Differences in gross motor and fine motor outcomes for toddlers after early complex cardiac surgery.

OBJECTIVES: To determine whether gross motor scores of toddlers after complex cardiac surgery were different from fine motor scores and were adequately represented by motor composite scores and, whether acute care predictors and chronic childhood health markers of gross motor scores differed from those of fine motor. METHODS: This prospective inception-cohort outcomes study included 171 toddlers after complex cardiac surgery with cardiopulmonary bypass at age <6 months, born in Northern Alberta from 2009 to 2019, and without known chromosomal abnormalities. At a mean (standard deviation) age of 21.7 (3.7) months, the Bayley Scales of Infant and Toddler Development-III determined motor composite and scaled scores (normative values, 100 (15), 10 (3), respectively). The same variables from surgery and assessment were analysed using multivariate regression to predict gross and fine motor scores; results expressed as effect size (95% confidence interval) with % variance. RESULTS: Composite, fine, and gross motor scores were 89.7 (14.2), 9.4 (2.5), and 7.2 (2.7), respectively. Predictive variables accounted for 21.2% of the variance for fine motor, and 36.9% for gross motor. Multivariate analysis for gross motor scores included toddlers need for cardiac medication, effect size (95% confidence interval) -0.801 (-1.62, -0.02), gastrostomy, -1.35 (-2.39, -0.319), and single ventricle, -0.93 (-1.71, -0.15). These same variables did not predict fine motor scores. CONCLUSION: Gross motor skills commonly were lower than fine motor skills for toddlers after complex cardiac surgery. Predictors for gross motor scores differed from fine motor scores. Separate reporting of gross motor scores could lead to improved identification of predictors of delay and to optimised early intervention.

The Alberta Infant Motor Scale as an Outcomes Measure of Gross Motor Abilities after Early Complex Cardiac Surgery.

To address the research hypothesis that the Alberta Infant Motor Scale (AIMS) completed following complex cardiac surgery (CCS) is a useful outcomes measure this study determined: (1) AIMS scores at age 8 months after CCS; (2) predictive validity of AIMS at 8 months for Bayley Scales of Infant and Toddler Development-III Gross Motor-scaled scores (GMSS) and diagnosis of cerebral palsy (CP) at 21 months; and (3) predictive demographic and surgical variables of AIMS scores. A prospective cohort study of 250/271 (92.3%) surviving children from Northern Alberta (born 2009-2020) who had CCS at age < 6 months determined AIMS scores at age mean (SD) 8.6 (2.4) and the GMSS at 21.9 (3.8) months. Gross motor delay was defined as AIMS < 5th percentile and GMSS as < 4 (-2SD). Predictions using multiple logistic regressions were expressed as Odds Ratios (OR) and 95% Confidence Interval (CI). Of children, 100/250 (40%) had AIMS < 5th predicting GMSS < 4 (n = 43); sensitivity, specificity, positive, and negative predictive values were 88%, 71%, 40%, and 97%. Hospitalization days were independently associated with AIMS < 5th, OR 1.02 (95% CI 1.007, 1.032; p = 0.005). Excluding hospital days, ventilation days independently predicted AIMS < 5th, OR 1.08 (95% CI 1.038, 1.125, p < 0.001. Gross motor delay determine by AIMS scores of < 5th percentile occurred in 40% of survivors with good prediction of continued delay. Delay determined by AIMS was predicted by longer hospitalization and ventilation; further investigations about the causes are required. AIMS results provide opportunity for early motor intervention.

Long COVID as a functional somatic symptom disorder caused by abnormally precise prior expectations during Bayesian perceptual processing: A new hypothesis and implications for pandemic response.

