Exploring the "misfolding problem" by systematic discovery and analysis of functional-but-degraded proteins.

In both health and disease, the ubiquitin-proteasome system (UPS) degrades point mutants that retain partial function but have decreased stability compared with their wild-type counterparts. This class of UPS substrate includes routine translational errors and numerous human disease alleles, such as the most common cause of cystic fibrosis, ΔF508-CFTR. Yet, there is no systematic way to discover novel examples of these "minimally misfolded" substrates. To address that shortcoming, we designed a genetic screen to isolate functional-but-degraded point mutants, and we used the screen to study soluble, monomeric proteins with known structures. These simple parent proteins yielded diverse substrates, allowing us to investigate the structural features, cytotoxicity, and small-molecule regulation of minimal misfolding. Our screen can support numerous lines of inquiry, and it provides broad access to a class of poorly understood but biomedically critical quality-control substrates.

Yca1 metacaspase: diverse functions determine how yeast live and let die.

The Yca1 metacaspase was discovered due to its role in the regulation of apoptosis in Saccharomyces cerevisiae. However, the mechanisms that drive apoptosis in yeast remain poorly understood. Additionally, Yca1 and other metacaspase proteins have recently been recognized for their involvement in other cellular processes, including cellular proteostasis and cell cycle regulation. In this minireview, we outline recent findings on Yca1 that will enable the further study of metacaspase multifunctionality and novel apoptosis pathways in yeast and other nonmetazoans. In addition, we discuss advancements in high-throughput screening technologies that can be applied to answer complex questions surrounding the apoptotic and nonapoptotic functions of metacaspase proteins across a diverse range of species.

Cognitive Aids for the Management of Thoracic Anesthesia Emergencies: Consensus Guidelines on Behalf of a Canadian Thoracic Taskforce.

A cognitive aid is a tool used to help people accurately and efficiently perform actions. Similarly themed cognitive aids may be collated into a manual to provide relevant information for a specific context (eg, operating room emergencies). Expert content and design are paramount to facilitate the utility of a cognitive aid, especially during a crisis when accessible memory may be limited and distractions may impair task completion. A cognitive aid does not represent a rigid approach to problem-solving or a replacement for decision-making. Successful cognitive aid implementation requires dedicated training, access, and culture integration. Here the authors present a set of evidence-based cognitive aids for thoracic anesthesia emergencies developed by a Canadian thoracic taskforce.

Improving skills retention after advanced structured resuscitation training: A systematic review of randomized controlled trials.

AIMS: To systematically evaluate the literature on interventions that improve skills retention following advanced structured resuscitation training programs designed for healthcare professionals. METHODS: A systematic review of MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, ERIC, and Scopus was performed. Only randomized controlled trials investigating skills retention following advanced structured resuscitation training programs for healthcare professionals between inception to November 21, 2018 were included. Publications that assessed only knowledge acquisition were excluded. Relevant data from included studies were extracted and study quality was critically appraised, both independently and in duplicate by multiple reviewers. The risk of bias was assessed with the Cochrane Risk of Bias tool and the Medical Education Research Study Quality Instrument (MERSQI). Due to significant clinical heterogeneity in SRT training, study designs and interventions, a qualitative synthesis was used to summarize findings. MAIN RESULTS: Sixteen studies, with a combined total of 1192 participants, were included in the final analysis. The majority of studies were conducted in North America and involved trainees or novice learners. ACLS was the most extensively studied, followed by NRP, ALS, and ATLS. Skills retention at 6 months was the most commonly used primary endpoint assessed using a simulated resuscitation checklist with either an adopted or created assessment tool. Most studies demonstrated a positive impact on skills retention when an interactive intervention or simulation was used. However, merely having a high-fidelity mannequin alone for simulation was found to have minimal effect on skills retention in the absence of other changes in content delivery. Booster sessions were found to be minimally effective in reinforcing long-term skills retention; however, most studies examining this intervention had small sample sizes and were underpowered. CONCLUSIONS: Simulation-based interventions, refresher courses and adjustments to the content delivery of advanced structured resuscitation training courses were found to have the greatest impact on skills retention. However, due to significant heterogeneity and methodological flaws in the available studies, no definitive conclusions can be made regarding other interventions. Overall, there is a paucity of skills retention research and further high-quality randomized controlled trials are needed to determine the optimal intervention and design for resuscitation training that would maximize skills retention.

Evidence for the Use of Ultrasound Imaging in Pediatric Regional Anesthesia: A Systematic Review.

An earlier review to evaluate the quality and outcomes of studies assessing ultrasound imaging in regional anesthesia for the pediatric population considered articles published from 1994 to 2009 and showed some evidence in support of block-related outcomes (block onset, success, duration) and process-related outcomes (performance time, local anesthetic dose, and spread). At that time, strong evidence in the form of randomized controlled trials and well-designed prospective observational studies was limited, leading to a call for additional research. The current systematic review (2009-2014) compares and updates the evidence for ultrasound-guided pediatric regional anesthesia published since our last review. Using the MEDLINE and EMBASE databases, we included in this review studies examining ultrasound imaging for nerve localization in the pediatric population between 2009 and March 2014 (meta-analyses, systematic reviews, randomized controlled trials, controlled studies without randomization, observational studies, comparative studies, and case series involving at least 10 patients). In the current review, we identified 24 and 13 articles evaluating peripheral nerve blocks and neuraxial anesthesia, respectively. WHAT'S NEW: Studies in the current review provide stronger evidence and have addressed a number of outcomes that were previously inconsistent or lacked strength in evidence. In the current systematic review, we identified more studies in a shorter period compared with the previous review, and these studies contain higher levels of evidence compared with what we previously found. Randomized controlled trials and well-designed prospective observational studies have replaced case series. Stronger evidence from the literature suggests that ultrasound-guided peripheral blocks decrease block performance time when compared with nerve stimulation (but take longer than the landmark technique), increase block success, and increase block quality (as measured by analgesic consumption, block duration, and pain scores). Ultrasound guidance in neuraxial blocks improves needling time, predicts epidural depth, allows visualization of the catheter and local anesthetic spread, and improves block quality. Furthermore, we identified 2 large-scale prospective studies describing the incidence of adverse events and complications in pediatric regional anesthesia. The increase in evidence presented in this review reflects the efficacy and prevalent use of ultrasound imaging in pediatric regional anesthesia.

The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis.

BACKGROUND: Primary brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures. The epidemiology of these tumors is poorly understood. The aim of our study is to systematically review the latest literature on the incidence and prevalence of primary brain tumors. METHODS: The systematic review and meta-analysis were conducted according to a predetermined protocol and established guidelines. Only studies reporting on data from 1985 onward were included. Articles were included if they met the following criteria: (i) original research, (ii) population based, (iii) reported an incidence or prevalence estimate of primary brain tumors. RESULTS: From the 53 eligible studies overall, 38 were included in the meta-analysis. A random-effects model found the overall incidence rate of all brain tumors to be 10.82 (95% CI: 8.63-13.56) per 100 000 person-years. The incidence proportion estimates were heterogeneous, even among the same tumor subtypes, and ranged from 0.051 per 100 000 (germ cell tumors) to 25.48 per 100 000 (all brain tumors). There were insufficient data to conduct a meta-analysis of the prevalence of primary brain tumors. CONCLUSIONS: There is a need for more accurate and comparable incidence and prevalence estimates of primary brain tumors across the world. A standardized approach to the study of the epidemiology of these tumors is needed to better understand the burden of brain tumors and the possible geographical variations in their incidence.

Perspectives on neurological patient registries: a literature review and focus group study.

BACKGROUND: Patient registries represent a well-established methodology for prospective data collection with a wide array of applications for clinical research and health care administration. An examination and synthesis of registry stakeholder perspectives has not been previously reported in the literature. METHODS: To inform the development of future neurological registries we examined stakeholder perspectives about such registries through a literature review followed by 3 focus groups comprised of a total of 15 neurological patients and 12 caregivers. RESULTS: (1) LITERATURE REVIEW: We identified 6,435 abstracts after duplicates were removed. Of these, 410 articles underwent full text review with 24 deemed relevant to perspectives about neurological and non-neurological registries and were included in the final synthesis. From a patient perspective the literature supports altruism, responsible use of data and advancement of research, among others, as motivating factors for participating in a patient registry. Barriers to participation included concerns about privacy and participant burden (i.e. extra clinic visits and associated costs). (2) Focus groups: The focus groups identified factors that would encourage participation such as: having a clear purpose; low participant burden; and being well-managed among others. CONCLUSIONS: We report the first examination and synthesis of stakeholder perspectives on registries broadly with a specific focus on neurological patient registries. The findings of the broad literature review were congruent with the neurological patient and caregiver focus groups. We report common themes across the literature and the focus groups performed. Stakeholder perspectives need to be considered when designing and operating patient registries. Emphasizing factors that promote participation and mitigating barriers may enhance patient recruitment.

