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ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:
1. Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-
2. Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)
3. Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.
Previous research on the depression scale of the Patient Health Questionnaire (PHQ-9) has found that different latent factor models have maximized empirical measures of goodness-of-fit. The clinical relevance of these differences is unclear. We aimed to investigate whether depression screening accuracy may be improved by employing latent factor model-based scoring rather than sum scores.
We used an individual participant data meta-analysis (IPDMA) database compiled to assess the screening accuracy of the PHQ-9. We included studies that used the Structured Clinical Interview for DSM (SCID) as a reference standard and split those into calibration and validation datasets. In the calibration dataset, we estimated unidimensional, two-dimensional (separating cognitive/affective and somatic symptoms of depression), and bi-factor models, and the respective cut-offs to maximize combined sensitivity and specificity. In the validation dataset, we assessed the differences in (combined) sensitivity and specificity between the latent variable approaches and the optimal sum score (⩾10), using bootstrapping to estimate 95% confidence intervals for the differences.
The calibration dataset included 24 studies (4378 participants, 652 major depression cases); the validation dataset 17 studies (4252 participants, 568 cases). In the validation dataset, optimal cut-offs of the unidimensional, two-dimensional, and bi-factor models had higher sensitivity (by 0.036, 0.050, 0.049 points, respectively) but lower specificity (0.017, 0.026, 0.019, respectively) compared to the sum score cut-off of ⩾10.
In a comprehensive dataset of diagnostic studies, scoring using complex latent variable models do not improve screening accuracy of the PHQ-9 meaningfully as compared to the simple sum score approach.
Barriers to research participation by racial and ethnic minority group members are multi-factorial, stem from historical social injustices and occur at participant, research team, and research process levels. The informed consent procedure is a key component of the research process and represents an opportunity to address these barriers. This manuscript describes the development of the Strengthening Translational Research in Diverse Enrollment (STRIDE) intervention, which aims to improve research participation by individuals from underrepresented groups.
We used a community-engaged approach to develop an integrated, culturally, and literacy-sensitive, multi-component intervention that addresses barriers to research participation during the informed consent process. This approach involved having Community Investigators participate in intervention development activities and using community engagement studios and other methods to get feedback from community members on intervention components.
The STRIDE intervention has three components: a simulation-based training program directed toward clinical study research assistants that emphasizes cultural competency and communication skills for assisting in the informed consent process, an electronic consent (eConsent) framework designed to improve health-related research material comprehension and relevance, and a “storytelling” intervention in which prior research participants from diverse backgrounds share their experiences delivered via video vignettes during the consent process.
The community engaged development approach resulted in a multi-component intervention that addresses known barriers to research participation and can be integrated into the consent process of research studies. Results of an ongoing study will determine its effectiveness at increasing diversity among research participants.
This research communication addresses the hypothesis that, during the summer in the subtropics, natural tree shade helps to improve milk functional characteristics such as stability and acidity. Sixteen Holstein lactating cows were enrolled. The study consisted of three periods (pre-stress, heat stress and post-stress) based on allocating grazing cows into two treatments (with and without access to shade during the Heat Stress period). Overall THI during the trial was (mean ± se) 76.0 ± 3.4. Access to shade prevented the heat stress-related decrease in milk stability both in the ethanol and in the coagulation time test, as well as maintained milk acidity within an acceptable range (14 to 18°D).
The pharmacotherapy of epilepsy is a complex process guided by evidence-based research and clinical experience. Some patients achieve seizure freedom upon treatment with the first anti-seizure medication (ASM) prescribed, whereas others may be treated with two or three medications before one (or a combination) is found that reduces seizure frequency and/or severity with minimal side effects. Many patients demonstrate a partial response to treatment, leading to reduced seizure frequency and/or severity, but do not become completely seizure free. It is often stated that ~30% of epilepsy patients have seizures that cannot be controlled pharmacologically, and these patients are defined as having medication-resistant epilepsy (MRE). The International League Against Epilepsy (ILAE) published the following definition of MRE: ‘drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used ASM schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom’. Treatment success or sustained seizure freedom is defined as one year without seizures or three times the inter-seizure interval (whichever is longer). The ILAE definition provides a useful standard from which to work, and MRE can be clinically identified in patients that fail to achieve seizure freedom after multiple ASM trials. However, the ILAE definition of successful treatment does not account for partial response to pharmacotherapy. Indeed, many partial responders have improved quality of life, even if they are not seizure-free for one year or more.
