A Pilot Randomized Controlled Trial of Transcendental Meditation as Treatment for Posttraumatic Stress Disorder in Veterans.

Preliminary studies have demonstrated the efficacy of Transcendental Meditation (TM) for treating posttraumatic stress disorder (PTSD). The present study extended previous research with a pilot trial of TM as a treatment for PTSD via a single-blinded, randomized controlled design. veterans with PTSD (N = 40) were assigned to a TM intervention or treatment-as-usual (TAU) control group. Participants in the TM group engaged in 16 sessions over 12 weeks, primarily in a 60-min group format. Change in PTSD symptoms, measured via the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) was the primary outcome. Secondary outcomes included self-reported PTSD symptoms, depression, anxiety, sleep difficulties, anger, and quality of life (QoL). Assessments were conducted at baseline and 3-month follow-up. Mean CAPS-5 score decreases were significantly larger for participants in the TM group (M = -11.28, 95% CI [-17.35, -5.20]), compared to the TAU group (M = -1.62, 95% CI [-6.77, 3.52]), p = .012, d = -0.84. At posttest, 50.0% of veterans in the TM group no longer met PTSD diagnostic criteria as compared to 10.0% in the TAU group, p = .007. Adjusted mean changes on self-report measures of PTSD symptoms, depression, anxiety, and sleep difficulties indicated significant reductions in the TM group compared to TAU, ds = .80-1.16. There were no significant group differences regarding anger or QoL. These findings demonstrate the efficacy of TM as a treatment for veterans with PTSD and for comorbid symptoms. Combined with other research, they suggest that TM may be a tolerable, non-trauma-focused PTSD treatment.

Anxiety symptoms and disease severity in children and adolescents with Crohn disease.

OBJECTIVES: Children and adolescents diagnosed as having Crohn disease (CD), a type of inflammatory bowel disease (IBD), have increased vulnerability for anxiety symptoms that may be related to disease-related processes. The aims of this article are 3-fold: to report the proportion of pediatric patients with CD whose self-reported anxiety symptoms are indicative of distress, to describe the constellation of anxiety symptoms, and to examine the relation between anxiety and disease symptoms. METHODS: Retrospective medical chart review was performed for 93 youths with CD (ages 9-18 years) who had completed the Screen for Child Anxiety Related Disorders during their gastroenterology visit. Medical records were reviewed for demographic and disease characteristics. the Harvey-Bradshaw Index (HBI) was used as a measure of CD activity. RESULTS: Thirty percent of the youths reported experiencing elevated anxiety symptoms (Screen for Child Anxiety Related Disorder score >20), and 50% had scored above the cutoff in 1 or more anxiety domains, with school anxiety, general anxiety, and separation anxiety symptoms reported most frequently. Youth rated with moderate/severe disease activity on the HBI (n = 4) self-reported more anxiety symptoms compared with youth with inactive disease (n = 78, P = 0.03). Greater school anxiety was significantly associated with decreased well-being (P = 0.003), more abdominal pain (P < 0.001), and the number of loose stools (P = 0.01). Having extraintestinal symptoms was significantly associated with higher somatic/panic anxiety (P = 0.01). CONCLUSIONS: Implementing a brief anxiety screen in tertiary pediatric settings may be one approach to identify young patients with CD in distress. Health care providers should consider periodic assessment of school anxiety among youth with CD.

Nimodipine-induced hypotension but not nitroglycerin-induced hypotension preserves long- and short-term memory in adult mice.

