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Objective: To examine the association between noninvasive respiratory support (NRS) or tracheal intubation (TI) during stabilization in infants born at 23-25 weeks of gestation and severe brain injury (sBI) or death, and significant neurodevelopmental impairment (sNDI)., Study Design: A retrospective cohort study of infants born at 23° /7 -25 6/7  weeks of gestation in Canada. We compared infants successfully managed with NRS or TI during 30 minutes after birth. The primary outcomes were sBI or death before discharge, and sNDI among survivors with follow-up data at 18-24 months corrected age. The associations between exposures and outcomes were assessed using logistic regression models, and propensity score-matched analyses., Results: The mean (SD) of gestational age and birth weight were 24.6 (0.6), 24.3 (0.7) weeks [P < .01], and 757 (173), 705 (130) grams [P < .01] in the NRS, and tracheal intubation (TI) groups, respectively, and 77% of infants in the NRS group were intubated by 7 days of age. sBI or death occurred in 25% (283/1118), and 36% (722/2012) of infants in the NRS and TI groups, respectively (aOR and 95% CI 0.74 [0.60, 0.91]). Among survivors with follow-up data, sNDI occurred in 17% (96/551), and 23% (218/937) of infants in the NRS and TI groups, respectively (aOR [95% CI] 0.77 [0.60, 0.99]). In the propensity score-matched analyses (NRS vs TI), results were consistent for sBI or death (OR [95% CI] 0.72 [0.60, 0.86]), but not for sNDI (OR [95% CI] 0.78 [0.58, 1.05])., Conclusions: Infants born at 23-25 weeks who were successfully managed with NRS, compared with TI, in the first 30 minutes after birth had lower odds of sBI or death before discharge, but had no significant differences in neurodevelopmental outcomes among survivors., Competing Interests: Declaration of Competing Interest Organizational support for the Canadian Neonatal Network (CNN) was provided by the Maternal-Infant Care (MiCare) Research Centre at Mount Sinai Hospital in Toronto, Ontario, Canada. MiCare is supported by a team grant from the Canadian Institutes of Health Research (CIHR) (CTP 87518), and by the participating hospitals. R.L. is supported by Alberta Children's Hospital Research Institute (ACHRI) Trainee Small Research Grant (Supervisor: Ayman Abou Mehrem). The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

To determine: (i) frequency of probable post-traumatic stress disorder (PTSD) in mothers of infants after complex cardiac surgery (CCS), (ii) predictors of probable PTSD, and (iii) impact on child neurodevelopment. The Impact of Event Scale-Revised (IES-R) was administered to 60 mothers of infants ≥ 6 months after CCS at ≤ 6 weeks of age. The IES-R measures response to a specific traumatic event: Scores < 24, no concern; 24-32, clinical concern; and ≥ 33, probable diagnosis of PTSD. Post-survey childhood outcomes obtained at 21-months used Bayley Scales of Infant and Toddler Development-Third Edition. Multiple logistic and linear regressions were used to predict high IES-R scores from peri-operative and demographic variables and determine association between maternal IES-R scores and outcomes, reported as Odds Ratio (OR) and Effect Size (ES) with 95% Confidence Intervals (95% CI). IES-R scores ≥ 33 occurred in 14/60 (23%) of mothers. Significant risk factors for IES-R ≥ 33 were days of ventilation after first surgery, OR 1.149 (95% CI 1.037, 1.273), p = 0.008, and birth weight z-scores, OR 0.352 (0.140, 0.881), p = 0.026. Bayley cognitive, language, and motor scores were significantly lower for children whose mothers had IES-R ≥ 33. The IES-R was independently associated with cognitive, ES -0 .23 (95%CI -0 0.39, -0 0.08), p = 0.036 and language, ES -0 0.17 (95%CI -0 0.33, -0 0.06), p = 0.043 scores. Probable PTSD occurred in 23% of mothers ≥ 6 month after discharge of their infant following CCS. Toddlers of mothers with probable PTSD had lower cognitive and language scores suggesting a relation between PTSD and development requiring further study., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Ethical Approval: This study was performed in line with the principles of the Declaration of Helsinki. Informed consents were obtained from the children’s parents for enrollment, acute variable data collection, developmental assessment, and outcomes. The most recent ethics approval was in August 2024 by the University of Alberta Health Research Ethics Board (Pro00001030)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic Chagas cardiomyopathy is associated with an unbalanced immune response and impaired heart function, and available drugs do not prevent its development. Zileuton (Zi), a 5-lypoxigenase inhibitor, affects inflammatory/pro-resolution mediators. Herein, Zi treatment in the early phase of infection reduced parasitemia associated mainly with the direct effect of Zi on the parasite, and the enzyme epoxide hydrolase was the potential molecular target behind the trypanocidal effect. In the intermediate acute phase of infection, Zi reduced the number of innate and adaptive inflammatory cells, increased the level of SOCS2 expression in the heart associated with lower inflammation, and improved cardiac function. Zi treatment initiated in the chronic stage increased the level of SOCS2 expression in the heart, reduced inflammation, and improved cardiac function. Our data suggest that Zi protects against Trypanosoma cruzi infection by acting directly on the parasite and reducing heart damage and is a promising option for the treatment of Chagas disease.