When comparing the efficay of antipsychotics in clinical studies it would be of high practical relevance to know which doses of the respective drugs would result in equivalent blocking of dopamine-D2-receptors. This study aimed to find clinically applicable dose equivalents for haloperidol, risperidone and olanzapine.
As the occurrence of EPS correlates closely with a blockade of about 80% or more of dopamin-D2-receptors the proportion of patients developing EPS in relation to various doses of either Haloperidol (n=5252), risperidone (n=5017) or olanzapine (n =5029) was calculated. This retrospective, observational study included 20.252 inpatients from 20 hospitals with a diagnosis of schizophrenia and related disorders (ICD10 F20-25). The prescription of anticholinergic medication was utilized as surrogate parameter for the occurrence of EPS. OR, RR and NNH under different doses of AP were calculated and data entered into a probit model to predict the risk of EPS over a continuous dose range. For filtering the data ToscanaJ (FBA) was used.
1.) Same doses of risperidone and haloperidol induced the same proportion of EPS, reflected in a constant dose ratio of both drugs of ∼ 1:1 over the whole dose range.
2.) Over the whole dose range there was no linear relation between olanzapine on one hand and haloperidol and risperidone on the other hand.
3.) The results were corroborated by the probit analysis.
Previous clinical trials comparing olanzapine, risperidone and haloperidol found higher risks of EPS for Haloperidol. We propose a new model to calculate dose equivalents.
A proinflammatory state in a subgroup of depressed patients has been reported repeatedly, for example an increase in interleukin-6 and tumour necrosis factor-a is well documented. Treatment with COX-2 inhibitors down-regulate increased inflammatory markers. Therefore an adjunctive treatment of depression with COX-2 in combination with an antidepressant might lead to a better clinical outcome.
To prove or disapprove the hypothesis of a better clinical outcome in the group with add-on celecoxib to sertraline in terms of improvement of HamD-17 and MADRS scores from baseline to endpoint.
This is a dual-center, randomized, double-blind, placebo-controlled, parallel group phase IIa study to investigate the mean change in clinical outcome and in serum expression of inflammation markers from baseline to endpoint (week 6) in patients with major depression (HAMD-17 ≥ 22) treated with celecoxib in combination with sertraline compared to sertraline combined with placebo. 51 depressed patients of both gender, aged between 18 and 60 without any recent inflammatory related disease were enrolled. The study comprises six study visits (6x ratings including HAMD-17 and MADRS, 3x blood collections) during six weeks of treatment and a follow-up visit 10 weeks after baseline.
Results and Conclusion
The study was completed quite recently and the results are in progress.
Non-suicidal self-injury (NSSI) is an increasing phenomenon among adolescents. So far, comparable data on prevalence and psychosocial correlates are still rare due to different definitions, study samples, and measures.
To investigate the prevalence and associated psychosocial factors of occasional and repetitive non-suicidal self-injury (NSSI) and its relationship to suicide attempts in a representative adolescent samples from eleven European countries.
Cross sectional assessment of adolescents was performed within the European Union funded project, Saving and Empowering Young Lives in Europe (SEYLE), which was conducted in eleven European countries. The representative sample comprised 12,068 adolescents (F/M: 6,717/5,351; mean age: 14.9±0.89) recruited from randomly selected schools. Frequency of NSSI was assessed by a modified version of the Deliberate Self-Harm Inventory (DSHI) and the Paykel Suicide Scale. Additionally, a broad range of demographic, social and psychological factors was assessed.