BACKGROUND: Acute hypotension may be implicated in cognitive dysfunction. L-type calcium channel blockers in the setting of hypoxia are protective of learning and memory. We tested the hypothesis that hypotension induced by nimodipine (NIMO) and nicardipine (NICA) would be protective of long- and short-term memory compared to hypotension induced by nitroglycerin (NTG). METHODS: Forty Swiss-Webster mice (30 to 35 g, 6 to 8 weeks) were randomized into 4 groups for i.p. injection immediately after passive avoidance (PA) learning on day 0: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. PA training latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock (0.3 mA; 2-second duration) was automatically delivered. On day 2 latencies were recorded during a testing trial during which no shock was delivered. Latencies >900 seconds were assigned this value. Lower testing latency is indicative of an impairment of long-term associative memory. Forty-nine additional mice were randomized into similar groups for object recognition testing (ORT) and given i.p. injections on day 0. ORT measures short-term memory by exploiting the tendency of mice to prefer novel objects where a familiar object is present. On day 5 during training, 2 identical objects were placed in a circular arena and mice explored both for 15 minutes. A testing trial was conducted 1 hour later for 3 minutes after a novel object replaced a familiar one. Mice with intact memory spend about 65% of the time exploring the novel object. Mice with impaired memory devote equal time to each object. Recognition index (RI) is defined as the ratio of time spent exploring the novel object to time spent exploring both objects was the measure of memory. Mean arterial blood pressure (MAP), cerebral bloodflow, and body and brain oxygenation (PO(2)) studies were done in separate groups of mice to determine the dosages for matched degrees of hypotension and the physiological profile of each treatment. RESULTS: The median PA latencies for the different conditions were as follows: NTG (219.5 ± 93.5 second semi-interquartile range [SIQR]), NICA (372.5 ± 75.5 second SIQR), NIMO (540 ± 200 second SIQR) and saline (804 ± 257.5 second SIQR). Rank methods were used to analyze the PA latencies for significant differences. NTG latency was significantly shorter than NIMO latency (P = 0.012) and saline latency (P = 0.006), but not NICA latency (P = 0.126). ORT RI values showed a similar pattern. We found that NTG RI (47.2 ± 5.9% SEM) was different from NIMO RI (60.2 ± 4.6% SEM, P = 0.031) and different from saline RI (66.9 + 3.7% SEM, P = 0.006). Physiological experiments showed that MAP decreased to 45 to 50 mm Hg in all animals who became minimally responsive to external stimuli within 10 to 15 minutes of injection. Intergroup differences for MAP, body and brain oxygenation, and cerebral bloodflow were not statistically significant. CONCLUSION: Acute hypotension induced by NIMO was protective of 2 categories of memory formation relevant to the clinical posttreatment period. Both immediate long-term associative memory consolidation as measured by the PA learning paradigm and delayed short-term working memory function as measured by the ORT paradigm were significantly improved compared to matched levels of hypotension induced by NTG. These results indicate the utility of further investigation of l-type calcium channel blockers as a potential means of preserving cognition in the setting of hypotensive and low flow states.

Nothing to Fear but Fear Itself: A Mechanistic Test of Unconscious Exposure.

BACKGROUND: While effective, exposure therapy can be distressing, which creates problems with treatment acceptance. Can exposure be effectively delivered unconsciously-and thus without causing phobic people to experience distress? No study has tested this hypothesis in a sufficiently rigorous experiment that selected between mechanisms for reducing fear unconsciously. METHODS: We conducted a psychophysiological experiment of an unconscious exposure intervention to discern its mechanism of therapeutic action. We identified 98 highly spider-phobic participants with a validated fear questionnaire and a Behavioral Avoidance Test in which they gradually approached and exhibited impairment of a live tarantula, which was indicative of a DSM-5 diagnosis of specific phobia. These participants were randomized to viewing unconscious exposure to spiders, visible exposure to spiders, or unconscious exposure to flowers (control). In a novel psychophysiological design, concurrent changes in sympathetic arousal and subjective fear were monitored throughout exposure. Shortly thereafter, phobic participants approached the tarantula again in order to measure exposure-induced changes in real-life avoidance behavior and experienced fear. RESULTS: Unconscious exposure did not induce concurrent changes in sympathetic arousal or subjective fear, and subsequently reduced fear of the tarantula. Visible exposure to the same phobic stimuli, by contrast, induced significant arousal and fear, but did not affect fear of the tarantula. Levels of arousal during exposure moderated effects on fear of the tarantula: lower arousal during unconscious exposure, but not during conscious exposure, predicted greater fear reduction. CONCLUSIONS: Unconscious exposure reduces fear by generating new implicit learning of nonaversive, stimulus-response associations that facilitate fear extinction in phobic persons.

Development and implementation of a simple and rapid extraction-free saliva SARS-CoV-2 RT-LAMP workflow for workplace surveillance.

