PRSet: Pathway-based polygenic risk score analyses and software.

Polygenic risk scores (PRSs) have been among the leading advances in biomedicine in recent years. As a proxy of genetic liability, PRSs are utilised across multiple fields and applications. While numerous statistical and machine learning methods have been developed to optimise their predictive accuracy, these typically distil genetic liability to a single number based on aggregation of an individual's genome-wide risk alleles. This results in a key loss of information about an individual's genetic profile, which could be critical given the functional sub-structure of the genome and the heterogeneity of complex disease. In this manuscript, we introduce a 'pathway polygenic' paradigm of disease risk, in which multiple genetic liabilities underlie complex diseases, rather than a single genome-wide liability. We describe a method and accompanying software, PRSet, for computing and analysing pathway-based PRSs, in which polygenic scores are calculated across genomic pathways for each individual. We evaluate the potential of pathway PRSs in two distinct ways, creating two major sections: (1) In the first section, we benchmark PRSet as a pathway enrichment tool, evaluating its capacity to capture GWAS signal in pathways. We find that for target sample sizes of >10,000 individuals, pathway PRSs have similar power for evaluating pathway enrichment as leading methods MAGMA and LD score regression, with the distinct advantage of providing individual-level estimates of genetic liability for each pathway -opening up a range of pathway-based PRS applications, (2) In the second section, we evaluate the performance of pathway PRSs for disease stratification. We show that using a supervised disease stratification approach, pathway PRSs (computed by PRSet) outperform two standard genome-wide PRSs (computed by C+T and lassosum) for classifying disease subtypes in 20 of 21 scenarios tested. As the definition and functional annotation of pathways becomes increasingly refined, we expect pathway PRSs to offer key insights into the heterogeneity of complex disease and treatment response, to generate biologically tractable therapeutic targets from polygenic signal, and, ultimately, to provide a powerful path to precision medicine.

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.

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.

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.

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.

Surface boulder banding indicates Martian debris-covered glaciers formed over multiple glaciations.

Glacial landforms, including lobate debris aprons, are a global water ice reservoir on Mars preserving ice from past periods when high orbital obliquity permitted nonpolar ice accumulation. Numerous studies have noted morphological similarities between lobate debris aprons and terrestrial debris-covered glaciers, an interpretation supported by radar observations. On Earth and Mars, these landforms consist of a core of flowing ice covered by a rocky lag. Terrestrial debris-covered glaciers advance in response to climate forcing driven by obliquity-paced changes to ice mass balance. However, on Mars, it is not known whether glacial landforms emplaced over the past 300 to 800 formed during a single, long deposition event or during multiple glaciations. Here, we show that boulders atop 45 lobate debris aprons exhibit no evidence of monotonic comminution but are clustered into bands that become more numerous with increasing latitude, debris apron length, and pole-facing flow orientation. Boulder bands are prominent at glacier headwalls, consistent with debris accumulation during the current Martian interglacial. Terrestrial glacier boulder bands occur near flow discontinuities caused by obliquity-driven hiatuses in ice accumulation, forming internal debris layers. By analogy, we suggest that Martian lobate debris aprons experienced multiple cycles of ice deposition, followed by ice destabilization in the accumulation zone, leading to boulder-dominated lenses and subsequent ice deposition and continued flow. Correlation between latitude and boulder clustering suggests that ice mass-balance works across global scales on Mars. Lobate debris aprons may preserve ice spanning multiple glacial/interglacial cycles, extending Mars climate records back hundreds of millions of years.

Mapping anorexia nervosa genes to clinical phenotypes.

BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes. METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

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.

Altered gene expression and PTSD symptom dimensions in World Trade Center responders.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p < 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants.

Biallelic pathogenic variants in the COASY gene have been associated with two distinct disease phenotypes, that is, COASY-protein associated neurodegeneration (CoPAN) and pontocerebellar hypoplasia type 12 (PCH 12). We present two siblings that independently presented with significant hypotonia and respiratory insufficiency at birth. Comprehensive genetic testing revealed homozygous variants within COASY, however, the progressive clinical and neuroradiologic findings described here are unique and have not been described previously. Magnetic resonance imaging showed progressive diffuse parenchymal loss throughout the bilateral cerebral hemispheres and atrophy of the basal ganglia and brainstem. As such, this article brings forth two additional cases of COASY-related disorder with abnormal newborn screening acylcarnitine profiles resembling carnitine palmitoyl transferase 1a (CPT1a) deficiency in two siblings who presented at birth with contractures, marked hypotonia and absent respiratory drive.

