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Objectives: Previous studies have reported that mode of delivery, particularly cesarean delivery (CD), is associated with neurodevelopmental outcomes in children. This study evaluates behavioral and neuropsychological test scores in children based on mode of delivery., Methods: Children enrolled in the Raine Study from Western Australia, born between 1989 and 1992 by instrumental vaginal delivery (IVD), elective CD, and non-elective CD, were compared to those with spontaneous vaginal delivery (SVD). The primary outcome was the Child Behavior Checklist (CBCL) administered at age 10. Secondary outcomes included evaluations of language, motor function, cognition, and autistic traits. Multivariable linear regression was used to evaluate score differences by mode of delivery adjusted for sociodemographic and clinical characteristics, and Poisson regression was used to evaluate for increased risk of clinical deficit., Results: Of 2,855 children, 1770 (62.0 %) were delivered via SVD, 480 (16.8 %) via IVD, 346 (12.1 %) via elective CD, and 259 (9.1 %) via non-elective CD. Non-elective CD was associated with higher (worse) CBCL Internalizing (+2.09; 95 % CI 0.49, 3.96; p=0.01) scores, and elective CD was associated with lower (worse) McCarron Assessment of Neuromuscular Development (MAND) (-3.48; 95 % CI -5.61, -1.35; p=0.001) scores. Differences were not seen in other outcomes, and increased risk of clinical deficit was not observed with either the CBCL Internalizing or MAND scores., Conclusions: Differences in behavior and motor function were observed in children delivered by CD, but given that score differences were not associated with increased incidence of clinical deficit, clinical significance may be limited., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Observational studies of anesthetic neurotoxicity may be biased because children requiring anesthesia commonly have medical conditions associated with neurobehavioral problems. This study takes advantage of a natural experiment associated with appendicitis to determine whether anesthesia and surgery in childhood were specifically associated with subsequent neurobehavioral outcomes., Methods: This study identified 134,388 healthy children with appendectomy and examined the incidence of subsequent externalizing or behavioral disorders (conduct, impulse control, oppositional defiant, attention-deficit hyperactivity disorder) or internalizing or mood or anxiety disorders (depression, anxiety, or bipolar disorder) when compared to 671,940 matched healthy controls as identified in Medicaid data between 2001 and 2018. For comparison, this study also examined 154,887 otherwise healthy children admitted to the hospital for pneumonia, cellulitis, and gastroenteritis, of which only 8% received anesthesia, and compared them to 774,435 matched healthy controls. In addition, this study examined the difference-in-differences between matched appendectomy patients and their controls and matched medical admission patients and their controls., Results: Compared to controls, children with appendectomy were more likely to have subsequent behavioral disorders (hazard ratio, 1.04; 95% CI, 1.01 to 1.06; P = 0.0010) and mood or anxiety disorders (hazard ratio, 1.15; 95% CI, 1.13 to 1.17; P < 0.0001). Relative to controls, children with medical admissions were also more likely to have subsequent behavioral (hazard ratio, 1.20; 95% CI, 1.18 to 1.22; P < 0.0001) and mood or anxiety (hazard ratio, 1.25; 95% CI, 1.23 to 1.27; P < 0.0001) disorders. Comparing the difference between matched appendectomy patients and their matched controls to the difference between matched medical patients and their matched controls, medical patients had more subsequent neurobehavioral problems than appendectomy patients., Conclusions: Although there is an association between neurobehavioral diagnoses and appendectomy, this association is not specific to anesthesia exposure and is stronger in medical admissions. Medical admissions, generally without anesthesia exposure, displayed significantly higher rates of these disorders than appendectomy-exposed patients., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Recent studies report conflicting results regarding the relationship between labour epidural analgesia (LEA) in mothers and neurodevelopmental disorders in their offspring. We evaluated behavioural and neuropsychological test scores in children of mothers who used LEA., Methods: Children enrolled in the Raine Study from Western Australia and delivered vaginally from a singleton pregnancy between 1989 and 1992 were evaluated. Children exposed to LEA were compared with unexposed children. The primary outcome was the parent-reported Child Behaviour Checklist (CBCL) reporting total, internalising, and externalising behavioural problem scores at age 10 yr. Score differences, an increased risk of clinical deficit, and a dose-response based on the duration of LEA exposure were assessed. Secondary outcomes included language, motor function, cognition, and autistic traits., Results: Of 2180 children, 850 (39.0%) were exposed to LEA. After adjustment for covariates, exposed children had minimally increased CBCL total scores (+1.41 points; 95% confidence interval [CI] 0.09 to 2.73; P=0.037), but not internalising (+1.13 points; 95% CI -0.08 to 2.34; P=0.066) or externalising (+1.08 points; 95% CI -0.08 to 2.24; P=0.068) subscale subscores. Increased risk of clinical deficit was not observed for any CBCL score. For secondary outcomes, score differences were inconsistently observed in motor function and cognition. Increased exposure duration was not associated with worse scores in any outcomes., Conclusions: Although LEA exposure was associated with slightly higher total behavioural scores, there was no difference in subscores, increased risk of clinical deficits, or dose-response relationship. These results argue against LEA exposure being associated with consistent, clinically significant neurodevelopmental deficits in children., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: The association between prenatal exposure to general anaesthesia for maternal surgery during pregnancy and subsequent risk of disruptive or internalising behavioural disorder diagnosis in the child has not been well-defined., Methods: A nationwide sample of pregnant women linked to their liveborn infants was evaluated using the Medicaid Analytic eXtract (MAX, 1999-2013). Multivariate matching was used to match each child prenatally exposed to general anaesthesia owing to maternal appendectomy or cholecystectomy during pregnancy with five unexposed children. The primary outcome was diagnosis of a disruptive or internalising behavioural disorder in children. Secondary outcomes