A kinase-cGAS cascade to synthesize a therapeutic STING activator.

The introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence1-3. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents4,5. Here we describe the discovery and construction of an enzymatic cascade to MK-1454, a highly potent stimulator of interferon genes (STING) activator under study as an immuno-oncology therapeutic6,7 (ClinicalTrials.gov study NCT04220866 ). From two non-natural nucleotide monothiophosphates, MK-1454 is assembled diastereoselectively in a one-pot cascade, in which two thiotriphosphate nucleotides are simultaneously generated biocatalytically, followed by coupling and cyclization catalysed by an engineered animal cyclic guanosine-adenosine synthase (cGAS). For the thiotriphosphate synthesis, three kinase enzymes were engineered to develop a non-natural cofactor recycling system in which one thiotriphosphate serves as a cofactor in its own synthesis. This study demonstrates the substantial capacity that currently exists to use biosynthetic approaches to discover and manufacture complex, non-natural molecules.

Tissue specific innate immune responses impact viral infection in Drosophila.

All organisms sense and respond to pathogenic challenge. Tissue-specific responses are required to combat pathogens infecting distinct cell types. Cyclic dinucleotides (CDNs) are produced endogenously downstream of pathogen recognition or by pathogens themselves which bind to STING to activate NF-kB-dependent antimicrobial gene expression programs. It remains unknown whether there are distinct immune responses to CDNs in Drosophila tissues. Here, we investigated tissue specific CDN-STING responses and uncovered differences in gene-induction patterns across tissues that play important roles in viral infections. Using tissue-and cell-specific genetic studies we found that dSTING in the fat body controls CDN-induced expression of dSTING-regulated gene 1 (Srg1) but not dSTING-regulated gene 2 (Srg2) or 3 (Srg3). In contrast, the gastrointestinal tract largely controls expression of Srg2 and Srg3. We found that Srg3 is antiviral against the natural fly pathogen Drosophila C virus and the human arthropod-borne Rift Valley Fever virus (RVFV), but not other arthropod-borne viruses including Sindbis virus and dengue virus. Furthermore, we found that Srg3 has an important role in controlling RVFV infection of the ovary which has important implications in understanding vertical transmission of viruses and RVFV in mosquitoes. Overall, our study underscores the importance of tissue-specific responses in antiviral immunity and highlights the complex tissue regulation of the CDN-STING pathway.

Clinical metagenomics.

Clinical metagenomic next-generation sequencing (mNGS), the comprehensive analysis of microbial and host genetic material (DNA and RNA) in samples from patients, is rapidly moving from research to clinical laboratories. This emerging approach is changing how physicians diagnose and treat infectious disease, with applications spanning a wide range of areas, including antimicrobial resistance, the microbiome, human host gene expression (transcriptomics) and oncology. Here, we focus on the challenges of implementing mNGS in the clinical laboratory and address potential solutions for maximizing its impact on patient care and public health.

Boat encounter with the 2019 Java bioluminescent milky sea: Views from on-deck confirm satellite detection.

"Milky seas" are massive swaths of uniformly and steadily glowing ocean seen at night. The phenomenon is thought to be caused by luminous bacteria, but details of milky sea composition, structure, cause, and implications in nature remain largely uncertain. Between late July and early September 2019, specialized low-light satellite sensors detected a possible bioluminescent milky sea south of Java, Indonesia, spanning >100,000 km2. Upon learning of these findings, crew members of the yacht Ganesha reached out to confirm and share details of their personal encounter with this same event. Here, we document Ganesha's experience as recalled by the crew, compare their course to satellite data, and assess their photography of this milky sea.

Preterm Sex Differences in Neurodevelopment and Brain Development from Early Life to 8 Years of Age.