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.

A scoping review of implementation considerations for harm reduction vending machines.

BACKGROUND: Community-based harm reduction vending machines (HRVM) are not new to the field of public health; numerous countries have implemented them in response to the needs of people who use drugs over the last three decades. However, until recently, few existed in the United States. Given the rapidity with which communities are standing up harm reduction vending machines, there is a pressing need for a consolidated examination of implementation evidence. This scoping review summarizes existing literature using multiple implementation science frameworks. METHODS: The scoping review was conducted in five stages including (1) Identify the research question; (2) Identify relevant studies; (3) Select the publications based on inclusion/exclusion criteria; (4) Review and extract data; and, (5) Summarize results. PubMed, Embase, and Web of Science were searched and authors screened publications in English from any year. Data were extracted by applying implementation constructs from RE-AIM and the Consolidated Framework for Implementation Research (CFIR). Both frameworks provided a useful lens through which to develop knowledge about the facilitators and barriers to HRVM implementation. The review is reported according to PRISMA guidelines. RESULTS: After applying the full inclusion and exclusion criteria, including the intervention of interest ("vending machines") and population of interest ("people who use drugs"), a total of 22 studies were included in the scoping review. None of the studies reported on race, making it difficult to retroactively apply a racial equity lens. Among those articles that examined effectiveness, the outcomes were mixed between clear effectiveness and inconclusive results. Evidence emerged, however, to address all CFIR constructs, and positive outcomes were observed from HRVM's after-hour availability and increased program reach. RECOMMENDATIONS: HRVM implementation best practices include maximizing accessibility up to 24 h, 7 days a week, offering syringe disposal options, ensuring capability of data collection, and allowing for anonymity of use. Organizations that implement HRVM should establish strong feedback loops between them, their program participants, and the broader community upfront. Considerations for future research include rigorous study designs to evaluate effectiveness outcomes (e.g. reduced drug overdose deaths) and examination of HRVM reach among ethnic and racial communities.

Implicit bias of encoded variables: frameworks for addressing structured bias in EHR-GWAS data.

The 'discovery' stage of genome-wide association studies required amassing large, homogeneous cohorts. In order to attain clinically useful insights, we must now consider the presentation of disease within our clinics and, by extension, within our medical records. Large-scale use of electronic health record (EHR) data can help to understand phenotypes in a scalable manner, incorporating lifelong and whole-phenome context. However, extending analyses to incorporate EHR and biobank-based analyses will require careful consideration of phenotype definition. Judgements and clinical decisions that occur 'outside' the system inevitably contain some degree of bias and become encoded in EHR data. Any algorithmic approach to phenotypic characterization that assumes non-biased variables will generate compounded biased conclusions. Here, we discuss and illustrate potential biases inherent within EHR analyses, how these may be compounded across time and suggest frameworks for large-scale phenotypic analysis to minimize and uncover encoded bias.

Fixed-target serial crystallography at the Structural Biology Center.

Serial synchrotron crystallography enables the study of protein structures under physiological temperature and reduced radiation damage by collection of data from thousands of crystals. The Structural Biology Center at Sector 19 of the Advanced Photon Source has implemented a fixed-target approach with a new 3D-printed mesh-holder optimized for sample handling. The holder immobilizes a crystal suspension or droplet emulsion on a nylon mesh, trapping and sealing a near-monolayer of crystals in its mother liquor between two thin Mylar films. Data can be rapidly collected in scan mode and analyzed in near real-time using piezoelectric linear stages assembled in an XYZ arrangement, controlled with a graphical user interface and analyzed using a high-performance computing pipeline. Here, the system was applied to two ß-lactamases: a class D serine ß-lactamase from Chitinophaga pinensis DSM 2588 and L1 metallo-ß-lactamase from Stenotrophomonas maltophilia K279a.

Amino Acid Nitrogen Isotope Ratios Respond to Fish and Meat Intake in a 12-Week Inpatient Feeding Study of Men.