Effective management of the COVID-19 pandemic requires widespread and frequent testing of the population for SARS-CoV-2 infection. Saliva has emerged as an attractive alternative to nasopharyngeal samples for surveillance testing as it does not require specialized personnel or materials for its collection and can be easily provided by the patient. We have developed a simple, fast, and sensitive saliva-based testing workflow that requires minimal sample treatment and equipment. After sample inactivation, RNA is quickly released and stabilized in an optimized buffer, followed by reverse transcription loop-mediated isothermal amplification (RT-LAMP) and detection of positive samples using a colorimetric and/or fluorescent readout. The workflow was optimized using 1,670 negative samples collected from 172 different individuals over the course of 6 months. Each sample was spiked with 50 copies/µL of inactivated SARS-CoV-2 virus to monitor the efficiency of viral detection. Using pre-defined clinical samples, the test was determined to be 100% specific and 97% sensitive, with a limit of detection of 39 copies/mL. The method was successfully implemented in a CLIA laboratory setting for workplace surveillance and reporting. From April 2021-February 2022, more than 30,000 self-collected samples from 755 individuals were tested and 85 employees tested positive mainly during December and January, consistent with high infection rates in Massachusetts and nationwide.

Does the MRI/fMRI Procedure Itself Confound the Results of Meditation Research? An Evaluation of Subjective and Neurophysiological Measures of TM Practitioners in a Simulated MRI Environment.

Early research into meditation, including Transcendental Meditation (TM), relied exclusively on EEG to measure brain activity during meditation practice. Since the advent of neural imaging, MRI, and later fMRI, have dominated this field. Unfortunately, the use of this technology rests on the questionable assumption that lying down in a confining tube while exposed to very loud sounds would not interfere with the meditation practice. The present study was designed to assess the effects of the fMRI procedure on both the subjective and neurophysiological responses of short and long-term TM practitioners. Twenty-three TM practitioners volunteered to participate in this study: 11 short-term meditators, averaging 2.2 years practice, and 12 long-term meditators, averaging 34.8 years. The repeated-measures design included two activities for each participant, eyes-closed rest, and TM practice, in each of three conditions: sitting quietly in an upright position (normal TM practice); lying quietly in a supine position; and lying, with earplugs, inside a simulated fMRI tube (simMRI), while exposed to 110 dB recordings of an actual fMRI machine. Subjective experiences were collected after each activity in each condition. Physiological arousal was recorded using skin conductance levels. Scalp EEG was averaged into eight frequency bands within frontal and parietal leads; eLORETA software was used to explore the 3-D cortical distribution of EEG sources. During the simMRI condition, participants reported having more shallow meditation experiences, and greater agitation/distraction. Skin conductance levels paralleled self-reports, decreasing least during the simMRI condition. Frontal and parietal power decreased from sitting to simMRI in the alpha2 through gamma bands. Parietal power was higher during rest compared to TM in the alpha1 through beta2 bands. Frontal and parietal alpha1 coherence were highest during the simMRI condition. The eLORETA analysis revealed that the default mode network was more active during TM when sitting compared to the simMRI condition. The responses to the supine condition were generally between sitting and simMRI, with some significant exceptions. In conclusion, these data indicate that the fMRI procedure itself (high dB noise; lying down) strongly influences subjective and neurophysiological responses during meditation practice, and may therefore confound the interpretation of results from fMRI studies.

Automated comparative auditing of NCIT genomic roles using NCBI.

Biomedical research has identified many human genes and various knowledge about them. The National Cancer Institute Thesaurus (NCIT) represents such knowledge as concepts and roles (relationships). Due to the rapid advances in this field, it is to be expected that the NCIT's Gene hierarchy will contain role errors. A comparative methodology to audit the Gene hierarchy with the use of the National Center for Biotechnology Information's (NCBI's) Entrez Gene database is presented. The two knowledge sources are accessed via a pair of Web crawlers to ensure up-to-date data. Our algorithms then compare the knowledge gathered from each, identify discrepancies that represent probable errors, and suggest corrective actions. The primary focus is on two kinds of gene-roles: (1) the chromosomal locations of genes, and (2) the biological processes in which genes play a role. Regarding chromosomal locations, the discrepancies revealed are striking and systematic, suggesting a structurally common origin. In regard to the biological processes, difficulties arise because genes frequently play roles in multiple processes, and processes may have many designations (such as synonymous terms). Our algorithms make use of the roles defined in the NCIT Biological Process hierarchy to uncover many probable gene-role errors in the NCIT. These results show that automated comparative auditing is a promising technique that can identify a large number of probable errors and corrections for them in a terminological genomic knowledge repository, thus facilitating its overall maintenance.