OBJECTIVE: To examine sex differences in neurodevelopmental outcomes and brain development from early life to 8 years in males and females born preterm. STUDY DESIGN: This was a prospective cohort study of infants born very preterm (24-32 weeks of gestation) and followed to 8 years with standardized measures of neurodevelopment. Brain magnetic resonance imaging scans were performed soon after birth, term-equivalent age, and 8 years. The relationship between sex, severe brain injury, early pain exposure, fractional anisotropy, and neurodevelopmental outcomes were assessed using multivariable generalized estimating equations. RESULTS: Males (n = 78) and females (n = 66) were similar in clinical risk factors. Male sex was associated with lower cognitive scores (ß = -3.8, P = .02) and greater motor impairment (OR, 1.8; P = .04) across time. Male sex was associated with lower superior white matter fractional anisotropy across time (ß = -0.01; P = .04). Sex moderated the association between severe brain injury, early pain, and neurodevelopmental outcomes. With severe brain injury, males had lower cognitive scores at 3 years of age (P < .001). With increasing pain, females had lower cognitive scores at 8 years of age (P = .008), and males had greater motor impairment at 4.5 years of age (P = .001) and 8 years of age (P = .05). CONCLUSIONS: Males born preterm had lower cognitive scores and greater motor impairment compared with females, which may relate to differences in white matter maturation. The association between severe brain injury, early pain exposure, and neurodevelopmental outcomes was moderated by sex, indicating a differential response to early-life adversity in males and females born preterm.

Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Brain health in preterm infants: importance of early-life pain and analgesia exposure.

"Everyday" exposures in the neonatal period, such as pain, may impact brain health in preterm infants. Specifically, greater exposure to painful procedures in the initial weeks after birth have been related to abnormalities in brain maturation and growth and poorer neurodevelopmental outcomes in preterm infants. Despite an increasing focus on the importance of treating pain in preterm infants, there is a lack of consensus of optimal approaches to managing pain in this population. This may be due to recent findings suggesting that commonly used analgesic and sedative medications in preterm infants may also have adverse effects of brain maturation and neurodevelopmental outcomes. This review provides an overview of potential impacts of pain and analgesia exposure on preterm brain health while highlighting research areas in need of additional investigations for the development of optimal pain management strategies in this population.

Home-ics: how experiences of the home impact biology and child neurodevelopmental outcomes.

Studies on the -omics of child neurodevelopmental outcomes, e.g. genome, epigenome, microbiome, metabolome, and brain connectome aim to enable data-driven precision health to improve these outcomes, or deliver the right intervention, to the right child, at the right time. However, evidence suggests that neurodevelopmental outcomes are shaped by modifiable socioenvironmental factors. Everyday exposures including family and neighbourhood-level socioeconomic status, housing conditions, and interactions with those living in the home, are strongly associated with child health and have been suggested to alter -omics. Our aim was to review and understand the biological pathways by which home factors contribute to child neurodevelopment outcomes. We review studies suggestive of the home factors contributing to neurodevelopmental outcomes that encompass the hypothalamic-pituitary-adrenal axis, the brain, the gut-brain-axis, and the immune system. We thus conceptualize home-ics as the study of how the multi-faceted living environment can impact neurodevelopmental outcomes through biology and highlight the importance of targeting the modifiable aspects of a child's home to optimize outcomes. We encourage clinicians and health care providers to routinely assess home factors in patient encounters, and counsel families on modifiable aspects of the home. We conclude by discussing clinical and policy implications and future research directions of home-ics. IMPACT: Home-ics can be conceptualized as the study of how home factors may shape child neurodevelopmental outcomes through altering biology. Targeting modifiable aspects of a child's home environment (e.g. parenting style, early intervention, enriched environment) may lead to improved neurodevelopmental outcomes. Clinicians should routinely assess home factors and counsel families on modifiable aspects of the home.

Management of Traumatic Duodenal Injury: Is There a Role for Early Parenteral Nutrition?

