Medical Complexity, Language Use, and Outcomes in the Pediatric ICU.

OBJECTIVES: To determine whether use of a language other than English (LOE) would be associated with medical complexity, and whether medical complexity and LOE together would be associated with worse clinical outcomes. METHODS: The primary outcome of this single-site retrospective cohort study of PICU encounters from September 1, 2017, through August 31, 2022 was an association between LOE and medical complexity. Univariable and multivariable analyses were performed between demographic factors and medical complexity, both for unique patients and for all encounters. We investigated outcomes of initial illness severity (using Pediatric Logistic Organ Dysfunction-2), length of stay (LOS), days without mechanical ventilation or organ dysfunction using a mixed effects regression model, controlling for age, sex, race and ethnicity, and insurance status. RESULTS: There were 6802 patients and 10 011 encounters. In multivariable analysis for all encounters, Spanish use (adjusted odds ratio [aOR], 1.29; 95% confidence interval [CI], 1.11-1.49) and language other than English or Spanish (LOES) (aOR, 1.36; 95% CI, 1.02-1.80) were associated with medical complexity. Among unique patients, there remained an association between use of Spanish and medical complexity in multivariable analysis (aOR, 1.26; 95% CI, 1.05-1.52) but not between LOES and medical complexity (aOR, 1.30; 95% CI, 0.92-1.83). Children with medical complexity (CMC) who used an LOES had fewer organ dysfunction-free days (P = .003), PICU LOS was 1.53 times longer (P = .01), and hospital LOS was 1.45 times longer (P = .01) compared with CMC who used English. CONCLUSIONS: Use of an LOE was independently associated with medical complexity. CMC who used an LOES had a longer LOS.

DNA methylation networks underlying mammalian traits.

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

The Impact of Non-English Language Preference on Pediatric Hospital Outcomes.

OBJECTIVES: To characterize the relationship between non-English language preference (NELP) and hospital outcomes including length of stay (LOS), time of discharge, emergency department return visits, readmissions, and cost for pediatric general medicine inpatients. METHODS: We conducted a retrospective analysis at an urban, quaternary care, free-standing children's hospital. Patients ages 0 to 18 admitted to any general medicine service between January 1, 2017, and December 31, 2019 were included. Patients were divided into 3 language preference categories: English, Spanish, and non-Spanish NELP. Single and multifactor regression analysis was used to model differences in outcome measures by language preference adjusted for technology dependence. RESULTS: A total of 4820 patients met criteria. In adjusted models, the average LOS for English-speaking patients was 126 hours; LOS for patients who preferred Spanish was not significantly different, whereas LOS for patients with non-Spanish NELP was 50% longer (P < .001). English-speaking patients were discharged earliest in the day (mean 3:08 pm), with patients who preferred Spanish discharged 0.5 hours later and patients with non-Spanish NELP discharged 1.1 hours later than English-speaking patients (P < .001). Patients with NELP were found to be technology-dependent more frequently (P < .001) than the English preference group. Emergency department return visits, readmissions, and cost were not significantly different between groups. CONCLUSIONS: NELP was associated with longer length of stay and discharges later in the day. The most pronounced differences occurred in patients with non-Spanish NELP who also had more frequent technology dependence and more limited access to interpreters.

Hospital Discharge Instructions: Characteristics, Accessibility, and National Guideline Adherence.

OBJECTIVES: The content of pediatric hospital discharge instructions is highly variable. This study aimed to describe the characteristics, accessibility per patient literacy level and language, and national guideline adherence of pediatric hospital discharge instructions. METHODS: This retrospective study assessed discharge instructions at a tertiary children's hospital. Patient and instruction characteristics, including patient health literacy level, grade level of instructions, patient language preference, and language of instructions were collected via chart review and electronic medical record query. Standard admission processes assessed health literacy via Brief Health Literacy Screening. The association between demographic and clinical characteristics and adherence to Solutions for Patient Safety guidelines was analyzed by using unadjusted and adjusted analysis methods. RESULTS: Of 240 discharge instructions, 25% were missing at least 1 recommended content area: signs of worsening, where to seek help, or medication reconciliation. A patient health literacy deficit was identified in 15%; the mean grade level of instructions was 10.1. Limited English proficiency was reported among 17% one quarter of whom received language concordant instructions. Use of discharge instruction templates and discharge services were associated with improved guideline adherence (P <.001). Almost one-half of the study population had a complex medical history, which was associated with decreased guideline adherence (P = .04). CONCLUSIONS: One-quarter of discharge instructions for this predominantly medically complex population failed to meet national standards. Accessibility was often limited by the reading grade level or discordant language of instructions. Templates may be a valuable tool for improving discharge instruction content, accessibility, and adherence to national guidelines.