This review proposes a model of Long-COVID where the constellation of symptoms are in fact genuinely experienced persistent physical symptoms that are usually functional in nature and therefore potentially reversible, that is, Long-COVID is a somatic symptom disorder. First, we describe what is currently known about Long-COVID in children and adults. Second, we examine reported "Long-Pandemic" effects that create a risk for similar somatic symptoms to develop in non-COVID-19 patients. Third, we describe what was known about somatization and somatic symptom disorder before the COVID-19 pandemic, and suggest that by analogy, Long-COVID may best be conceptualized as one of these disorders, with similar symptoms and predisposing, precipitating, and perpetuating factors. Fourth, we review the phenomenon of mass sociogenic (functional) illness, and the concept of nocebo effects, and suggest that by analogy, Long-COVID is compatible with these descriptions. Fifth, we describe the current theoretical model of the mechanism underlying functional disorders, the Bayesian predictive coding model for perception. This model accounts for moderators that can make symptom inferences functionally inaccurate and therefore can explain how to understand common predisposing, precipitating, and perpetuating factors. Finally, we discuss the implications of this framework for improved public health messaging during a pandemic, with recommendations for the management of Long-COVID symptoms in healthcare systems. We argue that the current public health approach has induced fear of Long-COVID in the population, including from constant messaging about disabling symptoms of Long-COVID and theorizing irreversible tissue damage as the cause of Long-COVID. This has created a self-fulfilling prophecy by inducing the very predisposing, precipitating, and perpetuating factors for the syndrome. Finally, we introduce the term "Pandemic-Response Syndrome" to describe what previously was labeled Long-COVID. This alternative perspective aims to stimulate research and serve as a lesson learned to avoid a repeat performance in the future.

Infants less than or equal to 2.5 kg have increased mortality and worse motor neurodevelopmental outcomes at 2 years of age after Norwood-Sano palliation.

Objectives: In infants with single-ventricle congenital heart disease, prematurity and low weight at the time of the Norwood operation are risk factors for mortality. Reports assessing outcomes (including neurodevelopment) post Norwood palliation in infants ≤2.5 kg are limited. Methods: All infants who underwent a Norwood-Sano procedure between 2004 and 2019 were identified. Infants ≤2.5 kg at the time of the operation (cases) were matched 3:1 with infants >3.0 kg (comparisons) for year of surgery and cardiac diagnosis. Demographic and perioperative characteristics, survival, and functional and neurodevelopmental outcomes were compared. Results: Twenty-seven cases (mean ± standard deviation: weight 2.2 ± 0.3 kg and age 15.6 ± 14.1 days at surgery) and 81 comparisons (3.5 ± 0.4 kg and age 10.9 ± 7.9 days at surgery) were identified. Post-Norwood, cases had a longer time to lactate ≤2 mmol/L (33.1 ± 27.5 vs 17.9 ± 12.2 hours, P < .001), longer duration of ventilation (30.5 ± 24.5 vs 18.6 ± 17.5 days, P = .005), greater need for dialysis (48.1% vs 19.8%, P = .007), and greater need for extracorporeal membrane oxygenation support (29.6% vs 12.3%, P = .004). Cases had significantly greater postoperative (in-hospital) (25.9% vs 1.2%, P < .001) and 2-year (59.2% vs 11.1%, P < .001) mortality. Neurodevelopmental assessment showed the following for cases versus comparisons, respectively: cognitive delay (18.2% vs 7.9%, P = .272), language delay (18.2% vs 11.1%, P = .505), and motor delay (27.3% vs 14.3%, P = .013). Conclusions: Infants ≤2.5 kg at Norwood-Sano palliation have significantly increased postoperative morbidity and mortality up to 2-year follow-up. Neurodevelopmental motor outcomes were worse in these infants. Additional studies are warranted to assess the outcome of alternative medical and interventional treatment plans in this patient population.

Should the Criterion for Brain Death Require Irreversible or Permanent Cessation of Function? Irreversible: The UDDA Revision Series.

I argue that death is irreversible and not merely permanent. Irreversible means a state cannot be reversed and entails permanence. Permanent means a state will not be reversed and includes cases where the state could still be reversed though a decision has been made not to attempt this reversal. This distinction is important, as we shall see. Four reasons are given for why death must be irreversible and not merely permanent: no mortal can return from the state of death; unacceptable implications regarding culpability for actions and omissions; death is a physiologic state; and irreversibility is inherent in the standards to diagnose brain death. Four objections are considered including the following: permanence is the medical standard, permanence was the intent of the President's Commission on defining death, irreversible requires many hours to occur, and we should change terminology to reflect our case intuition. These objections are discussed and rejected. Finally, I clarify my views to conclude that the criterion for biological death is irreversible loss of circulation.