included diagnoses for a range of other neuropsychiatric disorders., Results: We matched 34,271 prenatally exposed children with 171,355 unexposed children in the database. Prenatally exposed children were more likely than unexposed children to receive a diagnosis of a disruptive or internalising behavioural disorder (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.23-1.40). For secondary outcomes, increased hazards of disruptive (HR, 1.32; 95% CI, 1.24-1.41) and internalising (HR, 1.36; 95% CI, 1.20-1.53) behavioural disorders were identified, and also increased hazards of attention-deficit/hyperactivity disorder (HR, 1.32; 95% CI, 1.22-1.43), behavioural disorders (HR, 1.28; 95% CI, 1.14-1.42), developmental speech or language disorders (HR, 1.16; 95% CI, 1.05-1.28), and autism (HR, 1.31; 95% CI, 1.05-1.64)., Conclusions: Prenatal exposure to general anaesthesia is associated with a 31% increased risk for a subsequent diagnosis of a disruptive or internalising behavioural disorder in children. Caution is advised when making any clinical decisions regarding care of pregnant women, as avoidance of necessary surgery during pregnancy can have detrimental effects on mothers and their children., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Context: For patients with advanced cancer, high intensity treatment at the end of life is measured as a reflection of the quality of care. Use of specialist palliative care has been promoted to improve care quality, but whether its use is associated with decreased treatment intensity on a population-level is unknown., Objectives: To determine whether receipt of specialist palliative care use is associated with differences in end-of-life quality metrics in patients with metastatic cancer., Methods: Retrospective propensity-matched cohort of patients age ≥ 65 who died with metastatic cancer in U.S. hospitals with palliative care programs that participated in the National Palliative Care Registry in 2018-2019. Cox proportional hazards regression was used to assess the impact of specialist palliative care on use of chemotherapy in the last 14 days of life, use of intensive care unit (ICU) in the last 30 days of life, use of hospice, and hospice enrollment ≥ three days., Results: After 1:2 matching, our cohort consisted of 15,878 exposed and 31,756 unexposed patients. Receipt of specialist palliative care was associated with a decrease in use of chemotherapy (adjusted hazard ratio (aHR) 0.59 [0.50-0.70]) and ICU at the end of life (aHR 0.86 [0.80-0.92]), and an increase in hospice use (aHR 1.92 [1.85-1.99]) and hospice enrollment for ≥three days (aHR 2.00 [1.93-2.07])., Conclusion: On a population-level, use of specialist palliative care was associated with improved metrics for quality end-of-life care for patients dying with metastatic cancer, underscoring the importance of its integration into cancer care., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This article reviews recent advances and controversies of developmental anesthesia neurotoxicity research with a special focus on the unanswered questions in the field both from clinical and preclinical perspectives., Recent Findings: Observational cohort studies of prenatal and early childhood exposure to anesthesia have reported mixed evidence of an association with impaired neurodevelopment. Meta-analyses of currently available studies of early childhood exposure to anesthesia suggest that, while limited to no change in general intelligence can be detected, more subtle deficits in specific neurodevelopmental domains including behavior and executive function may be seen. Several studies have evaluated intraoperative blood pressure values and neurocognitive outcomes and have not found an association. Although many animal studies have been performed, taking into consideration other peri-operative exposures such as pain and inflammation may help with translation of results from animal models to humans., Summary: Advances have been made in the field of developmental anesthetic neurotoxicity over the past few years, including the recognition that anesthetic exposure is associated with deficits in certain cognitive domains but not others. Although the most important question of whether anesthetic agents actually cause long-term neurodevelopmental effects in children has still not been answered, results from recent studies will guide further studies necessary to inform clinical decision-making in children., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The effect of prenatal marijuana exposure (PME) on child neurodevelopment remains poorly understood. Prior studies have demonstrated inconsistent results., Objectives: This study evaluated the association between PME and neuropsychological test scores in late childhood and early adulthood, accounting for a wide range of parental characteristics., Methods: This study evaluated participants from the Raine Study, a cohort of 2868 children born between 1989 and 1992. Children whose mothers provided information on marijuana use during pregnancy were included. The primary outcome was the Clinical Evaluation of Language Fundamentals (CELF) at age 10. Secondary outcomes included the Peabody Picture Vocabulary Test (PPVT), Child Behaviour Checklist (CBCL), McCarron Assessment of Neuromuscular Development (MAND), Coloured Progressive Matrices (CPM), Symbol Digit Modality Test (SDMT) and Autism Spectrum Quotient (AQ) scores. Exposed and unexposed children were matched by propensity score using optimal full matching. Missing covariate data were imputed using multiple imputation. Inverse probability of censoring weighting (IPCW) was used to adjust for missing outcome data. Linear regression within matched sets, adjusted by IPCW, evaluated score differences between exposed and unexposed children. As a secondary analysis, modified Poisson regression, adjusted by match weights and IPCW, evaluated the risk of clinical deficit in each outcome following PME., Results: Of the 2804 children in this cohort, 285 (10.2%) had PME. After optimal full matching and IPCW, exposed children scored similarly on CELF Total (-0.33 points, 95% confidence interval [CI] -4.71, 4.05), Receptive (+0.65 points, 95% CI -4.08, 5.38) or Expressive (-0.53 points, 95% CI -5.07, 4.02). PME was not associated with secondary outcomes or risks of clinical deficit in any neuropsychological assessments., Conclusions: After adjusting for sociodemographic and clinical covariates, PME was not associated with worse neuropsychological test scores at age 10 or autistic traits at 19-20., (© 2023 John Wiley & Sons Ltd.