Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.

Evaluating Access to Prescription Medications in the Atopic Dermatitis Patient Population in the USA.

INTRODUCTION: Despite advances in atopic dermatitis (AD) treatments, many patients face challenges obtaining medications. This study aimed to determine the frequency and causes of insurance coverage delays and denials for AD prescriptions and characterize the associated wait times and extent to which patients understand what to do when faced with a coverage issue. METHODS: This was a cross-sectional, observational study in which adult U.S. residents (aged 18+ years) with AD or caregivers of pediatric U.S. patients with AD (aged 0-17 years) completed an online survey (3 June-16 July 2021). RESULTS: Respondents (N = 978) were primarily adults with AD (81.8%), female (67.7%), and white (70.2%). There were 645 insurance delays or denials for AD prescriptions, with 48.1% (470/978) of respondents experiencing at least one delay/denial in the past year. Most delays/denials were for topical steroids (39.2%, 253/645), the most highly used prescription treatment class (83.9%, 821/978). However, the highest rate of delay/denials was for biologics, of which 43.6% (109/250) of all prescriptions faced a delay or denial. Denials were caused primarily by step therapy (27.6%) and delays by prior authorization (55.1%). Only 56.0% of respondents said they would know what to do if they faced an issue with AD prescription coverage. CONCLUSIONS: Patients with AD frequently experience insurance-related barriers to obtaining recommended therapies, and many do not know how to respond when these barriers arise. Strategies to improve timely therapeutic access are needed.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

Radiological measurements of the feet of normal Straight Egyptian Arabian horses in Qatar.

The Arabian horse has been identified as carrying a risk locus for equine metabolic syndrome, predisposing this breed to development of laminitis. Radigraphy of the equine foot is widely considered the main diagnostic imaging technique for evaluation of the laminitic horse. Knowledge of 'normal' breed values allows assessment of the degree and severity of radiological changes associated with laminitis. The objective of this study was to investigate the normal values for radiological measurements of the feet of the Straight Egyptian Arabian horse in Qatar. The design was a clinical prospective study. Radiographs of the fore and hind feet of 10 clinically normal adult Straight Egyptian Arabian horses were taken. On the lateromedial views, 17 measurements were taken (13 distances and four angles). On the horizontal dorsopalmar/plantar views, two measurements were taken. On the dorsal 45 degree, proximo-palmarodistal oblique projections, four measurements were taken. Normal reference ranges were reported for radiological measurements of the feet of the Straight Egyptian Arabian horse. Several variables showed significant differences between fore and hind feet, including hoof angle, distal wall thickness, and two proximal inner layer measurements (p < 0.05). In addition, the Straight Egyptian Arabian horse was found to have a number of measurements which varied from previously published reports. The results reported within provide a useful reference for normal radiographic measurements of the Straight Egyptian Arabian horse with relevance for laminitis.

In vivo disentanglement of diffusion frequency-dependence, tensor shape, and relaxation using multidimensional MRI.

Diffusion MRI with free gradient waveforms, combined with simultaneous relaxation encoding, referred to as multidimensional MRI (MD-MRI), offers microstructural specificity in complex biological tissue. This approach delivers intravoxel information about the microstructure, local chemical composition, and importantly, how these properties are coupled within heterogeneous tissue containing multiple microenvironments. Recent theoretical advances incorporated diffusion time dependency and integrated MD-MRI with concepts from oscillating gradients. This framework probes the diffusion frequency, ω $$ \omega $$ , in addition to the diffusion tensor, D $$ \mathbf{D} $$ , and relaxation, R 1 $$ {R}_1 $$ , R 2 $$ {R}_2 $$ , correlations. A D ω - R 1 - R 2 $$ \mathbf{D}\left(\omega \right)-{R}_1-{R}_2 $$ clinical imaging protocol was then introduced, with limited brain coverage and 3 mm3 voxel size, which hinder brain segmentation and future cohort studies. In this study, we introduce an efficient, sparse in vivo MD-MRI acquisition protocol providing whole brain coverage at 2 mm3 voxel size. We demonstrate its feasibility and robustness using a well-defined phantom and repeated scans of five healthy individuals. Additionally, we test different denoising strategies to address the sparse nature of this protocol, and show that efficient MD-MRI encoding design demands a nuanced denoising approach. The MD-MRI framework provides rich information that allows resolving the diffusion frequency dependence into intravoxel components based on their D ω - R 1 - R 2 $$ \mathbf{D}\left(\omega \right)-{R}_1-{R}_2 $$ distribution, enabling the creation of microstructure-specific maps in the human brain. Our results encourage the broader adoption and use of this new imaging approach for characterizing healthy and pathological tissues.