Review: Current trends, challenges, and success stories in adjuvant research.

Vaccine adjuvant research is being fueled and driven by progress in the field of innate immunity that has significantly advanced in the past two decades with the discovery of countless innate immune receptors and innate immune pathways. Receptors for pathogen-associated molecules (PAMPs) or host-derived, danger-associated molecules (DAMPs), as well as molecules in the signaling pathways used by such receptors, are a rich source of potential targets for agonists that enable the tuning of innate immune responses in an unprecedented manner. Targeted modulation of immune responses is achieved not only through the choice of immunostimulator - or select combinations of adjuvants - but also through formulation and systematic modifications of the chemical structure of immunostimulatory molecules. The use of medium and high-throughput screening methods for finding immunostimulators has further accelerated the identification of promising novel adjuvants. However, despite the progress that has been made in finding new adjuvants through systematic screening campaigns, the process is far from perfect. A major bottleneck that significantly slows the process of turning confirmed or putative innate immune receptor agonists into vaccine adjuvants continues to be the lack of defined in vitro correlates of in vivo adjuvanticity. This brief review discusses recent developments, exciting trends, and notable successes in the adjuvant research field, albeit acknowledging challenges and areas for improvement.

Non-Intentional N-Acetylcysteine Overdose Associated with Cerebral Edema and Brain Death.

N-acetylcysteine is the established treatment for acetaminophen toxicity. This medication's complex dosing schedule engenders a high incidence of medication errors. While nuisance side effects are common, only rare case reports describe serious outcomes associated with N-acetylcysteine administration, all of which take place in the setting of non-intentional N-acetylcysteine overdose. This case report contributes to a small but growing literature that suggests that large N-acetylcysteine overdose may have devastating outcomes. We describe a 15-year-old female who presented with stage III acetaminophen toxicity and who received a non-intentional 6-fold overdose of intravenous N-acetylcysteine due to a medication prescribing error. During the N-acetylcysteine infusion dosing error, the patient had clinical deterioration including seizure followed by cerebral edema and brain herniation that progressed to brain death. She developed agitation and worsening headache within 2 h of the dosing error, which progressed to seizure and intubation 14 h into the dosing error. Although possibly due to hepatic encephalopathy, at the time she developed fixed dilated pupils, her lactate, international normalized ratio, aspartate aminotransferase, and alanine aminotransferase had all improved. On review of the literature, other case reports of seizures (n = 4) and cerebral edema with brain herniation (n = 3) were found, suggesting our patient was not an isolated case. Clinicians need to be aware of the common occurrence of dosing errors for N-acetylcysteine infusions. We suggest institutions review their N-acetylcysteine ordering, dosing, and mixing protocols in order to avoid similar rare errors in the future. Iatrogenic overdose of N-acetylcysteine can cause seizure, cerebral edema, and brain death.

Frequent Preservation of Neurologic Function in Brain Death and Brainstem Death Entails False-Positive Misdiagnosis and Cerebral Perfusion.

Some patients who have been diagnosed as "dead by neurologic criteria" continue to exhibit certain brain functions, most commonly, neuroendocrine functions. This preservation of neurologic function after the diagnosis of "brain death" or "brainstem death" is an ongoing source of controversy and concern in the medical, bioethics, and legal literatures. Most obviously, if some brain function persists, then it is not the case that all functions of the entire brain have ceased and hence, declaring such a patient to be "dead" would be a false positive, in any nation with so-called "whole brain death" laws. Furthermore, and perhaps more concerning, the preservation of any brain function necessarily entails the preservation of some amount of brain perfusion, thereby raising the concern as to whether additional areas of neural tissue may remain viable, including areas in the brainstem. These and other considerations cast significant doubt on the reliability of diagnosing either "brain death" or "brainstem death."

A complicated Glenn procedure: risk factors and association with adverse long-term neurodevelopmental and functional outcomes.