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Some studies have found surgery and anesthesia in children to be associated with neurodevelopmental deficits, but specific reasons for this association have not been fully explored. This study evaluates intraoperative mean arterial pressure (MAP) during a single ambulatory procedure in children and subsequent mental disorder diagnoses., Methods: A retrospective observational study was performed including children ≥28 days and <18 years of age with intraoperative electronic anesthetic records between January 1, 2009, and April 30, 2017, at our institution. Eligible children were categorized based on their mean intraoperative MAP relative to other children of the same sex and similar age: category 1 (very low): children with mean intraoperative MAP values below the 10th percentile, category 2 (low): mean MAP value ≥10th and <25th percentiles, category 3 (reference): mean MAP value ≥25th and <75th percentiles, category 4 (high): mean MAP value ≥75th and <90th percentile, and category 5 (very high): mean MAP value ≥90th percentile. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) and ICD, Tenth Revision, Clinical Modification (ICD-10)-coded mental disorders were identified in hospital and outpatient claims, with a median duration of follow-up after surgery of 120 days (interquartile range [IQR], 8-774.5 days). Cox proportional hazards models evaluated the hazard ratio (HR) of time to first mental disorder diagnosis associated with intraoperative blood pressure category between the end of surgery and censoring, with the primary analysis adjusting for demographic, anesthetic, comorbidity, and procedure-type variables as potential confounders., Results: A total of 14,724 eligible children who received general anesthesia for a single ambulatory surgical procedure were identified. After adjusting for all available potential confounders, when compared to the reference, there were no statistically significant differences in mental disorder diagnosis risk based on intraoperative mean MAP category. Compared to reference, children in the very low and low blood pressure categories reported HRs of 1.00 (95% confidence interval [CI], 0.74-1.35) and 1.10 (95% CI, 0.87-1.41) for a mental disorder diagnosis, respectively, and children in the high and very high categories reported HRs of 0.87 (95% CI, 0.68-1.12) and 0.76 (95% CI, 0.57-1.03), respectively., Conclusions: Presence in a predefined mean intraoperative MAP category was not associated with subsequent mental disorder diagnoses within our follow-up period. However, the limitations of this study, including uncertainty regarding what constitutes an adequate blood pressure in children, may limit the ability to form definitive conclusions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Purpose of Review: Nearly 100 clinical studies have been published evaluating neurodevelopmental outcomes in children following surgery and anesthesia. These studies have reported mixed results, likely attributable at least in part to significant heterogeneity in their study designs, types and numbers of exposures, patient populations evaluated, and most importantly, the outcomes that were assessed. This review aims to summarize the results from clinical studies evaluating behavioral outcomes in children exposed to surgery and anesthesia., Recent Findings: Children with early exposure to surgery and anesthesia were found to have limited to no differences in intelligence when compared with unexposed children. However, several studies have reported more behavioral problems in children exposed to general anesthesia. An increased incidence of attention-deficit hyperactivity disorder has also been reported in anesthetic exposed children, particularly after multiple exposures., Summary: Nearly all clinical studies of anesthetic neurotoxicity are observational in nature, so the associations between anesthetic exposure and behavioral deficits cannot yet be directly attributed to the anesthetic medication. However, the finding of deficits in some neurodevelopmental domains and not others will help guide the selection of appropriate outcomes in future studies of anesthetic neurotoxicity that can further evaluate whether anesthetic medications have an impact on neurodevelopment in children., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Native Hawaiians are disproportionately affected by type 2 diabetes mellitus (DM), a chronic metabolic, non-communicable disease characterized by hyperglycemia and systemic inflammation. Unrelenting systemic inflammation  frequently leads to a cascade of multiple comorbidities associated with DM, including cardiovascular disease, microvascular complications, and renal dysfunction. Yet few studies have examined the link between chronic inflammation at a cellular level and its relationship to standard DM therapies such as diabetes-specific lifestyle and social support education, well recognized as the cornerstone of clinical standards of diabetes care. This pilot study was initiated to explore the association of monocyte inflammation using epigenetic, immunologic, and clinical measures following a 3-month diabetes-specific social support program among high-risk Native Hawaiian adults with DM., Results: From a sample of 16 Native Hawaiian adults with DM, monocytes enriched from peripheral blood mononuclear cells (PBMCs) of 8 individuals were randomly selected for epigenomic analysis. Using the Illumina HumanMethylation450 BeadChip microarray, 1,061 differentially methylated loci (DML) were identified in monocytes of participants at baseline and 3 months following a DM-specific social support program (DM-SSP). Gene ontology analysis showed that these DML were enriched within genes involved in immune, metabolic, and cardiometabolic pathways, a subset of which were also significantly differentially expressed. Ex vivo analysis of immune function showed improvement post-DM-SSP compared with baseline, characterized by attenuated interleukin 1β and IL-6 secretion from monocytes. Altered cytokine secretion in response to the DM-SSP was significantly associated with changes in the methylation and gene expression states of immune-related genes in monocytes between intervention time points., Conclusions: Our pilot study provides preliminary evidence of changes to inflammatory monocyte activity, potentially driven by epigenetic modifications, 3 months following a DM-specific SSP intervention. These novel alterations in the trajectory of monocyte inflammatory states were identified at loci that regulate transcription of immune and metabolic genes in high-risk Native Hawaiians with DM, suggesting a relationship between improvements in psychosocial behaviors and shifts in the immunoepigenetic patterns following a diabetes-specific SSP. Further research is warranted to investigate how social support influences systemic inflammation via immunoepigenetic modifications in chronic inflammatory diseases such as DM., (© 2022. The Author(s).)