Objective: Epilepsy is one of the most prevalent chronic neurological diseases, presenting a high frequency of psychiatric disorders (PD). This study sought to evaluate the clinical and sociodemographic profile of patients with epilepsy (PWE) attended at a regional reference psychiatric emergency unit., Methods: A retrospective, cross-sectional, and descriptive observational study was conducted utilizing a patient record database of individuals with epilepsy who were attended in a regional reference psychiatric emergency unit between January 2018 and August 2022., Results: Out of the 31,800 psychiatric emergency visits, 260 (0.8 %) were of patients with epilepsy (ICD-10: G40). The majority were males (63.5 %) with a mean age of 42.11±15.39 years, single marital status (154; 59.25 %) and elementary education (75; 28.9 %). Most of them (203; 78.1 %) presented at least one psychiatric comorbidity at the emergency visit, but 109 (41.9 %) were not receiving any psychiatric follow-up. A total of 106 patients (40.8 %) had experienced at least one past psychiatric hospitalization., Conclusions: The occurrence of PD is highly prevalent in PWE, and probably with a high frequency of psychiatric emergencies occurring among them. Further studies are needed to assess such patient profile, particularly involving data from psychiatric emergency units., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Disorders of gastrointestinal motility are the major physiologic problem in chagasic megacolon. The contraction mechanism is complex and controlled by different cell types such as enteric neurons, smooth muscle, telocytes, and an important pacemaker of the intestine, the interstitial cells of Cajal (ICCs). The role of ICCs in the progression of acute and chronic Chagas disease remains unclear. In the present work, we investigate the aspects of ICCs in a long-term model of Chagas disease that mimics the pathological aspects of human megacolon. Different subsets of ICCs isolated from Auerbach's myenteric plexuses and muscle layers of control and Trypanosoma cruzi infected animals were determined by analysis of CD117, CD44, and CD34 expression by flow cytometer. Compared with the respective controls, the results showed a reduced frequency of mature ICCs in the acute phase and three months after infection. These results demonstrate for the first time the phenotypic distribution of ICCs associated with functional dysfunction in a murine model of chagasic megacolon. This murine model proved valuable for studying the profile of ICCs as an integrative system in the gut and as a platform for understanding the mechanism of chagasic megacolon development.

Aim: Parents of children born preterm have identified outcomes to be measured for audit and research at 18-24 months of age: child well-being, quality of life/function, socio-emotional/behavioural outcomes, respiratory, feeding, sleeping, and caregiver mental health. The aim was to identify the best tools to measure these seven domains., Methods: Seven working groups completed literature reviews and evaluated potential tools to measure these outcomes in children aged 18-24 months. A group of experts and parents voted on the preferred tools in a workshop and by questionnaire. Consensus was 80% agreement., Results: Consensus was obtained for seven brief, inexpensive, parent friendly valid measures available in English or French for use in a minimum dataset and potential alternative measures for use in funded research., Conclusion: Valid questionnaires and tools to measure parent-identified outcomes in young preterm children exist. This study will facilitate research and collection of data important to families., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Craniosynostosis is a congenital abnormality resulting in the premature fusion of one or more cranial sutures and usually requires surgical correction in the first year of life. While the majority of craniosynostosis cases represent isolated, nonsyndromic defects, approximately 25% are linked to a genetic diagnosis. Craniosynostosis has been associated with developmental delay. Therefore, historically in Manitoba, all children with surgically managed craniosynostosis were referred to the Child Development Clinic (CDC) for developmental assessment. There are currently prolonged wait times for neurodevelopmental assessments at CDC, leading to the need to better prioritize children who require neurodevelopmental assessment. The aim of the study was then to determine the developmental outcomes of preschool children requiring craniosynostosis surgery in Manitoba from July 1, 2016 through December 1, 2021. In this retrospective cohort study, clinical records were reviewed to evaluate the developmental outcomes of patients who were assessed at CDC for surgically managed craniosynostosis. Out of 67 children included in this study, 18% demonstrated global developmental delay, 24% demonstrated mild developmental delay, and 58% were developmentally appropriate across all levels. The presence of a genetic syndrome, multisutural craniosynostosis, and parental socioeconomic status were associated with risk of global developmental delay. The findings of this study suggest that while not all children with craniosynostosis present with developmental delay, those with suspected or confirmed syndromic involvement, multisutural cranyosinostosis, and/or low SES, should be referred for neurodevelopmental evaluation., Competing Interests: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae . transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.

Objectives: The risk of attention deficit hyperactivity disorder (ADHD) following multiple exposures to anesthesia has been debated. Our objective was to systematically review the literature to examine the association between multiple exposures to general anesthesia before age 5 and subsequent diagnosis of ADHD., Methods: A systematic search of EMBASE, PubMed, and SCOPUS was performed using key search terms in February 2022. We included studies that: were published after 1980, included only otherwise healthy children who experienced two or more exposures to general anesthetic before age 5, diagnosed ADHD by a medical professional before age 19 years after exposure to general anesthetic, were cross-sectional, case-control, or cohort study, and were published in English. The results (expressed as hazard ratios [HR] and associated 95% confidence intervals [CI]) were pooled using meta-analytic techniques. Studies which did not present their results as HR and 95% CI were analyzed separately. GRADE was used to determine the certainty of the findings. PRISMA guidelines were followed at each stage of the review., Results: Eight studies (196,749 children) were included. Five reported HR and 95% CI and were subsequently pooled for meta-analysis. Multiple exposures to anesthesia were associated with diagnosis of ADHD before the 19th year of life (HR: 1.71; 95% CI: 1.59, 1.84). Two of the three studies not used in the meta-analysis also found an increased risk of ADHD diagnosis following multiple anesthetic exposures., Conclusions: There was an association between multiple early exposures to general anesthesia and later diagnosis of ADHD., Competing Interests: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Functional foods containing probiotics are generally administered as dairy products. Non-dairy beverages are another possibility, but probiotic functionality must be confirmed in such vehicles. In the present study, a craft wheat beer brewed with the probiotic yeast Saccharomyces cerevisiae UFMG A-905 (905) was evaluated in a murine model of Salmonella Typhimurium infection. Unfiltered or filtered beer brewed with 905, a commercial wheat beer used as a negative control, or saline were administered orally to mice before and during oral S. Typhimurium challenge. High fecal levels of yeast were only counted in mice treated with the unfiltered 905 beer, which also had reduced mortality and body weight loss due to S. Typhimurium infection. Increased levels of intestinal IgA, translocation to liver and spleen, liver and intestinal lesions, pro-inflammatory cytokines in liver and ileum, and hepatic and intestinal myeloperoxidase and eosinophilic peroxidase activities were observed in animals infected with S. Typhimurium. All these parameters were reduced by the treatment with unfiltered 905 beer. In conclusion, the results show that a craft wheat beer brewed with S. cerevisiae UFMG A-905 maintained the probiotic properties of this yeast when administered orally to mice challenged with S. Typhimurium., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autism spectrum disorder (ASD) is a developmental disorder characterized by deficits in social interaction/communication, restricted interests, and repetitive behaviors. Recent discussions have emerged worldwide regarding the heterogeneity around presentation/etiology and comorbidities. This study aimed to determine the frequency and characteristics of comorbidities among children diagnosed with ASD in Manitoba and to evaluate differences in presentation between those with and without medical comorbidities. We conducted a retrospective chart review of >1900 electronic charts at the only publicly funded referral site for children ≤6 years requiring evaluation for ASD in Manitoba. All children aged 0-6 years diagnosed with ASD at this site between May 2016 and September 2021 were identified. χ 2 and t -tests were used to compare groups. Of the total of 1858 children identified, 1452 (78.1%) were boys, 251 (13.5%) were prematurely born, and 539 (29.0%) had ≥1 medical comorbidity. Global developmental delay (GDD) was diagnosed in 428 (23.0%). The age of referral and diagnosis did not differ between groups. Comorbidities were more common among premature children (16.0% vs. 12.5%, p : 0.005) and children with comorbid GDD (34.9% vs. 18.2%, p < 0.001). Neurological comorbidities were most common (37.1%). No sex difference in the overall presence of comorbidities was found (boys = 77.1% vs. 78.5%, p : 0.518); however, girls had a higher incidence of neurological comorbidities, e.g., cerebral palsy, seizures, hypotonia (14.8% vs. 9.64%, p : 0.009), as well as genetic comorbidities (4.92% vs. 2.75%, p : 0.04). The high rates of associated neurological conditions, GDD, and prematurity add heterogeneity to this group leading to potential difficulties with prognosis and service allocation. Primary vs. secondary ASD can be a way of separating individuals based on relevant medical comorbidities.

