Stent vs. Stent-less Ileal Conduits After Radical Cystectomies: Is There Difference In Early Postoperative Outcomes?

Placing ureteral stents at the ureteroileal anastomosis for radical cystectomy with ileal conduit (RCIC) diversion has long been common practice, which has recently been called into question. In this study, we aim to investigate the difference in 30-day outcomes between patients who did and did not receive ureteral stents after RCIC.https://jdc.jefferson.edu/urologyfposters/1003/thumbnail.jp

Nitric oxide sensing in plants is mediated by proteolytic control of group VII ERF transcription factors

Nitric oxide (NO) is an important signaling compound in prokaryotes and eukaryotes. In plants, NO regulates critical developmental transitions and stress responses. Here, we identify a mechanism for NO sensing that coordinates responses throughout development based on targeted degradation of plant-specific transcriptional regulators, the group VII ethylene response factors (ERFs). We show that the N-end rule pathway of targeted proteolysis targets these proteins for destruction in the presence of NO, and we establish them as critical regulators of diverse NO-regulated processes, including seed germination, stomatal closure, and hypocotyl elongation. Furthermore, we define the molecular mechanism for NO control of germination and crosstalk with abscisic acid (ABA) signaling through ERF-regulated expression of ABSCISIC ACID INSENSITIVE5 (ABI5). Our work demonstrates how NO sensing is integrated across multiple physiological processes by direct modulation of transcription factor stability and identifies group VII ERFs as central hubs for the perception of gaseous signals in plants

People Efficiently Explore the Solution Space of the Computationally Intractable Traveling Salesman Problem to Find Near-Optimal Tours

Humans need to solve computationally intractable problems such as visual search, categorization, and simultaneous learning and acting, yet an increasing body of evidence suggests that their solutions to instantiations of these problems are near optimal. Computational complexity advances an explanation to this apparent paradox: (1) only a small portion of instances of such problems are actually hard, and (2) successful heuristics exploit structural properties of the typical instance to selectively improve parts that are likely to be sub-optimal. We hypothesize that these two ideas largely account for the good performance of humans on computationally hard problems. We tested part of this hypothesis by studying the solutions of 28 participants to 28 instances of the Euclidean Traveling Salesman Problem (TSP). Participants were provided feedback on the cost of their solutions and were allowed unlimited solution attempts (trials). We found a significant improvement between the first and last trials and that solutions are significantly different from random tours that follow the convex hull and do not have self-crossings. More importantly, we found that participants modified their current better solutions in such a way that edges belonging to the optimal solution (“good” edges) were significantly more likely to stay than other edges (“bad” edges), a hallmark of structural exploitation. We found, however, that more trials harmed the participants' ability to tell good from bad edges, suggesting that after too many trials the participants “ran out of ideas.” In sum, we provide the first demonstration of significant performance improvement on the TSP under repetition and feedback and evidence that human problem-solving may exploit the structure of hard problems paralleling behavior of state-of-the-art heuristics

A randomized controlled trial investigation of a non-stimulant in attention deficit hyperactivity disorder (ACTION): Rationale and design

<p>Abstract</p> <p>Background</p> <p>The ACTION study (<it>Attention deficit hyperactivity disorder Controlled Trial Investigation Of a Non-stimulant) </it>is a multi-center, double-blind, randomized cross-over trial of the non-stimulant medication, Atomoxetine, in children and adolescents with attention deficit hyperactivity disorder (ADHD). The primary aims are to examine the efficacy of atomoxetine for improving cognition and emotional function in ADHD and whether any improvements in these outcomes are more pronounced in participants with comorbid anxiety; and to determine if changes in these outcomes after atomoxetine are more reliable than changes in diagnostic symptoms of ADHD. This manuscript will describe the methodology and rationale for the ACTION study.</p> <p>Methods</p> <p>Children and adolescents aged 6 - 17 y with ADHD will be enrolled. Clinical interview and validated scales will be used to confirm diagnosis and screen for exclusion criteria, which include concurrent stimulant use, and comorbid psychiatric or neurological conditions other than anxiety. Three assessment sessions will be conducted over the 13-week study period: Session 1 (Baseline, pre-treatment), Session 2 (six weeks, atomoxetine or placebo), and Session 3 (13 weeks, cross-over after one-week washout period). The standardized touch-screen battery, "IntegNeuro™", will be used to assess cognitive and emotional function. The primary measure of response will be symptom ratings, while quality of life will be a secondary outcome. Logistic regression will be used to determine predictors of treatment response, while repeated measures of analysis will determine any differences in effect of atomoxetine and placebo.</p> <p>Results</p> <p>The methodology for the ACTION study has been detailed.</p> <p>Conclusions</p> <p>The ACTION study is the first controlled trial to investigate the efficacy of atomoxetine using objective cognitive and emotional function markers, and whether these objective measures predict outcomes with atomoxetine in ADHD with and without comorbid anxiety. First enrollment was in March 2008. The outcomes of this study will be a significant step towards a 'personalized medicine' (and therefore a more efficient) approach to ADHD treatment.</p> <p>Trial registration</p> <p>Australian and New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ANZCTRN12607000535471.aspx">ANZCTRN12607000535471</a>.</p

Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection

IMPORTANCE Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. OBJECTIVES To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. EXPOSURE SARS-CoV-2 detected via nucleic acid testing. MAIN OUTCOMES AND MEASURES Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. RESULTS Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference. 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; >= 7 symptoms: aOR, 4.59 [95% CI, 2.50 8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321[2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391[10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). CONCLUSIONS AND RELEVANCE In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.This studywas supported by grants from the Canadian Institutes of Health Research (operating grant: COVID-19-clinical management); the Alberta Health Services-University of Calgary-Clinical Research Fund; the Alberta Children's Hospital Research Institute; the COVID-19 Research Accelerator Funding Track (CRAFT) Program at the University of California, Davis; and the Cincinnati Children's Hospital Medical Center Division of Emergency Medicine Small Grants Program. Dr Funk is supported by the University of Calgary Eyes-High PostDoctoral Research Fund. Dr Freedman is supported by the Alberta Children's Hospital Foundation Professorship in Child Health andWellness

Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats

Introduction Hydrogen sulfide (H2S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H2S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H2S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses. Methods Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 ± 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-κB (NF-κB), phosphorylated Inhibitor κB (P-IκB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O2 -) were also measured by electron paramagnetic resonance. Results At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 ± 32 versus 101 ± 17 mmHg, P &lt; 0.05). CBF was better maintained in NaHS-treated rats (1.9 ± 1.6 versus 4.4 ± 1.9 ml/minute P &lt; 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IκB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O2 - release in both aorta and heart (P &lt; 0.05). Conclusions NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR)

Digital IAPT: the effectiveness & cost-effectiveness of internet-delivered interventions for depression and anxiety disorders in the Improving Access to Psychological Therapies programme: study protocol for a randomised control trial

BACKGROUND: Depression and anxiety are common mental health disorders worldwide. The UK's Improving Access to Psychological Therapies (IAPT) programme is part of the National Health Service (NHS) designed to provide a stepped care approach to treating people with anxiety and depressive disorders. Cognitive Behavioural Therapy (CBT) is widely used, with computerised and internet-delivered cognitive behavioural therapy (cCBT and iCBT, respectively) being a suitable IAPT approved treatment alternative for step 2, low- intensity treatment. iCBT has accumulated a large empirical base for treating depression and anxiety disorders. However, the cost-effectiveness and impact of these interventions in the longer-term is not routinely assessed by IAPT services. The current study aims to evaluate the clinical and cost-effectiveness of internet-delivered interventions for symptoms of depression and anxiety disorders in IAPT. METHODS: The study is a parallel-groups, randomised controlled trial examining the effectiveness and cost-effectiveness of iCBT interventions for depression and anxiety disorders, against a waitlist control group. The iCBT treatments are of 8 weeks duration and will be supported by regular post-session feedback by Psychological Wellbeing Practitioners. Assessments will be conducted at baseline, during, and at the end of the 8-week treatment and at 3, 6, 9, and 12-month follow-up. A diagnostic interview will be employed at baseline and 3-month follow-up. Participants in the waitlist control group will complete measures at baseline and week 8, at which point they will receive access to the treatment. All adult users of the Berkshire NHS Trust IAPT Talking Therapies Step 2 services will be approached to participate and measured against set eligibility criteria. Primary outcome measures will assess anxiety and depressive symptoms using the GAD-7 and PHQ-9, respectively. Secondary outcome measures will allow for the evaluation of long-term outcomes, mediators and moderators of outcome, and cost-effectiveness of treatment. Analysis will be conducted on a per protocol and intention-to-treat basis. DISCUSSION: This study seeks to evaluate the immediate and longer-term impact, as well as the cost effectiveness of internet-delivered interventions for depression and anxiety. This study will contribute to the already established literature on internet-delivered interventions worldwide. The study has the potential to show how iCBT can enhance service provision, and the findings will likely be generalisable to other health services. TRIAL REGISTRATION: Current Controlled Trials ISRCTN ISRCTN91967124. DOI: https://doi.org/10.1186/ISRCTN91967124 . Web: http://www.isrctn.com/ISRCTN91967124 . Clinicaltrials.gov : NCT03188575. Trial registration date: June 8, 2017 (prospectively registered)

Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies