The Carbon Stable Isotope Ratio (CIR) as an Objective Biomarker of Added Sugar Intake: A Scoping Review of Current Evidence in Human Nutrition.

Objective biomarkers of dietary intake are needed to advance nutrition research. The carbon stable isotope ratio (C13/C12; CIR) holds promise as an objective biomarker of added sugar (AS) and sugar-sweetened beverage (SSB) intake. This systematic scoping review presents the current evidence on CIRs from human studies. Search results (through April 12, 2024) yielded 6,297 studies and 24 final articles. Studies were observational (n=12), controlled feeding (n=10), or dietary interventions (n=2). CIRs were sampled from blood (n=23), hair (n=5), breath (n= 2), and/or adipose tissue (n=1). Most (n=17) conducted whole tissue (i.e., bulk) analysis, eight used compound specific isotope analysis (CSIA), and/or two studies used methods appropriate for analyzing breath. Studies were conducted in three concentrated geographic regions of the U.S. (n=7 Virginia; n=5 Arizona; n=4 Alaska), with only two studies conducted in other countries. Studies that used CSIA to examine the CIR from the non-essential amino acid alanine (CIR-Ala; n=4) and CIR analyzed from breath (n=2) provided the most robust evidence for CIR as an objective biomarker of AS and SSBs (R2 range 0.36-0.91). Studies using bulk analysis of hair or blood showed positive, but modest and more variable associations with AS and SSBs (R2 range 0.05-0.48). Few studies showed no association, particularly in non-U.S. populations and those with low AS and SSB intakes. Two studies provided evidence for CIR to detect changes in SSB intake in response to dietary interventions. Overall, the most compelling evidence supports CIR-Ala as an objective indicator of AS intake and breath CIR as an indicator of short term AS intake. Considering how to adjust for underlying dietary patterns remains an important area of future work and emerging methods using breath and CSIA warrant additional investigation. More evidence is needed to refine the utility and specificity of CIRs to measure AS and SSB intake.

Identifying Patients at Risk for Alcohol-Exposed Pregnancies: The Importance of Addressing Multiple Risk Factors.

BACKGROUND: The increasing prevalence of fetal alcohol spectrum disorders is a critical public health issue. Two behaviors, consuming alcohol and using less effective pregnancy prevention, may result in alcohol-exposed pregnancies (AEPs) in individuals who can become pregnant. In the context of alcohol screening and brief intervention (SBI) services, cutoff scores on widely used alcohol risk assessments (eg, Alcohol Use Disorders Identification Test, U.S. version [USAUDIT]) may fail to identify individuals whose relatively low alcohol consumption may still put them at risk for an AEP due to their pregnancy prevention method. METHODS: To identify this gap in alcohol SBI service delivery, we examined data from 2 reproductive healthcare systems implementing alcohol SBI, to explore the prevalence of individuals who met both of the following risk conditions: reported any alcohol use on the USAUDIT and a pregnancy prevention method less than 88% effective. Electronic health records for individuals aged 18 to 49 presenting for preventive care in 2021 were analyzed. RESULTS: Of 11 567 screened, 7638 reported some alcohol use, but screened at a lower-risk level and were not flagged to receive an alcohol-focused brief intervention (BI). Of these, 1477 were using a method of pregnancy prevention that was less than 88% effective. In addition, 118 of the 1676 who screened positive on the USAUDIT were using less effective contraception and did not receive a BI. In summary, the number of individuals at risk of an AEP who did not receive an alcohol BI was 1595 (13.8%) of the total patients screened for at-risk alcohol use. CONCLUSIONS: There is a need for system modifications to assess multiple behaviors simultaneously and alert providers when a combination of behaviors increases a specific health risk, such as an AEP. Tailored alcohol BIs that include the risks/benefits of various pregnancy prevention methods to reduce AEPs provide opportunities to enhance the reach of standard alcohol SBI services.

Retrospective cohort study identifying pulmonary complications in a cohort of patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi organ involvement. One of the most common manifestations is pulmonary disease with a reported prevalence between 5%-90%. PURPOSE: Given this wide range of prevalence, there is a need to more closely define types of pulmonary disease in SLE and associated risk factors. RESEARCH DESIGN: We sought to characterize the presentation of pulmonary manifestations in an established SLE cohort using electronic health record data. STUDY SAMPLE: All patients were >18 years of age and had confirmed SLE by a rheumatologist using SLICC or 2019 ACR/EULAR classification criteria. 220 patients with imaging were included in this study; average age was 42.5 years, 86.7% identified as female, 60.5% identified as white, 37.3% as Black, and 1.82% as Asian. ANALYSIS: Generalized estimating equations were utilized to analyze the data, accounting for its repeated measured nature. RESULTS: We found an association between smoking (present/prior smoker) and radiologist reported disease on computerized tomography (CT) scan, as well as an association between smoking (present/prior smoker), older age, and male sex with having pulmonary disease identified on chest X-ray. The most common findings on CT and X-ray were increased lung density (24%, 12%) and atelectasis (18%, 10%). The most common disease found on CT was pleural effusion (24%) and mediastinal/axillary lymphadenopathy (16%). CONCLUSION: While our study is limited by the retrospective nature, our results show that certain factors, namely smoking, older age, or male sex should prompt clinicians to have a higher suspicion for lung disease in SLE patients.