Objective: To describe the distribution of peak bilirubin levels among infants born before 29 weeks of gestation in the first 14 days of life and to study the association between quartiles of peak bilirubin levels at different gestational ages and neurodevelopmental outcomes., Study Design: Multicenter, retrospective, nationwide cohort study of neonatal intensive care units in the Canadian Neonatal Network and Canadian Neonatal Follow-Up Network, including neonates born preterm at 22 0/7 to 28 6/7  weeks of gestation born between 2010 and 2018. Peak bilirubin levels were recorded during the first 14 days of age. Main outcome was significant neurodevelopmental impairment, defined as cerebral palsy with Gross Motor Function Classification System ≥3, or Bayley III-IV scores of <70 in any domain, or visual impairment, or bilateral hearing loss requiring hearing aids., Results: Among 12 554 included newborns, median gestational age was 26 weeks (IQR 25-28) and birth weight was 920 g (IQR 750-1105 g). The median peak bilirubin values increased as gestational age increased (112 mmol/L [6.5 mg/dL] at 22 weeks and 156 mmol/L [9.1 mg/dL] at 28 weeks). Significant neurodevelopmental impairment was identified in 1116 of 6638 (16.8%) of children. Multivariable analyses identified an association between peak bilirubin in the highest quartile and neurodevelopmental impairment (aOR 1.27, 95% CI 1.01-1.60) and receipt of hearing aid/cochlear implant (aOR 3.97, 95%CI: 2.01-7.82) compared with the lowest quartile., Conclusion: In this multicenter cohort study, peak bilirubin levels in neonates of <29 weeks of gestation increased with gestational age. Peak bilirubin values in the highest gestational age-specific quartile were associated with significant neurodevelopmental and hearing impairments., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Parental mental health services in neonatal follow-up programs (NFUPs) are lacking though needed. This study aimed to determine (1) the unmet mental health needs of parents and (2) the parent and provider perspectives on barriers and opportunities to increase mental health service access. Study 1 : Parents in a central Canadian NFUP ( N = 49) completed a mixed-method online survey (analyzed descriptively and by content analysis) to elucidate their mental health, related service use, barriers to service use, and service preferences. Study 2 : Virtual focus groups with NFUP service providers ( N = 5) were run to inform service improvements (analyzed by reflexive thematic analysis). The results show that parents endorsed a 2-4 times higher prevalence of clinically significant depression (59.2%), anxiety (51.0%), and PTSD (26.5%) than the general postpartum population. Most parents were not using mental health services (55.1%) due to resource insecurity among parents (e.g., time, cost) and the organization (e.g., staffing, training, referrals). Consolidating parents' and service providers' perspectives revealed four opportunities for service improvements: bridging services, mental health screening, online psychoeducation, and peer support. Findings clarify how a central Canadian NFUP can address parental mental health in ways that are desired by parents and feasible for service providers.