Importance: Clinical studies of neurodevelopmental outcomes after anesthetic exposure have evaluated a range of outcomes with mixed results., Objective: To examine via meta-analyses the associations between exposure to general anesthesia and domain-specific neurodevelopmental outcomes in children., Data Sources: PubMed/MEDLINE, Embase, CINAHL, Web of Science and the Cochrane Library were searched from inception to August 31, 2021., Study Selection: Inclusion criteria were exposures to procedures requiring general anesthesia at younger than 18 years and evaluation of long-term neurodevelopmental function after exposure. Studies lacking unexposed controls or focused on children with major underlying comorbidities were excluded., Data Extraction and Synthesis: Extracted variables included effect size; hazard, risk, or odds ratio; number of exposures; procedure type; major comorbidities; age of exposure and assessment; presence of unexposed controls; and study design. Studies were independently reviewed by 2 coders, and review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model., Main Outcomes and Measures: The main outcomes were standardized mean differences (SMD) for scores in the neurodevelopmental domains of academics, behavioral problems, cognition, executive function, general development, language, motor function, nonverbal reasoning, social cognition, and hazard and risk of neurodevelopmental disorder diagnoses., Results: A total of 31 studies contributed data for meta-analysis. For each of the assessed neurodevelopmental domains, the numbers of children evaluated ranged from 571 to 63 315 exposed and 802 to 311 610 unexposed. Children with any exposure (single or multiple) had significantly worse behavioral problems scores, indicating more behavioral problems (SMD, -0.10; 95% CI, -0.18 to -0.02; P = .02), and worse scores in academics (SMD, -0.07; 95% CI -0.12 to -0.01; P = .02), cognition (SMD, -0.03; 95% CI, -0.05 to 0.00; P = .03), executive function (SMD, -0.20; 95% CI, -0.32 to -0.09; P < .001), general development (SMD, -0.08; 95% CI, -0.13 to -0.02; P = .01), language (SMD, -0.08; 95% CI, -0.14 to -0.02; P = .01), motor function (SMD, -0.11; 95% CI, -0.21 to -0.02; P = .02), and nonverbal reasoning (SMD, -0.15; 95% CI, -0.27 to -0.02; P = .02). Higher incidences of neurodevelopmental disorder diagnoses were also reported (hazard ratio, 1.19; 95% CI, 1.09 to 1.30; P < .001; risk ratio, 1.81; 95% CI, 1.25 to 2.61; P = .002)., Conclusions and Relevance: These findings support the hypothesis that associations between anesthetic exposure during childhood and subsequent neurodevelopmental deficits differ based on neurodevelopmental domain.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Objectives: The Pasifika Prediabetes Youth Empowerment Programme (PPYEP) was a community-based research project that aimed to investigate empowerment and co-design modules to build the capacity of Pasifika youth to develop community interventions for preventing prediabetes., Methods: This paper reports findings from a formative evaluation process of the programme using thematic analysis. It emphasises the adoption, perceptions and application of empowerment and co-design based on the youth and community providers' experiences., Results: We found that the programme fostered a safe space, increased youth's knowledge about health and healthy lifestyles, developed their leadership and social change capacities, and provided a tool to develop and refine culturally centred prediabetes-prevention programmes. These themes emerged non-linearly and synergistically throughout the programme., Conclusions: Our research emphasises that empowerment and co-design are complementary in building youth capacity in community-based partnerships in health promotion. Implications for public health: Empowerment and co-design are effective tools to develop and implement culturally tailored health promotion programmes for Pasifika peoples. Future research is needed to explore the programme within different Pasifika contexts, health issues and Indigenous groups., (© 2021 The Authors.)

l-2-Haloacid dehalogenases, industrially and environmentally important enzymes that catalyse cleavage of the carbon-halogen bond in S-2-halocarboxylic acids, were known to hydrolyse chlorinated, brominated and iodinated substrates but no activity towards fluorinated compounds had been reported. A screen for novel dehalogenase activities revealed four l-2-haloacid dehalogenases capable of defluorination. We now report crystal structures for two of these enzymes, Bpro0530 and Rha0230, as well as for the related proteins PA0810 and RSc1362, which hydrolyse chloroacetate but not fluoroacetate, all at ∼2.2 Å resolution. Overall structure and active sites of these enzymes are highly similar. In molecular dynamics (MD) calculations, only the defluorinating enzymes sample more compact conformations, which in turn allow more effective interactions with the small fluorine atom. Structural constraints, based on X-ray structures and MD calculations, correctly predict the defluorination activity of the homologous enzyme ST2570., (© 2021 Wiley-VCH GmbH.)