INTRODUCTION: Traumatic duodenal injuries are complex in nature and pose major challenges to trauma surgeons. These injuries are associated with high mortality rates ranging from 18% to 30% and require prompt, comprehensive care. Traumatic injury induces a hypercatabolic state that mobilizes body energy stores, leading to muscle wasting, delayed healing, and potential multi-organ failure. Nutritional support is vital in keeping up with the metabolic demands of traumatically injured patients. However, exactly when and how nutrition should be provided for traumatic duodenal injuries is unclear. We hypothesize that patients who sustain high-grade duodenal injuries (grades III-V) will be unable to tolerate enteral nutrition (EN) and may benefit from early initiation of total parenteral nutrition (TPN). METHODS: In this retrospective chart review study, we queried the trauma registry for patients admitted between January 2018 and December 2022 with duodenal injury. Individuals under the age of 18 and individuals who were pregnant were excluded. Twenty-eight patients met the inclusion/exclusion criteria. The primary endpoint was median number of days from initial injury to supplemental nutrition. We also evaluated the route used to achieve adequate nutrition based on duodenal injury grade (I-V), mortality based on duodenal injury grade, morbidity based on route of nutrition supplementation (hospital length of stay [LOS], intensive care unit LOS, and ventilator days), and complications based on route of nutrition supplementation. RESULTS: Of the 28 patients analyzed, 11 received EN, 10 received TPN (6 of which survived to transition to EN), and 7 died within 3 d of admission and did not receive any form of nutrition. The median number of days post-trauma to toleration of enteral feeding (defined as by mouth or tube feeding that meet total caloric needs based on nutritionist recommendations) was 4 d for those who did tolerate and maintained tolerance of enteral feeding, compared to 7.5 d post-trauma to initiate total parenteral feeding (P = 0.061). Injury grades I and II tolerated EN within a median of 6 d, whereas injury grades III and IV showed inability to tolerate EN until after a median of 22 d or longer (P = 0.02). Mortality increased as injury grade increased. Patients who received TPN were more likely to develop abscesses than those receiving EN (80% vs 27%, P = 0.03) but not more likely to develop a duodenal leak (P = 0.31). Patients who received TPN had longer hospital LOS (35.5 d vs 9 d, P = 0.008), longer intensive care unit LOS (17 d vs 4 d, P = 0.005), and increased ventilator days (9 d vs 1 d, P = 0.005) when compared to patients who received EN. CONCLUSIONS: Individuals with higher grade duodenal injuries showed inability to tolerate EN until after a median of 22 d, and therefore, consideration should be given to initiating TPN early to mitigate the catabolic effects of malnutrition. Further studies need to be done with a larger number of patients to evaluate the effects of malnutrition in these patients.

Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni.

Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni, is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni. In addition to known waixenicins A (1) and B (2), we purified six xenicane diterpenes, 7S,8S-epoxywaixenicins A (3) and B (4), 12-deacetylwaixenicin A (5), waixenicin E (6), waixenicin F (7), and 20-acetoxyxeniafaraunol B (8). We elucidated the structures of 3-8 by NMR and MS analyses. Compounds 1, 2, 3, 4, and 6 inhibited TRPM7 activity in a cell-based assay, while 5, 7, and 8 were inactive. A preliminary SAR emerged showing that alterations to the nine-membered ring of 1 did not reduce activity, while the 12-acetoxy group, in combination with the dihydropyran, appears to be necessary for TRPM7 inhibition. The bioactive compounds are proposed to be latent electrophiles by formation of a conjugated oxocarbenium ion intermediate. Whole-cell patch-clamp experiments demonstrated that waixenicin A inhibition is irreversible, consistent with a covalent inhibitor, and showed nanomolar potency for waixenicin B (2). Conformational analysis (DFT) of 1, 3, 7, and 8 revealed insights into the conformation of waixenicin A and congeners and provided information regarding the stabilization of the proposed pharmacophore.

Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries.

AIM: To examine whether antenatal diagnosis modifies relationships between neonatal brain volumes and 18-month neurodevelopmental outcomes in children with transposition of the great arteries (TGA). METHOD: In a retrospective cohort of 139 children with TGA (77 antenatally diagnosed), we obtained total brain volumes (TBVs) on pre- (n = 102) and postoperative (n = 112) magnetic resonance imaging. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Generalized estimating equations with interaction terms were used to determine whether antenatal diagnosis modified associations between TBVs and neurodevelopmental outcomes accounting for postmenstrual age at scan, brain injury, and ventricular septal defect. RESULTS: Infants with postnatal diagnosis had more preoperative hypotension (35% vs 14%, p = 0.004). The interactions between antenatal diagnosis and TBVs were significantly related to cognitive (p = 0.003) outcomes. Specifically, smaller TBVs were associated with lower cognitive scores in infants diagnosed postnatally; this association was attenuated in those diagnosed antenatally. INTERPRETATION: Antenatal diagnosis modifies associations between neonatal brain volume and 18-month cognitive outcome in infants with TGA. These findings suggest that antenatal diagnosis may be neuroprotective, possibly through improved preoperative clinical status. These data highlight the need to improve antenatal diagnosis rates. WHAT THIS PAPER ADDS: Antenatal diagnosis of transposition of the great arteries modified relationships between neonatal brain volume and neurodevelopment. Smaller brain volumes related to poorer cognitive scores with postnatal diagnosis only. There was more preoperative hypotension in the postnatal diagnosis group.