Importance: Children born preterm may experience learning challenges at school. However, there is a paucity of data on the school readiness of these children as they prepare to begin grade 1., Objective: To examine the association between prematurity and school readiness in a population-based cohort of children., Design, Setting, and Participants: This cohort study was conducted in the province of Manitoba, Canada, and involved 2 cohorts of children in kindergarten at the time of data collection. The population-based cohort included children born between January 1, 2000, and December 31, 2011, whose school readiness was assessed in kindergarten using the Early Development Instrument (EDI) data. The sibling cohort comprised children born preterm and their closest-in-age siblings born full term. Data were analyzed between March 12 and September 28, 2021., Exposures: Preterm birth, defined as gestational age (GA) less than 37 weeks., Main Outcomes and Measures: The primary outcome was vulnerability in the EDI, defined as a score below the tenth percentile of the Canadian population norms for any 1 or more of the 5 EDI domains (physical health and well-being, social competence, emotional maturity, language and cognitive development, and communication skills and general knowledge). Logistic regression models were used to identify the factors associated with vulnerability in the EDI. P values were adjusted for multiplicity using the Simes false discovery method., Results: Of 86 829 eligible children, 63 277 were included, of whom 4352 were preterm (mean [SD] GA, 34 [2] weeks; 2315 boys [53%]) and 58 925 were full term (mean [SD] GA, 39 (1) weeks; 29 885 boys [51%]). Overall, 35% of children (1536 of 4352) born preterm were vulnerable in the EDI compared with 28% of children (16 449 of 58 925) born full term (adjusted odds ratio [AOR], 1.32; 95% CI, 1.23-1.41; P < .001]). Compared with children born full term, those born preterm had a higher percentage of vulnerability in each of the 5 EDI domains. In the population-based cohort, prematurity (34-36 weeks' GA: AOR, 1.23 [95% CI, 1.14-1.33]; <34 weeks' GA: AOR, 1.72 [95% CI, 1.48-1.99]), male sex (AOR, 2.24; 95% CI, 2.16-2.33), small for gestational age (AOR, 1.31; 95% CI, 1.23-1.40), and various maternal medical and sociodemographic factors were associated with EDI vulnerability. In the sibling cohort, EDI outcomes were similar for both children born preterm and their siblings born full term except for the communication skills and general knowledge domain (AOR, 1.39; 95% CI, 1.07-1.80) and Multiple Challenge Index (AOR, 1.43; 95% CI, 1.06-1.92), whereas male sex (AOR, 2.19; 95% CI, 1.62-2.96) and maternal age at delivery (AOR, 1.53; 95% CI, 1.38-1.70) were associated with EDI vulnerability., Conclusions and Relevance: Results of this study suggest that, in a population-based cohort, children born preterm had a lower school-readiness rate than children born full term, but this difference was not observed in the sibling cohort. Child and maternal factors were associated with lack of school readiness among this population-based cohort.

Objective: To describe the early neurodevelopmental outcomes following fetal exposure to previable preterm prelabour rupture of membranes (pPPROM)., Methods: This was a secondary analysis of a subgroup of neonates born following pPPROM from a retrospective cohort study (2009-2015). Surviving infants who underwent standardized neurodevelopmental evaluation at 18-24 months corrected age (CA) between 2017 and 2019 were eligible for inclusion. Data abstracted from hospital charts were linked to prospectively collected developmental outcomes stored in an electronic database from a regional neonatal follow-up clinic. The primary outcome was Bayley-III composite scores (compared to the population mean 100, standard deviation (SD) 15). Secondary outcomes included presence of cerebral palsy, vision loss, hearing impairment, and requirement of rehabilitation therapy. Descriptive statistics were used to present results., Results: 25.7% (19/74) of neonates born after pPPROM survived to hospital discharge, but only 21.6% (16/74) survived to 18-24 months CA. Of these, 9 infants were eligible for follow-up at the regional clinic and 7 had developmental outcomes stored in the electronic database. Infants exposed to pPPROM exhibited Bayley-III scores more than 1 SD below the population mean across all three domains: cognitive 84.9 (SD 12.2); motor 82.3 (SD 11.5); and language 66.4 (SD 18.9). There were particular deficiencies in language development with 71% (5/7) scoring more than 2 SDs below the population mean. There were no cases of cerebral palsy., Conclusions: Only 1 in 5 infants born following expectantly managed pPPROM survived to 18-24 months CA. These infants born after pPPROM had significantly lower Bayley-III scores and particular deficiencies in language development. Better understanding of early neurodevelopmental challenges following pPPROM will help refine counselling of families contemplating expectant management and provide insights into the postnatal educational resources required to improve long-term developmental outcomes for these children., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Christy L. Pylypjuk et al.)

Objective: To evaluate changes in mortality or significant neurodevelopmental impairment (NDI) in children born at <29 weeks of gestation in association with national quality improvement initiatives., Study Design: This longitudinal cohort study included children born at 22 0/7 to 28 6/7  weeks of gestation who were admitted to Canadian neonatal intensive care units between 2009 and 2016. The primary outcome was a composite rate of death or significant NDI (Bayley Scales of Infant and Toddler Development, Third Edition score <70, severe cerebral palsy, blindness, or deafness requiring amplification) at 18-24 months corrected age. To evaluate temporal changes, outcomes were compared between epoch 1 (2009-2012) and epoch 2 (2013-2016). aORs were calculated for differences between the 2 epochs accounting for differences in patient characteristics., Results: The 4426 children included 1895 (43%) born in epoch 1 and 2531 (57%) born in epoch 2. Compared with epoch 1, in epoch 2 more mothers received magnesium sulfate (56% vs 28%), antibiotics (69% vs 65%), and delayed cord clamping (37% vs 31%) and fewer infants had a Score for Neonatal Acute Physiology, version II >20 (31% vs 35%) and late-onset sepsis (23% vs 27%). Death or significant NDI occurred in 30% of children in epoch 2 versus 32% of children in epoch 1 (aOR, 0.86; 95% CI, 0.75-0.99). In epoch 2, there were reductions in the need for hearing aids or cochlear implants (1.4% vs 2.6%; aOR, 0.50; 95% CI, 0.31-0.82) and in blindness (0.6% vs.1.4%; aOR, 0.38; 95% CI, 0.18-0.80)., Conclusions: Among preterm infants born at <29 weeks of gestation, composite rates of death or significant NDI and rates of visual and hearing impairment were significantly lower in 2013-2016 compared with 2009-2012., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/aims: Chagasic megacolon is caused by Trypanosoma cruzi , which promotes in several cases, irreversible segmental colonic dilation. This alteration is the major anatomic-clinical disorder, characterized by the enteric nervous system and muscle wall structural damage. Herein, we investigate how T. cruzi -induced progressive colonic structural changes modulate the colonic contractile pattern activity., Methods: We developed a murine model of T. cruzi -infection that reproduced long-term modifications of the enlarged colon. We evaluated colonic and total intestinal transit time in animals. The patterns of motor response at several time intervals between the acute and chronic phases were evaluated using the organ bath assays. Enteric motor neurons were stimulated by electric field stimulation. The responses were analyzed in the presence of the nicotinic and muscarinic acetylcholine receptor antagonists. Western blot was performed to evaluate the expression of nicotinic and muscarinic receptors. The neurotransmitter expression was analyzed by real-time polymerase chain reaction., Results: In the chronic phase of infection, there was decreased intestinal motility associated with decreased amplitude and rhythmicity of intestinal contractility. Pharmacological tests suggested a defective response mediated by acetylcholine receptors. The contractile response induced by acetylcholine was decreased by atropine in the acute phase while the lack of its action in the chronic phase was associated with tissue damage, and decreased expression of choline acetyltransferase, nicotinic subunits of acetylcholine receptors, and neurotransmitters., Conclusions: T. cruzi -induced damage of smooth muscles was accompanied by motility disorders such as decreased intestinal peristalsis and cholinergic system response impairment. This study allows integration of the natural history of Chagasic megacolon motility disorders and opens new perspectives for the design of effective therapeutic.

