Comparison of scores on Patient Health Questionnaire-9, Edinburgh Postnatal Depression Scale and Hospital Anxiety and Depression - Depression subscale scores by administration mode: An individual participant data differential item functioning meta-analysis.

Administration mode of patient-reported outcome measures (PROMs) may influence responses. We assessed if Patient Health Questionnaire-9 (PHQ-9), Edinburgh Postnatal Depression Scale (EPDS) and Hospital Anxiety and Depression Scale - Depression subscale (HADS-D) item responses and scores were associated with administration mode. We compared (1) self-administration versus interview-administration; within self-administration (2) research or medical setting versus private; and (3) pen-and-paper versus electronic; and within interview-administration (4) in-person versus phone. We analysed individual participant data meta-analysis datasets with item-level data for the PHQ-9 (N = 34,529), EPDS (N = 16,813), and HADS-D (N = 16,768). We used multiple indicator multiple cause models to assess differential item functioning (DIF) by administration mode. We found statistically significant DIF for most items on all measures due to large samples, but influence on total scores was negligible. In 10 comparisons conducted across the PHQ-9, EPDS, and HADS-D, Pearson's correlations and intraclass correlation coefficients between latent depression symptom scores from models that did or did not account for DIF were between 0.995 and 1.000. Total PHQ-9, EPDS, and HADS-D scores did not differ materially across administration modes. Researcher and clinicians who evaluate depression symptoms with these questionnaires can select administration methods based on patient preferences, feasibility, or cost.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Immobilising an acid-cleavable dimeric phthalocyanine on gold nanobipyramids for intracellular pH detection and photodynamic elimination of cancer cells.

An acetal-linked dimeric phthalocyanine has been synthesised and immobilised on the surface of gold nanobipyramids. The resulting nanocomposite serves as a highly sensitive probe for intracellular pH through its acid-responsive fluorescence and surface-enhanced Raman scattering signals. The phthalocyanine units released in the acidic intracellular environment can also effectively eliminate the cancer cells upon light irradiation, rendering this simple fabricated nanosystem a bimodal and bifunctional theranostic agent.

Successful Cardiac Resynchronization Therapy Reduces Negative Septal Work in Patient-Specific Models of Dyssynchronous Heart Failure.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches.

rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels.

Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.

The Johns Hopkins Physician-Scientist Training Program to Enhance Institutional Retention and Entry Into Academic Positions: An Evaluation of Program Effectiveness and Outcomes.

PURPOSE: The Johns Hopkins Physician-Scientist Training Program (PSTP) was implemented to overcome well-documented challenges in training and retaining physician-scientists by providing physician-scientist pathway training for residents and clinical fellows. The program's core tenets include monthly seminars, individualized feedback on project proposals, access to mentors, and institutional funding opportunities. This study evaluated the effectiveness and outcomes of the PTSP and provides a framework for replication. METHOD: A query of institutional demographic data and bibliometric variables of the PSTP participants (2017-2020) at a single academic medical center was conducted in 2021. In addition, a voluntary survey collected personal and program evaluation information. RESULTS: Of 145 PSTP scholars, 59 (41%) were women, and 41 (31%), 8 (6%), and 6 (5%) of scholars self-identified as Asian, Hispanic, and Black, respectively. Thirty-three (23%) scholars received PSTP research support or career development microgrants. Of 66 PSTP graduates, 29 (44%) remained at Johns Hopkins as clinical fellows or faculty. Of 48 PSTP graduates in a post-training position, 42 (88%) were in academia, with the majority, 29 (76%), holding the rank of assistant professor. Fifty-nine of 140 available participants responded to the survey (42% response rate). The top-cited reason for joining the PSTP was exposure to mentors and administration (50/58 respondents, 86%), followed by seeking scholarly opportunities (37/58 respondents, 64%). Most scholars intended to continue a career as a physician-scientist. CONCLUSIONS: The PSTP provides internal research support and institutional oversight. Although establishing close mentor-mentee relationships requires individualized approaches, the PSTP provided structured academic pathways that enhanced participating scholars' ability to apply for grants and jobs. The vast majority continued their careers as physician-scientists after training. In light of the national evidence of a "leaky physician-scientist pipeline," programs such as the PSTP can be critical to entry into early academic career positions and institutional retention.

Sirtuin 3 Mediated by Spinal cMyc-Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model.

BACKGROUND: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats. METHODS: Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested. RESULTS: In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region. CONCLUSION: These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc-EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids.