Associations between tripartite dimensions of internalizing symptoms and transition readiness in a sample of emerging adults with and without chronic physical health conditions.

OBJECTIVE: Theoretical models note psychosocial functioning as a key influence on transition readiness skills (TRS) among emerging adults (EA), but little is known about the relative importance of unique vs. shared anxiety and depressive dimensions, operationalized according to Clark and Watson's (1991) tripartite model, in contributing to TRS. Moreover, although development of TRS is important for all EA, few studies have examined whether the strength of relationships between internalizing symptoms and TRS vary between EA with and without chronic physical health conditions (CHC). Given the links between suboptimal TRS and adverse health outcomes, additional research is needed. This study examined individual and additive associations between three internalizing symptom dimensions (anxious arousal, anhedonic depression, and general distress) and TRS, as well as the moderating role of CHC status. METHOD: One hundred twenty-six EA completed an online survey measuring TRS and internalizing symptoms. The sample was 70.6% women, 39.7% of minoritized racial identity, and 21.2% Hispanic ethnicity. The mean participant age was 21.23 years. RESULTS: In two of three regression models, anhedonic depression alone was significantly related to TRS. CHC moderated the relationship between internalizing and TRS in only two of nine models. In both cases, internalizing symptoms were negatively associated with TRS for those without CHCs, but not for those with CHCs. CONCLUSIONS: Assessment of anhedonic depression may be particularly useful in identifying youth at risk for suboptimal TRS regardless of CHC status. Moreover, interventions such as behavioral activation to improve TRS skill attainment warrant additional investigation.

Examining the psychometric properties of the CEFIS-AYA using item response theory.

OBJECTIVE: The COVID-19 Exposure and Family Impact Scale, Adolescent and Young Adult Version (CEFIS-AYA; Schwartz, L. A., Lewis, A. M., Alderfer, M. A., Vega, G., Barakat, L. P., King-Dowling, S., Psihogios, A. M., Canter, K. S., Crosby, L., Arasteh, K., Enlow, P., Hildenbrand, A. K., Kassam-Adams, N., Pai, A., Phan, T. L., Price, J., Schultz, C. L., Sood, E., Wood, J., & Kazak, A. (2022). COVID-19 exposure and family impact scales for adolescents and young adults. Journal of Pediatric Psychology, 47, 631-640. https://doi.org/10.1093/jpepsy/jsac036) was developed to assess the pandemic's effects on adolescents and young adults (AYA). Via principal component analysis, measure developers examined the structure and reliability of the CEFIS-AYA and identified seven exposure and five impact components. This study built upon prior work through use of item response theory (IRT) models to characterize the dimensionality of the CEFIS-AYA, determine the strength of relations between items and underlying trait(s), and examine associations between trait scores and pandemic-related distress. METHODS: This was a secondary analysis of data collected between July 2020 and July 2021 from three studies of emerging adults (ages 18-29; N = 834). RESULTS: The CEFIS-AYA structure was multidimensional, with the strongest support for five traits. Trait 1 represented pandemic impact on social/emotional functioning and self-care. Trait 2 reflected other pandemic disruptions. Trait 3 represented pandemic disruptions to education and/or other milestones. Trait 4 represented pandemic impact on physical well-being. Trait 5 assessed pandemic disruptions to work/financial circumstances. Item loadings and parameters indicated variability in how consistently trait level was associated with item endorsement. Trait scores did not predict distress, except that increases in Trait 3 were associated with lower distress. CONCLUSIONS: The present study examined the psychometric properties of the CEFIS-AYA among emerging adults using a statistical framework better suited for modeling categorical data. The identified dimensional structure was relatively consistent with the initial psychometric evaluation of the CEFIS-AYA, albeit more parsimonious. However, replication is critical in light of sample demographic characteristics.