Engineering hypervirulence in a mycoherbicidal fungus for efficient weed control.

Agents proposed for biocontrol of major weeds in arable row-crop agriculture have not met expectations because an evolutionary balance has developed between microorganism and weed, even when the mycoherbicide is used inundatively at very high levels (>10(4)spores/cm<(2)). Sufficient virulence can be achieved by transferring genes to the microorganism, tipping the evolutionary balance. Virulence was increased ninefold and was more rapidly effected; furthermore, the requirement for a long duration at high humidity was decreased by introducing NEP1 encoding a phytotoxic protein, to an Abutilon theophrasti-specific, weakly mycoherbicidal strain of Colletotrichum coccodes. The parent strain was at best infective on juvenile cotyledons of this intransigent weed. The transgenic strain was lethal through the three-leaf stage, a sufficient time window to control this asynchronously germinating weed. Strategies of coupling virulence genes with fail-safe mechanisms to prevent spread (due to broadened host range) and to mitigate transgene introgression into crop pathogens could be very useful in the biocontrol of major weeds in row crops.

Why the resistance to statistical innovations? A comment on Sharpe (2013).

Sharpe's (2013) article considered reasons for the apparent resistance of substantive researchers to the adoption of newer statistical methods recommended by quantitative methodologists, and possible ways to reduce that resistance, focusing on improved communication. The important point that Sharpe missed, however, is that because research methods vary radically from one subarea of psychology to another, a particular statistical innovation may be much better suited to some subareas than others. Although there may be some psychological or logistical explanations that account for resistance to innovation in general, to fully understand the resistance to any particular innovation, it is necessary to consider how that innovation impacts specific subareas of psychology. In this comment, I focus on the movement to replace null hypothesis significance testing (NHST) with reports of effect sizes and/or confidence intervals, and consider its possible impact on research in which only the direction of the effect is meaningful, and there is no basis for predicting specific effect sizes (and very large samples are rarely used). There are numerous examples of these studies in social psychology, for instance, such as those that deal with priming effects. I use a study in support of terror management theory as my main example. I conclude that the degree to which statistical reformers have overgeneralized their criticisms of NHST, and have failed to tailor their recommendations to different types of research, may explain some of the resistance to abandoning NHST. Finally, I offer suggestions for improved communication to supplement those presented by Sharpe. (PsycINFO Database Record

Mitral Valve Replacement With Sapien 3 Transcatheter Valve in Severe Mitral Annular Calcification.

Transcatheter valve implantation in the mitral position with severe calcific mitral stenosis has been described in patients who are at an increased risk for conventional mitral valve surgical procedures. We report the direct deployment of the Sapien 3 valve in the mitral position with severe mitral annular calcification through a sternotomy in an arrested heart in two cases.

Predictive value of grade point average (GPA), Medical College Admission Test (MCAT), internal examinations (Block) and National Board of Medical Examiners (NBME) scores on Medical Council of Canada qualifying examination part I (MCCQE-1) scores.

BACKGROUND: To determine whether the pre-medical Grade Point Average (GPA), Medical College Admission Test (MCAT), Internal examinations (Block) and National Board of Medical Examiners (NBME) scores are correlated with and predict the Medical Council of Canada Qualifying Examination Part I (MCCQE-1) scores. METHODS: Data from 392 admitted students in the graduating classes of 2010-2013 at University of Manitoba (UofM), College of Medicine was considered. Pearson's correlation to assess the strength of the relationship, multiple linear regression to estimate MCCQE-1 score and stepwise linear regression to investigate the amount of variance were employed. RESULTS: Complete data from 367 (94%) students were studied. The MCCQE-1 had a moderate-to-large positive correlation with NBME scores and Block scores but a low correlation with GPA and MCAT scores. The multiple linear regression model gives a good estimate of the MCCQE-1 (R2 =0.604). Stepwise regression analysis demonstrated that 59.2% of the variation in the MCCQE-1 was accounted for by the NBME, but only 1.9% by the Block exams, and negligible variation came from the GPA and the MCAT. CONCLUSIONS: Amongst all the examinations used at UofM, the NBME is most closely correlated with MCCQE-1.

Needs assessment: towards a more responsive Canadian Society of Nephrology Annual General Meeting (CSN AGM) program.