Introduction: New York State implemented an 11-week elective surgery ban in response to the coronavirus disease-2019 (COVID-19) pandemic, during which pediatric patients from the 10 New York Presbyterian network hospitals requiring urgent or emergent surgical procedures were cared for at Morgan Stanley Children's Hospital (MSCH)., Materials and Methods: Data was abstracted from the electronic medical record of all patients aged 0 to 20 years who had surgery at MSCH from March 23, 2020 to June 7, 2020. Comparative analysis of demographic and clinical data elements between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive and negative cohorts was conducted using the Fisher exact tests., Results: A total of 505 surgical procedures were performed in 451 patients, with 32 procedures (6.3%) performed in 21 SARS-CoV-2-positive children. The prevalence of SARS-CoV-2 positivity in Medicaid beneficiaries was more than twice the prevalence in commercially insured (6.8% vs. 2.6%, P=0.04) children. SARS-CoV-2-positive patients were more likely to undergo multiple surgical procedures (23.8% vs. 7.2%, P=0.02), and to have higher American Society of Anesthesiologists (ASA) class designations (69.8% III to V vs. 47.4% I to II, P=0.03). There was no significant difference in the prevalence of SARS-CoV-2 positivity across sex, age, race, or ethnicity groups, or in emergent case status or surgical procedure type. Thirty-day mortality rate was <0.1% overall, with no deaths in the SARS-CoV-2-positive group., Conclusions: During the first wave of the COVID-19 pandemic in New York City, we found a higher prevalence of SARS-CoV-2 positivity in urgent/emergent pediatric surgical patients compared with other institutions in the United States. SARS-CoV-2-positive patients were more likely to be Medicaid beneficiaries, were clinically more complex, and had more surgical procedures., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate neurodevelopmental and mental disorders after PICU hospitalization in children requiring invasive mechanical ventilation for severe respiratory illness., Design: Retrospective longitudinal observational cohort., Setting: Texas Medicaid Analytic eXtract data from 1999 to 2012., Patients: Texas Medicaid-enrolled children greater than or equal to 28 days old to less than 18 years old hospitalized for a primary respiratory illness, without major chronic conditions predictive of abnormal neurodevelopment., Interventions: We examined rates of International Classification of Diseases, 9th revision-coded mental disorder diagnoses and psychotropic medication use following discharge among children requiring invasive mechanical ventilation for severe respiratory illness, compared with general hospital patients propensity score matched on sociodemographic and clinical characteristics prior to admission. Children admitted to the PICU for respiratory illness not necessitating invasive mechanical ventilation were also compared with matched general hospital patients as a negative control exposure., Measurements and Main Results: Of 115,335 eligible children, 1,351 required invasive mechanical ventilation and were matched to 6,755 general hospital patients. Compared with general hospital patients, children requiring invasive mechanical ventilation had increased mental disorder diagnoses (hazard ratio, 1.43 [95% CI, 1.26-1.64]; p < 0.0001) and psychotropic medication use (hazard ratio, 1.67 [1.34-2.08]; p < 0.0001) following discharge. Seven-thousand seven-hundred eighty children admitted to the PICU without invasive mechanical ventilation were matched to 38,900 general hospital patients and had increased mental disorder diagnoses (hazard ratio, 1.08 [1.02-1.15]; p = 0.01) and psychotropic medication use (hazard ratio, 1.11 [1.00-1.22]; p = 0.049)., Conclusions: Children without major comorbidity requiring invasive mechanical ventilation for severe respiratory illness had a 43% higher incidence of subsequent mental disorder diagnoses and a 67% higher incidence of psychotropic medication use. Both increases were substantially higher than in PICU patients with respiratory illness not necessitating invasive mechanical ventilation. Invasive mechanical ventilation is a life-saving therapy, and its application is interwoven with underlying health, illness severity, and PICU management decisions. Further research is required to determine which factors related to invasive mechanical ventilation and severe respiratory illness are associated with abnormal neurodevelopment. Given the increased risk in these children, identification of strategies for prevention, neurodevelopmental surveillance, and intervention after discharge may be warranted., Competing Interests: Dr. Geneslaw received funding from the Columbia University Department of Pediatrics Innovation Nucleation Fund. Dr. Hua’s institution received funding from the National Institute on Aging and the American Federation for Aging Research, and she received support for article research from the National Institutes of Health (NIH). Dr. Ing was supported by the Agency for Healthcare Research and Quality (AHRQ) under award number K08HS022941. Dr. Ing’s institution received funding from the AHRQ and the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Exposure to surgery and anesthesia in early childhood has been found to be associated with an increased risk of behavioral deficits. While the US Food and Drug Administration (FDA) has warned against prenatal exposure to anesthetic drugs, little