BACKGROUND: The natural abundance nitrogen stable isotope ratio (NIR) of whole tissue correlates with animal protein intakes, including meat and fish. Amino acid (AA) NIRs (NIRAAs) are more variable than the whole-tissue NIRs and may thus better differentiate among foods. OBJECTIVES: We evaluated whether NIRAAs were associated with intakes of fish and meat and whether these dietary associations were larger than with whole-tissue NIRs. METHODS: Men were recruited at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona, and randomly assigned to one of eight 12-wk inpatient dietary interventions, which varied the presence/absence of fish, meat, and sugar-sweetened beverages (SSBs) in all possible combinations. Fasting blood was drawn pre- and postintervention and plasma and RBC NIRAAs (free and protein-bound) were measured as secondary outcomes in 32 participants. Multivariable regression was used to determine responses of postintervention NIRAAs to dietary variables, and logistic regression was used to calculate receiver operating characteristic AUCs. RESULTS: Most plasma NIRAAs increased with fish and meat intakes, but to a greater extent with fish intake. The largest increase in response to fish intake was plasma NIRLeucine (ß = 2.19, SE = 0.26). The NIRThreonine decreased with both fish and meat intakes. Fewer RBC NIRAAs increased with fish intake, and only RBC NIRProline increased with meat intake. No plasma or RBC NIRAA responded to SSB intake. We identified fish intake with a high degree of accuracy using plasma NIRLeucine (corrected AUC, cAUC = 0.96) and NIRGlutamic acid/glutamine (cAUC = 0.93), and meat intake to a lower degree using plasma NIRProline (cAUC = 0.80) and RBC NIRProline (cAUC = 0.85). CONCLUSIONS: Plasma and RBC NIRAAs were associated with fish and meat intakes but were not superior to whole-tissue stable isotope biomarkers in identifying these intakes in a US diet. This trial is registered at www.clinicaltrials.gov as NCT01237093.

Examining Participant Dosage and Skill Utilization Associated with Receipt of a Perinatal Depression Preventive Intervention.

This study assessed participant, facilitator, and program-level characteristics associated with intervention dosage among women receiving an evidence-based perinatal depression preventive intervention, Mothers and Babies (MB). We also explored how intervention dosage affected the use and maintenance of core skills taught in the six-session group-based intervention. We conducted a secondary analysis of data from a cluster-randomized controlled trial in which 679 women enrolled in home visiting (HV) programs received MB prenatally. High dose of intervention was defined as attendance at > 50% of MB sessions, while MB skill utilization was measured by asking participants to indicate at 12 and 24 weeks postpartum the extent to which they used 12 core MB skills taught during the intervention. Age and racial concordance between participant and facilitator were significantly associated with intervention dosage. Those receiving higher intervention dosage tended to be older (27.25 ± 5.96 vs. 24.99 ± 5.60, p < 0.01, OR = 1.068 [1.038-1.098]), and received MB from a facilitator with a self-identified race similar to their own (58% vs. 48%, p = 0.04, OR = 1.485 [1.014-2.176]). Primary language of participants was marginally associated with dosage. Participants receiving a higher dose of intervention tended to exhibit greater MB skill utilization, on average at 24 weeks postpartum. These results can be used to identify strategies to promote intervention engagement. They further suggest that greater intervention dosage leads to increased use of core intervention skills that can promote improvements in participants' behaviors and thoughts.

Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist.

Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. Recent studies demonstrated estrogen receptor beta (ERß) exerts tumor suppressor functions in OCa. However, the status of ERß expression in OCSCs and the therapeutic utility of the ERß agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERß, particularly ERß isoform 1, is highly expressed in OCSCs and that ERß agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERß agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa.

VMAT2 Inhibitors for the Treatment of Tardive Dyskinesia.

Psychiatric nurses are at the forefront of optimizing psychiatric care, including educating patients and caregivers on the risks of antipsychotic-induced movement disorders such as tardive dyskinesia (TD). Nurses should be aware that all patients taking antipsychotics should be regularly monitored for the development of TD. Given the current pandemic and increase in telehealth, assessing for TD is challenging; however, evaluation can be successfully completed by implementing the best practices described in this paper. Once TD is diagnosed, nurses can reassure patients that safe and effective FDA-approved treatments for TD (e.g., valbenazine) are now available.

North Carolina's 2022-2026 Perinatal Health Strategic Plan: Addressing Perinatal Health Inequities Across the Life-Course.

North Carolina's Perinatal Health Equity Collective promotes the implementation of the 2022-2026 Perinatal Health Strategic Plan, building off its 2016-2020 predecessor. Through its overarching goals, the plan recognizes that reducing perinatal health inequities requires improving health care, strengthening families and communities, and addressing social, racial, and economic inequities across the life-course.