Analysis of Complications in Patients With a History of Cannabis Use and Tobacco Use Undergoing Implant-Based Breast Reconstruction.

BACKGROUND: There is limited information regarding the perioperative effects of marijuana in breast reconstructive surgeries. OBJECTIVES: The objective of this study was to explore the association between a history of cannabis use and postoperative complications in the setting of implant-based breast reconstruction. METHODS: Two databases, TriNetX and PearlDiver, were queried for patients undergoing implant-based breast reconstruction. Patients were divided into 4 groups based on active ICD-10 diagnostic codes: (1) cannabis use only, (2) tobacco use only, (3) cannabis and tobacco use, and (4) neither cannabis nor tobacco use. Associations with postoperative complications were analyzed with a logistic regression test. RESULTS: TriNetX search revealed that 327 patients had an active diagnosis of cannabis use only and 1118 had an active diagnosis of tobacco use only. Patients in the cannabis only cohort had a significantly increased risk of developing surgical site infection. Patients in the tobacco only cohort had significantly increased risk of developing wound dehiscence, need for debridement, and surgical site infection. The PearlDiver search included 472 patients who had an active diagnosis of both cannabis and tobacco use and 17,361 patients with a diagnosis of tobacco use only. Patients with a diagnosis of cannabis and tobacco use had a significantly increased risk of developing postoperative complications including surgical site infection, wound dehiscence, need for incision and drainage, and debridement. CONCLUSIONS: Patients undergoing implant-based breast reconstruction with an active diagnosis of cannabis with or without tobacco use were at increased risk of developing postoperative complications, and the risk was even higher in patients using both tobacco and cannabis.

Protocol for a Randomized Multiple Center Trial of Conservative Versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU): Oxygen in Pediatric Intensive Care.

OBJECTIVES: Oxygen administration is a fundamental part of pediatric critical care, with supplemental oxygen offered to nearly every acutely unwell child. However, optimal targets for systemic oxygenation are unknown. Oxy-PICU aims to evaluate the clinical effectiveness and cost-effectiveness of a conservative peripheral oxygen saturation (Sp o2 ) target of 88-92% compared with a liberal target of more than 94%. DESIGN: Pragmatic, open, multiple-center, parallel group randomized control trial with integrated economic evaluation. SETTING: Fifteen PICUs across England, Wales, and Scotland. PATIENTS: Infants and children age more than 38 week-corrected gestational age to 16 years who are accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. INTERVENTION: Adjustment of ventilation and inspired oxygen settings to achieve an Sp o2 target of 88-92% during invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Randomization is 1:1 to a liberal Sp o2 target of more than 94% or a conservative Sp o2 target of 88-92% (inclusive), using minimization with a random component. Minimization will be performed on: age, site, primary reason for admission, and severity of abnormality of gas exchange. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred to after randomization. The primary clinical outcome is a composite of death and days of organ support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support, and discharge outcomes. This trial received Health Research Authority approval on December 23, 2019 (reference: 272768), including a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee (reference number: 19/EE/0362). Trial findings will be disseminated in national and international conferences and peer-reviewed journals.

A Curriculum for Residents to Develop Successful Quality Improvement Projects.

BACKGROUND: Quality improvement (QI) education in residency training has become critical for numerous reasons, but little has been written about factors that lead to successful improvement projects within residency training. METHODS: A quality improvement curriculum for third-year psychiatry residents was developed. The percentage of resident projects that have been successfully implemented was calculated. Residents completed the QI Knowledge Application Tool adapted for psychiatry before and after the curriculum to assess knowledge and skills. RESULTS: Eighteen of 19 resident projects were successfully implemented. QI Knowledge Application Tool scores improved from 4.8 to 8.1 (P = 0.0053) after completion of the curriculum. CONCLUSIONS: Residents are able to implement successful projects and to increase their knowledge and skills in quality improvement when given appropriate resources and incentives.

Applying reinforcement learning techniques to detect hepatocellular carcinoma under limited screening capacity.