The pharmacoepidemiology of selective serotonin reuptake inhibitors for children and adolescents in Canada from 2005 to 2009: a database analysis.

OBJECTIVE: The aim of this study was to describe the frequency and trends in prescriptions and recommendations for selective serotonin reuptake inhibitors (SSRIs) for mental health disorders in children and adolescents in Canada from 2005 to 2009. METHOD: Data were extracted from databases supplied by IMS Brogan (IMS), a proprietary source of pharmacoepidemiologic data. Analyses were performed to obtain descriptive statistics on SSRI prescriptions dispensed, SSRI drug recommendation frequency, reasons for drug recommendations (therapeutic indication), and median duration of use of SSRIs in Canadian children. Canadian census data were used to assess whether changes in SSRI use were related to changes in the number of children in Canada over the time period studied. RESULTS: SSRI prescriptions written by pediatricians increased by 39 %, while SSRI drug recommendations by all specialists for children and adolescents increased by 44 % over the 5-year interval. Over the 5-year period studied, fluoxetine was the most commonly recommended and dispensed SSRI. The use of escitalopram has increased while the use of paroxetine has declined. Between 2005 and 2009, the two most common therapeutic indications for SSRI recommendations were mood disorder (50 %) and anxiety disorder (25 %). Median treatment duration was less than 1 year, with duration generally increasing with patient age. CONCLUSIONS: The increase in use of SSRIs in Canadian children and adolescents from 2005 to 2009 suggests that the effects of public health warnings concerning suicidal thinking and behavior associated with these drugs are now dissipating. This may be attributable to the FDA's pediatric approvals for fluoxetine and escitalopram, the growing comfort of clinicians with using SSRIs in children, limited availability of psychosocial treatments, and the influence of marketing. The use of paroxetine has continued to decline, likely because of specific warnings directed toward this agent and limited evidence supporting its efficacy.

The pharmacoepidemiology of antipsychotic medications for Canadian children and adolescents: 2005-2009.

OBJECTIVE: To describe the frequency and trends of use of antipsychotics in Canadian children and adolescents from 2005 to 2009. METHODS: We performed analyses on the IMS Brogan databases on drug recommendation (prescribed drug) frequency, reasons for recommendations (therapeutic indication), and duration of use of antipsychotics, psychostimulants, and selective serotonin reuptake inhibitors (SSRIs) for Canadian children between 2005 and 2009. Changes in the number of and reasons for drug recommendations over the 5-year period are highlighted by using descriptive statistics. RESULTS: Antipsychotic drug recommendations by all specialists for children increased by 114% from 2005 to 2009. In contrast, psychostimulant and SSRI drug recommendations increased by 36% and 44%, respectively. The majority of antipsychotic drug recommendations were for second-generation antipsychotics (SGAs). Attention-deficit/hyperactivity disorder (ADHD) was the most common therapeutic indication associated with an SGA recommendation. Antipsychotic drug recommendations for children with ADHD more than tripled between 2005 and 2009. The average duration of antipsychotic use in children varied by drug and age group. For risperidone, median duration of use was 90 days in children aged 1-6, 180 days in children aged 7-12, and 200 days in children aged 13-18. CONCLUSION: The use of antipsychotics in Canadian children greatly increased from 2005 to 2009. Comparison of antipsychotic data with psychostimulant and SSRI data shows that there has been a disproportionate increase in antipsychotic use over this interval, despite the lack of approval for pediatric use by Health Canada. Postmarketing surveillance activities of antipsychotic use in children appear appropriate.

The pharmacoepidemiology of antipsychotics for adults with schizophrenia in Canada, 2005 to 2009.