Multiomic foundations of human prefrontal cortex tissue function.

The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Patient and Caregiver Perspectives on the Relationship Between Atopic Dermatitis Symptoms and Mental Health.

Background: Atopic dermatitis (AD) patients have increased likelihood of developing depression and anxiety. The patient and caregiver's perceptions of the correlation of mental health (MH) and AD symptoms are not well understood. Objective: To evaluate patient-reported MH symptoms and their correlation with AD disease severity and understand patient-perceived associations of AD with impacts to their MH. Methods: Adult AD patients (18+ years) or caregivers of AD patients (8-17 years) were recruited to complete a survey about MH and their perception of its relationship with AD. Results: Of 1496 respondents, 954 met inclusion criteria and completed the survey. Respondents were primarily adults (83.3%) with moderate AD (31.4%). In total, 26.0% reported MH symptoms >10 days per month, and most adults (65.5%) scored in the borderline/abnormal range on the Hospital Anxiety and Depression Scale. Most (70.6%) respondents perceived their MH was negatively affected by AD in the past 12 months. AD severity impacted the perception of the relationship between AD and MH; respondents were more likely to believe MH was impacted by AD when they/their child had severe AD. Conclusion: Our study highlights patient and caregiver awareness of the detrimental impact of AD on MH. Addressing MH in AD care settings early in the disease journey may be beneficial.

Open Science Practices in Psychiatric Genetics: A Primer.

Open science ensures that research is transparently reported and freely accessible for all to assess and collaboratively build on. Psychiatric genetics has led among the health sciences in implementing some open science practices in common study designs, such as replication as part of genome-wide association studies. However, thorough open science implementation guidelines are limited and largely not specific to data, privacy, and research conduct challenges in psychiatric genetics. Here, we present a primer of open science practices, including selection of a research topic with patients/nonacademic collaborators, equitable authorship and citation practices, design of replicable, reproducible studies, preregistrations, open data, and privacy issues. We provide tips for informative figures and inclusive, precise reporting. We discuss considerations in working with nonacademic collaborators and distributing research through preprints, blogs, social media, and accessible lecture materials. Finally, we provide extra resources to support every step of the research process.

The value of additional electrodes when stereo-electroencephalography is inconclusive.

OBJECTIVE: Stereo-electroencephalography (SEEG) is the preferred method for intracranial localization of the seizure-onset zone (SOZ) in drug-resistant focal epilepsy. Occasionally SEEG evaluation fails to confirm the pre-implantation hypothesis. This leads to a decision tree regarding whether the addition of SEEG electrodes (two-step SEEG - 2sSEEG) or placement of subdural electrodes (SDEs) after SEEG (SEEG2SDE) would help. There is a dearth of literature encompassing this scenario, and here we aimed to characterize outcomes following unplanned two-step intracranial EEG (iEEG). METHODS: All 225 adult SEEG cases over 8 years at our institution were reviewed to extract patient data and outcomes following a two-step evaluation. Three raters independently quantified benefits of additional intracranial electrodes. The relationship between two-step iEEG benefit and clinical outcome was then analyzed. RESULTS: Fourteen patients underwent 2sSEEG and nine underwent SEEG2SDE. In the former cohort, the second SEEG procedure was performed for these reasons-precise localization of the SOZ (36%); defining margins of eloquent cortex (21%); and broadening coverage in the setting of non-localizable seizure onsets (43% of cases). Sixty-four percent of 2sSEEG cases were consistently deemed beneficial (Light's κ = 0.80). 2sSEEG performed for the first two indications was much more beneficial than when onsets were not localizable (100% vs 17%, p = .02). In the SEEG2SDE cohort, SDEs identified the SOZ and enabled delineation of margins relative to eloquent cortex in all cases. SIGNIFICANCE: The two-step iEEG is useful if the initial evaluation is broadly concordant with the original electroclinical hypothesis, where it can clarify onset zones or delineate safe surgical margins; however, it provides minimal benefit when the implantation hypothesis is erroneous, and we recommend that 2sSEEG not be generally utilized in such cases. SDE implantation after SEEG minimizes the need for SDEs and is helpful in delineating surgical boundaries relative to ictal-onset zones and eloquent cortex.