We investigate the problem faced by a healthcare system wishing to allocate its constrained screening resources across a population at risk for developing a disease. A patient's risk of developing the disease depends on his/her biomedical dynamics. However, knowledge of these dynamics must be learned by the system over time. Three classes of reinforcement learning policies are designed to address this problem of simultaneously gathering and utilizing information across multiple patients. We investigate a case study based upon the screening for Hepatocellular Carcinoma (HCC), and optimize each of the three classes of policies using the indifference zone method. A simulation is built to gauge the performance of these policies, and their performance is compared to current practice. We then demonstrate how the benefits of learning-based screening policies differ across various levels of resource scarcity and provide metrics of policy performance.

The role of astrocytic γ-aminobutyric acid in the action of inhalational anesthetics.

BACKGROUND: Inhalational anesthetics target the inhibitory extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. Both neuronal and glial GABA mediate tonic inhibition of the extrasynaptic GABAA receptors. However, the role of glial GABA during inhalational anesthesia remains unclear. This study aimed to evaluate whether astrocytic GABA contributes to the action of different inhalational anesthetics. METHODS: Gene knockout of monoamine oxidase B (MAOB) was used to reduce astrocytic GABA levels in mice. The hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane were assessed by evaluating the loss of righting reflex (LORR) and tail-pinch withdrawal response (LTWR) in MAOB knockout and wild-type mice. Minimum alveolar concentration (MAC) for LORR, time to LORR, MAC for LTWR and time to LTWR of isoflurane, sevoflurane, and desflurane were assessed. RESULTS: Time to LORR and time to LTWR with isoflurane were significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001 and P = 0.032, respectively). Time to LORR with 0.8 MAC of sevoflurane was significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001), but not with 1.0 MAC of sevoflurane (P=0.217). MAC for LTWR was significantly higher in MAOB knockout mice exposed to sevoflurane (P < 0.001). With desflurane, MAOB knockout mice had a significantly higher MAC for LORR (P = 0.003) and higher MAC for LTWR (P < 0.001) than wild-type mice. CONCLUSIONS: MAOB knockout mice showed reduced sensitivity to the hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane. Behavioral tests revealed that the hypnotic and immobilizing effects of inhalational anesthetics would be mediated by astrocytic GABA.

Improving screening for hepatocellular carcinoma by incorporating data on levels of α-fetoprotein, over time.

BACKGROUND & AIMS: Current screening algorithms for hepatocellular carcinoma (HCC) view each testing interval independently, without considering prior test results. We investigated whether measurements of α-fetoprotein (AFP), over time, can be used to identify patients most likely to develop HCC. METHODS: We performed a nested case-control study using data from subjects in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial; 82 patients with HCC were matched 1:3 to individuals without HCC (controls), using bootstrap methods to ensure similar follow-up times between groups. We assessed the independent association between development of HCC and the following: (1) most recent level of AFP, (2) standard deviation in level of AFP, and (3) rate of increase in AFP using a multiple logistic regression that included patient-specific risk factors such as age, platelet count, and smoking status. RESULTS: In bivariable analysis, all 3 AFP metrics were associated with HCC development; the most strongly associated was the standard deviation of AFP (odds ratio, 1.03 per unit increase in standard deviation; P < .001). Incorporating the standard deviation of AFP and rate of AFP increase, along with patient-specific risk factors, improved the prognostic accuracy to an area under the receiver-operating characteristic curve of 0.81, compared with 0.76 when only the most recent AFP level was used. CONCLUSIONS: Patterns of AFP test results can more accurately identify patients with hepatitis C and advanced fibrosis or cirrhosis most likely to develop HCC, compared with most recent AFP test results.

Optimizing metaproteomics database construction: lessons from a study of the vaginal microbiome.

