Predicting mental and psychomotor delay in very pre-term infants using machine learning.

BACKGROUND: Very preterm infants are at elevated risk for neurodevelopmental delays. Earlier prediction of delays allows timelier intervention and improved outcomes. Machine learning (ML) was used to predict mental and psychomotor delay at 25 months. METHODS: We applied RandomForest classifier to data from 1109 very preterm infants recruited over 20 years. ML selected key predictors from 52 perinatal and 16 longitudinal variables (1-22 mo assessments). SHapley Additive exPlanations provided model interpretability. RESULTS: Balanced accuracy with perinatal variables was 62%/61% (mental/psychomotor). Top predictors of mental and psychomotor delay overlapped and included: birth year, days in hospital, antenatal MgSO4, days intubated, birth weight, abnormal cranial ultrasound, gestational age, mom's age and education, and intrauterine growth restriction. Highest balanced accuracy was achieved with 19-month follow-up scores and perinatal variables (72%/73%). CONCLUSIONS: Combining perinatal and longitudinal data, ML modeling predicted 24 month mental/psychomotor delay in very preterm infants ½ year early, allowing intervention to start that much sooner. Modeling using only perinatal features fell short of clinical application. Birth year's importance reflected a linear decline in predicting delay as birth year became more recent. IMPACT: Combining perinatal and longitudinal data, ML modeling was able to predict 24 month mental/psychomotor delay in very preterm infants ½ year early (25% of their lives) potentially advancing implementation of intervention services. Although cognitive/verbal and fine/gross motor delays require separate interventions, in very preterm infants there is substantial overlap in the risk factors that can be used to predict these delays. Birth year has an important effect on ML prediction of delay in very preterm infants, with those born more recently (1989-2009) being increasing less likely to be delayed, perhaps reflecting advances in medical practice.

Expression patterns and clinical significance of estrogen receptor in non-small cell lung cancer.

BACKGROUND: Lung cancer death remains the highest among all malignancies. Gender differences show women have an increased cancer incidence while men have worse outcomes. These observations identified that some lung carcinomas express estrogen receptors (ER). This is a promising target as antiestrogen drugs can reduce tumors and improve survival. However, there is a limited understanding of ER distribution and its clinical significance to properly design antiestrogen drug clinical trials. Thus, we comprehensively analyzed ERα and ERß expression patterns by gender, cancer cell type, and receptor location in lung cancer. METHODS: We conducted a systematic review using the PubMed database from all-time through October 2022, using MeSH terms with the keywords "lung cancer," "estrogen receptor," and "immunohistochemistry." We identified 120 studies with 21 reports being evaluated based on our inclusion criteria. RESULTS: We examined 4874 lung cancers from 5011 patients. ERß is the predominant form of ER expressed, mainly found in the nucleus. The ERß positivity rate is 51.5% in males versus 55.5% in females and was not statistically different. In contrast, ERα is predominately extranuclear in location, and ERα expression varies by gender. Males had a positivity rate of 31% versus 26.6% in females, which is statistically different. ERα is associated with a worse prognosis in some studies, while it had no effect in others. Overall, ERß was associated with a better prognosis. CONCLUSION: We characterized ER expression patterns in 4874 lung cancers. Over 50% expressed ERß with equal rates in both sexes and was associated with a better prognosis. ERα expression was slightly higher in males (31%) than females (26.6%) and was associated with a poor prognosis. Our findings suggest estrogen signaling may be a promising drug target in lung cancer.

The Global Jukebox: A public database of performing arts and culture.

Standardized cross-cultural databases of the arts are critical to a balanced scientific understanding of the performing arts, and their role in other domains of human society. This paper introduces the Global Jukebox as a resource for comparative and cross-cultural study of the performing arts and culture. The Global Jukebox adds an extensive and detailed global database of the performing arts that enlarges our understanding of human cultural diversity. Initially prototyped by Alan Lomax in the 1980s, its core is the Cantometrics dataset, encompassing standardized codings on 37 aspects of musical style for 5,776 traditional songs from 1,026 societies. The Cantometrics dataset has been cleaned and checked for reliability and accuracy, and includes a full coding guide with audio training examples (https://theglobaljukebox.org/?songsofearth). Also being released are seven additional datasets coding and describing instrumentation, conversation, popular music, vowel and consonant placement, breath management, social factors, and societies. For the first time, all digitized Global Jukebox data are being made available in open-access, downloadable format (https://github.com/theglobaljukebox), linked with streaming audio recordings (theglobaljukebox.org) to the maximum extent allowed while respecting copyright and the wishes of culture-bearers. The data are cross-indexed with the Database of Peoples, Languages, and Cultures (D-PLACE) to allow researchers to test hypotheses about worldwide coevolution of aesthetic patterns and traditions. As an example, we analyze the global relationship between song style and societal complexity, showing that they are robustly related, in contrast to previous critiques claiming that these proposed relationships were an artifact of autocorrelation (though causal mechanisms remain unresolved).