Genetically Regulated Gene Expression in the Brain Associated With Chronic Pain: Relationships With Clinical Traits and Potential for Drug Repurposing.

BACKGROUND: Chronic pain is a common, poorly understood condition. Genetic studies including genome-wide association studies have identified many relevant variants, which have yet to be translated into full understanding of chronic pain. Transcriptome-wide association studies using transcriptomic imputation methods such as S-PrediXcan can help bridge this genotype-phenotype gap. METHODS: We carried out transcriptomic imputation using S-PrediXcan to identify genetically regulated gene expression associated with multisite chronic pain in 13 brain tissues and whole blood. Then, we imputed genetically regulated gene expression for over 31,000 Mount Sinai BioMe participants and performed a phenome-wide association study to investigate clinical relationships in chronic pain-associated gene expression changes. RESULTS: We identified 95 experiment-wide significant gene-tissue associations (p < 7.97 × 10-7), including 36 unique genes and an additional 134 gene-tissue associations reaching within-tissue significance, including 53 additional unique genes. Of the 89 unique genes in total, 59 were novel for multisite chronic pain and 18 are established drug targets. Chronic pain genetically regulated gene expression for 10 unique genes was significantly associated with cardiac dysrhythmia, metabolic syndrome, disc disorders/dorsopathies, joint/ligament sprain, anemias, and neurologic disorder phecodes. Phenome-wide association study analyses adjusting for mean pain score showed that associations were not driven by mean pain score. CONCLUSIONS: We carried out the largest transcriptomic imputation study of any chronic pain trait to date. Results highlight potential causal genes in chronic pain development and tissue and direction of effect. Several gene results were also drug targets. Phenome-wide association study results showed significant associations for phecodes including cardiac dysrhythmia and metabolic syndrome, thereby indicating potential shared mechanisms.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Lysine-specific demethylase 1 as a therapeutic cancer target: observations from preclinical study.

INTRODUCTION: Lysine-specific histone demethylase 1A (KDM1A/LSD1) has emerged as an important therapeutic target in various cancer types. LSD1 regulates a wide range of biological processes that influence cancer development, progression, metastasis, and therapy resistance. However, recent studies have revealed novel aspects of LSD1 biology, shedding light on its involvement in immunogenicity, antitumor immunity, and DNA damage response. These emerging findings have the potential to be leveraged in the design of effective LSD1-targeted therapies. AREAS COVERED: This paper discusses the latest developments in the field of LSD1 biology, focusing on its role in regulating immunogenicity, antitumor immunity, and DNA damage response mechanisms. The newfound understanding of these mechanisms has opened possibilities for the development of novel LSD1-targeted therapies for cancer treatment. Additionally, the paper provides an overview of LSD1 inhibitor-based combination therapies for the treatment of cancer. EXPERT OPINION: Exploiting LSD1 role in antitumor immunity and DNA damage response provides cues to not only understand the LSD1-resistant mechanisms but also rationally design new combination therapies that are more efficient and less toxic than monotherapy. The exploration of LSD1 biology and the development of LSD1-targeted therapies hold great promise for the future of cancer treatment.

Developing a nutrition screening tool for children with cystic fibrosis ages 0 to 2 years: Children with cystic fibrosis nutrition screening tool.