OBJECTIVE: To describe the frequency and trends in the use of antipsychotics for adults with schizophrenia in Canada from 2005 to 2009. METHODS: Analyses were performed on IMS Brogan's Canadian Disease and Therapeutic Index (CDTI). The CDTI is a national physician panel study consisting of a representative sample of physicians both geographically and by specialty. Weighting adjustments are made to estimate national drug recommendations. Quarterly, panel physicians record all therapeutic recommendations during a 2-day period, including patient age, sex, and indication. Antipsychotic recommendations were estimated using CDTI data in which schizophrenia was listed as the indication. RESULTS: First-generation antipsychotic (FGA) recommendations for adults with schizophrenia increased by 38% between 2005 and 2009, from 329 380 to 454 960 recommendations. There were notable increases in recommendations for chlorpromazine, loxapine, zuclopenthixol, and flupentixol. Second-generation antipsychotic (SGA) recommendations increased to a much lesser extent (9%), which was mostly attributable to an increase in recommendations for clozapine. Drug recommendations for olanzapine decreased by 9%. CONCLUSION: The rate of increase of FGA use is now greater than that of SGAs. This may be due to data from recent comparative trials, which suggest that clinical efficacy, and the rate of neurological side effects is similar between FGAs and SGAs. The decreasing use of olanzapine may be due to metabolic adverse effects. The increased use of clozapine may be due to data on its superiority in patients who are treatment resistant.

Metabolic and neurological complications of second-generation antipsychotic use in children: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Available evidence indicates that the use of antipsychotics, especially second-generation antipsychotics (SGAs), for children with mental health disorders has increased dramatically. Given the demonstrated metabolic and neurological adverse effects seen in adult patients on these medications, detailed evaluation of the risk for these adverse effects in children is appropriate. OBJECTIVE: The aim of the study was to assess the evidence for specific metabolic and neurological adverse effects associated with the use of SGAs in children. DATA SOURCES: MEDLINE (1996-May 2010) and EMBASE (1996-May 2010) databases were searched using highly sensitive search strategies for clinical trials in a paediatric population (children up to age 18 years). STUDY SELECTION: We included any double-blind, randomized controlled trial (RCT) of SGA medications conducted specifically in a paediatric population for the treatment of a mental health disorder. This included the medications risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone and paliperidone. The primary outcomes assessed for this review were metabolic and neurological adverse effects, as measured using physical examination manoeuvres, rating scales or laboratory tests. A total of 35 RCTs were included in the analysis, but not all studies had data that could be used in the meta-analysis. DATA EXTRACTION: Abstracts retrieved from the searches were reviewed independently by two different reviewers for potential relevant articles. Full-text articles were then read in detail independently by two different reviewers to see if inclusion criteria were fulfilled. Data were extracted independently by two review authors from included studies and entered onto pre-designed summary forms. Clinical trials were evaluated for methodological quality using quality criteria developed by the US Preventive Services Task Force. Based on the fulfilment of quality criteria, studies were rated as good, fair or poor. DATA SYNTHESIS: Meta-analysis was performed on the data for synthesis, and was carried out for commonly reported outcomes for each medication individually, in comparison with placebo or another drug. Odds ratios (ORs) with 95% confidence intervals for binary outcomes were used. For continuous outcomes, mean differences were used to analyze the data. Meta-analysis revealed that mean weight gain compared with placebo was highest for olanzapine at 3.47 kg (95% CI 2.94, 3.99) followed by risperidone at 1.72 kg (95% CI 1.17, 2.26), quetiapine at 1.41 kg (95% CI 1.10, 1.81) and aripiprazole at 0.85 kg (95% CI 0.58, 1.13). Olanzapine and clozapine treatment were associated with the highest rate of metabolic laboratory abnormalities in cholesterol and triglycerides. Prolactin elevation occurred with risperidone and olanzapine therapy. Higher odds of extrapyramidal symptoms compared with placebo were seen in children treated with risperidone (OR 3.55; 95% CI 2.04, 5.48) and aripiprazole (OR 3.70; 95% CI 2.37, 5.77). Elevated rates of extrapyramidal symptoms were also experienced with olanzapine use. CONCLUSIONS: There is good evidence to support the existence of both metabolic and neurological adverse effects in children treated with these medications. Proper attention and vigilance to potential metabolic and neurological adverse effects is necessary, and should be considered part of the standard of care.