Metaproteomics, a method for untargeted, high-throughput identification of proteins in complex samples, provides functional information about microbial communities and can tie functions to specific taxa. Metaproteomics often generates less data than other omics techniques, but analytical workflows can be improved to increase usable data in metaproteomic outputs. Identification of peptides in the metaproteomic analysis is performed by comparing mass spectra of sample peptides to a reference database of protein sequences. Although these protein databases are an integral part of the metaproteomic analysis, few studies have explored how database composition impacts peptide identification. Here, we used cervicovaginal lavage (CVL) samples from a study of bacterial vaginosis (BV) to compare the performance of databases built using six different strategies. We evaluated broad versus sample-matched databases, as well as databases populated with proteins translated from metagenomic sequencing of the same samples versus sequences from public repositories. Smaller sample-matched databases performed significantly better, driven by the statistical constraints on large databases. Additionally, large databases attributed up to 34% of significant bacterial hits to taxa absent from the sample, as determined orthogonally by 16S rRNA gene sequencing. We also tested a set of hybrid databases which included bacterial proteins from NCBI RefSeq and translated bacterial genes from the samples. These hybrid databases had the best overall performance, identifying 1,068 unique human and 1,418 unique bacterial proteins, ~30% more than a database populated with proteins from typical vaginal bacteria and fungi. Our findings can help guide the optimal identification of proteins while maintaining statistical power for reaching biological conclusions. IMPORTANCE Metaproteomic analysis can provide valuable insights into the functions of microbial and cellular communities by identifying a broad, untargeted set of proteins. The databases used in the analysis of metaproteomic data influence results by defining what proteins can be identified. Moreover, the size of the database impacts the number of identifications after accounting for false discovery rates (FDRs). Few studies have tested the performance of different strategies for building a protein database to identify proteins from metaproteomic data and those that have largely focused on highly diverse microbial communities. We tested a range of databases on CVL samples and found that a hybrid sample-matched approach, using publicly available proteins from organisms present in the samples, as well as proteins translated from metagenomic sequencing of the samples, had the best performance. However, our results also suggest that public sequence databases will continue to improve as more bacterial genomes are published.

Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants.

TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were shown to have antidepressant-like effects, providing evidence for the channel's potential as a therapeutic target. However, currently there is no good pharmacological inhibitor specifically targeting TREK-1 containing K2p channels that also displays similar antidepressant-like effects. Here, we sought to find selective and potent inhibitors for TREK-1 related dimers both in vitro and in vivo. We synthesized and evaluated 2-hydroxy-3-phenoxypropyl piperidine derivatives yielding a library from which many TREK-1 targeting candidates emerged. Among these, hydroxyl-phenyl- (2a), piperidino- (2g), and pyrrolidino- (2h) piperidinyl substituted compounds showed high potencies to TREK-1 homodimers with significant antidepressant-like effects in forced swim test and tail suspension test. Interestingly, these compounds were found to have high potencies to TWIK-1/TREK-1 heterodimers. Contrastingly, difluoropiperidinyl-4-fluorophenoxy (3e) and 4-hydroxyphenyl-piperidinyl-4-fluorophenoxy (3j) compounds had high potencies to TREK-1 homodimer but lower potency to TWIK-1/TREK-1 heterodimers without significant antidepressant-like effects. We observed positive correlation between inhibition potency to TWIK-1/TREK-1 and immobility time, and no correlation between inhibition potency to TREK-1 homodimer and immobility time. This was consistent with molecular docking simulations of selected compounds to TREK-1 homodimeric and TWIK-1/TREK-1 heterodimeric models. Existing antidepressant fluoxetine was also found to potently inhibit TWIK-1/TREK-1 heterodimers. Our study reveals novel potent TWIK-1/TREK-1 inhibitors 2a, 2g, and 2h as potential antidepressants and suggest that the TWIK-1/TREK-1 heterodimer could be a potential novel molecular therapeutic target for antidepressants.

Legacy and emerging per- and polyfluoroalkyl substances (PFASs) in Australian biosolids.