Assessment of Physician Needs and Access to Inflammatory Bowel Disease Specialty Care Resources in a National Integrated Health System.

BACKGROUND: The barriers to providing high-quality inflammatory bowel disease (IBD) care go beyond educational needs alone to include access to IBD-related resources such as medications, laboratory testing, and multidisciplinary teams. We assessed the needs and resource constraints of physicians caring for Veterans with IBD to inform efforts to improve access to high-quality care. METHODS: We conducted a national observational survey study in July 2021 of gastroenterologists (GIs) and primary care providers (PCPs) caring for Veterans with IBD within the Veterans Health Administration with the intent of including physicians from all 18 Veterans Integrated Service Networks (VISN). We reported descriptive statistics and compared responses between gastroenterologists (GIs) and primary care providers (PCPs), practice locations, and years of experience using χ2 tests. RESULTS: Overall, 173 of 2241 eligible physicians completed the survey, representing an individual physician response rate of 7.7% and VISN response rate of 18 out of 18 (100%). We identified several areas of IBD care where GIs and PCPs reported discomfort including medication prescribing, treatment strategies, and special populations. Further, variability in access to IBD services and awareness of the availability of IBD-targeted medications and laboratory tests was common. This survey also highlights the frequency with which PCPs were identified among the highest volume IBD providers in their facility. CONCLUSIONS: Variation in GIs' and PCPs' comfort with IBD treatment and access to IBD resources is common and needs to be considered in leveraging virtual care and educational programs and managing the expansion of IBD support and resources within VA.

Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenome.

Background: Previous epidemiological research has linked posttraumatic stress disorder (PTSD) with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records provide an opportunity to overcome clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex. Methods: PTSD was defined among biobank participants (N = 145,959) in 3 major healthcare systems using 2 ICD code-based definitions: broad (≥1 PTSD or acute stress codes vs. 0; n cases = 16,706) and narrow (≥2 PTSD codes vs. 0; n cases = 3325). Using a phenome-wide association study design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified phenome-wide association study analyses including a sex × diagnosis interaction term in each logistic regression. Results: A substantial number of phecodes were significantly associated with PTSDNarrow (61%) and PTSDBroad (83%). While the strongest associations were shared between the 2 definitions, PTSDBroad captured 334 additional phecodes not significantly associated with PTSDNarrow and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed in that PTSDBroad was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients. Conclusions: This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using electronic health records.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that some people develop following a traumatic event. In addition to mental symptoms, PTSD can impact human health in ways other ways; for example, there are many known conditions that co-occur with PTSD, such as cardiovascular conditions. In this study, we set out to understand the breadth and degree to which PTSD co-occurs with medical outcomes in a sample of over 146,000 patients across 3 large medical systems. We found that both narrowly and broadly defined PTSD diagnosis co-occurred with hundreds of medical conditions, and the strongest associations were with other psychiatric disorders, respiratory conditions (asthma, GERD), sleep-related conditions, and pain. These results provide insights into future genetic studies of PTSD in large-scale biobanks and deepen our understanding of the complex needs of patients with PTSD.

What Next for Eating Disorder Genetics? Replacing Myths With Facts to Sharpen Our Understanding.

Substantial progress has been made in the understanding of anorexia nervosa (AN) and eating disorder (ED) genetics through the efforts of large-scale collaborative consortia, yielding the first genome-wide significant loci, AN-associated genes, and insights into metabo-psychiatric underpinnings of the disorders. However, the translatability, generalizability, and reach of these insights are hampered by an overly narrow focus in our research. In particular, stereotypes, myths, assumptions and misconceptions have resulted in incomplete or incorrect understandings of ED presentations and trajectories, and exclusion of certain patient groups from our studies. In this review, we aim to counteract these historical imbalances. Taking as our starting point the Academy for Eating Disorders (AED) Truth #5 "Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations, and socioeconomic statuses", we discuss what we do and do not know about the genetic underpinnings of EDs among people in each of these groups, and suggest strategies to design more inclusive studies. In the second half of our review, we outline broad strategic goals whereby ED researchers can expand the diversity, insights, and clinical translatability of their studies. Appeared originally in Mol Psychiatry 2022; 27:3929-3938.

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer.

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

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.

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.

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.

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.

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.