BACKGROUND: A critical feature of any continuing medical education (CME) program is the inclusion of a needs assessment for its target audience. This assessment must identify both perceived and unperceived needs, so as to best capture the entire spectrum of learning opportunities for the group. OBJECTIVE: We describe the process developed by the Canadian Society of Nephrology (CSN) to enhance the educational effectiveness of its Annual General Meeting program. DESIGN: The design of this study is the analysis of a survey questionnaire and of the Canadian Organ Replacement Registry (CORR) database. PARTICIPANTS: We surveyed members of the CSN and analyzed patient data from CORR aggregated by center. MEASUREMENTS: We tabulated votes in the survey by topic. We assessed the extent to which centers achieved CSN guideline targets on the clinical management of patients on dialysis. METHODS: Perceived needs: a CSN panel constructed a list of topics, which was amplified by the inclusion of topics based on members' text responses to open-ended questions during previous iterations of this process. CSN members specified their top five choices, using an online survey instrument. Unperceived needs: an expert panel determined achievable thresholds for a number of quality metrics associated with dialysis. The quality metrics were identified from CSN guidelines. Using patient data in the CORR database, we generated center-specific performance estimates for each quality metric and constructed ratios comparing the performance of each center with the achievable threshold. We triangulated the results of the two assessments. RESULTS: The response rate for the perceived needs assessment survey was 16 %. This assessment identified "Primary and Secondary Glomerulonephritis" as the non-dialysis topics and "Infectious Complications of Dialysis Access" and "Volume Status and Hypertension on Dialysis" as the dialysis topics with the highest perceived learning needs. In the unperceived needs assessment, "Vascular Access Type" and "Vascular Access Monitoring" were identified as having the highest learning needs. Triangulation identified "Vascular Access Type" and "Vascular Access Monitoring" as high needs topics. LIMITATIONS: Perceived needs assessment: Some topics were much more general than others, which could have led to over-selection. The response rate of 16 % limits the robustness of generalization to the membership as a whole or to all meeting attendees. Unperceived needs assessment: The assessment was limited by the data that CORR actually collects; many aspects of general nephrology practice, including glomerulonephritis, are not covered. The level of evidence underlying the various guidelines was variable, and in some cases, poor. A validated approach to data analysis in this area is lacking. CONCLUSIONS: To our knowledge, this is the first published example of a needs assessment for a nephrology CME event that considers both the perceived and unperceived needs of the membership. The results of this exercise are currently being used to assist in the development of a more responsive CME program.