Context: Children with critical CHD are at risk for neurodevelopmental impairments, including delays in expressive and receptive language development. However, no study has synthesised the literature regarding language abilities in children with this condition., Objective: We summarised the literature regarding expressive and receptive language in preschool children with critical CHD., Data Sources: MEDLINE, Embase, Scopus, Child Development and Adolescent Studies, ERIC, PsycINFO, and CINAHL., Study Selection: We included studies published between January, 1990 and 1 July, 2021, focused on children aged ≤5 years with critical CHD requiring a complex cardiac procedure at age <1 year. Language ability was documented using standardised, validated tools assessing both expressive and receptive language outcomes., Data Extraction: Data (study, patient and language characteristics, and results) were extracted by two reviewers., Results: Seventeen studies were included. Among children 2-5 years old with critical CHD, there were statistically significant deficits in overall (standardised mean difference: -0.46; 95 % confidence interval: -0.56, -0.35), expressive (standardised mean difference: -0.45;95 % confidence interval: -0.54, -0.37), and receptive (standardised mean difference: -0.32; 95 % confidence interval: -0.40, -0.23) language compared to normative data. Results reported as medians were similar to meta-analysis findings. Subgroup analysis showed that children with univentricular physiology had lower language scores than children with biventricular physiology., Conclusions: Preschool children with critical CHD had statistically significantly lower language outcomes compared to expected population norms. Healthcare professionals should test early and often for language deficits, referring to individually tailored supports.

This comparison study of two groups within an inception cohort aimed to compare the frequency of motor impairment between preschool children with univentricular and biventricular critical congenital heart disease (CHD) not diagnosed with cerebral palsy/acquired brain injury, describe and compare their motor profiles and explore predictors of motor impairment in each group.Children with an intellectual quotient <70 or cerebral palsy/acquired brain injury were excluded. Motor skills were assessed with the Movement Assessment Battery for Children-2. Total scores <5th percentile indicated motor impairment. Statistical analysis included χ2 test and multiple logistic regression analysis.At a mean age of 55.4 (standard deviation 3.77) months, motor impairment was present in 11.8% of those with biventricular critical CHD, and 32.4% (p < 0.001) of those with univentricular critical CHD. The greatest difference between children with biventricular and univentricular CHD was seen in total test scores 8.73(2.9) versus 6.44(2.8) (p < 0.01) and in balance skills, 8.84 (2.8) versus 6.97 (2.5) (p = 0.001). Manual dexterity mean scores of children with univentricular CHD were significantly below the general population mean (>than one standard deviation). Independent odds ratio for motor impairment in children with biventricular critical CHD was presence of chromosomal abnormality, odds ratio 10.9 (CI 2.13-55.8) (p = 0.004); and in children with univentricular critical CHD odds ratio were: postoperative day 1-5 highest lactate (mmol/L), OR: 1.65 (C1.04-2.62) (p = 0.034), and dialysis requirement any time before the 4.5-year-old assessment, OR: 7.8 (CI 1.08-56.5) (p = 0.042).Early assessment of motor skills, particularly balance and manual dexterity, allows for intervention and supports that can address challenges during the school years.

The gastrointestinal and respiratory systems are colonized by a complex ecosystem of microorganisms called the microbiota. These microorganisms co-evolved over millions of years with the host, creating a symbiotic relationship that is fundamental for promoting host homeostasis by producing bioactive metabolites and antimicrobial molecules, and regulating the immune and inflammatory responses. Imbalance in the abundance, diversity, and function of the gut microbiota (known as dysbiosis) have been shown to increase host susceptibility to infections in the lungs, suggesting crosstalk between these organs. This crosstalk is now referred to as the gut-lung axis. Hence, the use of probiotics, prebiotics, and synbiotics for modulation of gut microbiota has been studied based on their effectiveness in reducing the duration and severity of respiratory tract infections, mainly owing to their effects on preventing pathogen colonization and modulating the immune system. This review discusses the role and responses of probiotics, prebiotics, and synbiotics in the gut-lung axis in the face of lung infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cruz, Ricci and Vieira.)