Pediatric Hospital Medicine Resident Elective: A Novel Resident Curriculum for an Evolving Field.

Background Although 8-10% of pediatric residents pursue a career in Pediatric Hospital Medicine (PHM), many report an incomplete understanding of PHM careers and would benefit from a PHM elective. Methodology We followed Kern's six-step curriculum development framework. A general needs assessment via literature review revealed a lack of published PHM elective curricula. A targeted needs assessment was conducted by surveying national PHM fellowship program directors, national PHM fellows, local junior PHM attendings, and local pediatric residents. Content analysis from these surveys was used to develop a PHM resident elective curriculum. The curriculum was implemented and evaluated through an experience log and written reflections. Results Needs assessment surveys were completed by fellowship directors (22/61, 36%), fellows (36/103, 35%), attendings (10/26, 38%), and residents (15/98, 15%). Common themes included the importance of academic experiences, mentorship, non-teaching and non-inpatient clinical experiences, community hospital experience, and the desire to address knowledge gaps. Significant variability in survey responses suggested the importance of an individualized curriculum. Goals, objectives, and aligned educational strategies were developed to provide a breadth of clinical experiences, mentorship, and PHM-focused academic activities, with an emphasis on individualization. Implementation of the curriculum began in July 2021 and four residents enrolled in 2021-2022. The curricular evaluation demonstrated the achievement of objectives and improved resident awareness of PHM opportunities, clinical skill development, ancillary shadowing, and academic opportunities. Conclusions A PHM resident elective was developed using Kern's six-step approach with input from national fellows and fellowship program directors to address educational gaps and increase exposure to PHM careers. The next steps include the evaluation of the impact of the PHM elective on career choice and preparedness of residents.

Interactive Inpatient Asthma Education: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Inpatient asthma education interventions provide benefit compared with usual care, but evaluation of the most effective educational model is needed. We compared the impact of interactive versus didactic inpatient pediatric asthma education on subsequent emergency department (ED) visits and hospitalizations. METHODS: Children (aged 2‒16) with asthma admitted to a tertiary care children's hospital with an asthma exacerbation between October 2016 and June 2017 were randomly assigned to interactive or didactic (control) asthma education. The primary outcome was asthma ED visits at 6 and 12 months; secondary outcomes included hospitalizations (6 and 12 months), inhaler technique, asthma knowledge, symptoms, quality of life, and parental management skills at baseline, discharge, and/or 12 months. RESULTS: One hundred forty participants (69 interactive, 71 control) completed the study. There were no differences in ED visits at 6 or 12 months. Compared to controls, the interactive group had fewer hospitalizations (10.1% vs 22.5%; P = .04) at 6 months. Inhaler technique in the interactive group improved at discharge (mean change 4.07 [95% confidence interval (CI): 3.21-4.94]) and remained increased at 12 months (P = .03). Patient-reported asthma symptoms and quality of life were similar in both groups at baseline (19.9 vs 20.62, best possible score 8) and significantly improved in the interactive group at 12 months (least square mean change, 3.52 vs -1.75; P < .01). CONCLUSIONS: There were no differences in ED visits; however, the interactive education reduced asthma hospitalizations over a 6-month period. These findings demonstrate that educational delivery methods can play a role in improving clinical outcomes for asthma.

Hepatitis B Vaccine Refusal in the Newborn Period.

Perinatal hepatitis B (HepB) infection is a serious condition in the pediatric population, with up to 90% of exposed infants progressing to chronic infection. The cornerstone of prevention is the birth dose of the HepB vaccine. In 2018, the Advisory Committee on Immunization Practices updated their guidelines for the birth dose of the HepB vaccine. These new guidelines included a refined timeline on when the HepB vaccine should be given, including for infants born to women with known HepB infection, unknown HepB status, and universal guidelines regardless of maternal HepB status. However, despite these guidelines, up to 25% of infants do not receive the birth dose of HepB vaccine. Individual provider commitment to administration of the vaccine remains fundamental, but institutional policies also have significant influence in ensuring appropriate vaccine administration for infants. [Pediatr Ann. 2021;50(8):e343-e347.].

