS: Mean HR and SpO2 were generally similar among VLBW infants at three NICUs from birth through 6 weeks of age, but bradycardia and desaturation events differed in the first 2 weeks after birth. This highlights the importance of developing predictive analytics tools at multiple sites. IMPACT: HR and SpO2 analytics can be useful for predicting adverse events in VLBW infants in the NICU, but inter-site differences must be taken into account in developing predictive algorithms. Although mean HR and SpO2 patterns were similar in VLBW infants at three NICUs, inter-site differences in the number of bradycardia events and duration of desaturation events were found. Inter-site differences in bradycardia and desaturation events among VLBW infants should be considered in the development of predictive algorithms.

Blood pressure extremes and severe IVH in preterm infants.

BACKGROUND: The optimal upper and lower limits of blood pressure in preterm infants are not known. Exceeding these thresholds may contribute to intraventricular hemorrhage (IVH). METHODS: Preterm infants born ≤30 weeks GA were identified. Infants had continuous measurement of mean arterial blood pressure (MABP) for 7 days and cranial ultrasound imaging. IVH was classified as severe IVH (grade 3/4), no severe IVH (no IVH; grade 1/2), or no IVH. Mean ± SEM MABP values from hours 1-168 were calculated and sorted into bins 2 mm Hg wide. The normalized proportion of each recording spent in each bin was then calculated. Candidate limits were identified by comparison of MABP distribution in those with severe IVH vs. those without severe IVH. RESULTS: Eighty-five million measurements were made from 157 infants. Mean EGA was 25.2 weeks; mean BW was 749 g; 65/157 female; inotrope use in 59/157; grade 3/4 IVH in 29/157. Infants with severe IVH spent significantly more time with extreme MABP measurements (<23 mm Hg or >46 mm Hg) compared to those without severe IVH (12% vs. 8% of recording, p = 0.02). CONCLUSIONS: Infants who developed severe IVH had substantially more unstable MABP and spent a significantly greater period of time with MABP outside of the optimal range.

Gestational age-dependent relationship between cerebral oxygen extraction and blood pressure.

BackgroundPremature infants may lack mature cerebrovascular autoregulatory function and fail to adapt oxygen extraction to decreasing systemic perfusion.MethodsInfants ≤28 weeks of gestational age (GA) were recruited. Systemic oxygen saturation (SpO2), mean arterial blood pressure (MABP), and cerebral saturation (near-infrared spectroscopy, SctO2) were measured continuously over the first 72 h. Resulting data underwent error-processing. For each remaining 10 m window, the mean MABP and fractional tissue oxygen extraction (FTOE) were calculated. The infants were divided into two groups (23-25 and 26-28 weeks). The median FTOE at low, medium, and high MABP values (empirically defined within each group based on the 25th and 75th centile) were compared between estimated gestational age (EGA) groups.ResultsSample n=68, mean±SD GA=25.5±1.3 weeks, and birthweight (BW)=823±195 g. The median FTOE in the more preterm group vs. more mature group was statistically different at lower value of MABP (P<0.01) and higher values of MABP (P=0.01), but not at medium values (P=0.55).ConclusionThe more mature group (GA 26-28 weeks) displayed an appropriate increase in oxygen extraction during hypotension, steadily decreasing as MABP increased, suggesting mature autoregulation. An opposite response was noted in the more preterm group, suggesting an inability to mount a compensatory response when BP is outside of the physiologic range.