Objective: To give providers a better understanding of how to use the electronic health record (EHR), improve efficiency, and reduce burnout., Materials and Methods: All ambulatory providers were offered at least 1 one-on-one session with an "optimizer" focusing on filling gaps in EHR knowledge and lack of customization. Success was measured using pre- and post-surveys that consisted of validated tools and homegrown questions. Only participants who returned both surveys were included in our calculations., Results: Out of 1155 eligible providers, 1010 participated in optimization sessions. Pre-survey return rate was 90% (1034/1155) and post-survey was 54% (541/1010). 451 participants completed both surveys. After completing their optimization sessions, respondents reported a 26% improvement in mean knowledge of EHR functionality (P < .01), a 19% increase in the mean efficiency in the EHR (P < .01), and a 17% decrease in mean after-hours EHR usage (P < .01). Of the 401 providers asked to rate their burnout, 32% reported feelings of burnout in the pre-survey compared to 23% in the post-survey (P < .01). Providers were also likely to recommend colleagues participate in the program, with a Net Promoter Score of 41., Discussion: It is possible to improve provider efficiency and feelings of burnout with a personalized optimization program. We ascribe these improvements to the one-on-one nature of our program which provides both training as well as addressing the feeling of isolation many providers feel after implementation., Conclusion: It is possible to reduce burnout in ambulatory providers with personalized retraining designed to improve efficiency and knowledge of the EHR., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Acute chagasic encephalitis is a clinically severe central nervous system (CNS) manifestation. However, the knowledge of the nervous form of Chagas disease is incomplete. The role of the muscarinic acetylcholine receptor (mAChR) on mice behavior and brain lesions induced by Trypanosoma cruzi (Colombian strain) was herein investigated in mice treated with the mAChR agonist and antagonist (carbachol and atropine), respectively. Immunosuppressed or non-immunosuppressed mice were intracerebroventricularly (icv) or intraperitoneally (ip) infected. All groups were evaluated 15 d.p.i. (days post infection). Intraperitoneally infected animals had subpatent parasitemia. Patent parasitemia occurred only in icv infected mice. The blockade of mAChR increased the parasitemia, parasitism and lesions compared to its activation. Infected not treated (INT ip) mice did not present meningitis and encephalitis, regardless of immunosuppression. INT icv brains presented higher cellularity, discrete signs of cellular degeneration, frequent presence of parasites and focal meningitis. The immunosuppressed atropine + icv mice presented increased intracellular parasitism associated with degenerative parenchymal changes, while carbachol + icv mice presented discrete meningitis, preservation of the cortex and absence of relevant parasitism. Cholinergic receptor blockage increased impairment of coordination vs. receptor activation. Muscarinic cholinergic pathway seems to be involved in immune mediated cell invasion events while its blockade favored infection evolution, brain lesions, and behavioral alterations.

There is a growing consensus that the balance between the persistence of infection and the host immune response is crucial for chronification of Chagas heart disease. Extrapolation for chagasic megacolon is hampered because research in humans and animal models that reproduce intestinal pathology is lacking. The parasite-host relationship and its consequence to the disease are not well-known. Our model describes the temporal changes in the mice intestine wall throughout the infection, parasitism, and the development of megacolon. It also presents the consequence of the infection of primary myenteric neurons in culture with Trypanosoma cruzi ( T. cruzi ). Oxidative neuronal damage, involving reactive nitrogen species induced by parasite infection and cytokine production, results in the denervation of the myenteric ganglia in the acute phase. The long-term inflammation induced by the parasite's DNA causes intramuscular axonal damage, smooth muscle hypertrophy, and inconsistent innervation, affecting contractility. Acute phase neuronal loss may be irreversible. However, the dynamics of the damages revealed herein indicate that neuroprotection interventions in acute and chronic phases may help to eradicate the parasite and control the inflammatory-induced increase of the intestinal wall thickness and axonal loss. Our model is a powerful approach to integrate the acute and chronic events triggered by T. cruzi , leading to megacolon., (Copyright © 2020 Ricci, Béla, Moraes, Bahia, Mazzeti, Oliveira, Andrade, Radí, Piacenza and Arantes.)

Digestive and cardiodigestive forms of Chagas' disease are observed in 2% to 27% of the patients, depending on their geographic location, Trypanosoma cruzi strain and immunopathological responses. The aim of this work was to evaluate the role of NOD2 innate immune receptor in the pathogenesis of the digestive system in Chagas' disease. Patients with digestive form of the disease showed lower mRNA expression of NOD2, higher expression of RIP2 and α-defensin 6, compared to indeterminate form, detected by Real-time PCR in peripheral blood mononuclear cells. In addition, there was a negative correlation between the expression of NOD2 and the degree of dilation of the esophagus, sigmoid and rectum in those patients. The infection of NOD2-/- mice with T. cruzi strain isolated from the digestive patient induced a decrease in intestinal motility. Histopathological analysis of the colon and jejunum of NOD2-/- and wild type C57BL/6 animals revealed discrete inflammatory foci during the acute phase of infection. Interestingly, during the chronic phase of the infection there was inflammation and hypertrophy of the longitudinal and circular muscular layer more pronounced in the colon and jejunum from NOD2-/- animals, when compared to wild type C57BL/6 mice. Together, our results suggest that NOD2 plays a protective role against the development of digestive form of Chagas' disease., Competing Interests: The authors have declared that no competing interests exist.

While terms such as 'essential' and 'nonessential' used amidst the COVID-19 pandemic may serve a practical purpose, they also pose a risk of obstructing our view of the harmful indirect health consequences of this crisis. SARS-CoV-2 cases and deaths in children are minimal compared to adults, but the pandemic impacts other 'essential' aspects of children's health including child development and the associated areas of paediatric behaviour, mental health, and maltreatment. Alongside the management of severe SARS-CoV-2 cases in emergency rooms and intensive care units, continuing to care for children with developmental disabilities must also be concurrently championed as 'essential' during this crisis. The potentially devastating lifelong effects of the pandemic and isolation on an already vulnerable population demand that action be taken now. Video conferences and phone calls are 'essential' instruments we can use to continue to provide quality care for our patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ST2 receptor plays an important role in the gut such as permeability regulation, epithelium regeneration, and promoting intestinal immune modulation. Here, we studied the role of ST2 receptor in a murine model of oral infection with Brucella abortus , its influence on gut homeostasis and control of bacterial replication. Balb/c (wild-type, WT) and ST2 deficient mice (ST2 -/- ) were infected by oral gavage and the results were obtained at 3 and 14 days post infection (dpi). Our results suggest that ST2 -/- are more resistant to B. abortus infection, as a lower bacterial colony-forming unit (CFU) was detected in the livers and spleens of knockout mice, when compared to WT. Additionally, we observed an increase in intestinal permeability in WT-infected mice, compared to ST2 -/- animals. Breakage of the intestinal epithelial barrier and bacterial dissemination might be associated with the presence of the ST2 receptor; since, in the knockout mice no change in intestinal permeability was observed after infection. Together with enhanced resistance to infection, ST2 -/- produced greater levels of IFN-γ and TNF-α in the small intestine, compared to WT mice. Nevertheless, in the systemic model of infection ST2 plays no role in controlling Brucella replication in vivo. Our results suggest that the ST2 receptor is involved in the invasion process of B. abortus by the mucosa in the oral infection model., Competing Interests: The authors declare no conflict of interest.