BACKGROUND: For children with cystic fibrosis (CF), achieving and maintaining optimal growth by the age of 2 years is critical for future health outcomes. A standardized nutrition screening is needed to identify growth problems, enable timely interventions, and improve nutritional outcomes for children (0 to 2 years) with CF. The purpose of this study was to develop a nutrition screening tool for children (0 to 2 years) with CF to identify nutrition risk at every clinical encounter. METHODS: A retrospective cross-sectional study was used to develop a nutrition screening tool to determine if nutrition interventions needed to change (at-risk) or continue (not at-risk). Retrospective data for pertinent nutrition factors were collected for 99 children attending an accredited CF clinic. The nutrition factors were compared to a dietitian assessment. A stepwise discriminant analysis determined weight-for-age (WFA) and weight-for-length (WFL) z-scores were significant. Then anthropometric data and corresponding dietitian assessment results were collected for children with CF attending two other accredited CF clinics (n = 29, n = 30). Discriminant analysis was used to determine sensitivity and specificity of the nutrition factors and to create a nutrition screening tool equation. RESULTS: The nutrition screening model that included WFA z-score, LFA z-score, WFL z-score, and weight change velocity adequacy determined nutrition risk the best. The sensitivity was 89.7 %, specificity 83.2 %, NPV 93.3 %, and PPV 75.4 % for this model. CONCLUSION: The nutrition screening tool equation developed in this study standardizes the process to identify children (0 to 2 years) with CF at nutrition risk. Further validation is needed.

Facilitating OPAT in rural areas.

A sizable portion of the United States' population lives in a rural setting. Coupled with a limited number of infectious diseases providers, this has created a need for innovative practice models to deliver outpatient antimicrobial therapy and clinical monitoring in rural settings. This article reviews existing literature regarding outpatient parenteral antimicrobial therapy in rural settings and explores existing barriers and potential solutions that may be of assistance to providers looking to provide these services.

In vivo disentanglement of diffusion frequency-dependence, tensor shape, and relaxation using multidimensional MRI.

Diffusion MRI with free gradient waveforms, combined with simultaneous relaxation encoding, referred to as multidimensional MRI (MD-MRI), offers microstructural specificity in complex biological tissue. This approach delivers intravoxel information about the microstructure, local chemical composition, and importantly, how these properties are coupled within heterogeneous tissue containing multiple microenvironments. Recent theoretical advances incorporated diffusion time dependency and integrated MD-MRI with concepts from oscillating gradients. This framework probes the diffusion frequency, ω, in addition to the diffusion tensor, D, and relaxation, R1, R2, correlations. A D(ω)-R1-R2 clinical imaging protocol was then introduced, with limited brain coverage and 3 mm3 voxel size, which hinder brain segmentation and future cohort studies. In this study, we introduce an efficient, sparse in vivo MD-MRI acquisition protocol providing whole brain coverage at 2 mm3 voxel size. We demonstrate its feasibility and robustness using a well-defined phantom and repeated scans of five healthy individuals. Additionally, we test different denoising strategies to address the sparse nature of this protocol, and show that efficient MD-MRI encoding design demands a nuanced denoising approach. The MD-MRI framework provides rich information that allows resolving the diffusion frequency dependence into intravoxel components based on their D(ω)-R1-R2 distribution, enabling the creation of microstructure-specific maps in the human brain. Our results encourage the broader adoption and use of this new imaging approach for characterizing healthy and pathological tissues.

ARFID Genes and Environment (ARFID-GEN): study protocol.

BACKGROUND: The Avoidant Restrictive Food Intake Disorder - Genes and Environment (ARFID-GEN) study is a study of genetic and environmental factors that contribute to risk for developing ARFID in children and adults. METHODS: A total of 3,000 children and adults with ARFID from the United States will be included. Parents/guardians and their children with ARFID (ages 7 to 17) and adults with ARFID (ages 18 +) will complete comprehensive online consent, parent verification of child assent (when applicable), and phenotyping. Enrolled participants with ARFID will submit a saliva sample for genotyping. A genome-wide association study of ARFID will be conducted. DISCUSSION: ARFID-GEN, a large-scale genetic study of ARFID, is designed to rapidly advance the study of the genetics of eating disorders. We will explicate the genetic architecture of ARFID relative to other eating disorders and to other psychiatric, neurodevelopmental, and metabolic disorders and traits. Our goal is for ARFID to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: ARFID-GEN is a registered clinical trial: clinicaltrials.gov NCT05605067.