Importance of circadian timing for aging and longevity.

Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.

Comparing Software Determination of Readmission Preventability With Chart Review, Provider, and Family Assessments.

OBJECTIVES: To explore the concordance between software, chart reviewer, provider, and parent perspectives when assessing whether readmissions are preventable or clinically related to the initial admission. METHODS: Providers and parents of patients readmitted within 3 days to a tertiary children's hospital were enrolled in this single-site observational study. 3M Potentially Preventable Readmissions Grouping Software, chart reviewers, discharge and readmission providers, and parents assessed if readmissions were clinically related to the index admission or potentially preventable. Agreement between perspectives was measured by using Cohen's κ values. RESULTS: The software found 67 of 118 (57%) clinically related readmissions; the identical 67 of 118 cases (57%) were found to be potentially preventable. Chart reviewers found 107 of 125 (86%) clinically related and 60 of 125 (47%) preventable readmissions compared to 68 of 92 (74%) and 27 of 92 (28%) for discharge physicians and 69 of 93 (74%) and 33 of 93 (34%) for readmitting physicians. Parents reported 9 of 36 (25%) preventable readmissions. Cohen κ values revealed no to minimal agreement on clinical relatedness of readmissions between software and chart reviewer, discharge provider, and readmission provider (0.12-0.20), whereas chart reviewers and providers had weak to moderate agreement with each other (0.43-0.75). There was no to minimal agreement on preventability between software and the other perspectives (-0.04 to 0.21), whereas chart reviewers and providers had minimal to weak agreement (0.27-0.56). CONCLUSIONS: Measurement of preventable readmissions remains problematic, and using financial penalties for readmissions on the basis of software determinations may be unwise given low levels of agreement. Chart review supplemented by information from providers and families offers a more inclusive way to identify potentially preventable readmissions.

The malaria parasite has an intrinsic clock.

Malarial rhythmic fevers are the consequence of the synchronous bursting of red blood cells (RBCs) on completion of the malaria parasite asexual cell cycle. Here, we hypothesized that an intrinsic clock in the parasite Plasmodium chabaudi underlies the 24-hour-based rhythms of RBC bursting in mice. We show that parasite rhythms are flexible and lengthen to match the rhythms of hosts with long circadian periods. We also show that malaria rhythms persist even when host food intake is evenly spread across 24 hours, suggesting that host feeding cues are not required for synchrony. Moreover, we find that the parasite population remains synchronous and rhythmic even in an arrhythmic clock mutant host. Thus, we propose that parasite rhythms are generated by the parasite, possibly to anticipate its circadian environment.

Critical Errors in Inhaler Technique among Children Hospitalized with Asthma.

Past studies have not evaluated inhaler use in hospitalized children with asthma. The objectives of this study were to evaluate inhaler technique in hospitalized pediatric patients with asthma and identify risk factors for improper use. We conducted a prospective cross-sectional study in a tertiary children's hospital for children 2-16 years of age admitted for an asthma exacerbation, and inhaler technique demonstrations were analyzed. Of 113 participants enrolled, 55% had uncontrolled asthma, and 42% missed a critical step in inhaler technique. More patients missed a critical step when they used a spacer with mouthpiece instead of a spacer with mask (75% [51%-90%] vs 36% [27%-46%]) and were older (7.8 [6.7-8.9] vs 5.8 [5.1-6.5] years). Patients using the spacer with mouthpiece remained significantly more likely to miss a critical step when adjusting for other clinical covariates (odds ratio 6.95 [1.71-28.23], P = .007). Hospital-based education may provide teachable moments to address poor proficiency, especially for older children using a mouthpiece.

Pediatric Readmissions Within 3 Days of Discharge: Preventability, Contributing Factors, and Necessity.