Biosolids samples were collected from 19 Australian WWTPs during 2018 that cover a range of catchment types (urban, rural, industrial waste discharges) and treatment technologies. Samples were analysed for 44 PFAS using isotope dilution and alkaline extraction coupled with quantification with LC-MS/MS. The Σ44PFAS mean concentration was 260 ng/g dry weight (dw) and ranged between 4.2 and 910 ng/g dw. The dominant compound class detected were the di-substituted phosphate esters (Σ3PAPs mean 140 ng/g dw; range ND - 730 ng/g dw) which contributed 45% of the total mean Σ44PFAS mass, followed by perfluoroalkyl carboxylic acids (Σ11PFCAs mean 39 ng/g dw; range 2.3-120 ng/g dw) contributing 17%, and the perfluoroalkyl sulfonates (Σ8PFSAs mean 28 ng/g dw; range 0.9-220 ng/g) which contributed 16%. Using the population data supplied by the participating WWTPs, the mean annual estimated biosolids-associated PFAS contribution is 6 mg per person per year and ranged between 0.6 mg and 15 mg. A similar population normalised concentration regardless of WWTP, region or capacity suggests that the domestic environment provides the baseline PFAS loading. Statistically significant higher Σ44PFAS and PFOS concentrations were observed at urban locations. A weak correlation was observed between annual mass of PFAS associated with each individual WWTP and their percentage industrial waste contribution. This may be important for elevated PFAS concentrations observed in WWTPs with higher industrial waste inputs and requires further research.

Evaluation of Cyto-genotoxicity of Perfluorooctane Sulfonate (PFOS) to Allium cepa.

Per- and polyfluoroalkyl substances (PFAS) have emerged as contaminants of global concern. Among several PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent and bioaccumulative compounds. We investigated the cyto-genotoxic potential of PFOS to Allium cepa root meristem cells. The A. cepa root tips were exposed to 6 different concentrations (1-100 mg L-1 ) of PFOS for 48 h. Reduction in mitotic index and chromosomal aberrations was measured as genotoxic endpoints in meristematic root cells. Exposure to PFOS significantly affected cell division by reducing the miotic index at higher concentrations (>10 mg L-1 ). The median effect concentration of PFOS to elicit cytotoxicity based on the mitotic index was 43.2 mg L-1 . Exposure to PFOS significantly increased chromosomal aberrations at concentrations >25 mg L-1 . The common aberrations were micronuclei, vagrant cells, and multipolar anaphase. The alkaline comet assay revealed a genotoxic potential of PFOS with increased tail DNA percentage at concentrations >25 mg L-1 . To our knowledge, this is the first study to report the cyto-genotoxic potential of PFOS in higher plants. Environ Toxicol Chem 2021;40:792-798. © 2020 SETAC.

Brominated flame retardants (BFRs) in Western Australian biosolids and implications for land application.

This study evaluates the prevalence of eight priority polybrominated diphenyl ethers (PBDEs; -28, -47, -99, -100, -153, -154, -183 and -209) and six novel brominated flame retardants (NBFRs; pentabromotoluene (PBT), pentabromoethylbenzene (PBEB), hexabromobenzene (HBB), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) and decabromodiphenyl ethane (DBDPE)) in biosolids samples from 15 wastewater treatment plants (WWTPs) in Western Australia. Analytes were extracted using selective pressurized liquid extraction (S-PLE) and quantified by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) operated in electron impact (EI) ionization mode. ∑8PBDE levels in biosolids ranged from 11 to 18,000 µg/kg dw with a median concentration of 1800 µg/kg dw. BDE-209 was the most prevalent congener constituting a median of 98% of ∑8PBDE concentrations in samples with BDE-99, -47 and -100 each typically contributing less than 3% to total levels. NBFRs were detected in 71% of samples with ∑6NBFR levels ranging between ND-1100 µg/kg dw (median; 600 µg/kg dw). Levels of DBDPE greatly exceeded those of all other NBFRs, while the next most prevalent compounds were EH-TBB and HBB. Australia produced approximately 327,000 dry tonnes of biosolids in 2017, of which approximately 75% was beneficially utilized on farmland as a fertilizer. Based on these results, an estimated 440 kg of BDE-209 and 150 kg of DBDPE are applied to agricultural land via biosolids applications annually in Australia. This study provides the first account of NBFR concentrations in Australian biosolids.

Long-term Intracellular Recording of Optogenetically-induced Electrical Activities using Vertical Nanowire Multi Electrode Array.