Allogenic Vertebral Body Adherent Mesenchymal Stromal Cells Promote Muscle Recovery in Diabetic Mouse Model of Limb Ischemia.

BACKGROUND: Chronic limb threatening ischemia (CLTI) carries a significant risk for amputation especially in diabetic patients with poor options for revascularization. Phase I trials have demonstrated efficacy of allogeneic mesenchymal stromal cells (MSC) in treating diabetic CLTI. Vertebral bone adherent mesenchymal stromal cells (vBA-MSC) are derived from vertebral bodies of deceased organ donors which offer the distinct advantage of providing a 1,000x greater yield compared to that of living donor bone aspiration. This study describes the effects of intramuscular injection of allogenic vBA-MSC in promoting limb perfusion and muscle recovery in a diabetic CLTI mouse model. METHODS: A CLTI mouse model was created through unilateral ligation of the femoral artery in male polygenic diabetic TALLYHO mice. Treated mice were injected with vBA-MSC into the gracilis muscle of the ischemic limb 7 days post ligation. Gastrocnemius or tibialis muscle was assessed post-mortem for fibrosis by collagen staining, capillary density via immunohistochemistry, and mRNA by quantitative real time PCR. Laser Doppler perfusion imaging and plantar flexion muscle testing were performed to quantify changes in limb perfusion and muscle function. RESULTS: Compared to vehicle control, treated mice demonstrated indicators of muscle recovery including decreased fibrosis, increased perfusion, muscle torque, and angiogenesis. PCR analysis of muscle obtained 7- and 30-days post vBA-MSC injection showed an upregulation in expression of MyoD1 (p = 0.03) and MyH3 (p = 0.008) mRNA representing muscle regeneration, VEGF-A (p = 0.002 ; p = 0.004) signifying angiogenesis as well as IL-10 (p < 0.001), T regulatory cell marker Foxp3 (p = 0.04), and M2-biased macrophage marker Mrc1 (CD206) (p = 0.02). CONCLUSIONS: These findings indicate human allogeneic vBA-MSC ameliorate ischemic muscle damage and rescue muscle function. These results in a murine model will enable further studies to develop potential therapies for diabetic CLTI patients.

Nursing home leader response during COVID-19: a qualitative descriptive study about use of external resources during the pandemic.

BACKGROUND: US nursing homes were ground zero for COVID-19 and nursing home leaders faced multiple challenges to keep residents and staff safe. Understanding the leader's role and their use of external resources to rapidly respond to the pandemic is important to better prepare for the next infectious disease outbreak emergency. The purpose of this study is to describe Missouri nursing home leaders' use of external resources to manage challenges encountered during the pandemic. METHODS: This qualitative descriptive study uses data from semi-structured interviews conducted with leaders from 24 Midwestern nursing homes between March 2022 and March 2023. Interviews were transcribed verbatim and analyzed using Dedoose software. Directed content analysis, guided by Donabedian's Structure, Process, Outcome framework, was used for analysis. Interviews were conducted as part of a larger mixed-methods study focused on developing knowledge and recommendations to improve US nursing homes' capacity to respond to infectious disease outbreaks. RESULTS: Forty-three interviews were conducted across the 24 homes. Participants included administrators (n = 24), nurse leaders (n = 19), and infection preventionists (n = 16). Six sub-categories of external resources/support were used by leaders to manage challenges during the pandemic:1) corporate support and communications, 2) statewide resources, 3) community-based resources, 4) health care coalitions focused on emergency response planning, 5) existing affiliations with local organizations i.e., hospitals, and 6) community members and families. Corporate support was a primary resource; however, it was limited to chain-based homes. Leaders from standalone homes seemed most reliant on statewide agencies, existing affiliations, and other community-based resources due to their lack of corporate connections. Health care coalitions were few, but when available, helped nursing homes prepare for the pandemic onset. Family and community members were vital despite being off-site from nursing homes at the pandemic onset. CONCLUSION: Leaders played a pivotal role in accessing and using external resources to manage challenges during the pandemic. Statewide and community-based agencies and existing affiliations were particularly critical for standalone homes who otherwise had little to no means of support. Federal, state and local agencies must consider opportunities to build multi-agency regional collaborations, local health care coalitions and community-based partnerships that include nursing homes as member. Finally, community members and family were important in providing support, thus closing visitation is a double-edged sword that needs careful, future consideration.