CONTEXTE: Un aspect crucial de tout programme d'enseignement médical continu (EMC) est l'inclusion d'une évaluation des besoins de la clientèle cible. Cet examen se doit de permettre l'identification tant des besoins perçus que des besoins non perçus afin de mieux cerner les occasions d'apprentissage pour le groupe. OBJECTIFS DE L'ÉTUDE: Cet article fait la description de la démarche mise au point par la Société de Néphrologie du Canada (SNC) dans le cadre du programme de son assemblée générale annuelle. Cette démarche vise accroître l'efficacité de la formation. PLAN DE L'ÉTUDE: On a procédé à l'analyse des réponses obtenues lors d'une enquête auprès des membres ainsi qu'à la consultation des métadonnées du Registre Canadien des Insuffisances et des Transplantations d'Organes (RCITO). PARTICIPANTS: Le sondage a été mené auprès des membres de la SCN et on a procédé à l'examen des données du RCITO cumulées dans chaque centre de soins. MESURES: La compilation des réponses au sondage a été effectuée par catégories. Nous avons également évalué dans quelle mesure avaient été atteints les objectifs d'orientation fixés par les lignes directrices de la SCN quant à la conduite du traitement clinique des patients sous dialyse. MÉTHODOLOGIE: Un premier volet s'attardait à définir les besoins perçus. Pour ce faire, le comité de la SCN a dressé une liste de thèmes. Cette liste s'est par la suite allongée avec l'ajout de sujets tirés des réponses des membres aux questions ouvertes colligées lors des versions antérieures du sondage. Les membres de la SCN ont spécifié les cinq thèmes qu'ils jugeaient les plus importants par le biais d'un instrument de sondage en ligne. Un second volet se penchait sur les besoins non perçus. Dans ce deuxième cas, un groupe d'experts a déterminé les seuils réalisables pour un certain nombre de paramètres de la qualité associés à la dialyse. L'identification de ces paramètres était tirée des lignes directrices de la SCN. À l'aide des données des patients contenues dans le RCITO, une appréciation de la performance de chaque centre de soins a été produite pour chacun des paramètres identifiés. Des ratios ont ensuite été construits en comparant la performance de chaque centre de soins avec le seuil réalisable établi précédemment. De plus, les résultats des deux analyses ont été triangulés. RÉSULTATS: Le taux de réponse pour le sondage sur l'analyse des besoins perçus a été de 16 %. Cet examen a permis d'identifier les besoins perçus à considérer en matière de formation pour les futurs néphrologues. Du côté des sujets non reliés directement à la dialyse elle-même, on retrouve la glomérulonéphrite primaire et secondaire ainsi que les complications infectieuses liées au cathéter. Quant aux sujets directement reliés à la dialyse, on a pu identifier la volémie et l'hypertension en dialyse. En ce qui concerne les besoins non perçus, le type d'accès vasculaire et la surveillance de celui-ci ont été identifiés comme étant des sujets important à couvrir lors de la formation. Ces deux derniers sujets sont également ressortis comme très importants à considérer dans les besoins de formation lors de la triangulation des résultats. LIMITES DE L'ÉTUDE: Dans le cas des besoins perçus, certains sujets étaient de nature très générale et ceci pourrait avoir conduit à une sélection excessive. Qui plus est, le très faible taux de réponse limite la robustesse d'une généralisation des résultats à tous les membres ayant participé à l'assemblée. Du côté des besoins non perçus, l'analyse est limitée par les données du RCITO où plusieurs aspects de la pratique générale en néphrologie, notamment la prise en charge de la glomérulonéphrite, ne sont pas couverts. Le degré d'éléments probants sous-jacent les différents principes directeurs s'est avéré variable et dans certains cas, médiocre. Une approche validée face à l'analyse des données dans ce domaine est manquante. CONCLUSIONS: À notre connaissance, cette enquête constitue la première analyse publiée des besoins, réalisée lors d'un événement d'EMC en néphrologie, qui prend en considération les besoins perçus et non perçus de ses membres. Les résultats de cet exercice sont actuellement utilisés dans le développement d'un programme d'EMC mieux adapté.

Patient-reported Anxiety: A Possible Predictor of Pediatric Inflammatory Bowel Disease Health Care Use.

BACKGROUND: Anxiety is linked with adverse health-related outcomes and increased health-seeking behaviors among patients with chronic illness. Yet, this relationship has received little attention in pediatric inflammatory bowel disease. The aim of this study was to examine whether anxiety symptoms predicted youth at increased risk for repeated disease relapse and greater gastrointestinal health care use over the subsequent 12 months. METHODS: Eighty-six pediatric patients aged 11 to 18 years (M = 14.7, SD = 2.0), and their caregivers completed a validated anxiety questionnaire during a gastrointestinal specialty appointment (baseline). Medical records were reviewed for the subsequent year to record the number of disease relapses and gastrointestinal health care services and generate disease activity scores at baseline and 12 months. Analysis of variance was used to examine anxiety levels between those who experienced ≤1 versus ≥2 disease relapses. Poisson regressions were used to model the relationship between child- and caregiver-reported anxiety and health care use, controlling for disease activity. RESULTS: The sample was predominantly white (81%) and male (56%). Patients with higher anxiety at baseline (M = 19.6; SD = 13.7) had more frequent (≥2) disease relapses compared with those with lower anxiety at baseline (M = 12.6; SD = 10.3). Higher anxiety, irrespective of reporter, also predicted greater total gastrointestinal health care use (P < 0.01). This included hospital-based interventions (P < 0.01), but not office encounters or outpatient endoscopic procedures. Findings remained significant after controlling for disease severity (P < 0.05). CONCLUSIONS: Assessment of anxiety may be one mechanism by which to identify those youth who are most vulnerable for disease exacerbation and costly interventions in the near future.

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.

BACKGROUND: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. METHODS: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. RESULTS: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. CONCLUSIONS: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00957359.

Performance of currently available risk models in a cohort of mechanically supported high-risk percutaneous coronary intervention--From the PROTECT II randomized trial.