Overall lifetime prevalence of NSSI was 27.6%; 19.7% reported occasional NSSI and 7.8% repetitive NSSI. Lifetime prevalence ranged from 17.1% to 38.6% across countries. Suicidality, anxiety and depression had the highest odds ratios for both occasional and repetitive NSSI.
Results suggest high lifetime prevalence of NSSI in European adolescents, with significant country differences. A strong association of NSSI with both psychopathology and risk-behaviours, including family-related neglect and peer-related rejection/victimization could be found. These results, combined with the observed gender and country differences, support the need for a multidimensional approach to better understand the development of NSSI and facilitate culturally adapted prevention/intervention.
The updated common rule, for human subjects research, requires that consents “begin with a ‘concise and focused’ presentation of the key information that will most likely help someone make a decision about whether to participate in a study” (Menikoff, Kaneshiro, Pritchard. The New England Journal of Medicine. 2017; 376(7): 613–615.). We utilized a community-engaged technology development approach to inform feature options within the REDCap software platform centered around collection and storage of electronic consent (eConsent) to address issues of transparency, clinical trial efficiency, and regulatory compliance for informed consent (Harris, et al. Journal of Biomedical Informatics 2009; 42(2): 377–381.). eConsent may also improve recruitment and retention in clinical research studies by addressing: (1) barriers for accessing rural populations by facilitating remote consent and (2) cultural and literacy barriers by including optional explanatory material (e.g., defining terms by hovering over them with the cursor) or the choice of displaying different videos/images based on participant’s race, ethnicity, or educational level (Phillippi, et al. Journal of Obstetric, Gynecologic, & Neonatal Nursing. 2018; 47(4): 529–534.).
We developed and pilot tested our eConsent framework to provide a personalized consent experience whereby users are guided through a consent document that utilizes avatars, contextual glossary information supplements, and videos, to facilitate communication of information.
The eConsent framework includes a portfolio of eight features, reviewed by community stakeholders, and tested at two academic medical centers.
Early adoption and utilization of this eConsent framework have demonstrated acceptability. Next steps will emphasize testing efficacy of features to improve participant engagement with the consent process.
We have analyzed Chandra/High Energy Transmission Grating spectra of the X-ray emission line gas in the Seyfert galaxy NGC 4151. The zeroth-order spectral images show extended H- and He-like O and Ne, up to a distance r ˜ 200 pc from the nucleus. Using the 1st-order spectra, we measure an average line velocity ˜230 km s–1, suggesting significant outflow of X-ray gas. We generated Cloudy photoionization models to fit the 1st-order spectra; the fit required three distinct emission-line components. To estimate the total mass of ionized gas (M) and the mass outflow rates, we applied the model parameters to fit the zeroth-order emission-line profiles of Ne IX and Ne X. We determined an M ≍ 5.4 × 105Mʘ. Assuming the same kinematic profile as that for the [O III] gas, derived from our analysis of Hubble Space Telescope/Space Telescope Imaging Spectrograph spectra, the peak X-ray mass outflow rate is approximately 1.8 Mʘ yr–1, at r ˜ 150 pc. The total mass and mass outflow rates are similar to those determined using [O III], implying that the X-ray gas is a major outflow component. However, unlike the optical outflows, the X-ray emitting mass outflow rate does not drop off at r > 100pc, which suggests that it may have a greater impact on the host galaxy.
We present spatially resolved kinematics of ionized gas in the narrow-line region (NLR) and extended narrow-line region (ENLR) in a sample of nearby active galaxies. Utilizing long-slit spectroscopy from Apache Point Observatory (APO)13s ARC 3.5 m Telescope and Hubble Space Telescope (HST) we analyzed the strong λ5007 Å [O III] emission line profiles and mapped the radial velocity distribution of gas at increasing radii from the center. We identified the extents of Active Galactic Nuclei (AGN) driven outflows in our sample and determined the distances at which the observed gas kinematics is being dominated by the rotation of the host galaxy. We also measured the effectiveness of radiative driving of the ionized gas using mass distribution profiles calculated with two-dimensional modeling of surface brightness profiles in our targets. Finally, we compared our kinematic results of the outflow sizes with the maximum distances at which the gas is being radiatively driven to investigate whether these outflows are capable of disrupting or evacuating the star-forming gas at these distances.