OBJECTIVES: Among pediatric 30-day readmissions, 20% to 30% are preventable, and ∼25% are within 3 days of discharge. We investigated the preventability, contributing factors, and necessity of 3-day pediatric readmissions. METHODS: We enrolled patients who were readmitted within 3 days at a freestanding tertiary children's hospital in this single-site observational study from July 2016 to February 2017. We performed chart reviews and interviews with discharge and readmission providers and families. Preventability was defined by the chart reviewer's determination. Contributing factors for readmission, demographics, and clinical characteristics were analyzed for association with preventability and necessity. We analyzed qualitative data using content analysis. RESULTS: Of the 125 readmission cases included, 60 (48%) were preventable per chart reviewer compared with 27 of 92 (29%) per discharge providers, 33 of 93 (35%) per readmission providers, and 9 of 36 (25%) per families. Preventability was associated with the following contributing factors: problems with clinical decision-making in 54 of 125 (43%) readmissions (P < .001), issues with the discharge process in 25 of 125 (20%) readmissions (P = .01), clinically related admission and readmission (P = .004), and weekday of initial discharge (P = .02). Seventeen percent were unnecessary per readmission provider. Clinically unnecessary readmissions were associated with Hispanic ethnicity (P = .02), outside-hospital transfer (P = .05), and problems with clinical decision-making (P = .01). Qualitative data highlighted disagreement on readiness for discharge and the necessity of readmission among various providers and family. CONCLUSIONS: More than one-half of 3-day readmissions were considered either preventable or unnecessary. Clinical decision-making, discharge processes, and improving consensus among families and providers may be valuable areas for future efforts to reduce readmission.

HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections.

Transcriptional regulation of numerous interferon-regulated genes, including Toll-like receptor 3 (Tlr3), which encodes an innate immune sensor of viral double-stranded RNA, depends on the interferon regulatory factor 1 (IRF1) and IRF2 transcription factors. We detected specific abrogation of macrophage responses to polyinosinic-polycytidylic acid (poly(I:C)) resulting from three independent N-ethyl-N-nitrosourea-induced mutations in host cell factor C2 (Hcfc2). Hcfc2 mutations compromised survival during influenza virus and herpes simplex virus 1 infections. HCFC2 promoted the binding of IRF1 and IRF2 to the Tlr3 promoter, without which inflammatory cytokine and type I IFN responses to the double-stranded RNA analogue poly(I:C) are reduced in mouse macrophages. HCFC2 was also necessary for the transcription of a large subset of other IRF2-dependent interferon-regulated genes. Deleterious mutations of Hcfc2 may therefore increase susceptibility to diverse infectious diseases.

Mice under Caloric Restriction Self-Impose a Temporal Restriction of Food Intake as Revealed by an Automated Feeder System.

Caloric restriction (CR) extends lifespan in mammals, yet the mechanisms underlying its beneficial effects remain unknown. The manner in which CR has been implemented in longevity experiments is variable, with both timing and frequency of meals constrained by work schedules. It is commonplace to find that nocturnal rodents are fed during the daytime and meals are spaced out, introducing prolonged fasting intervals. Since implementation of feeding paradigms over the lifetime is logistically difficult, automation is critical, but existing systems are expensive and not amenable to scale. We have developed a system that controls duration, amount, and timing of food availability and records feeding and voluntary wheel-running activity in mice. Using this system, mice were exposed to temporal or caloric restriction protocols. Mice under CR self-imposed a temporal component by consolidating food intake and unexpectedly increasing wheel-running activity during the rest phase, revealing previously unrecognized relationships among feeding, metabolism, and behavior.

The mouse liver displays daily rhythms in the metabolism of phospholipids and in the activity of lipid synthesizing enzymes.

The circadian system involves central and peripheral oscillators regulating temporally biochemical processes including lipid metabolism; their disruption leads to severe metabolic diseases (obesity, diabetes, etc). Here, we investigated the temporal regulation of glycerophospholipid (GPL) synthesis in mouse liver, a well-known peripheral oscillator. Mice were synchronized to a 12:12 h light-dark (LD) cycle and then released to constant darkness with food ad libitum. Livers collected at different times exhibited a daily rhythmicity in some individual GPL content with highest levels during the subjective day. The activity of GPL-synthesizing/remodeling enzymes: phosphatidate phosphohydrolase 1 (PAP-1/lipin) and lysophospholipid acyltransferases (LPLATs) also displayed significant variations, with higher levels during the subjective day and at dusk. We evaluated the temporal regulation of expression and activity of phosphatidylcholine (PC) synthesizing enzymes. PC is mainly synthesized through the Kennedy pathway with Choline Kinase (ChoK) as a key regulatory enzyme or through the phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway. The PC/PE content ratio exhibited a daily variation with lowest levels at night, while ChoKα and PEMT mRNA expression displayed maximal levels at nocturnal phases. Our results demonstrate that mouse liver GPL metabolism oscillates rhythmically with a precise temporal control in the expression and/or activity of specific enzymes.

Daily rhythms of glycerophospholipid synthesis in fibroblast cultures involve differential enzyme contributions.