The G Protein-Coupled Serotonin 1A Receptor Augments Protein Kinase Cε-Mediated Neurogenesis in Neonatal Mouse Hippocampus-PKCε-Mediated Signaling in the Early Hippocampus.

The neurotransmitter serotonin (5-HT) plays an important role in mood disorders. It has been demonstrated that 5-HT signaling through 5-HT1A receptors (5-HT1A-R) is crucial for early postnatal hippocampal development and later-life behavior. Although this suggests that 5-HT1A-R signaling regulates early brain development, the mechanistic underpinnings of this process have remained unclear. Here we show that stimulation of the 5-HT1A-R at postnatal day 6 (P6) by intrahippocampal infusion of the agonist 8-OH-DPAT (D) causes signaling through protein kinase Cε (PKCε) and extracellular receptor activated kinase ½ (ERK1/2) to boost neuroblast proliferation in the dentate gyrus (DG), as displayed by an increase in bromodeoxy-uridine (BrdU), doublecortin (DCX) double-positive cells. This boost in neuroproliferation was eliminated in mice treated with D in the presence of a 5-HT1A-R antagonist (WAY100635), a selective PKCε inhibitor, or an ERK1/2-kinase (MEK) inhibitor (U0126). It is believed that hippocampal neuro-progenitors undergoing neonatal proliferation subsequently become postmitotic and enter the synaptogenesis phase. Double-staining with antibodies against bromodeoxyuridine (BrdU) and neuronal nuclear protein (NeuN) confirmed that 5-HT1A-R → PKCε → ERK1/2-mediated boosted neuroproliferation at P6 also leads to an increase in BrdU-labeled granular neurons at P36. This 5-HT1A-R-mediated increase in mature neurons was unlikely due to suppressed apoptosis, because terminal deoxynucleotidyl transferase dUTP nick-end labeling analysis showed no difference in DNA terminal labeling between vehicle and 8-OH-DPAT-infused mice. Therefore, 5-HT1A-R signaling through PKCε may play an important role in micro-neurogenesis in the DG at P6, following which many of these new-born neuroprogenitors develop into mature neurons.

Autism Spectrum Disorder Decision Tree Subgroups Predict Adaptive Behavior and Autism Severity Trajectories in Children with ASD.

A recent cross-sectional analysis of PDD Behavior Inventory (PDDBI) data, analyzed with a classification and regression tree algorithm, yielded a decision tree (the Autism Spectrum Disorder-Decision Tree or ASD-DT) that detected three behaviorally distinct ASD subgroups: minimally verbal, verbal, and atypical. These subgroups differed in PDDBI profiles and in factors previously reported to be predictors of autism severity and adaptive behavior trajectories. We retrospectively analyzed trajectories of adaptive skills and autism severity in these subgroups, defined by ASD-DTs calculated from initial evaluation PDDBIs. Results confirmed predictions that each subgroup had distinct trajectories that varied with the type of adaptive behavior assessed suggesting that the ASD-DT has prognostic value that could be helpful for both clinical and research applications.

Infant twins' social interactions with caregivers and same-age siblings.

The study of twin behavior offers the opportunity to study differential patterns of social and communicative interactions in a context where the adult partner and same-age peer are equally familiar. We investigated the development of social engagement, communicative gestures, and imitation in 7- to 25-month-old twins. Twin dyads (N=20 pairs) participated in 10-min, semi-structured play sessions, with the mother seated in a chair completing paperwork for half the session, and on the floor with her children for the other half. Overall, twins engaged more with their mothers than with their siblings: they showed objects and imitated speech and object use more frequently when interacting with their mothers than with their siblings. When the mother was otherwise engaged, the twins played with toys separately, observed each other's toy play, or were unengaged. These results demonstrate that adult scaffolding of social interactions supports increased communicative bids even in a context where both familiar peers and adults are available as communicative partners.

Effects of antidepressants on longevity and dementia onset among adults with Down syndrome: a retrospective study.

OBJECTIVE: To investigate the effects of antidepressants on longevity, age at dementia onset, and survival after onset among adults with Down syndrome, controlling for late-onset seizures, trisomy 21 mosaicism, and cholinesterase inhibitor use. METHOD: The charts of 357 adults with Down syndrome (mean age at first visit = 46.3 years, SD = 9.0) evaluated in a metropolitan diagnostic and research clinic between 1990 and 2008 were reviewed. Seventeen patients had trisomy 21 mosaicism; 155 patients were diagnosed with depressive disorders using DSM-III-R and IV criteria, 78 of whom received antidepressants for over 90 days. Of 160 patients who developed dementia, the estimated mean age at onset was 52.8 years. Fifty-six patients (demented and nondemented) had late-onset seizures. Longevity and age at estimated onset among those receiving and not receiving antidepressants were compared. Cox proportional hazards models examined risks for dementia onset and death. RESULTS: The mean age at dementia onset among those receiving antidepressants before onset was 53.75 years versus 52.44 years among others. Proportional hazards models showed a significant delay of onset among those taking antidepressants (hazard ratio = 0.69; 95% CI, 0.48-0.98; P = .038). Mean age at death or at end of study for those receiving antidepressants was 54.71 years; among others, it was 52.60 years (hazard ratio = 0.63; 95% CI, 0.42-0.94; P = .024). Among the 35 adults with late-onset seizures and dementia who died, mean survival after seizure onset was 4.23 years. CONCLUSIONS: The findings in this retrospective study revealed that antidepressant use was associated with delayed dementia onset and increased longevity in adults with Down syndrome; mean survival after late-onset seizures was longer than previously reported. Further studies, however, are needed to confirm these associations, optimally in a clinical trial to confirm causality.

Single-base resolution of mouse offspring brain methylome reveals epigenome modifications caused by gestational folic acid.

BACKGROUND: Epigenetic modifications, such as cytosine methylation in CpG-rich regions, regulate multiple functions in mammalian development. Maternal nutrients affecting one-carbon metabolism during gestation can exert long-term effects on the health of the progeny. Using C57BL/6 J mice, we investigated whether the amount of ingested maternal folic acid (FA) during gestation impacted DNA methylation in the offspring's cerebral hemispheres. Reduced representation bisulfite sequencing at single-base resolution was performed to analyze genome-wide DNA methylation profiles. RESULTS: We identified widespread differences in the methylation patterns of CpG and non-CpG sites of key developmental genes, including imprinted and candidate autism susceptibility genes (P <0.05). Such differential methylation of the CpG and non-CpG sites may use different mechanisms to alter gene expressions. Quantitative real time reverse transcription-polymerase chain reaction confirmed altered expression of several genes. CONCLUSIONS: These finding demonstrate that high maternal FA during gestation induces substantial alteration in methylation pattern and gene expression of several genes in the cerebral hemispheres of the offspring, and such changes may influence the overall development. Our findings provide a foundation for future studies to explore the influence of gestational FA on genetic/epigenetic susceptibility to altered development and disease in offspring.

Neonatal Intensive-Care Unit Graduates Show Persistent Difficulties in an Intra-Dimensional Shift Card Sort.

Neonatal intensive-care unit (NICU) graduates, a group at risk for attention problems and ADHD, performed an intra-dimensional shift card sort at 34, 42, 51, and 60 months to assess executive function and to examine effects of individual risk factors. In the 'silly' game, children sorted cards (airplanes and dogs) so they were not the same as targets. In the 'same' game they did the opposite. Performance on the 'silly' game was poor, especially when it was presented first. Success in following 'silly' game rules improved with age, and was significantly linked to maternal education and birth weight for gestational age, a measure of intrauterine stress. Degree of CNS injury differentiated children who completed the task from children who did not, and also affected the need to repeat instructions in the 'same' game. These results confirm an increased likelihood of impairments in executive function during preschool years in NICU graduates.

The development of selective attention and inhibition in NICU graduates during the preschool years.