Continuous recording of intracellular activities in single cells is required for deciphering rare, dynamic and heterogeneous cell responses, which are missed by population or brief single-cell recording. Even if the field of intracellular recording is constantly proceeding, several technical challenges are still remained to conquer this important approach. Here, we demonstrate long-term intracellular recording by combining a vertical nanowire multi electrode array (VNMEA) with optogenetic stimulation to minimally disrupt cell survival and functions during intracellular access and measurement. We synthesized small-diameter and high-aspect-ratio silicon nanowires to spontaneously penetrate into single cells, and used light to modulate the cell's responsiveness. The light-induced intra- and extracellular activities of individual optogenetically-modified cells were measured simultaneously, and each cell showed distinctly different measurement characteristics according to the cell-electrode configuration. Intracellular recordings were achieved continuously and reliably without signal interference and attenuation over 24 hours. The integration of two controllable techniques, vertically grown nanowire electrodes and optogenetics, expands the strategies for discovering the mechanisms for crucial physiological and dynamic processes in various types of cells.

A Quality Improvement Curriculum for Psychiatry Residents.

Introduction: Quality improvement (QI) is an increasingly important aspect of health care and residency education. There is relatively little research describing QI curricula for residents in psychiatry. Although QI curricula have been published in MedEdPORTAL, the current resource represents the first such curriculum specific to psychiatry residents. This resource aims to present a QI curriculum for psychiatry residents. Methods: The University of Wisconsin psychiatry residency program implemented a QI curriculum for our PGY 3 psychiatry residents in 2010. The initial version of the curriculum has undergone marked changes over the ensuing years, reflecting feedback received from learners and faculty instructors, as well as ongoing review of the literature, to ascertain best practices in this area of medical education. Steps taken have included faculty training, development of evaluation forms, and implementation of elements to increase accountability for successful, sustainable project development. Results: During the 8 completed years of this curriculum, 77 PGY 3 psychiatry residents have completed it. The Quality Improvement Knowledge Application Tool adapted for psychiatry was completed by PGY 3 residents in advance of and upon completion of the curriculum for the first 2 years of the curriculum; results demonstrated a significant improvement in scores as a measurement of QI knowledge and skills. Thirty-one of 32 resident teams (97%) have implemented a QI project. Discussion: Our QI curriculum for PGY 3 psychiatry residents has been successful in equipping residents with QI knowledge and having them implement QI projects.

Indirect and Direct Evidence for 3-D Activation During Left Atrial Flutter: Anatomy of Epicardial Bridging.

OBJECTIVES: This study sought to describe arrhythmia characteristics using ultra-high density (UHD) mapping of macro-re-entrant left atrial flutter (LAFL) which propagate via epicardial bridging (EB), and highlight regional anatomy that poses challenges to ablation. BACKGROUND: Three-dimensional propagation via EB may contribute to the maintenance and complexity of LAFL. METHODS: UHD activation maps of macro-re-entrant LAFL created with a mini-electrode basket catheter were analyzed between June 2015 and March 2020. EB was defined as a region of wave front discontinuity with focal activation distal to an activation gap. Regions of EB were correlated with anatomic structures known to have specialized epicardial bundles. Direct evidence of EB was obtained via percutaneous epicardial access (n = 22) with simultaneous epicardial recordings during endocardial activation gaps. RESULTS: Among 159 patients who underwent LA endocardial procedures with UHD mapping, 43 patients with 47 macro-re-entrant LAFLs were included in this analysis. Evidence of EB was present in 38% of LAFLs. Four anatomic areas of EB were observed: coronary sinus (17%), vein of Marshall (28%), Bachmann's region (33%), and region of the septopulmonary bundle (22%). All 47 LAFLs were successfully ablated. Percutaneous epicardial mapping yielded direct evidence for EB in 9 patients with LAFL (41%). At 23 ± 13 months, 70% remained free from recurrent LAFL. CONCLUSIONS: In a selected population, UHD mapping demonstrates evidence of EB in 38% of cases of LAFL involving 4 distinct epicardial anatomic regions. Identification of discontinuous 3-dimensional activation patterns with attention to correlative regional LA anatomy may reduce the incidence of ablation failures for complex re-entry.