OBJECTIVES: To determine potentially modifiable risk factors for a complicated Glenn procedure (cGP) and whether a cGP predicted adverse neurodevelopmental and functional outcomes. A cGP was defined as post-operative death, heart transplant, extracorporeal life support, Glenn takedown, or prolonged ventilation. METHODS: All 169 patients having a Glenn procedure from 2012 to 2017 were included. Neurodevelopmental assessments were performed at age 2 years in consenting survivors (n = 156/159 survivors). The Bayley Scales of Infant and Toddler Development-3rd Edition (Bayley-III) and the Adaptive Behavior Assessment System-2nd Edition (ABAS-II) were administered. Adaptive functional outcomes were determined by the General Adaptive Composite (GAC) score from the ABAS-II. Predictors of outcomes were determined using univariate and multiple variable linear or Cox regressions. RESULTS: Of patients who had a Glenn procedure, 10/169 (6%) died by 2 years of age and 27/169 (16%) had a cGP. Variables statistically significantly associated with a cGP were the inotrope score on post-operative day 1 (HR 1.04, 95%CI 1.01, 1.06; p = 0.010) and use of inhaled nitric oxide post-operatively (HR 7.31, 95%CI 3.19, 16.76; p < 0.001). A cGP was independently statistically significantly associated with adverse Bayley-III Cognitive (ES -10.60, 95%CI -17.09, -4.11; p = 0.002) and Language (ES -11.43, 95%CI -19.25, -3.60; p = 0.004) scores and adverse GAC score (ES -14.89, 95%CI -22.86, -6.92; p < 0.001). CONCLUSIONS: Higher inotrope score and inhaled nitric oxide used post-operatively were associated with a cGP. A cGP was independently associated with adverse 2-year neurodevelopmental and functional outcomes. Whether early recognition and intervention for risk of a cGP can prevent adverse outcomes warrants study.

Evaluating the Prevalence and Factors Associated With an Optimal Neurodevelopmental Outcome in 4- to 6-Year-Old Children With Fontan Circulation.

BACKGROUND: We sought to evaluate the prevalence and factors associated with "optimal" neurodevelopmental outcomes in 4- to 6-year-old children with Fontan circulation. METHODS: Patients followed through the Western Canadian Complex Pediatric Therapies Follow-Up Program, and born between September 1996 and December 2015, were included. Optimal neurodevelopmental outcome was defined as full-scale intelligence quotient; visual-motor integration; adaptive behaviour assessment system-general adaptive composite scores of ≥ 80 each; and the absence of chronic motor disability, permanent hearing loss, visual impairment, and seizure disorder. Multivariable regression models and decision algorithms evaluated variables associated with optimal outcomes. RESULTS: The Fontan procedure was completed on 225 children, with neurodevelopmental outcome data available for 205 (mean [standard deviation]) age at Fontan 3.4 (0.9) years, 37% female). Optimal neurodevelopmental outcome was identified in 55% (112 of 205). Factors independently associated with optimal neurodevelopmental outcome were female sex (odds ratio [OR], 2.1; 95% confidence interval [CI] 1.1-4.1), years of maternal schooling (OR, 1.2 [1.1-1.4]), age at Fontan (years) (OR, 0.97 [0.94-1.0]), need for concomitant atrioventricular valve (AVV) intervention (OR, 0.4 [0.2-1.0]), and time (hours) for lactate to be ≤ 2 mmol/L (OR, 0.9 [0.8-1.0]). Of those with Fontan completion < 3.25 years, without concomitant AVV intervention and lactate normalization within 8 hours post-Fontan, 87% (27 of 31) had optimal neurodevelopmental outcomes. CONCLUSIONS: Optimal neurodevelopmental outcome was present in more than one-half of 4- to 6-year-old children with Fontan circulation in this cohort study, with important associated factors identified, including potentially modifiable factors such as younger age at Fontan surgery and lack of concomitant AVV intervention.

Risk factors for unplanned paediatric intensive care unit admission after anaesthesia-an international multicentre study.