Neurodevelopmental outcomes at 18 months of children diagnosed with CHD compared to children born very preterm.

OBJECTIVE: To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm. METHODS: A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months. RESULTS: Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5-5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05). CONCLUSIONS: Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.

Preterm Neurodevelopmental Trajectories from 18 Months to 4.5 Years.

OBJECTIVE: To assess the longitudinal trajectory of cognitive, language, and motor outcomes from 18 months to 4.5 years of age in children born very preterm. STUDY DESIGN: This was a prospective cohort study of 163 infants born very preterm (born 24-32 weeks of gestation) followed longitudinally and assessed with neurodevelopmental scales and magnetic resonance imaging of the brain. Outcomes at 18 months and 3 years were assessed with the Bayley Scales of Infant and Toddler Development, 3rd Edition, and at 4.5 years with the Wechsler Preschool and Primary Scale of Intelligence-III and the Movement Assessment Battery for Children. Cognitive, language, and motor outcomes were categorized as below-average, average, and above-average, and compared across time. Clinical data were analyzed using ANOVA, χ2 tests, and linear regression. RESULTS: Cognitive and language trajectories were stable from 18 months to 4.5 years for all outcome groups. Motor impairment increased over time, with a greater proportion of children having motor deficits at 4.5 years. Children with below-average cognitive and language outcomes at 4.5 years had more clinical risk factors, greater white matter injury, and lower maternal education. Children with severe motor impairment at 4.5 years were born earlier, had more clinical risk factors, and demonstrated greater white matter injury. CONCLUSIONS: Children born preterm have stable cognitive and language trajectories, while motor impairment increased at 4.5 years. These results highlight the importance of continued developmental surveillance for children born preterm into preschool age.

Critical congenital heart disease beyond HLHS and TGA: neonatal brain injury and early neurodevelopment.

BACKGROUND: Characterization of brain injury and neurodevelopmental (ND) outcomes in critical congenital heart disease (cCHD) has primarily focused on hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA). This study reports brain injury and ND outcomes among patients with heterogeneous cCHD diagnoses beyond HLHS and TGA. METHODS: This prospective cohort study included infants with HLHS, TGA, or heterogenous "Other cCHD" including left- or right-sided obstructive lesions, anomalous pulmonary venous return, and truncus arteriosus. Brain injury on perioperative brain MRI and ND outcomes on the Bayley-II at 30 months were compared. RESULTS: A total of 218 participants were included (HLHS = 60; TGA = 118; "Other cCHD" = 40, including 8 with genetic syndromes). Pre-operative (n = 209) and post-operative (n = 189) MRI showed similarly high brain injury rates across groups, regardless of cardiopulmonary bypass exposure. At 30 months, participants with "Other cCHD" had lower cognitive scores (p = 0.035) compared to those with HLHS and TGA, though worse ND outcome in this group was driven by those with genetic disorders. CONCLUSIONS: Frequency of brain injury and neurodevelopmental delay among patients with "Other cCHD" is similar to those with HLHS or TGA. Patients with all cCHD lesions are at risk for impaired outcomes; developmental and genetic screening is indicated. IMPACT: This study adds to literature on risk of brain injury in patients with critical congenital heart disease (cCHD) diagnoses other than hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), a heterogenous cohort of patients that has often been excluded from imaging studies. Children with cCHD beyond HLHS and TGA have similarly high rates of acquired brain injury. The high rate of neurodevelopmental impairment in this heterogenous group of cCHD diagnoses beyond HLHS and TGA is primarily driven by patients with comorbid genetic syndromes such as 22q11.2 deletion syndrome.

Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants.

BACKGROUND: We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment. METHODS: Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition. RESULTS: Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days). CONCLUSIONS: Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants. IMPACT: In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.