A validated clinical MRI injury scoring system in neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Deep nuclear gray matter injury in neonatal hypoxic-ischemic encephalopathy (HIE) is associated with worse neurodevelopmental outcomes. We previously published a qualitative MRI injury scoring system utilizing serial T1-weighted, T2-weighted and diffusion-weighted imaging (DWI), weighted for deep nuclear gray matter injury. OBJECTIVES: To establish the validity of the MRI scoring system with neurodevelopmental outcome at 18-24 months. MATERIALS AND METHODS: MRI scans from neonates with moderate to severe HIE treated with therapeutic hypothermia were evaluated. Signal abnormality was scored on T1-weighted, T2-weighted and DWI sequences and assessed using an established system in five regions: (a) subcortical: caudate nucleus, globus pallidus and putamen, thalamus and the posterior limb of the internal capsule; (b) white matter; (c) cortex, (d) cerebellum and (e) brainstem. MRI injury was graded as none, mild, moderate or severe. Inter-rater reliability was tested on a subset of scans by two independent and blinded neuroradiologists. Surviving infants underwent the Bayley Scales of Infant and Toddler Development-III (Bayley-III) at 18-24 months. Data were analyzed using univariate and multivariate linear and logistic regression. RESULTS: Fifty-seven eligible neonates underwent at least one MRI scan in the first 2 weeks of life. Mean postnatal age at scan 1 was 4±2 days in 50/57 (88%) neonates and 48/54 (89%) surviving infants underwent scan 2 at 10±2 days. In 54/57 (95%) survivors, higher MRI injury grades were significantly associated with worse outcomes in the cognitive, motor and language domains of the Bayley-III. CONCLUSION: A qualitative MRI injury scoring system weighted for deep nuclear gray matter injury is a significant predictor of neurodevelopmental outcome at 18-24 months in neonates with HIE.

A novel method for assessing cerebral autoregulation in preterm infants using transfer function analysis.

BACKGROUND: Autoregulatory dysfunction is an important contributor to brain injury in premature infants, particularly intraventricular hemorrhage (IVH). The autoregulatory system acts as a filter that dampens the systemic blood flow to follow a normal cerebral perfusion profile. METHODS: Simultaneous arterial blood pressure and cerebral near-infrared spectroscopy (NIRS) data were collected from infants born before 28 wk estimated gestational age. The resulting data were preprocessed and then divided into nonoverlapping 20-min epochs. The transfer function estimate was calculated to determine dampening ability. RESULTS: Sixty-two infants were prospectively recruited with a mean estimated gestational age of 25.4 ± 1.3 wk and birth weight of 832 ± 199 g. 67% were male, 24/62 had IVH, 17/62 received dopamine, 47/62 had antenatal steroid exposure, and 22/62 received fentanyl.Advancing estimated gestational age and birth weight z-score predicted stronger dampening while African-American race and IVH of any grade predicted weaker dampening. CONCLUSION: This preliminary report suggests an impairment in dampening ability associated with immaturity, decreased birth weight z-score, and African-American race. Decreased dampening is also associated with IVH, although these results cannot distinguish between decreased dampening as an antecedent or sequela of IVH. These observations should be studied in a larger sample.

Early electrographic seizures, brain injury, and neurodevelopmental risk in the very preterm infant.

BACKGROUND: Previous studies of very preterm (VPT) infants have shown a wide range of seizure prevalence and association with intraventricular hemorrhage (IVH), white matter injury (WMI), and death. However, the impact of seizures on neurodevelopment is not well known. We hypothesized that seizures in the first 3 d after VPT birth would be associated with increased radiographic brain injury and later neurodevelopmental risk. METHODS: For 72 h after birth, 95 VPT infants underwent amplitude-integrated electroencephalogram monitoring. High and low seizure burdens were related to radiographic brain injury, death in the neonatal period, and children's Bayley III (Bayley Scales of Infant Development) performance at 2 y corrected age in a subgroup of 59 infants. RESULTS: The overall incidence of seizures in this sample was 48%. High seizure burden was associated with increased risk of IVH on day 1; IVH, WMI, and death on day 2; and high-grade IVH on day 3. The presence of seizures on any day was associated with decreased language performance at age 2, even after controlling for family social risk. CONCLUSION: Seizures during the first 3 d after birth are common and are associated with an increased risk of IVH, WMI, and death. They were also associated with poorer early language development.

Racial and geographic disparities in neonatal brain care.

In this review, we explore race-based disparities in neonatology and their impact on brain injury and neurodevelopmental outcomes. We discuss the historical context of healthcare discrimination, focusing on the post-Civil War era and the segregation of healthcare facilities. We highlight the increasing disparity in infant mortality rates between Black and White infants, with premature birth being a major contributing factor, and emphasize the role of prenatal factors such as metabolic syndrome and toxic stress in affecting neonatal health. Furthermore, we examine the geographic and historical aspects of racial disparities, including the consequences of redlining and limited access to healthcare facilities or nutritious food options in Black communities. Finally, we delve into the higher incidence of brain injuries in Black neonates, as well as disparities in adverse neurodevelopmental outcome. This evidence underscores the need for comprehensive efforts to address systemic racism and provide equitable access to healthcare resources.