BACKGROUND: Procedural risk scores facilitate clinical decision making by using individual patient characteristics to estimate the risk of adverse events. The performance of PCI-based risk scores is not well-described among patients undergoing hemodynamically supported high risk PCI. METHODS AND RESULTS: A total of 427 patients with unprotected left main disease, last remaining vessel or three-vessel disease with severely reduced left ventricular function underwent supported high-risk PCI with an intra-aortic balloon pump (IABP, N = 211) or a left ventricular assist device (Impella 2.5, N = 216) as part of the PROTECT II trial. We examined the performance of the additive Euroscore, logistic Euroscore, STS mortality score, STS morbidity and mortality score, Mayo Clinic risk score and New York state PCI risk score on the endpoint of 90-day mortality in this unique high-risk population. Mean age was 67.2 ± 10.9 years; 65.8% of patients were in NYHA class III/IV, and mean LVEF was 24%. All-cause 90-day mortality was 10.4%. The scores were generally correlated (p < 0.0001 for all comparisons), with R(2) values ranging from 0.28 (STS morbidity/mortality and Mayo Clinic) to 0.68 (logistic Euroscore and STS mortality). However, receiver-operator curves for 90-day all-cause mortality for all risk scores demonstrated poor discriminatory performance with c-statistics of 0.542-0.616. Calibration of the risk scores was not poor, but varied according to the specific score examined. CONCLUSION: The discriminatory capacity of currently available risk models is suboptimal when applied to a cohort of mechanically supported complex high-risk PCI. A risk score designed specifically for this population could help to further refine risk assessment.

Risk factors for progression of aortic atheroma in stroke and transient ischemic attack patients.

BACKGROUND AND PURPOSE: Aortic atheroma is an independent risk factor for stroke and undergoes temporal progression. Clinical and risk factor associations of such progression are unknown. Hyperhomocysteinemia has been linked with atherosclerosis, including that in the cerebral vasculature. This study investigated associations between elevated homocysteine levels and other stroke vascular risk factors and the risk of aortic atheroma progression in patients with cerebrovascular disease. METHODS: Fifty-seven stroke and 21 transient ischemic attack patients underwent multiplanar transesophageal echocardiograms within 1 month of symptom onset and again at 9 months. Aortic atheroma was graded and stratified by use of existing criteria. Stroke risk factors; use of anticoagulant, antiplatelet, and hypolipidemic drugs; and clinical and etiological subtypes of stroke were recorded and compared in patients stratified for the presence or absence of aortic atheroma progression. RESULTS: Of the 78, 29 (37%) progressed, 32 (41%) remained unchanged, and 17 (22%) regressed. Progression was most marked at the aortic arch (P=0.005), followed by the ascending segment (P<0.04). In nearly two thirds of the patients in whom aortic atheroma remained unchanged over 9 months, no atheroma was evident on baseline transesophageal echocardiogram. Only homocysteine levels > or =14.0 micromol/L (P=0.02), total anterior cerebral infarct (P=0.02), and large-artery atherosclerosis (P=0.005) significantly correlated with progression. CONCLUSIONS: Among vascular risk factors, elevated homocysteine levels are associated with aortic atheroma progression. Stroke and transient ischemic attack patients with aortic atheroma should undergo assessment of homocysteine levels, which, if elevated, may be treated with vitamins in an effort to arrest aortic atheroma progression.

Natural selection and algorithmic design of mRNA.

Messenger RNA (mRNA) sequences serve as templates for proteins according to the triplet code, in which each of the 4(3) = 64 different codons (sequences of three consecutive nucleotide bases) in RNA either terminate transcription or map to one of the 20 different amino acids (or residues) which build up proteins. Because there are more codons than residues, there is inherent redundancy in the coding. Certain residues (e.g., tryptophan) have only a single corresponding codon, while other residues (e.g., arginine) have as many as six corresponding codons. This freedom implies that the number of possible RNA sequences coding for a given protein grows exponentially in the length of the protein. Thus nature has wide latitude to select among mRNA sequences which are informationally equivalent, but structurally and energetically divergent. In this paper, we explore how nature takes advantage of this freedom and how to algorithmically design structures more energetically favorable than have been built through natural selection. In particular: (1) Natural Selection--we perform the first large-scale computational experiment comparing the stability of mRNA sequences from a variety of organisms to random synonymous sequences which respect the codon preferences of the organism. This experiment was conducted on over 27,000 sequences from 34 microbial species with 36 genomic structures. We provide evidence that in all genomic structures highly stable sequences are disproportionately abundant, and in 19 of 36 cases highly unstable sequences are disproportionately abundant. This suggests that the stability of mRNA sequences is subject to natural selection. (2) Artificial Selection--motivated by these biological results, we examine the algorithmic problem of designing the most stable and unstable mRNA sequences which code for a target protein. We give a polynomial-time dynamic programming solution to the most stable sequence problem (MSSP), which is asymptotically no more complex than secondary structure prediction. We show that the corresponding least stable sequence problem (LSSP) is NP-complete, and develop two heuristics for the construction of such sequences. We have implemented these algorithms, and present experimental results placing the high/low stability sequences in context with both wildtype and random encodings. Our implementation has already been applied to the design of RNA "code-words" creating little or no secondary structure in RNA computing (Brenneman and Condon, 2001; Marathe et al., 2001), and we anticipate a variety of other applications of this work to sequence design problems (Skiena, 2001).