Neonatal intensive care unit (NICU) graduates have a higher incidence of attention problems including attention deficit hyperactivity disorder (ADHD). Thus, we examined the effect of risk factors (birth weight (BW), central nervous system (CNS) injury, gender, maternal education) on attention/inhibition during reaction time, continuous performance and Go/No-Go tasks at 42, 51, and 60 months (n = 271). Very low BW NICU graduates (<1,500 g) performed worse than typical BW ones (>2,500 g), displaying poorer target/non-target discrimination. Males responded faster than females, but made more false alarms and random responses. Despite short duration tasks, attention waned. Performance improved with age, but even at 60 months children had difficulty inhibiting random responding.

Brain region-specific decrease in the activity and expression of protein kinase A in the frontal cortex of regressive autism.

Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP-dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.

Early medical and behavioral characteristics of NICU infants later classified with ASD.

OBJECTIVES: Recent evidence suggests higher prevalence of autism spectrum disorder (ASD) in NICU graduates. This aim of this study was to identify retrospectively early behaviors found more frequently in NICU infants who went on to develop ASD. METHODS: Twenty-eight NICU graduates who later received a diagnosis of ASD were compared with 2169 other NICU graduates recruited from 1994 to 2005. They differed in gender, gestational age, and birth cohort. These characteristics were used to draw a matched control sample (n=112) to determine which, if any, early behaviors discriminated subsequent ASD diagnosis. Behavioral testing at targeted ages (adjusted for gestation) included the Rapid Neonatal Neurobehavioral Assessment (hospital discharge, 1 month), Arousal-Modulated Attention (hospital discharge, 1 and 4 months), and Bayley Scales of Infant Development (multiple times, 4-25 months). RESULTS: At 1 month, children with ASD but not control children had persistent neurobehavioral abnormalities and higher incidences of asymmetric visual tracking and arm tone deficits. At 4 months, children with ASD had continued visual preference for higher amounts of stimulation than did control children, behaving more like newborns. Unlike control children, children with ASD had declining mental and motor performance by 7 to 10 months, resembling infants with severe central nervous system involvement. CONCLUSIONS: Differences in specific behavior domains between NICU graduates who later receive a diagnosis of ASD and matched NICU control children may be identified in early infancy. Studies with this cohort may provide insights to help understand and detect early disabilities, including ASD.

Breast arterial calcifications on mammograms do not predict coronary heart disease at coronary angiography.

PURPOSE: To examine, in women who underwent cardiac catheterization, whether breast arterial calcifications (BACs) seen at screening mammography correlate with coronary heart disease (CHD) seen at coronary angiography. MATERIALS AND METHODS: In an institutional review board-approved, HIPAA-compliant study, 172 women (mean age, 64.29 years +/- 11.97 [standard deviation]) who underwent coronary angiography were recruited, interviewed, and assigned to two groups: those with (CHD+) and those without (CHD-) CHD. The severity and location of the CHD were considered. Their mammograms were reviewed by a breast imaging specialist who was blinded to the CHD status. Student t test, chi(2), and multiple logistic regression tests were performed as appropriate. Presence of BAC was noted and correlated with presence of CHD and presence of cardiac risk factors. RESULTS: There were 104 women with and 68 women without CHD. Thirty-seven (36%) women in the CHD+ group versus 20 (29%) in the CHD-group (P = .40) had BAC. The mean age of the patients with BAC, 72 years +/- 9.8, was significantly older than the mean age of the patients without BAC, 60.4 years +/- 11.1 (P < .001). Therefore, subjects were divided into those younger than 65 years and those 65 years and older. No correlation existed, despite the fact that BAC was associated with some cardiac risk factors. CONCLUSION: The authors did not observe a correlation between BAC and coronary angiography-detected CHD, even when CHD severity was considered. On the basis of these results, caution should be exercised when using screening mammography-detected BAC to identify patients with CHD.

A large scale study of the psychometric characteristics of the IBR Modified Overt Aggression Scale: findings and evidence for increased self-destructive behaviors in adult females with autism spectrum disorder.

The psychometric characteristics of the IBR Modified Overt Aggression Scale were studied in over 2,000 people with Intellectual Disability (ID). Reliability ranged from good to excellent. Aggression toward others and objects was highest in the youngest adults, in those in the moderate to severe range of ID, and in those with an autism spectrum diagnosis. Self-injury was highest in those in the severe to profound range of ID and in those with autism, particularly the females. Females with autism were also more likely to make the most self-deprecating statements. Our data suggest that adult females with autism are a unique group and support the notion that mood and anxiety disorders play a role in self-destructive behaviors in this population.