clinical evidence exists to support this recommendation. This study evaluates the association between prenatal exposure to general anesthesia due to maternal procedures during pregnancy and neuropsychological and behavioral outcome scores at age 10., Methods: This is an observational cohort study of children born in Perth, Western Australia, with 2 generations of participants contributing data to the Raine Study. In the Raine Study, the first generation (Gen1) are mothers enrolled during pregnancy, and the second generation (Gen2) are the children born to these mothers from 1989 to 1992 with neuropsychological and behavioral tests at age 10 (n=2024). In the primary analysis, 6 neuropsychological and behavioral tests were evaluated at age 10: Raven's Colored Progressive Matrices (CPM), McCarron Assessment of Neuromuscular Development (MAND), Peabody Picture Vocabulary Test (PPVT), Symbol Digit Modality Test (SDMT) with written and oral scores, Clinical Evaluation of Language Fundamentals (CELF) with Expressive, Receptive, and Total language scores, and Child Behavior Checklist (CBCL) with Internalizing, Externalizing, and Total behavior scores. Outcome scores of children prenatally exposed to general anesthesia were compared to children without prenatal exposure using multivariable linear regression models adjusting for demographic and clinical covariates (sex, race, income, and maternal education, alcohol or tobacco use, and clinical diagnoses: diabetes, epilepsy, hypertension, psychiatric disorders, or thyroid dysfunction). Bonferroni adjustment was used for the 6 independent tests in the primary analysis, so a corrected P value <.0083 (P = .05 divided by 6 tests, or a 99.17% confidence interval [CI]) was required for statistical significance., Results: Among 2024 children with available outcome scores, 22 (1.1%) were prenatally exposed to general anesthesia. Prenatally exposed children had higher CBCL Externalizing behavioral scores (score difference of 6.1 [99.17% CI, 0.2-12.0]; P = .006) than unexposed children. Of 6 tests including 11 scores and subscores, only CBCL Externalizing behavioral scores remained significant after multiple comparisons adjustment with no significant differences found in any other score., Conclusions: Prenatal exposure to general anesthetics is associated with increased externalizing behavioral problems in childhood. However, given the limitations of this study and that avoiding necessary surgery during pregnancy can have significant detrimental effects on the mother and the child, further studies are needed before changes to clinical practice are made., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Aim: Using a co-design approach, we describe exploratory findings of a community-based intervention to mobilise Pasifika communities into action, with the intent of reducing the risk factors of prediabetes., Method: A group of 25 Pasifika youth aged 15-24 years from two distinctive Pasifika communities in New Zealand were trained to lead a small-scale, community-based intervention programme (among 29 participants) over the course of eight weeks. The intervention, which targeted adults aged 25-44 years who were overweight or obese, employed both an empowerment-based programme and a co-design approach to motivate community members to participate in a physical-activity-based intervention programme., Results: Findings show significant reductions in total body weight and waist circumference, as well as improved physical activity., Conclusions: The strength of this intervention was evident in the innovative approach of utilising Pasifika-youth-led and co-designed approaches to motivate communities into healthier lifestyles. The approaches used in this project could be utilised in a primary healthcare setting as a community-wide strategy to reduce diabetes risk, particularly among Pasifika peoples., Competing Interests: Nil.

Elastin is a major polymeric protein of the extracellular matrix, providing critical properties of extensibility and elastic recoil. The rs2071307 genomic polymorphism, resulting in the substitution of a serine for a glycine residue in a VPG motif in tropoelastin, has an unusually high minor allele frequency in humans. A consequence of such allelic heterozygosity would be the presence of a heterogeneous elastin polymer in up to 50% of the population, a situation which appears to be unique to Homo sapiens. VPG motifs are extremely common in hydrophobic domains of tropoelastins and are the sites of transient β-turns that are essential for maintaining the conformational flexibility required for its function as an entropic elastomer. Earlier data demonstrated that single amino acid substitutions in tropoelastin can have functional consequences for polymeric elastin, particularly when present in mixed polymers. Here, using NMR and molecular dynamics approaches, we show the rs2071307 polymorphism reduces local propensity for β-turn formation, with a consequent increase in polypeptide hydration and an expansion of the conformational ensemble manifested as an increased hydrodynamic radius, radius of gyration and asphericity. Furthermore, this substitution affects functional properties of polymeric elastin, particularly in heterogeneous polymers mimicking allelic heterozygosity. We discuss whether such effects, together with the unusually high minor allele frequency of the polymorphism, could imply some some evolutionary advantage for the heterozygous state., (© 2020 Wiley Periodicals LLC.)