Computed tomography angiographic correlates of early computed tomography signs in acute ischemic stroke.

BACKGROUND AND PURPOSE: Early computed tomography (CT) signs of stroke signify major arterial occlusion. CT angiogram (CTA) is useful in detecting major arterial occlusion and may help triaging patients for intra-arterial thrombolysis. The correlation between the early signs of stroke and arterial occlusion on CTA was studied. METHODS: Consecutive patients with suspected acute anterior circulation ischemic stroke presenting within 6 hours of symptom onset underwent noncontrast CT of the head followed by CTA. The scans were later reviewed for evidence of early signs of stroke on CT scan and intracranial arterial occlusion on CTA. RESULTS: Sixteen of 65 patients had arterial occlusion on CTA; 12 (75%) of these showed the early CT signs of stroke. All the early signs except M2 "dot" sign significantly correlated with middle cerebral artery (MCA) occlusion on CTA. Hyperdense MCA sign was the only independent predictor of a MCA occlusion. CONCLUSION: In a small sample, early CT signs of stroke strongly correlated with arterial occlusion, with hyperdense MCA sign being the most predictive of a MCA occlusion.

Transgenically enhanced expression of indole-3-acetic Acid confers hypervirulence to plant pathogens.

ABSTRACT Fusarium oxysporum and F. arthrosporioides, pathogenic on Orobanche aegyptiaca, were transformed with two genes of the indole-3-acetamide (IAM) pathway leading to indole-3-acetic acid (IAA) to attempt to enhance virulence. Transgenic F. oxysporum lines containing both the tryptophan-2-monooxyngenase (iaaM) and indole-3-acetamide hydrolase (iaaH) genes produced significantly more IAA than the wild type. IAM accumulated in culture extracts of F. oxysporum containing iaaM alone. F. arthrosporioides containing only iaaM accumulated IAM and an unidentified indole. Some transformants of F. oxysporum expressing only the iaaM gene also produced more IAA than the wild type. Sub-threshold levels (that barely infect Orobanche) of transgenic F. oxysporum expressing both genes and of F. arthrosporioides expressing iaaM were more effective in suppressing the number and size of Orobanche shoots than the wild type on tomato plants grown in soil mixed with Orobanche seed. Stimulating an auxin imbalance enhanced pathogen virulence by affecting the host in a manner similar to low doses of auxin herbicides such as 2,4-dichlorophenoxy acetic acid.

From Agrobacterium to viral vectors: genome modification of plant cells by rare cutting restriction enzymes.

Researchers and biotechnologists require methods to accurately modify the genome of higher eukaryotic cells. Such modifications include, but are not limited to, site-specific mutagenesis, site-specific insertion of foreign DNA, and replacement and deletion of native sequences. Accurate genome modifications in plant species have been rather limited, with only a handful of plant species and genes being modified through the use of early genome-editing techniques. The development of rare-cutting restriction enzymes as a tool for the induction of site-specific genomic double-strand breaks and their introduction as a reliable tool for genome modification in animals, animal cells and human cell lines have paved the way for the adaptation of rare-cutting restriction enzymes to genome editing in plant cells. Indeed, the number of plant species and genes which have been successfully edited using zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and engineered homing endonucleases is on the rise. In our review, we discuss the basics of rare-cutting restriction enzyme-mediated genome-editing technology with an emphasis on its application in plant species.