Patient involvement in clinical research: Why, when, and how

The development of a patient-centered approach to medicine is gradually allowing more patients to be involved in their own medical decisions. However, this change is not happening at the same rate in clinical research, where research generally continues to be carried out on patients, but not with patients. This work describes the why, when, and how of more active patient participation in the research process. Specific measures are proposed to improve patient involvement in 1) setting priorities, 2) study leadership and design, 3) improved access to clinical trials, 4) preparation and oversight of the information provided to participants, 5) post-study evaluation of the patient experience, and 6) the dissemination and application of results. In order to achieve these aims, the relative emphases on the ethical principles underlying research need to be changed. The current model based on the principle of beneficence must be left behind, and one that upholds the ethical principles of autonomy and non maleficence should be embraced. There is a need to improve the level of information that patients and society as a whole have on research objectives and processes; the goal is to promote the gradual emergence of the expert patient

Negative cognitive schema modification as mediator of symptom improvement after electroconvulsive therapy in major depressive disorder

Background: Electroconvulsive therapy (ECT) is a potent option for treatment-resistant major depressive disorder (MDD). Cognitive models of depression posit that negative cognitions and underlying all-or-nothing negative schemas contribute to and perpetuate depressed mood. This study investigates whether ECT can modify negative schemas, potentially via memory reactivation, and whether such changes are related to MDD symptom improvement. Method: Seventy-two patients were randomized to either an emotional memory reactivation electroconvulsive therapy (EMR-ECT) or control memory reactivation electroconvulsive therapy (CMR-ECT) intervention prior to ECT-sessions in a randomized controlled trail. Emotional memories associated with patients' depression were reactivated before ECT-sessions. At baseline and after the ECT-course, negative schemas and depression severity were assessed using the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale HDRS. Mediation analyses were used to examine whether the effects of ECT on HDRS-scores were mediated by changes in DAS-scores or vice versa. Results: Post-ECT DAS-scores were significantly lower compared to baseline. Post-ECT, the mean HDRS-score of the whole sample (15.10 ± 8.65 [SD]; n = 59) was lower compared to baseline (24.83 ± 5.91 [SD]). Multiple regression analysis showed no significant influence of memory reactivation on schema improvement. Path analysis showed that depression improvement was mediated by improvement of negative cognitive schemas. Conclusion: ECT is associated with improvement of negative schemas, which appears to mediate the improvement of depressive symptoms. An emotional memory intervention aimed to modify negative schemas showed no additional effect

Effectiveness of Emotional Memory Reactivation vs Control Memory Reactivation Before Electroconvulsive Therapy in Adult Patients With Depressive Disorder A Randomized Clinical Trial:A Randomized Clinical Trial

Importance: Although electroconvulsive therapy (ECT) is often effective, approximately half of patients with depression undergoing ECT do not benefit sufficiently, and relapse rates are high. ECT sessions have been shown to weaken reactivated memories. The effect of emotional memory retrieval on cognitive schemas remains unknown. Objective: To assess whether emotional memory retrieval just before patients receive ECT sessions weakens underlying cognitive schemas, improves ECT effectiveness, increases ECT response, and reduces relapse rates. Design, Setting, and Participants: In this multicenter randomized clinical trial conducted from 2014 to 2018 in the departments of psychiatry in 3 hospitals in the Netherlands, 72 participants were randomized 1:1 to 2 parallel groups to receive either emotional memory reactivation (EMR-ECT) or control memory reactivation (CMR-ECT) interventions before ECT sessions. The Hamilton Depression Rating Scale (HDRS [total score range: 0-52, with 0-7 indicating no depression and ≥24 indicating severe depression]) was used to measure symptoms of depression during and after ECT, with a 6-month follow-up period. Participants were between ages 18 and 70 years with a primary diagnosis of unipolar major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) and in whom ECT was indicated. Data analysis was performed from July to November 2019. Interventions: EMR-ECT or CMR-ECT interventions prior to ECT sessions. Main Outcomes and Measures: Depression scores and relapse rates within 6 months were assessed with the HDRS and analyzed using logistic and linear multiple regression analyses. Results: A total of 66 patients (mean [SD] age, 49.3 [12.3] years; 39 [59.1%] women) were randomized to the EMR-ECT group (n = 32) or the CMR-ECT group (n = 34). Regardless of the memory intervention, 42.4% (28 of 66) of patients responded (≥50% decrease of symptom severity on the HDRS). Of patients who responded, 39.3% (11 of 28) relapsed within 6 months. Remission rates (CMR-ECT group, 29.4% [10 of 34] vs EMR-ECT group, 25.0% [8 of 32]; P = .58), mean (SD) HDRS scores after the ECT course (CMR-ECT group, 14.6 [8.6] vs EMR-ECT group, 14.9 [8.8]; P = .88), total mean (SD) number of required ECT sessions for response (CMR-ECT group, 14.9 [7.9] vs EMR-ECT group, 15.6 [7.3]; P = .39), and relapse rates (CMR-ECT group, 46.7% [7 of 15] vs EMR-ECT group, 30.8% [4 of 13]; P = .33) were not significantly altered by the intervention. Conclusions and Relevance: Study findings suggest that the EMR-ECT intervention just before patient receipt of ECT for depression did not improve effectiveness, increase speed of response, or reduce relapse rates after the ECT course compared with patients receiving CMR-ECT. Trial Registration: Trialregister.nl Identifier: NL4289

Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Experimental cancer immunology and therap

Brevicoryne brassicae aphids interfere with transcriptome responses of Arabidopsis thaliana to feeding by Plutella xylostella caterpillars in a density‑dependent manner

Plants are commonly attacked by multiple herbivorous species. Yet, little is known about transcriptional patterns underlying plant responses to multiple insect attackers feeding simultaneously. Here, we assessed= transcriptomic responses of Arabidopsis thaliana plants to simultaneous feeding by Plutella xylostella caterpillars and Brevicoryne brassicae aphids in comparison to plants infested by P. xylostella caterpillars alone, using microarray analysis. We particularly investigated how aphid feeding interferes with the transcriptomic response to P. xylostella caterpillars and whether this interference is dependent on aphid density and time since aphid attack. Various JA-responsive genes were up-regulated in response to feeding by P. xylostella caterpillars. The additional presence of aphids, both at low and high densities, clearly affected the transcriptional plant response to caterpillars. Interestingly, some important modulators of plant defense signalling, including WRKY transcription factor genes and ABA-dependent genes, were differentially induced in response to simultaneous aphid feeding at low or high density compared with responses to P. xylostella caterpillars feeding alone. Furthermore, aphids affected the P. xylostella-induced transcriptomic response in a density dependent manner, which caused an acceleration in plant response against dual insect attack at high aphid density compared to dual insect attack at low aphid density. In conclusion, our study provides evidence that aphids influence the caterpillar-induced transcriptional response of A. thaliana in a density-dependent manner. It highlights the importance of addressing insect density to understand how plant responses to single attackers interfere with responses to other attackers and thus underlines the importance of the dynamics of transcriptional plant responses to multiple herbivory

Evaluating the 'return on patient engagement initiatives' in medicines research and development: A literature review

Search strategy and inclusion criteria. We undertook a scoping literature review using a systematic search, including academic and grey literature with a focus on evaluation approaches or outcomes associated with patient engagement. No date limits were applied other than a cut-off of publications after July 2018. Data extraction and synthesis. Data were extracted from 91 publications, coded and thematically analysed. Main results. A total of 18 benefits and 5 costs of patient engagement were identified, mapped with 28 possible indicators for their evaluation. Several quantitative and qualitative methods were found for evaluation of benefits and costs of patient engagement. Discussion and conclusions. Currently available indicators and methods are of some use in measuring impact but are not sufficient to understand the pathway to impact, nor whether interaction between researchers and patients leads to change. We suggest that the impacts of patient engagement can best be determined not by applying single indicators, but a coherent set of measures

HDAC inhibition increases HLA class I expression in uveal melanoma

The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell sur

Aqueous Humor Biomarkers Identify Three Prognostic Groups in Uveal Melanoma

Purpose: To investigate whether we can identify different patterns of inflammation in the aqueous humor of a uveal melanoma (UM)-containing eye, and whether these are related to prognosis. Meth