Astrocytes Control Sensory Acuity via Tonic Inhibition in the Thalamus.

Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.

Bioinformatic discovery of a toxin family in Chryseobacterium piperi with sequence similarity to botulinum neurotoxins.

Clostridial neurotoxins (CNTs), which include botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT), are the most potent toxins known to science and are the causative agents of botulism and tetanus, respectively. The evolutionary origins of CNTs and their relationships to other proteins remains an intriguing question. Here we present a large-scale bioinformatic screen for putative toxin genes in all currently available genomes. We detect a total of 311 protein sequences displaying at least partial homology to BoNTs, including 161 predicted toxin sequences that have never been characterized. We focus on a novel toxin family from Chryseobacterium piperi with homology to BoNTs. We resequenced the genome of C. piperi to confirm and further analyze the genomic context of these toxins, and also examined their potential toxicity by expression of the protease domain of one C. piperi toxin in human cells. Our analysis suggests that these C. piperi sequences encode a novel family of metalloprotease toxins that are distantly related to BoNTs with similar domain architecture. These toxins target a yet unknown class of substrates, potentially reflecting divergence in substrate specificity between the metalloprotease domains of these toxins and the related metalloprotease domain of clostridial neurotoxins.

An investigation into per- and polyfluoroalkyl substances (PFAS) in nineteen Australian wastewater treatment plants (WWTPs).

Quantifying the emissions of per- and polyfluoroalkyl substances (PFAS) from Australian wastewater treatment plants (WWTP) is of high importance due to potential impacts on receiving aquatic ecosystems. The new Australian PFAS National Environmental Management Plan recommends 0.23 ng L-1 of PFOS as the guideline value for 99% species protection for aquatic systems. In this study, 21 PFAS from four classes were measured in WWTP solid and aqueous samples from 19 Australian WWTPs. The mean ∑21PFAS was 110 ng L-1 (median: 80 ng L-1; range: 9.3-520 ng L-1) in aqueous samples and 34 ng g-1 dw (median: 12 ng g-1 dw; range: 2.0-130 ng g-1 dw) in WWTP solids. Similar to WWTPs worldwide, perfluorocarboxylic acids were generally higher in effluent, compared to influent. Partitioning to solids within WWTPs increased with increasing fluoroalkyl chain length from 0.05 to 1.22 log units. Many PFAS were highly correlated, and PCA analysis showed strong associations between two groups: odd chained PFCAs, PFHxA and PFSAs; and 6:2 FTS with daily inflow volume and the proportion of trade waste accepted by WWTPs (as % of typical dry inflow). The compounds PFPeA, PFHxA, PFHpA, PFOA, PFNA, and PFDA increased significantly between influent and final effluent. The compounds 6:2 FTS and 8:2 FTS were quantified and F-53B detected and reported in Australian WWTP matrices. The compound 6:2 FTS was an important contributor to PFAS emissions in the studied Australian WWTPs, supporting the need for future research on its sources (including precursor degradation), environmental fate and impact in Australian aquatic environments receiving WWTP effluent.

Cultivating Innovative Pragmatic Cluster-Randomized Registry Trials Embedded in Hemodialysis Care: Workshop Proceedings From 2018.

Hemodialysis is a life-sustaining treatment for persons with kidney failure. However, those on hemodialysis still face a poor quality of life and a short life expectancy. High-quality research evidence from large randomized controlled trials is needed to identify interventions that improve the experiences, outcomes, and health care of persons receiving hemodialysis. With the support of the Canadian Institutes of Health Research and its Strategy for Patient-Oriented Research, the Innovative Clinical Trials in Hemodialysis Centers initiative brought together Canadian and international kidney researchers, patients, health care providers, and health administrators to participate in a workshop held in Toronto, Canada, on June 2 and 3, 2018. The workshop served to increase knowledge and awareness about the conduct of innovative, pragmatic, cluster-randomized registry trials embedded into routine hemodialysis care and provided an opportunity to discuss and build support for new trial ideas. The workshop content included structured presentations, facilitated group discussions, and expert panel feedback. Partnerships and promising trial ideas borne out of the workshop will continue to be developed to support the implementation of future large-scale trials.