Background Management of patients with hypoplastic left heart syndrome has benefited from advancements in medical and surgical care. Outcomes have improved, although survival and long-term functional and cognitive deficits remain a concern. Methods and Results This is a cohort study of all consecutive patients with hypoplastic left heart syndrome undergoing surgical palliation at a single center. We aimed to examine demographic and perioperative factors from each surgical stage for their association with survival and neurocognitive outcomes. A total of 117 consecutive patients from 1996 to 2010 underwent surgical palliation. Seventy patients (60%) survived to the Fontan stage and 68 patients (58%) survived to undergo neurocognitive assessment at a mean (SD) age of 56.6 months (6.4 months). Full-scale, performance, and verbal intelligence quotient, as well as visual-motor integration mean (SD) scores were 86.7 (16.1), 86.3 (15.8), 88.8 (17.2), and 83.2 (14.8), respectively. On multivariable analysis, older age at Fontan, sepsis peri-Norwood, lowest arterial partial pressure of oxygen postbidirectional cavopulmonary anastomosis, and presence of neuromotor disability pre-Fontan were strongly associated with lower scores for all intelligence quotient domains. Older age at Fontan and sepsis peri-Norwood remained associated with lower scores for all intelligence quotient domains in a subgroup analysis excluding patients with disability pre-Fontan or with chromosomal abnormalities. Conclusions Older age at Fontan and sepsis are among independent predictors of poor neurocognitive outcomes for patients with hypoplastic left heart syndrome. Further studies are required to identify the appropriate age range for Fontan completion, balancing a lower risk of acute and long-term hemodynamic complications while optimizing long-term neurocognitive outcomes.

Two billion people are chronically infected with Toxoplasma gondii worldwide with unknown consequences. Important neurological diseases have been associated to the brain infection, making essential to understand the neurophysiological changes associated with the neuronal encystment. T. gondii may subvert neuronal functions modifying neurotransmitter concentration in chronically infected mice but the molecular mechanisms involved are still unclear. Parasites were observed inside neuronal cells in cultures from 24-192 hs. The rate of infection increased with time. Neurite density decreased affecting network functionality. Neuronal survival was affected and we detected the presence of cysts inside neuronal bodies and dilated portions of neurites in association with a relative increase of TH-positive neuritic area without noticeable changes in DA immunofluorescence pattern. These results advance our knowledge of the interaction between T. gondii and the neuronal network of the host., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Kefir is a beverage obtained by fermentation of milk or sugar solution by lactic acid bacteria and yeasts, and several health benefits have been attributed to its ingestion, part of them being attributed to Lactobacillus species. The objective of the present study was to evaluate, in vivo , the probiotic potential of Lactobacillus diolivorans 1Z, isolated from Brazilian kefir grains. Initially, conventional mice were orally treated daily or not during 10 days with a suspension of L. diolivorans 1Z, and then orally challenged with Salmonella enterica serovar Typhimurium. Treatment with L. diolivorans 1Z resulted in higher survival (70%) of animals after the challenge with the pathogen than for not treated mice (0%). When germ-free mice were monoassociated (GN-PS group) or not (GN-CS group) with L. diolivorans 1Z and challenged after 7 days with S. Typhimurium, Salmonella fecal counts were significantly lower ( P < 0.05) for the GN-PS group when compared to the GN-CS group. Histopathological analysis revealed less damage to the ileum mucosa, as demonstrated by smallest perimeter of major lesions for mice of the GN-PS group in comparison to the group GN-CS ( P < 0.05). These findings were accompanied by a lower expression of IFN-γ and TNF-α in the intestinal tissue of GN-PS mice. Additionally, translocation of S. Typhimurium to liver was significantly lower in GN-PS than in GN-CS mice ( P < 0.05), and IgA levels in intestinal content and number of Kupffer cells in liver were higher. No difference was observed for hepatic cellularity between GN-PS and GN-CS groups ( P > 0.05), but the pattern of inflammatory cells present in the liver was predominantly of polymorphonuclear in GN-CS group and of mononuclear in the GN-PS group, and a higher hepatic expression of IL-10 and TGF-β was observed in GN-PS group. Concluding, L. diolivorans 1Z showed to be a potential probiotic strain that protected mice from death after challenge with S. Typhimurium, apparently by immunological modulation.

Functional abilities are needed for activities of daily living. In general, these skills expand with age. We hypothesised that, in contrast to what is normally expected, children surviving the Fontan may have deterioration of functional abilities, and that peri-Fontan stroke is associated with this deterioration. All children registered in the Western Canadian Complex Pediatric Therapies Follow-up Program who survived a Fontan operation in the period 1999-2016 were eligible for inclusion. At the age of 2 years (pre-Fontan) and 4.5 years (post-Fontan), the Adaptive Behavior Assessment System-II general adaptive composite score was determined (population mean: 100, standard deviation: 15). Deterioration of functional abilities was defined as ⩾1 standard deviation decrease in pre- to post-Fontan scores. Perioperative strokes were identified through chart review. Multivariable logistic regression analysis determined predictors of deterioration of functional abilities. Of 133 children, with a mean age at Fontan of 3.3 years (standard deviation 0.8) and 65% male, the mean (standard deviation) general adaptive composite score was 90.6 (17.5) at 2 years and 88.3 (19.1) at 4.5 years. After Fontan, deterioration of functional abilities occurred in 34 (26%) children, with a mean decline of 21.8 (7.1) points. Evidence of peri-Fontan stroke was found in 10 (29%) children who had deterioration of functional abilities. Peri-Fontan stroke (odds ratio 5.00 (95% CI 1.74, 14.36)) and older age at Fontan (odds ratio 1.67 (95% CI 1.02, 2.73)) predicted functional deterioration. The trajectory of functional abilities should be assessed in this population, as more than 25% experience deterioration. Efforts to prevent peri-Fontan stroke, and to complete the Fontan operation at an earlier age, may lead to reduction of this deterioration.