Objectives: Unplanned intensive care unit (ICU) admissions are associated with near-miss events, morbidity, and mortality. We describe the rate, resource utilization, and outcomes of paediatric patients urgently admitted directly to ICU post-anaesthesia compared to other sources of unplanned ICU admissions. Methods: We performed a secondary analysis of data from specialist paediatric hospitals in 7 countries. Patients urgently admitted to the ICU post-anaesthesia were combined and matched with 1 to 3 unique controls from unplanned ICU admissions from other locations by age and hospital. Demographic, clinical, and outcome variables were compared using the Wilcoxon rank-sum test for continuous variables and chi-square or Fisher's exact test for categorical variables. The effect of admission sources on binary outcomes was estimated using univariable conditional logistic regression models with stratification by matched set of anaesthesia and non-anaesthesia admission sources. Results: Most admissions were <1 year of age and for respiratory reasons. Admissions post-anaesthesia were shorter, occurred later in the day, and were more likely to be mechanically ventilated. Admissions post-anaesthesia were less likely to have had a previous ICU admission (4.8% compared to 11%, P=0.032) or PIM 'high-risk diagnosis' (9.5% versus 17.2%, P=0.035) but there was no difference in the number of subsequent ICU admissions. There was no difference in the PIM severity of illness score and no mortality difference between the groups. Conclusions: Young children and respiratory indications dominated unplanned ICU admissions post-anaesthesia, which was more likely later in the day and with mechanical ventilation.

Aggressive measures, rising inequalities, and mass formation during the COVID-19 crisis: An overview and proposed way forward.

A series of aggressive restrictive measures were adopted around the world in 2020-2022 to attempt to prevent SARS-CoV-2 from spreading. However, it has become increasingly clear the most aggressive (lockdown) response strategies may involve negative side-effects such as a steep increase in poverty, hunger, and inequalities. Several economic, educational, and health repercussions have fallen disproportionately on children, students, young workers, and especially on groups with pre-existing inequalities such as low-income families, ethnic minorities, and women. This has led to a vicious cycle of rising inequalities and health issues. For example, educational and financial security decreased along with rising unemployment and loss of life purpose. Domestic violence surged due to dysfunctional families being forced to spend more time with each other. In the current narrative and scoping review, we describe macro-dynamics that are taking place because of aggressive public health policies and psychological tactics to influence public behavior, such as mass formation and crowd behavior. Coupled with the effect of inequalities, we describe how these factors can interact toward aggravating ripple effects. In light of evidence regarding the health, economic and social costs, that likely far outweigh potential benefits, the authors suggest that, first, where applicable, aggressive lockdown policies should be reversed and their re-adoption in the future should be avoided. If measures are needed, these should be non-disruptive. Second, it is important to assess dispassionately the damage done by aggressive measures and offer ways to alleviate the burden and long-term effects. Third, the structures in place that have led to counterproductive policies should be assessed and ways should be sought to optimize decision-making, such as counteracting groupthink and increasing the level of reflexivity. Finally, a package of scalable positive psychology interventions is suggested to counteract the damage done and improve humanity's prospects.

Comparison of Two Automated Targeted Metabolomics Programs to Manual Profiling by an Experienced Spectroscopist for 1H-NMR Spectra.

Automated programs that carry out targeted metabolite identification and quantification using proton nuclear magnetic resonance spectra can overcome time and cost barriers that limit metabolomics use. However, their performance needs to be comparable to that of an experienced spectroscopist. A previously analyzed pediatric sepsis data set of serum samples was used to compare results generated by the automated programs rDolphin and BATMAN with the results obtained by manual profiling for 58 identified metabolites. Metabolites were selected using Student's t-tests and evaluated with several performance metrics. The manual profiling results had the highest performance metrics values, especially for sensitivity (76.9%), area under the receiver operating characteristic curve (0.90), precision (62.5%), and testing accuracy based on a neural net (88.6%). All three approaches had high specificity values (77.7-86.7%). Manual profiling by an expert spectroscopist outperformed two open-source automated programs, indicating that further development is needed to achieve acceptable performance levels.