Differential Cognitive Effects of Unilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: The aim of this study was to investigate the cognitive effects of unilateral directional versus ring subthalamic nucleus deep brain stimulation (STN DBS) in patients with advanced Parkinson's disease. METHODS: We examined 31 participants who underwent unilateral STN DBS (left n = 17; right n = 14) as part of an National Institutes of Health (NIH)-sponsored randomized, double-blind, crossover study contrasting directional versus ring stimulation. All participants received unilateral DBS implants in the hemisphere more severely affected by motor parkinsonism. Measures of cognition included verbal fluency, auditory-verbal memory, and response inhibition. We used mixed linear models to contrast the effects of directional versus ring stimulation and implant hemisphere on longitudinal cognitive function. RESULTS: Crossover analyses showed no evidence for group-level changes in cognitive performance related to directional versus ring stimulation. Implant hemisphere, however, impacted cognition in several ways. Left STN participants had lower baseline verbal fluency than patients with right implants (t [20.66 = -2.50, p = 0.02]). Verbal fluency declined after left (p = 0.013) but increased after right STN DBS (p < 0.001), and response inhibition was faster following right STN DBS (p = 0.031). Regardless of hemisphere, delayed recall declined modestly over time versus baseline (p = 0.001), and immediate recall was unchanged. INTERPRETATION: Directional versus ring STN DBS did not differentially affect cognition. Similar to prior bilateral DBS studies, unilateral left stimulation worsened verbal fluency performance. In contrast, unilateral right STN surgery increased performance on verbal fluency and response inhibition tasks. Our findings raise the hypothesis that unilateral right STN DBS in selected patients with predominant right brain motor parkinsonism could mitigate declines in verbal fluency associated with the bilateral intervention. ANN NEUROL 2024;95:1205-1219.

Disparities in Medical School Clerkship Grades Associated with Sex, Race, and Ethnicity: A Person-Centered Approach.

PURPOSE: To determine whether students' self-reported race/ethnicity and sex were associated with grades earned in 7 core clerkships. A person-centered approach was used to group students based on observed clerkship grade patterns. Predictors of group membership and predictive bias by race/ethnicity and sex were investigated. METHOD: Using data from 6 medical student cohorts at Johns Hopkins University School of Medicine (JHUSOM), latent class analysis was used to classify students based on clerkship grades. Multinomial logistic regression was employed to investigate if preclerkship measures and student demographic characteristics predicted clerkship performance-level groups. Marginal effects for United States Medical Licensing Exam (USMLE) Step 1 scores were obtained to assess the predictive validity of the test on group membership by race/ethnicity and sex. Predictive bias was examined by comparing multinomial logistic regression prediction errors across racial/ethnic groups. RESULTS: Three clerkship performance-level groups emerged from the data: low, middle, and high. Significant predictors of group membership were race/ethnicity, sex, and USMLE Step 1 scores. Black or African American students were more likely (odds ratio [OR] = 4.26) to be low performers than White students. Black or African American (OR = 0.08) and Asian students (OR = 0.41) were less likely to be high performers than White students. Female students (OR = 2.51) were more likely to be high performers than male students. Patterns of prediction errors observed across racial/ethnic groups showed predictive bias when using USMLE Step 1 scores to predict clerkship performance-level groups. CONCLUSIONS: Disparities in clerkship grades associated with race/ethnicity were found among JHUSOM students, which persisted after controlling for USMLE Step 1 scores, sex, and other preclerkship performance measures. Differential predictive validity of USMLE Step 1 exam scores and systematic error predictions by race/ethnicity show predictive bias when using USMLE Step 1 scores to predict clerkship performance across racial/ethnic groups.

Redescription of the tiger beetle Cicindelidia aeneicollis (Bates 1881) (Coleoptera: Cicindelidae) and discovery of new morphological variants from the Pacific Slope of Mexico.

The tiger beetle species, Cicindelidia aeneicollis (Bates 1881) is redescribed, as Bates original description was inadequate and did not accurately capture the character states or variation found within the species. The specific epithet aeneicollis is partially misleading as the proepisternum is mostly aeneous (bronze/copper) with the basal quarter to third being polychromatic, which the description does not convey. Some populations of this species from the western coast of Mexico exhibit significant variation in maculations, with individuals ranging from weakly marked (as in Bates description) to much more extensively marked.

The adaptor protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows.

Animals constantly integrate sensory information with prior experience to select behavioral responses appropriate to the current situation. Genetic factors supporting this behavioral flexibility are often disrupted in neuropsychiatric conditions, such as the autism-linked ap2s1 gene which supports acoustically evoked habituation learning. ap2s1 encodes an AP2 endocytosis adaptor complex subunit, although its behavioral mechanisms and importance have been unclear. Here, we show that multiple AP2 subunits regulate acoustically evoked behavior selection and habituation learning in zebrafish. Furthermore, ap2s1 biases escape behavior choice in sensory modality-specific manners, and broadly regulates action selection across sensory contexts. We demonstrate that the AP2 complex functions acutely in the nervous system to modulate acoustically evoked habituation, suggesting several spatially and/or temporally distinct mechanisms through which AP2 regulates escape behavior selection and performance. Altogether, we show the AP2 complex coordinates action selection across diverse contexts, providing a vertebrate model for ap2s1's role in human conditions including autism spectrum disorder.

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

Neuromorphometric associations with mood, cognition, and self-reported exercise levels in epilepsy and healthy individuals.

Regular physical activity may promote beneficial neuroplasticity, e.g., increased hippocampus volume. However, it is unclear whether self-reported physical exercise in leisure (PEL) levels are associated with the brain structure features demonstrated by exercise interventions. This pilot study investigated the relationship between PEL, mood, cognition, and neuromorphometry in patients with idiopathic generalized epilepsy (IGEs) compared to healthy controls (HCs). Seventeen IGEs and 19 age- and sex-matched HCs underwent magnetic resonance imaging (MRI) at 3T. The Baecke Questionnaire of Habitual Physical Activity, Profile of Mood States, and Montreal Cognitive Assessment (MoCA) assessed PEL, mood, and cognition, respectively. Structural MRI data were analyzed by voxel- and surface-based morphometry. IGEs had significantly lower PEL (p < 0.001), poorer mood (p = 0.029), and lower MoCA scores (p = 0.027) than HCs. These group differences were associated with reduced volume, decreased gyrification, and altered surface topology (IGEs < HCs) in frontal, temporal and cerebellar regions involved in executive function, memory retrieval, and emotional regulation, respectively. These preliminary results support the notion that increased PEL may promote neuroplasticity in IGEs, thus emphasizing the role of physical activity in promoting brain health in people with epilepsy.

Medical School Rankings: Time to End or Time to Amend?

ABSTRACT: The recent decisions of several medical schools to no longer participate in the rankings published annually by U.S. News & World Report have added greater visibility to the issues surrounding medical school rankings than ever before. While these announcements garnered significant attention in academic medicine and from the lay public, the authors believe these events are unlikely to eliminate rankings in medical education. In this article, the authors outline the potential harms of rankings in higher education, provide a rationale for why they will likely endure despite recent scrutiny, and offer suggestions for prospective students and the academic medical community to engage with rankings in a more productive way. Criticisms of medical school rankings have been noted for decades, including their use of subjective information and data with questionable relevance to the quality of students' education or the outcomes of their educational experience, methodological concerns, and the potential harms of ranking systems (such as schools diverting their focus and resources away from initiatives that benefit students to improve their ranking). At the same time, rankings are ubiquitous in today's culture and are powerful in human decision-making, so there is reason to believe that medical school rankings may weather the current storm. Given these concerns, the authors suggest students continue to use a variety of resources to obtain information about medical schools and consider how each school fits with their own educational needs. The authors also encourage medical schools, medical education organizations, and governing medical bodies to suggest different metrics that reflect quality in medical education and that are of importance to applicants.

Delirium Due to Potentially Avoidable Hospitalizations Among Older Adults.

