Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia

HEXACO Personality Predictors of Self, Victim, and Divine Forgiveness Among Christian College Students

Undergraduate Applie

Management of Sorafenib-Related Adverse Events: A Clinician’s Perspective

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). It is being evaluated in phase II and III clinical trials, which include treatment as a single agent (locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer [DTC]), as part of multimodality care (HCC), and in combination with chemotherapeutic agents (metastatic breast cancer). Sorafenib-related adverse events (AEs) that commonly occur across these tumor types include hand–foot skin reaction (HSFR), rash, upper and lower gastrointestinal (GI) distress (ie, diarrhea), fatigue, and hypertension. These commonly range from grade 1 to 3, per the Common Terminology Criteria for Adverse Events (CTCAE), and often occur early in treatment. The goal for the management of these AEs is to prevent, treat, and/or minimize their effects, thereby enabling patients to remain on treatment and improve their quality of life. Proactive management, along with ongoing patient education (before and during sorafenib treatment), can help to effectively manage symptoms, often without the need for sorafenib dose modification or drug holidays. Effective management techniques for common sorafenib-related AEs, as well other important disease sequelae not directly related to treatment, are presented. Recommendations and observations are based on physician/author experience and recommendations from published literature

Role of the Cyclooxygenase Pathway in Chemotherapy-Induced Oral Mucositis: A Pilot Study

Goals Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n=3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis. Materials and methods We collected blood, saliva, and oral mucosal biopsy specimens from three autologous HSCT patients at the following time-points before and after administration of conditioning chemotherapy: Day −10, +10, +28, and +100, where day 0 is day of transplant. RNA extracted from full-thickness tissue samples was measured by RT-PCR for the following: COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), IL-1β, and TNF-α. Blood and saliva samples were measured by ELISA for PGE2 and PGI2, which are markers of COX activity. Severity of oral mucositis was determined using the Oral Mucositis Index. Severity of pain due to oral mucositis was measured using a Visual Analog Scale. Relationships between the different variables were examined using Spearman rank correlation coefficients. Main results Mean mucositis and pain scores increased significantly after administration of chemotherapy and then gradually declined. The correlation between changes in mucositis and pain scores was strong and statistically significant. The following additional correlations were statistically significant: between tissue COX-1 and pain; between tissue mPGES and pain; between salivary PGE1 and pain; between salivary PGI2 and pain. Other relationships were not statistically significant. Conclusions Our finding of significant associations of pain scores with tissue COX-1 and mPGES, as well as salivary prostaglandins, is suggestive of a role for the cyclooxygenase pathway in mucositis, possibly via upregulation of pro-inflammatory prostaglandins. However, our small sample size may have contributed to the lack of significant associations between COX-2 and other inflammatory mediators with mucosal injury and pain. Thus, additional studies with larger numbers of subjects are warranted to confirm the involvement of the cyclooxygenase pathway in chemotherapy-induced mucositis

Human pluripotent stem cell-derived striatal interneurons: differentiation and maturation in vitro and in the rat brain

Striatal interneurons are born in the medial and caudal ganglionic eminences (MGE and CGE) and play an important role in human striatal function and dysfunction in Huntington's disease and dystonia. MGE/CGE-like neural progenitors have been generated from human pluripotent stem cells (hPSCs) for studying cortical interneuron development and cell therapy for epilepsy and other neurodevelopmental disorders. Here, we report the capacity of hPSC-derived MGE/CGE-like progenitors to differentiate into functional striatal interneurons. In vitro, these hPSC neuronal derivatives expressed cortical and striatal interneuron markers at the mRNA and protein level and displayed maturing electrophysiological properties. Following transplantation into neonatal rat striatum, progenitors differentiated into striatal interneuron subtypes and were consistently found in the nearby septum and hippocampus. These findings highlight the potential for hPSC-derived striatal interneurons as an invaluable tool in modeling striatal development and function in vitro or as a source of cells for regenerative medicine

5-Fluorouracil-induced cardiotoxicity mimicking myocardial infarction: a case report

BACKGROUND: Severe cardiotoxicity is a documented, but very unusual side-effect of intravenous 5-fluorouracil therapy. The mechanism producing cardiotoxicity is poorly understood. CASE PRESENTATION: A case of 5-fluorouracil-induced cardiotoxicity, possibly due to coronary artery spasm, and mimicking acute anterolateral myocardial infarction is presented and discussed. Electrocardiographs highlighting the severity of the presentation are included in the report along with coronary angiograms demonstrating the absence of significant coronary atherosclerosis. CONCLUSION: Severe 5-fluorouracil-induced cardiotoxicity is rare, but can be severe and may mimic acute myocardial infarction, leading to diagnostic and therapeutic dilemmas. Readministration of 5-fluorouracil is not advised following an episode of cardiotoxicity

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests

A novel Vision Zero leadership training model to support collaboration and strategic action planning

Introduction: While collaboration and cooperation are regarded as foundational to Vision Zero (VZ) and Safe Systems initiatives, there is little guidance on structuring VZ collaboration, conducting collaborative goal setting, and aligning tangible action across organizations. As part of a larger VZ mutual learning model, we developed a VZ Leadership Team Institute to support communities in collaborative VZ strategic planning and goal setting. The purpose of this paper is to describe the development and evaluation of the Institute, which can serve as a foundation for other initiatives seeking to move VZ planning and implementation forward in a collaborative, systems-aware manner.Methods: In June 2021, eight multi-disciplinary teams of 3–6 persons each (n = 42 participants) attended the Institute, representing leaders from communities of various sizes. Surveys were administered pre, immediately post, and 6 months following the Institute. We measured confidence in a range of skills (on a 5-point scale, 1: not confident to 5: very confident). Surveys also measured coalition collaboration pre-Institute and 6 months post-Institute (on a 4-point scale, 1: strongly disagree to 4: strongly agree).Results: The largest increases in confidence from pre- to immediately post-Institute were for collaboratively drafting objectives and actions for VZ goals (pre-mean: 2.6, SD: 0.9 to post-mean: 3.8, SD: 0.9); incorporating equity into goals (pre-mean: 2.8, SD: 1.0 to post-mean: 3.9, SD: 0.8); and knowing how to keep VZ planning and implementation efforts on track (pre-mean: 2.6, SD: 1.0 to post-mean: 3.7, SD: 0.7). For all measures, average confidence in skills decreased from immediately post-Institute to 6 months post-Institute, but remained greater than average scores pre-Institute. Several measures of coalition collaboration maintained high agreement across time, and mean agreement increased for reporting that the future direction of the coalition was clearly communicated to everyone (pre-mean: .6, SD: 0.8; 6 months post-mean: 3.1, SD: 0.4). However, average scores decreased for feeling like the coalition had adequate staffing (pre-mean: 3.0, SD: 0.6; 6 months post-mean: 2.3, SD: 0.5).Discussion: The Institute utilized innovative content, tools, and examples to support VZ coalitions’ collaborative and systems-aware planning and implementation processes. As communities work toward zero transportation deaths and serious injuries, providing effective support models to aid multidisciplinary planning and action around a Safe Systems approach will be important to accelerate progress toward a safer transportation system

Estimating the clinical effectiveness of cognitive behavioural therapy in the clinic: Evaluation of a CBT informed pain management programme

Randomized controlled trials and meta-analyses provide evidence for the efficacy of cognitive-behaviourally informed treatment (CBT) programmes for chronic pain. The current study aims to provide practice-based evidence for the effectiveness of CBT in routine clinical settings. Over a 10-year period 1013 pain patients were accepted into a 4 week in-patient pain management programme. Data from more than 800 patients was available at pre-treatment and at one month post-treatment and for around 600 patients at pre-treatment and at 9 months follow-up. Measures reported in this analysis were pain experience and interference, psychological distress (depression and anxiety), self-efficacy, catastrophizing, and walking. Change from pre-treatment to post-treatment and follow-up was assessed with conventional statistical tests, the computation of effect sizes and by the reliable change index (RCI) and clinically significant change (CSC) methodology. These analyses provide evidence of statistical improvement at post-treatment and follow-up and the RCI/CSC methodology suggested that between 1 in 3 and 1 in 7 (depending on the outcome measure) achieved clinically significant gains. There was also evidence that a small percentage of patients (1–2%) reliably deteriorated during the period of treatment. The limitations in the inferences that can be drawn from this study and of the methodology are discussed. A case is made for the application of benchmarking methods using data from RCTs in order to more fully evaluate practice and to generate better quality practice based evidence