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: 528 infants born <32 weeks' gestational age from two sequential prospective cohorts (cohort 1 2006 through 2012 and cohort 2 2014 through 2019) underwent early-life (median 32.7 weeks) and/or term-equivalent-age MRI (median 40.7 weeks). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI (n=152) 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 (over time). 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<0.001) 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.

SpaceOAR Complication Affecting the Treatment of Prostate Cancer.

A 60-year-old male presented with an elevated prostate-specific antigen (PSA) of 10 ng/ml. A transrectal ultrasound-guided prostate biopsy showed prostate adenocarcinoma GS 4+3 (grade 3) with 5 out of 12 cores positive for malignancy. He initially planned to have prostate stereotactic body radiation therapy (SBRT) with SpaceOAR gel insertion in his rectoprostatic space to reduce radiation to the rectum. Magnetic resonance imaging (MRI) two months after SpaceOAR insertion showed evidence of infiltration of the SpaceOAR within the anterior rectal wall. This delayed his treatment and he was started on a short course of androgen deprivation therapy with Leuprolide while waiting for absorption of the gel. After completion of androgen deprivation therapy, the patient was treated with external beam radiation therapy (EBRT) to the prostate, seminal vesicles, and pelvis to a total dose of 6000 centigray (cGy) in 20 fractions at a dose per fraction of 300 cGy. He did well after treatment with minimal side effects.

Positive parenting practices support children at neurological risk during COVID-19: a call for accessible parenting interventions.

Children and youth with neurological and/or neurodevelopmental conditions were at high risk for behavioral and mental health challenges during the COVID-19 pandemic. Positive and responsive parenting practices may be one way to prevent and manage potential difficulties in families. We aimed to identify whether positive parenting practices were associated with reduced behavioral concerns in children at neurological risk during the late stages and aftermath of the COVID-19 pandemic. In addition, we examined whether ongoing parental stress, anxiety, and depression impacted parenting practices during this time period. Families (N = 179) with children 4 to 15 years old (M = 7.11y, SD = 2.02) diagnosed with neurological (84.3%), neurodevelopmental (54.8%) or comorbid neurological and/or neurodevelopmental conditions (21.2%) were contacted to complete online questionnaires regarding demographics, parent stress, child behavior, COVID-19 conditions, and parenting practices. Multivariable linear regression (MLR) analyses examined the association between positive parenting practices and parenting competency measures with child behavioral outcomes, controlling for relevant covariates, including COVID-19 related stress. MLR were also run to determine whether parental mental health impacted parenting practices. More positive parenting practices predicted fewer child problem behaviors and lower intensity of problem behaviors. Similarly, a higher sense of satisfaction with parenting competence also predicted fewer child problem behaviors and lower intensity of problem behaviors. In addition, higher reported parental depression, anxiety, and stress significantly predicted fewer reported positive parenting practices. Findings points to the promising application of positive parenting interventions to support vulnerable families, as well as the need for parental mental health intervention to support parenting practices.

Pediatric Myeloid Sarcoma of the Testes Treated With Surgery and Adjuvant Radiation Therapy.

Myeloid sarcoma (MS) is a rare extramedullary tumor of immature granulocytic cells and is most often associated with acute myeloid leukemia (AML). Myeloid sarcomas can occur anywhere in the body but are seldom present in the testicles, especially in the pediatric population. The treatment of MS, especially testicular myeloid sarcoma (TMS) is not well defined in the literature and the role of radiation therapy in the treatment of TMS is even less well defined. In this case report, we discuss the treatment for TMS in a pediatric patient, review the literature, and discuss the role of radiation therapy in the treatment.

Genetic Mapping and Phenotypic Analysis of GstE14 E.4.1 on Eye and Antennae Development in Drosophila melanogaster.

Genetic screens are valuable for identifying novel genes involved in the regulation of developmental processes. To identify genes associated with cell growth regulation in Drosophila melanogaster , a mutagenesis screen was performed. Undergraduate students participating in Fly-CURE phenotypically characterized the E.4.1 mutant which is associated with rough eyes and antennae overgrowth. Following complementation analysis and subsequent genomic sequencing, E.4.1 was identified as a novel mutant allele of GstE14 , a gene involved in ecdysone biosynthesis important for the timing of developmental events. The abnormal eye and antenna phenotypes observed resulting from the loss of GstE14 suggest its role in tissue growth.

Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

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.

Pain Exposure and Brain Connectivity in Preterm Infants.

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown. Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants. Design, Setting, and Participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023. Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures. Main Outcome and Measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education. Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes. Conclusions and Relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism.

CLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different tissues. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated by hyperpolarization, rather than depolarization, of the plasma membrane. The molecular basis for the divergence in polarity of voltage gating among closely related homologs has been a long-standing mystery, in part because few CLC channel structures are available. Here, we report cryoEM structures of human CLC-2 at 2.46 - 2.76 Å, in the presence and absence of the selective inhibitor AK-42. AK-42 binds within the extracellular entryway of the Cl--permeation pathway, occupying a pocket previously proposed through computational docking studies. In the apo structure, we observed two distinct conformations involving rotation of one of the cytoplasmic C-terminal domains (CTDs). In the absence of CTD rotation, an intracellular N-terminal 15-residue hairpin peptide nestles against the TM domain to physically occlude the Cl--permeation pathway. This peptide is highly conserved among species variants of CLC-2 but is not present in other CLC homologs. Previous studies suggested that the N-terminal domain of CLC-2 influences channel properties via a "ball-and-chain" gating mechanism, but conflicting data cast doubt on such a mechanism, and thus the structure of the N-terminal domain and its interaction with the channel has been uncertain. Through electrophysiological studies of an N-terminal deletion mutant lacking the 15-residue hairpin peptide, we support a model in which the N-terminal hairpin of CLC-2 stabilizes a closed state of the channel by blocking the cytoplasmic Cl--permeation pathway.

Relationships between cortisol levels across early childhood and processing speed at age 4.5 years in children born very preterm.

Children born very low gestational age (VLGA, 29-32 weeks gestational age [GA]) display slower processing speed and altered hypothalamic pituitary adrenal (HPA) axis function, with greater effects in those born extremely low gestational age (ELGA; 24-28 weeks GA). We investigated trajectories of HPA axis activity as indexed by cortisol output and patterns across cognitive assessment at ages 1.5, 3 and 4.5 years, comparing children born ELGA and VLGA and associations with 4.5-year processing speed. In a prospective longitudinal cohort study, infants born very preterm (<33 weeks gestation) returned for developmental assessment at ages 1.5, 3, and 4.5 years. At each age, children completed standardized cognitive testing and saliva samples collected before (Pretest), during (During) and after (End) challenging cognitive tasks were assayed for cortisol. For the total group (n = 188), cortisol area under the curve with respect to ground (AUCg) decreased, while cortisol reactivity to challenge (Pre-test to During) increased from 1.5 to 3 years, remaining stable to 4.5 years. This longitudinal pattern was related to higher Processing Speed (WPPSI-IV) scores at 4.5 years. Children born ELGA displayed higher AUCg than VLGA, particularly at age 3, driven by higher Pre-test cortisol levels. Overall, relative to those born VLGA, children born ELGA displayed greater cortisol responsivity to cognitive challenge. A higher setpoint of cortisol levels at age 3-years in children born ELGA may reflect altered HPA axis regulation more broadly and may contribute to difficulties with information processing in this population, critical for academic and social success.

Re-irradiation of a Classic Kaposi's Sarcoma Using Volumetric Modulated Arc Therapy.

A black male in his 60s diagnosed with classic Kaposi's sarcoma presented with multiple cutaneous nodules and edema of the right foot and lower leg. He was initially treated with alitretinoin 1% topical treatment. However, 16 months after treatment with the alitretinoin, the skin lesions progressed, and he subsequently underwent a course of radiation therapy to a total dose of 2000 centigrays (cGy) in five fractions to his right foot and lower extremities. Approximately 1.5 years after the radiation therapy was completed, multiple new lesions developed on the right foot and distal lower leg. He then underwent a course of re-irradiation to this area using volumetric modulated arc therapy (VMAT) to a total dose of 3300 cGy in 11 fractions. At a four-week follow-up visit, the skin lesions had completely resolved; however, the patient experienced mild edema and tenderness of the right foot and lower leg. Although long-term outcomes need to be followed, re-irradiation showed positive short-term outcomes for classic Kaposi's sarcoma.

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.

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.

A 3-day 'stroke camp' addressed chronic disease self-management elements and perceived stress of survivors of stroke and their caregivers reduced: Survey results from the 14 US camps.

BACKGROUND: Stroke is a leading cause of disability for persons with stroke (PWS). Difficulty coping with long-term stress for PWS and their caregivers (CG) contributes to their poor health. Variations of chronic-disease self-management programs (CDSMPs) have reduced long-term stress in PWS and CGs. CDSMPs include training for decision-making, problem-solving, resource utilization, peer support, developing a patient-provider relationship, and environmental support. OBJECTIVE: This study examined whether a user-designed stroke camp addressed CDSMP domains, used consistent activities, and decreased stress in PWS and CG. METHODS: This open cohort survey study followed STROBE guidelines and assessed stress at four timepoints: 1 week before camp, immediately before camp, immediately after camp, and 1 month after camp. Mixed-model analysis examined changes in stress from the two baseline time points to the two post-camp time points. The research team reviewed documents and survey responses to assess activities described in camp documents and CDSMP domains across camps. POPULATION: PWS and CG who attended a camp in 2019. The PWS sample (n = 40) included50% males, aged 1-41-years post stroke, 60% with ischemic, one-third with aphasia, and 37.5% with moderate-severe impairment. CG sample (n = 24) was 60.8% female, aged 65.5 years, and had 7.4 years CG experience. RESULTS: Stress decreased significantly in PWS (Cohen's d = -0.61) and CGs (Cohen's d = -0.87) from pre- to post-camp. Activities addressing all but one CDSMP domains were evident across camps. CONCLUSIONS: Stroke camp is a novel model that addresses CDSMP domains, which may reduce stress in PWS and CG. Larger, controlled studies are warranted.

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.