BACKGROUND: Delirium is a common complication during acute care hospitalizations in older adults. A substantial percentage of admissions are for ambulatory care-sensitive conditions (ACSCs) or potentially avoidable hospitalizations-conditions that might be treated early in the outpatient setting to prevent hospitalization and hospital complications. METHODS: This retrospective cross-sectional study examined rates of delirium among older adults hospitalized for ACSCs. Participants were 39 933 older adults ≥65 years of age admitted from January 1, 2015 to December 31, 2019 to general inpatient units and ICUs of a large Southeastern academic medical center. Delirium was defined as a score ≥ 2 on the Nursing Delirium Screening Scale or positive on the Confusion Assessment Method for the Intensive Care Unit during admission, and ACSCs were identified from the primary admission diagnosis using standardized definitions. Generalized linear mixed models were used to examine the association between ACSCs and delirium, compared with admissions for non-ACSC diagnoses, adjusting for covariates and repeated observations for individuals with multiple admissions. RESULTS: Delirium occurred in 15.6% of admissions for older adults. Rates were lower for ACSC admissions versus admissions for other conditions (13.9% vs 15.8%, p < .001). Older age and higher comorbidity were significant predictors of the development of delirium. CONCLUSIONS: Rates of delirium among older adults hospitalized for ACSCs were lower than rates for non-ACSC hospitalization but still substantial. Optimizing the treatment of ACSCs in the outpatient setting is an important goal not only for reducing hospitalizations but also for reducing risks for hospital-associated complications such as delirium.

Electrostatic moiré potential from twisted hexagonal boron nitride layers.

Moiré superlattices host a rich variety of correlated electronic phases. However, the moiré potential is fixed by interlayer coupling, and it is dependent on the nature of carriers and valleys. In contrast, it has been predicted that twisted hexagonal boron nitride (hBN) layers can impose a periodic electrostatic potential capable of engineering the properties of adjacent functional layers. Here, we show that this potential is described by a theory of electric polarization originating from the interfacial charge redistribution, validated by its dependence on supercell sizes and distance from the twisted interfaces. This enables controllability of the potential depth and profile by controlling the twist angles between the two interfaces. Employing this approach, we further demonstrate how the electrostatic potential from a twisted hBN substrate impedes exciton diffusion in semiconductor monolayers, suggesting opportunities for engineering the properties of adjacent functional layers using the surface potential of a twisted hBN substrate.

Genome Wide Association Study of Neuropathic Ocular Pain.

Purpose: To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development. Design: Prospective study of individuals with NOP. Participants: Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic. Methods: The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P < 5 × 10-8. A gene-based analysis was performed using the multimarker analysis of genomic annotation software (in the functional mapping and annotation of GWAS online platform). The 13 865 778 single nucleotide polymorphisms (SNPs) from our GWAS analysis were mapped to 10 834 protein coding genes, and significant genes were run through gene set enrichment analysis. Main Outcome Measures: Identification of SNPs and protein products that may be associated with the development of NOP. Results: One hundred seventy-one SNPs reached a threshold of P < 10-5, of which 10 SNPs reached the suggestive level of significance of P < 5 × 10-7 and 1 SNP met our genome-wide significance threshold of P < 5 × 10-8. This lead SNP, rs140293404 (P = 1.23 × 10-8), is an intronic variant found within gene ENSG00000287251 coding for transcript ENST00000662732.1. Rs140293404 is in linkage disequilibrium with exon variant rs7926353 (r2 > 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 × 10-5), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 × 10-4), CTC-487M23.8 (P = 1.79 × 10-4), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 × 10-4), and signal recognition particle-19 (SRP19) (P = 2.56 × 10-4). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10-3) and olfactory signaling (false discovery rate = 1.63 × 10-2) pathways were enriched with the most significant genes. Conclusions: Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Depression screening tool accuracy individual participant data meta-analyses: data contribution was associated with multiple factors.

OBJECTIVES: To examine the proportion of eligible primary studies that contributed data, study characteristics associated with data contribution, and reasons for noncontribution using diagnostic test accuracy Individual Participant Data Meta-Analysis (IPDMA) data sets from the DEPRESsion Screening Data project. STUDY DESIGN AND SETTING: We reviewed data set contributions from four IPDMAs. A multivariable logistic regression model was fitted to evaluate study factors associated with data contribution. RESULTS: Of 456 eligible studies from four included IPDMAs, 295 (65%) contributed data. More recent year of publication and higher journal impact factor were associated with greater odds of data contribution. Studies conducted in Europe (excluding the United Kingdom), Oceania, Canada, the Middle East, Africa, and Central or South America (reference = the United States), that have recruitment from inpatient care or nonmedical settings (reference = outpatient), that reported screening accuracy results, or that drew negative conclusions (reference = positive conclusions) were more likely to contribute data. Studies of the Geriatric Depression Scale (reference = the Patient Health Questionnaire) or lacking funding information were negatively associated with data contribution. Over 80% of noncontributions were due to authors being unreachable or data being unavailable. CONCLUSION: The study identified factors associated with data contribution that may support future research to promote data contribution to IPDMAs.