Circadian clocks regulate the temporal organization of several biochemical processes, including lipid metabolism, and their disruption leads to severe metabolic disorders. Immortalized cell lines acting as circadian clocks display daily variations in [(32)P]phospholipid labeling; however, the regulation of glycerophospholipid (GPL) synthesis by internal clocks remains unknown. Here we found that arrested NIH 3T3 cells synchronized with a 2 h-serum shock exhibited temporal oscillations in a) the labeling of total [(3)H] GPLs, with lowest levels around 28 and 56 h, and b) the activity of GPL-synthesizing and GPL-remodeling enzymes, such as phosphatidate phosphohydrolase 1 (PAP-1) and lysophospholipid acyltransferases (LPLAT), respectively, with antiphase profiles. In addition, we investigated the temporal regulation of phosphatidylcholine (PC) biosynthesis. PC is mainly synthesized through the Kennedy pathway with choline kinase (ChoK) and CTP:phosphocholine cytidylyltranferase (CCT) as key regulatory enzymes. We observed that the PC labeling exhibited daily changes, with the lowest levels every ~28 h, that were accompanied by brief increases in CCT activity and the oscillation in ChoK mRNA expression and activity. Results demonstrate that the metabolisms of GPLs and particularly of PC in synchronized fibroblasts are subject to a complex temporal control involving concerted changes in the expression and/or activities of specific synthesizing enzymes.

Expression of novel opsins and intrinsic light responses in the mammalian retinal ganglion cell line RGC-5. Presence of OPN5 in the rat retina.

The vertebrate retina is known to contain three classes of photoreceptor cells: cones and rods responsible for vision, and intrinsically photoresponsive retinal ganglion cells (RGCs) involved in diverse non-visual functions such as photic entrainment of daily rhythms and pupillary light responses. In this paper we investigated the potential intrinsic photoresponsiveness of the rat RGC line, RGC-5, by testing for the presence of visual and non-visual opsins and assessing expression of the immediate-early gene protein c-Fos and changes in intracellular Ca(2+) mobilization in response to brief light pulses. Cultured RGC-5 cells express a number of photopigment mRNAs such as retinal G protein coupled receptor (RGR), encephalopsin/panopsin (Opn3), neuropsin (Opn5) and cone opsin (Opn1mw) but not melanopsin (Opn4) or rhodopsin. Opn5 immunoreactivity was observed in RGC-5 cells and in the inner retina of rat, mainly localized in the ganglion cell layer (GCL). Furthermore, white light pulses of different intensities and durations elicited changes both in intracellular Ca(2+) levels and in the induction of c-Fos protein in RGC-5 cell cultures. The results demonstrate that RGC-5 cells expressing diverse putative functional photopigments display intrinsic photosensitivity which accounts for the photic induction of c-Fos protein and changes in intracellular Ca(2+) mobilization. The presence of Opn5 in the GCL of the rat retina suggests the existence of a novel type of photoreceptor cell.

Inner retinal circadian clocks and non-visual photoreceptors: novel players in the circadian system.

Daily and annual changes in ambient illumination serve as specific stimuli that associate light with time and regulate the physiology of the organism through the eye. The eye acts as a dual sense organ linking light and vision, and detecting light that provides specific stimuli for non-classical photoreceptors located in the inner retina. These photoreceptors convey information to the master circadian pacemaker, the hypothalamic suprachiasmatic nuclei (SCN). Responsible for sensing the light that regulates several non-visual functions (i.e. behavior, pupil reflex, sleep, and pineal melatonin production), the retina plays a key role in the temporal symphony orchestra playing the musical score of life: it is intrinsically rhythmic in its physiological and metabolic activities. We discuss here recent evidence in support of the hypothesis that retinal oscillators distributed over different cell populations may act as clocks, inducing changes in the visual and circadian system according to the time of the day. Significant progress has recently been made in identifying photoreceptors/photopigments localized in retinal ganglion cells (RGCs) that set circadian rhythms and modulate non-visual functions. Autonomous retinal and brain oscillators could have a more complex organization than previously recognized, involving a network of "RGC clock/SCN clock cross-talk". The convergence of oscillatory and photoreceptive capacities of retinal cells could deeply impact on the circadian system, which in turn may be severely impaired in different retinal pathologies. The aim of this review is to discuss the state of the art on inner retinal cell involvement in the light and temporal regulation of health and disease.