L'hémodialyse constitue un traitement essentiel au maintien de la vie pour les personnes atteintes d'insuffisance rénale. Les patients hémodialysés voient cependant leur qualité et leur espérance de vie réduites. Des données de recherches probantes, provenant de vastes essais cliniques contrôlés à répartition aléatoire, sont nécessaires pour améliorer l'expérience, les résultats et les soins des patients hémodialysés. Grâce au soutien des Instituts de recherche en santé du Canada (IRSC) et de leur Stratégie de recherche axée sur le patient (SRAP), l'initiative sur les essais cliniques novateurs (ECN) en centres d'hémodialyse a réuni divers intervenants en santé rénale (chercheurs, patients, fournisseurs de soins et administrateurs), du Canada et de partout dans le monde, lors d'un colloque qui s'est tenu à Toronto les 2 et 3 juin 2018. Ce colloque a permis d'accroître la sensibilisation et les connaissances sur la conduite d'essais cliniques novateurs, répartis en grappes, pragmatiques et intégrés aux soins d'hémodialyse de routine. Cette rencontre a également fourni une occasion de discuter de nouvelles idées d'essais cliniques et de susciter les appuis nécessaires à leur réalisation. Le colloque s'est déroulé sous forme de présentations structurées, de discussions animées en groupe et de rétroaction de la part d'un comité d'experts. Les idées de recherche prometteuses et les partenariats issus de ce colloque continueront d'être développés pour soutenir la réalisation d'essais cliniques futurs de grande envergure.

High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid.

Histone modifications play a crucial role during embryonic stem (ES) cell differentiation. During differentiation, binding of polycomb repressive complex 2 (PRC2), which mediates trimethylation of lysine 27 on histone H3 (K27me3), is lost on developmental genes that are transcriptionally induced. We observed a global decrease in K27me3 in as little as 3 days after differentiation of mouse ES cells induced by retinoic acid (RA) treatment. The global levels of the histone K27 methyltransferase EZH2 also decreased with RA treatment. A loss of EZH2 binding and K27me3 was observed locally on PRC2 target genes induced after 3 days of RA, including Nestin. In contrast, direct RA-responsive genes that are rapidly induced, such as Hoxa1, showed a loss of EZH2 binding and K27me3 after only a few hours of RA treatment. Following differentiation induced by leukemia inhibitor factor (LIF) withdrawal without RA, Hoxa1 was not transcriptionally activated. Small interfering RNA-mediated knockdown of EZH2 resulted in loss of K27me3 during LIF withdrawal, but the Hoxa1 gene remained transcriptionally silent after loss of this repressive mark. Induction of histone hyperacetylation overrode the repressive K27me3 modification and resulted in Hoxa1 gene expression. Together, these data show that there are multiple temporal phases of derepression of PRC2 target genes during ES cell differentiation and that other epigenetic marks (specifically, increased acetylation of histones H3 and H4), in addition to derepression, are important for gene-specific transcriptional activation. This report demonstrates the temporal interplay of various epigenetic changes in regulating gene expression during early ES cell differentiation.

Response to Disclosure as an Indicator of Competence to Stand Trial.

Ethics guidelines recommend that forensic mental health professionals begin in-person assessments by explaining the nature and purpose of the examination. To learn whether evaluees have understood and can give consent, forensic practitioners may ask evaluees to paraphrase the explanation. This article explores how a forensic evaluee's disclosure response (DR) reveals substantive information relevant to the purposes of a forensic examination. We examined archival data from 255 reports on competence to stand trial (CST) that a Midwest public sector hospital had previously submitted to courts. We classified each evaluee's DR at one of three levels: DR = yes (accurate paraphrasing), DR = no (inability to paraphrase or provide a relevant response), or DR = other (an intermediate level implying a less-than-accurate response). None of the 28 DR = no evaluees was CST, and only 7 (17%) of the 48 DR = other evaluees were CST. Thus, a CST evaluee who cannot paraphrase an examiner's explanation is likely to be incompetent to stand trial, and an examiner would need to adduce a strong argument to support any opinion to the contrary.