Stanford Encyclopedia of Philosophy

A review of the Stanford Encyclopedia of Philosophy.&nbsp

Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders

OBJECTIVES: Accumulating evidence implicates altered DNA methylation in psychiatric disorders, including bipolar disorder (BD) and major depressive disorder (MDD). It is not clear, however, whether these changes are causative or result from illness progression or treatment. To disentangle these possibilities we profiled genome‐wide DNA methylation in well, unrelated individuals at high familial risk of mood disorder. DNA methylation was compared between individuals who subsequently developed BD or MDD [ill later (IL)] and those who remained well [well later (WL)]. METHODS: DNA methylation profiles were obtained from whole‐blood samples from 22 IL and 23 WL individuals using the Infinium HumanMethylation450 BeadChip. Differential methylation was assessed on a single‐locus and regional basis. Pathway analysis was performed to assess enrichment for particular biological processes amongst nominally significantly differentially methylated loci. RESULTS: Although no locus withstood correction for multiple testing, uncorrected P‐values provided suggestive evidence for altered methylation at sites within genes previously implicated in neuropsychiatric conditions, such as Transcription Factor 4 (TCF4) and Interleukin 1 Receptor Accessory Protein‐Like 1 ([IL1RAPL1]; P≤3.11×10(−5)). Pathway analysis revealed significant enrichment for several neurologically relevant pathways and functions, including Nervous System Development and Function and Behavior; these findings withstood multiple testing correction (q≤0.05). Analysis of differentially methylated regions identified several within the major histocompatibility complex (P≤.000 479), a region previously implicated in schizophrenia and BD. CONCLUSIONS: Our data provide provisional evidence for the involvement of altered whole‐blood DNA methylation in neurologically relevant genes in the aetiology of mood disorders. These findings are convergent with the findings of genome‐wide association studies

Correlations between fMRI activation and individual psychotic symptoms in un-medicated subjects at high genetic risk of schizophrenia

<p>Abstract</p> <p>Background:</p> <p>It has been proposed that different types of psychopathology in schizophrenia may reflect distinguishable pathological processes. In the current study we aimed to address such associations in the absence of confounders such as medication and disease chronicity by examining specific relationships between fMRI activation and individual symptom severity scores in un-medicated subjects at high genetic risk of schizophrenia.</p> <p>Methods:</p> <p>Associations were examined across two functional imaging paradigms: the Hayling sentence completion task, and an encoding/retrieval task, comprising encoding (at word classification) and retrieval (old word/new word judgement). Symptom severity was assessed using the positive and negative syndrome scale (PANSS). Items examined were hallucinations, delusions, and suspiciousness/persecution.</p> <p>Results:</p> <p>Associations were seen in the anterior middle temporal gyrus in relation to hallucination scores during the sentence completion task, and in the medial temporal lobe in association with suspiciousness/persecution scores in the encoding/retrieval task. Cerebellar activation was associated with delusions and suspiciousness/persecution scores across both tasks with differing patterns of laterality.</p> <p>Conclusion:</p> <p>These results support a role for the lateral temporal cortex in hallucinations and medial temporal lobe in positive psychotic symptoms. They also highlight the potential role of the cerebellum in the formation of delusions. That the current results are seen in un-medicated high risk subjects indicates these associations are not specific to the established illness and are not related to medication effects.</p

Assessment of Child, Mother, and Environmental Factors Associated with Undernutrition in Children Less than Five Years Old in a Maya Community in Yucatan, Mexico

The objective of this study was to examine child, mother, and environmental factors associated with undernutrition in children less than five years old in a Maya community in Yucatan, Mexico. This investigation was designed as a case-control study. All cases (n=42) of undernutrition were included, and a sample of 52 controls was randomly selected from the study population. The frequency of investigated exposure factors was compared between cases and controls by using logistic regression. Undernutrition was associated with child’s age (&gt; 36 months old; OR = 3.53; 95% CI = 1.04, 18.40) and mother’s marital status (married; OR = 0.29; 95% CI = 0.09, 0.90). The odds of undernutrition were 2.81 times higher in children infected with Giardia spp, but this association was not significant (P = 0.18) after controlling for child’s age and mother’s marital status. In conclusion, child’s age and mother’s marital status were associated with child undernutrition in study subjects. Futures studies on undernutrition in children should examine more carefully how mother’s marital status alone or in combination with other factors (e.g. socio-economic, psychological factors) can influence child nutrition