Objectives: The objectives of this study were to determine prevalence estimates of cerebral palsy (CP) among 5-year-old children in northern Alberta; to provide congenital, gestational age- and birth weight-specific, and postneonatal CP rates; and to describe motor subtypes and function., Methods: This population-based prevalence estimate study, part of the Canadian Cerebral Palsy Registry, reports confirmed CP diagnoses at age 5 years made by pediatric rehabilitation and child neurology specialists. Prevalence rates with 95% confidence intervals (CIs) used Alberta government denominators of same-age children and live births., Results: The Northern Alberta CP rate (birth years, 2008-2010) for 173 5-year-old children is 2.22 (95% CI 2.12, 2.32) per 1000 5-year-old children. The congenital CP rate is 1.99 (95% CI, 1.89-2.09) per 1000 live births; unilateral congenital CP, 1.0 (95% CI, 0.64-1.36) per 1000 live births; and postneonatal CP, 0.12 (95% CI, 0.1-0.14) per 1000 live births. Gestational age-specific rates are similar: age <28 weeks, 27.2 (95% CI, 23.05-31.35) and 28 to 31 weeks, 29.5 (95% CI, 25.78-33.22). Motor subtypes for 169 children (data missing, 4; male, 97; postnatal, 9) are: spastic, 148 (87.6%) including 31 (20.9%) with diplegia, 10 (6.8%) triplegia, 33 (22.2%) quadriplegia, 74 (50%) hemiplegia/monoplegia); and dyskinetic, 18 (10.6%) and ataxic, 3 (1.8%). A total of 107 (63.3%) ambulate without assistive devices and 111(65.7%) handle most objects with their hands independently., Conclusions: This is the fourth Canadian CP prevalence study; one from Quebec used a similar case ascertainment approach and two 1980s studies from Alberta and British Columbia used administrative databases. Northern Alberta CP rates are comparable with other developed countries. The hemiplegic subtype is the most common. Rates among preterm children have declined but are similar for the <28 and 28 to 31 gestation-week groups.

Objective: To compare the proportion of developmental delay in early complex cardiac surgery (CCS) survivors with and without gastrostomy tube feeding (GTF). To explore acute care predictors of GTF that might help improve care in CCS survivors., Study Group: This comparison study of 2 groups within an inception cohort included 334 CCS survivors after cardiopulmonary bypass at ≤6 weeks of age (2005-2012) who did not require extracorporeal membrane oxygenation or heart transplantation. Children were assessed at 21 ± 3 months with the Bayley Scales of Infant and Toddler Development-Third Edition and the Adaptive Behavior Assessment System-Second Edition: general adaptive composite score. Delay was determined by scores >2 SD below mean. The χ(2) test compared groups. Predictors of GTF were analyzed using multiple logistic regression analysis, results expressed as OR with 95% CI., Results: Of the survivors, 67/334 (20%) had GTF any time before the 21-month assessment. Developmental delays in children with GTF were cognitive in 16 (24%), motor in 18 (27%), language in 24 (36%) vs without GTF in 7 (3%), 8 (3%), and 32 (12%), respectively (P < .001). Gastrostomy group had almost 8 times the number of children delayed on the general adaptive composite score. Independent OR for GTF are presence of a chromosomal abnormality, OR 4.6 (95% CI 1.8, 12.0) (P = .002), single ventricle anatomy, OR 3.4 (95% CI 1.7, 6.8) (P < .001), total postoperative days of open sternum, OR 1.15 (95% CI 1.1, 1.3) (P = .031), and total number of hospital days at CCS, OR 1.03 (95% CI 1.1, 1.04) (P = .002)., Conclusions: GTF identifies CCS survivors at risk for delay, who would benefit from early developmental intervention. The described mostly nonmodifiable predictors may guide counseling of these children's families., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Objectives: Little is known about chronic neuromotor disability (CND) including cerebral palsy and motor impairments after acquired brain injury in children surviving early complex cardiac surgery (CCS). We sought to determine the frequency and presentation of CND in this population while exploring potentially modifiable acute care predictors., Methods: This prospective follow-up study included 549 children after CCS requiring cardiopulmonary bypass at ≤6 weeks of age. Groups included those with only 1 CCS, mostly biventricular CHD, and those with >1 CCS, predominantly single ventricle defects. At 4.5 years of age, 420 (94.6%) children received multidisciplinary assessment. Frequency of CND is given as percentage of assessed survivors. Predictors of CND were analyzed using multiple logistic regression analysis., Results: CND occurred in 6% (95% confidence interval [CI] 3.7%-8.2%) of 4.5-year survivors; for 1 CCS, 4.2% (CI 2.3%-6.1%) and >1, 9.8% (CI 7%-12.6%). CND presentation showed: hemiparesis, 72%; spasticity, 80%; ambulation, 72%; intellectual disability, 44%; autism, 16%; epilepsy, 12%; permanent vision and hearing impairment, 12% and 8%, respectively. Overall, 32% of presumed causative events happened before first CCS. Independent odds ratio for CND are age (days) at first CCS, 1.08 (CI 1.04-1.12; P < .001); highest plasma lactate before first CCS (mmol/L), 1.13 (CI 1.03-1.23; P = 0.008); and >1 CCS, 3.57 (CI 1.48-8.9; P = .005)., Conclusions: CND is not uncommon among CCS survivors. The frequency of associated disabilities characterized in this study informs pediatricians caring for this vulnerable population. Shortening the waiting period and reducing preoperative plasma lactate levels at first CCS may assist in reducing the frequency of CND., (Copyright © 2015 by the American Academy of Pediatrics.)