Accelerated prion disease pathogenesis in Toll-like receptor 4 signaling-mutant mice.

Prion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrP(Sc), in the brain. Toll-like receptors (TLRs) are a family of proteins that recognize microbial constituents and are central players in host innate immune responses. The TLR9 agonist unmethylated CpG DNA was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. Thus, it was predicted that ablation of TLR signaling would result in accelerated pathogenesis. C3H/HeJ (Tlr4(Lps-d)) mice, which possess a mutation in the TLR4 intracellular domain preventing TLR4 signaling, and strain-matched wild-type control (C3H/HeOuJ) mice were infected intracerebrally or intraperitoneally with various doses of scrapie inoculum. Incubation periods were significantly shortened in C3H/HeJ compared with C3H/HeOuJ mice, regardless of the route of infection or dose administered. At the clinical phase of disease, brain PrP(Sc) levels in the two strains of mice showed no significant differences by Western blotting. In addition, compared with macrophages from C3H/HeOuJ mice, those from C3H/HeJ mice were unresponsive to fibrillogenic PrP peptides (PrP residues 106 to 126 [PrP(106-126)] and PrP(118-135)) and the TLR4 agonist lipopolysaccharide but not to the TLR2 agonist zymosan, as measured by cytokine production. These data confirm that innate immune activation via TLR signaling interferes with scrapie infection. Furthermore, the results also suggest that the scrapie pathogen, or a component(s) thereof, is capable of stimulating an innate immune response that is active in the central nervous system, since C3H/HeJ mice, which lack the response, exhibit shortened incubation periods following both intraperitoneal and intracerebral infections.

CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils.

Prion diseases are characterized by conversion of the cellular prion protein (PrP(C)) to a protease-resistant conformer, the srapie form of PrP (PrP(Sc)). Humoral immune responses to nondenatured forms of PrP(Sc) have never been fully characterized. We investigated whether production of antibodies to PrP(Sc) could occur in PrP null (Prnp(-/-)) mice and further, whether innate immune stimulation with the TLR9 agonist CpG oligodeoxynucleotide (ODN) 1826 could enhance this process. Whether such stimulation could raise anti-PrP(Sc) antibody levels in wild-type (Prnp(+/+)) mice was also investigated. Prnp(-/-) and Prnp(+/+) mice were immunized with nondenatured 139A scrapie-associated fibrils (SAF), with or without ODN 1826, and were tested for titers of PrP-specific antibodies. In Prnp(-/-) mice, inclusion of ODN 1826 in the immunization regime increased anti-PrP titers more than 13-fold after two immunizations and induced, among others, antibodies to an N-terminal epitope, which were only present in the immune repertoire of mice receiving ODN 1826. mAb 6D11, derived from such a mouse, reacts with the N-terminal epitope QWNK in native and denatured forms of PrP(Sc) and recombinant PrP and exhibits a K(d) in the 10(-)(11) M range. In Prnp(+/+) mice, ODN 1826 increased anti-PrP levels as much as 84% after a single immunization. Thus, ODN 1826 potentiates adaptive immune responses to PrP(Sc) in 139A SAF-immunized mice. These results represent the first characterization of humoral immune responses to nondenatured, infectious PrP(Sc) and suggest methods for optimizing the generation of mAbs to PrP(Sc), many of which could be used for diagnosis and treatment of prion diseases.

The Willowbrook futures project: a longitudinal analysis of person-centered planning.

We conducted a longitudinal comparative evaluation of person-centered planning processes and outcomes for 20 individuals with intellectual disabilities and problem behavior (former residents of Willowbrook) and a matched contrast group, who received traditional interdisciplinary service planning (ISP). At the inception of the study, all participants were living in one of four other developmental centers (institutions) in New York City. Process and outcome data obtained from questionnaires completed by team members approximately every 8 months at four time periods showed that the rate of improvement in both person-centered planning process and outcomes for the intervention group was significantly greater than that of the comparison group. Eighteen of 19 person-centered planning participants moved to community living arrangements, as did 5 of 18 in the contrast group.