Background: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear., Methods: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses., Results: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001)., Conclusions: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

As an extension of a previous cross-sectional study, this study employed prospective data to test positive outcome expectancy beliefs as mediators of social media's influence on e-cigarette use progression among young adults. Self-report data were collected from 2327 young adult college students (Mean age = 21.2; SD = 2.1; 54% women) between 2017 and 2019, every 6-month, at 3 time-points. Structural equation modeling was used to test the mediational models. Among baseline never e-cigarette users, higher affect regulation expectancies-e.g., beliefs that e-cigarette use results in feeling good, reduced boredom and stress-mediated the effects of higher baseline social media e-cigarette exposure on e-cigarette use onset one year later. Among baseline lifetime e-cigarette users, higher positive sensory, positive "smoking" experience, and affect regulation expectancy beliefs mediated the effects of higher social media e-cigarette exposure at baseline on increased current e-cigarette use one year later. E-cigarette content on social media may persuade young adults to try e-cigarettes by imparting the sense that e-cigarettes make one feel good and help reduce stress. E-cigarette content on social media that promote e-cigarette flavors and e-cigarettes as cleaner and a socially more acceptable alternative to cigarettes may work to escalate e-cigarette use among experimenters. Efforts to prevent e-cigarette use onset and escalation may need to target the outcome expectancy beliefs influenced by social media., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Delirium is associated with increased hospital costs, health care complications, and increased mortality. Long-term consequences of delirium on cognition have not been synthesized and quantified via meta-analysis., Objective: To determine if an episode of delirium was an independent risk factor for long-term cognitive decline, and if it was, whether it was causative or an epiphenomenon in already compromised individuals., Data Sources: A systematic search in PubMed, Cochrane, and Embase was conducted from January 1, 1965, to December 31, 2018. A systematic review guided by Preferred Reporting Items for Systematic Reviews and Meta-analyses was conducted. Search terms included delirium AND postoperative cognitive dysfunction; delirium and cognitive decline; delirium AND dementia; and delirium AND memory., Study Selection: Inclusion criteria for studies included contrast between groups with delirium and without delirium; an objective continuous or binary measure of cognitive outcome; a final time point of 3 or more months after the delirium episode. The electronic search was conducted according to established methodologies and was executed on October 17, 2018., Data Extraction and Synthesis: Three authors extracted data on individual characteristics, study design, and outcome, followed by a second independent check on outcome measures. Effect sizes were calculated as Hedges g. If necessary, binary outcomes were also converted to g. Only a single effect size was calculated for each study., Main Outcomes and Measures: The planned main outcome was magnitude of cognitive decline in Hedges g effect size in delirium groups when contrasted with groups that did not experience delirium., Results: Of 1583 articles, data subjected from the 24 studies (including 3562 patients who experienced delirium and 6987 controls who did not) were included in a random-effects meta-analysis for pooled effect estimates and random-effects meta-regressions to identify sources of study variance. One study was excluded as an outlier. There was a significant association between delirium and long-term cognitive decline, as the estimated effect size (Hedges g) for 23 studies was 0.45 (95% CI, 0.34-0.57; P < .001). In all studies, the group that experienced delirium had worse cognition at the final time point. The I2 measure of between-study variability in g was 0.81. A multivariable meta-regression suggested that duration of follow-up (longer with larger gs), number of covariates controlled (greater numbers were associated with smaller gs), and baseline cognitive matching (matching was associated with larger gs) were significant sources of variance. More specialized subgroup and meta-regressions were consistent with predictions that suggested that delirium may be a causative factor in cognitive decline., Conclusions and Relevance: In this meta-analysis, delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients.

Background: Native Hawaiians and Pacific Islanders (NHPIs) experience a disproportionate burden of type 2 diabetes and related complications. Although diabetes self-management education and support (DSMES) interventions have generally yielded positive results, few NHPIs have been included in these studies, and even fewer studies have been evaluated using a randomized controlled trial design and/or implementation research methods. The purpose of this pilot study was to evaluate implementation outcomes of a culturally adapted diabetes self-management education intervention delivered by peer educators to Native Hawaiians and Pacific Islanders residing in Honolulu, Hawai'i., Methods: In three study sites, the peer educators and 48 participants randomized to the intervention were invited to participate in the mixed methods implementation research. We used a convergent parallel design to collect implementation data including fidelity, feasibility, acceptability, appropriateness, adoption, and sustainability. Data were collected from class observations, participants' class feedback, and post-intervention focus groups with participants and peer educators., Results: In 314 end-of-class feedback surveys, 97% of respondents expressed that they were satisfied or highly satisfied with the class content and activities, 98% reported that the classes and materials were very useful, 94% reported very applicable, and 93% reported materials were culturally appropriate. Respondents identified several aspects of the program as especially enjoyable: interactions with peer educators, meeting in groups, learning about other participants' experiences with diabetes, and the information presented in each class. Major themes that emerged from the end-of-intervention focus groups were the relevance of the educational materials, strategies to manage blood glucose, hands-on activities, cultural aspects of the program, including the stories and analogies used to convey information, and appreciation of the group format and peer educators., Conclusions: Results from this research support a culturally tailored, peer educator approach to DSMES among NHPIs. Delivery of the Partners in Care program is feasible in health care and community settings and is a reimbursable DSMES program., Trial Registration: Clinicaltrials.gov Identifier: NCT01093924 prospectively registered 01.20.09.

Background: Some recent clinical studies have found that early childhood exposure to anesthesia is associated with increased risks of behavioral deficits and clinical diagnoses of attention deficit hyperactivity disorder (ADHD). While diagnoses in claims data may be subject to inaccuracies, pharmacy claims are highly accurate in reflecting medication use. This study examines the association between exposure to surgery and anesthesia and subsequent ADHD medication use., Methods: Longitudinal data for children enrolled in Texas and New York Medicaid from 1999 to 2010 were used. We assessed the association between a single exposure to anesthesia before age 5 years for 1 of 4 common pediatric surgical procedures (pyloromyotomy, inguinal hernia repair, circumcisions outside the perinatal period, and tonsillectomy and/or adenoidectomy) and persistent ADHD medication use (event defined as the initial ADHD medication prescription, and persistent use defined as filling 2 or more ≥30-day prescriptions between 6 months following surgery until censoring). Exposed children (n = 42,687) were matched on propensity score (ie, the probability of receiving surgery) estimated in logistic regression including sociodemographic and clinical covariates, to children without anesthesia exposure before age 5 years (n = 213,435). Cox proportional hazards models were used to evaluate the hazard ratio (HR) of ADHD medication use following exposure. Nonpsychotropic medications served as negative controls to determine if exposed children simply had higher overall medication use., Results: Children with a single exposure to surgery and anesthesia were 37% more likely than unexposed children to persistently use ADHD medication (HR, 1.37; 95% confidence interval [CI], 1.30-1.44). The estimated HRs for common nonpsychotropic medication use following a single anesthetic exposure were 1.06 (95% CI, 1.04-1.07) for amoxicillin, 1.10 (95% CI, 1.08-1.12) for azithromycin, and 1.08 (95% CI, 1.05-1.11) for diphenhydramine. In comparison, the risk of using other psychotropic medication to treat conditions besides ADHD was also significantly higher, with HRs of 1.37 (95% CI, 1.24-1.51) for sedative/anxiolytics, 1.40 (95% CI, 1.25-1.58) for antidepressants, 1.31 (95% CI, 1.20-1.44) for antipsychotics, and 1.24 (95% CI, 1.10-1.40) for mood stabilizers., Conclusions: Medicaid-enrolled children receiving anesthesia for a single common pediatric surgical procedure under age 5 years were 37% more likely to require subsequent persistent use of ADHD medications than unexposed children. Because the increased use of ADHD medication is disproportionately higher than that of nonpsychotropic medications, unmeasured confounding may not account for all of the increase in ADHD medication use. By evaluating Medicaid data, this study assesses children who may be particularly vulnerable to neurotoxic exposures.