Improving Primary Care Follow-Up After Pediatric Hospitalization

BACKGROUND: Transitioning patient care to primary care physicians after pediatric hospitalization plays a critical role in children’s health. Follow-up appointments are an ideal time to provide education, address concerns, and arrange for continuity of care. This quality improvement (QI) study aimed to improve the percentages of primary care clinic follow-up within 7 days of hospital discharge. METHODS: Using the Plan-Do-Study-Act (PDSA) Model for Improvement, a multidisciplinary team examined pre-implementation data for patients discharged from the children’s hospital in February 2018. Electronic medical record (EMR) review was performed to determine if follow-up appointments were scheduled and attended within 7 days of discharge. Four week PDSA cycles were then completed by the medical residents, pediatric hospitalists and a care transition coordinator. Cycle 1 (n=25) involved developing an EMR-based shared patient list to identify all patients needing follow-up. In Cycle 2 (n=69), monthly standardized resident education was implemented to optimize use of the shared patient list. In Cycle 3 (n=81), a discharge appointment template was used to schedule appointments for patients discharged on weekends. RESULTS: Percent of appointments scheduled increased throughout the PDSA cycles from baseline (baseline - 60%; cycle 1 - 72%; cycle 2 - 74%; cycle 3 - 85%), as well as percent of appointments attended (baseline - 56%; cycle 1 - 56%; cycle 2 - 61%; cycle 3 - 70%) with p<0.001. Clinic follow-up was lower for patients with chronic illnesses but did improve from cycle 1 (42%) to cycle 3 (67%). The percentage of appointments scheduled for weekend discharges was not significantly different from weekday discharges, and increased from baseline over the course of the PDSA cycles. CONCLUSION: The number of follow-up appointments both scheduled and attended increased throughout the study, suggesting that the QI measures implemented were effective. Further interventions will focus on patient and system barriers to appointment attendance.N

Genetic Architectures of Adolescent Depression Trajectories in 2 Longitudinal Population Cohorts

Importance: Adolescent depression is characterized by diverse symptom trajectories over time and has a strong genetic influence. Research has determined genetic overlap between depression and other psychiatric conditions; investigating the shared genetic architecture of heterogeneous depression trajectories is crucial for understanding disease etiology, prediction, and early intervention. Objective: To investigate univariate and multivariate genetic risk for adolescent depression trajectories and assess generalizability across ancestries. Design, Setting, and Participants: This cohort study entailed longitudinal growth modeling followed by polygenic risk score (PRS) association testing for individual and multitrait genetic models. Two longitudinal cohorts from the US and UK were used: the Adolescent Brain and Cognitive Development (ABCD; N = 11876) study and the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 8787) study. Included were adolescents with genetic information and depression measures at up to 8 and 4 occasions, respectively. Study data were analyzed January to July 2023. Main Outcomes and Measures: Trajectories were derived from growth mixture modeling of longitudinal depression symptoms. PRSs were computed for depression, anxiety, neuroticism, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism in European ancestry. Genomic structural equation modeling was used to build multitrait genetic models of psychopathology followed by multitrait PRS. Depression PRSs were computed in African, East Asian, and Hispanic ancestries in the ABCD cohort only. Association testing was performed between all PRSs and trajectories for both cohorts. Results: A total sample size of 14112 adolescents (at baseline: mean [SD] age, 10.5 [0.5] years; 7269 male sex [52%]) from both cohorts were included in this analysis. Distinct depression trajectories (stable low, adolescent persistent, increasing, and decreasing) were replicated in the ALSPAC cohort (6096 participants; 3091 female [51%]) and ABCD cohort (8016 participants; 4274 male [53%]) between ages 10 and 17 years. Most univariate PRSs showed significant uniform associations with persistent trajectories, but fewer were significantly associated with intermediate (increasing and decreasing) trajectories. Multitrait PRSs - derived from a hierarchical factor model - showed the strongest associations for persistent trajectories (ABCD cohort: OR, 1.46; 95% CI, 1.26-1.68; ALSPAC cohort: OR, 1.34; 95% CI, 1.20-1.49), surpassing the effect size of univariate PRS in both cohorts. Multitrait PRSs were associated with intermediate trajectories but to a lesser extent (ABCD cohort: hierarchical increasing, OR, 1.27; 95% CI, 1.13-1.43; decreasing, OR, 1.23; 95% CI, 1.09-1.40; ALSPAC cohort: hierarchical increasing, OR, 1.16; 95% CI, 1.04-1.28; decreasing, OR, 1.32; 95% CI, 1.18-1.47). Transancestral genetic risk for depression showed no evidence for association with trajectories. Conclusions and Relevance: Results of this cohort study revealed a high multitrait genetic loading of persistent symptom trajectories, consistent across traits and cohorts. Variability in univariate genetic association with intermediate trajectories may stem from environmental factors. Multitrait genetics may strengthen depression prediction models, but more diverse data are needed for generalizability.</p