We used Space Telescope Imaging Spectrograph (STIS) long slit medium-resolution G430M and G750M spectra to analyze the extended [O III] λ5007 emission in a sample of twelve QSO2s from Reyes et al. (2008). The purpose of the study was to determine the properties of the mass outflows and their role in AGN feedback. We measured fluxes and velocities as functions of deprojected radial distances. Using photoionization models and ionizing luminosities derived from [O III], we were able to estimate the densities for the emission-line gas. From these results, we derived masses, mass outflow rates, kinetic energies and kinetic luminosity rates as a function of radial distance for each of the targets. Masses are several times 103 - 107 solar masses, which are comparable to values determined from a recent photoionization study of Mrk 34 (Revalski). Additionally, we are studying the possible role of X-ray winds in these QSO2s.
We investigate the processes of active galactic nuclei (AGN) feeding and feedback in the narrow line regions (NLRs) and host galaxies of nearby AGN through spatially resolved spectroscopy with the Gemini Near-Infrared Integral Field Spectrograph (NIFS) and the Hubble Space Telescope’s Space Telescope Imaging Spectrograph (STIS). We examine the connection between nuclear and galactic inflows and outflows by adding long-slit spectra of the host galaxies from Apache Point Observatory. We demonstrate that nearby AGN can be fueled by a variety of mechanisms. We find that the NLR kinematics can often be explained by in situ ionization and radiative acceleration of ambient gas, often in the form of dusty molecular spirals that may be the fueling flow to the AGN.
The deviation from thermodynamic equilibrium of the ion velocity distribution functions (VDFs), as measured by the Magnetospheric Multiscale (MMS) mission in the Earth’s turbulent magnetosheath, is quantitatively investigated. Making use of the unprecedented high-resolution MMS ion data, and together with Vlasov–Maxwell simulations, this analysis aims at investigating the relationship between deviation from Maxwellian equilibrium and typical plasma parameters. Correlations of the non-Maxwellian features with plasma quantities such as electric fields, ion temperature, current density and ion vorticity are found to be similar in magnetosheath data and numerical experiments, with a poor correlation between distortions of ion VDFs and current density, evidence that questions the occurrence of VDF departure from Maxwellian at the current density peaks. Moreover, strong correlation has been observed with the magnitude of the electric field in the turbulent magnetosheath, while a certain degree of correlation has been found in the numerical simulations and during a magnetopause crossing by MMS. This work could help shed light on the influence of electrostatic waves on the distortion of the ion VDFs in space turbulent plasmas.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
In 2013, the national surveillance case definition for West Nile virus (WNV) disease was revised to remove fever as a criterion for neuroinvasive disease and require at most subjective fever for non-neuroinvasive disease. The aims of this project were to determine how often afebrile WNV disease occurs and assess differences among patients with and without fever. We included cases with laboratory evidence of WNV disease reported from four states in 2014. We compared demographics, clinical symptoms and laboratory evidence for patients with and without fever and stratified the analysis by neuroinvasive and non-neuroinvasive presentations. Among 956 included patients, 39 (4%) had no fever; this proportion was similar among patients with and without neuroinvasive disease symptoms. For neuroinvasive and non-neuroinvasive patients, there were no differences in age, sex, or laboratory evidence between febrile and afebrile patients, but hospitalisations were more common among patients with fever (P < 0.01). The only significant difference in symptoms was for ataxia, which was more common in neuroinvasive patients without fever (P = 0.04). Only 5% of non-neuroinvasive patients did not meet the WNV case definition due to lack of fever. The evidence presented here supports the changes made to the national case definition in 2013.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.