Gaussian Boson Samplers are photonic quantum devices with the potential to perform intractable tasks for classical systems. As with other near-term quantum technologies, an outstanding challenge is to identify specific problems of practical interest where these devices can prove useful. Here, we show that Gaussian Boson Samplers can be used to predict molecular docking configurations, a central problem for pharmaceutical drug design. We develop an approach where the problem is reduced to finding the maximum weighted clique in a graph, and show that Gaussian Boson Samplers can be programmed to sample large-weight cliques, i.e., stable docking configurations, with high probability, even with photon losses. We also describe how outputs from the device can be used to enhance the performance of classical algorithms. To benchmark our approach, we predict the binding mode of a ligand to the tumor necrosis factor-α converting enzyme, a target linked to immune system diseases and cancer., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Objective: To evaluate healthcare utilization in Medicaid enrolled children with neonatal abstinence syndrome (NAS) in the first 2 years of life., Study Design: A retrospective, longitudinal cohort study evaluating Medicaid enrolled children born in New York (1999-2011) and Texas (1999-2010) was performed. Healthcare utilization, including inpatient days, emergency department and outpatient visits, and filled prescriptions in children after birth hospitalization was assessed. A tapered propensity-matching methodology was used, matching each child with NAS with 5 children without NAS, first on demographics, then on both demographics and clinical covariates (clinical diagnoses and congenital anomalies at birth). Poisson and negative binomial regression were used to calculate healthcare utilization ratios (HUR)., Results: In the first 2 years of life, children with NAS (n = 3799) had increased healthcare utilization with more inpatient days and emergency department visits than demographically similar children without NAS. This increased utilization however did not persist after matching on clinical covariates and performing multiple comparisons adjustment (inpatient days [HUR, 1.01; 95% CI, 0.88-1.16; P = .89], total emergency department visits [HUR, 1.06; 95% CI, 1.01-1.11; P = .02]). Children with NAS conversely had 9% fewer outpatient office visits (HUR, 0.91; 95% CI, 0.87-0.95; P < .0001)., Conclusions: A diagnosis of NAS does not appear to be an independent predictor of increased healthcare utilization in the first 2 years of life. These results differ from some other published studies, but may suggest that the increased healthcare utilization observed in children with NAS is due to higher incidences of perinatal complications and congenital anomalies in children with prenatal drug exposures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, also known as SCARB2) reveals a large cavity that traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. The detection of cholesterol within the LIMP-2 structure and the formation of cholesterol - like inclusions in LIMP-2 knockout mice suggested the possibility that LIMP2 transports cholesterol in lysosomes. We present results of molecular modeling, crosslinking studies, microscale thermophoresis and cell-based assays that support a role of LIMP-2 in cholesterol transport. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Depletion of LIMP-2 alters SREBP-2-mediated cholesterol regulation, as well as LDL-receptor levels. Our data indicate that LIMP-2 operates in parallel with Niemann Pick (NPC)-proteins, mediating a slower mode of lysosomal cholesterol export.

Many enzymes operate through half-of-the sites reactivity wherein a single protomer is catalytically engaged at one time. In the case of the homodimeric enzyme, fluoroacetate dehalogenase, substrate binding triggers closing of a regulatory cap domain in the empty protomer, preventing substrate access to the remaining active site. However, the empty protomer serves a critical role by acquiring more disorder upon substrate binding, thereby entropically favoring the forward reaction. Empty protomer dynamics are also allosterically coupled to the bound protomer, driving conformational exchange at the active site and progress along the reaction coordinate. Here, we show that at high concentrations, a second substrate binds along the substrate-access channel of the occupied protomer, thereby dampening interprotomer dynamics and inhibiting catalysis. While a mutation (K152I) abrogates second site binding and removes inhibitory effects, it also precipitously lowers the maximum catalytic rate, implying a role for the allosteric pocket at low substrate concentrations, where only a single substrate engages the enzyme at one time. We show that this outer pocket first desolvates the substrate, whereupon it is deposited in the active site. Substrate binding to the active site then triggers the empty outer pocket to serve as an interprotomer allosteric conduit, enabling enhanced dynamics and sampling of activation states needed for catalysis. These allosteric networks and the ensuing changes resulting from second substrate binding are delineated using rigidity-based allosteric transmission theory and validated by nuclear magnetic resonance and functional studies. The results illustrate the role of dynamics along allosteric networks in facilitating function.