Protocol for a randomized controlled trial examining multilevel prediction of response to behavioral activation and exposure-based therapy for generalized anxiety disorder.

BACKGROUND: Only 40-60% of patients with generalized anxiety disorder experience long-lasting improvement with gold standard psychosocial interventions. Identifying neurobehavioral factors that predict treatment success might provide specific targets for more individualized interventions, fostering more optimal outcomes and bringing us closer to the goal of "personalized medicine." Research suggests that reward and threat processing (approach/avoidance behavior) and cognitive control may be important for understanding anxiety and comorbid depressive disorders and may have relevance to treatment outcomes. This study was designed to determine whether approach-avoidance behaviors and associated neural responses moderate treatment response to exposure-based versus behavioral activation therapy for generalized anxiety disorder. METHODS/DESIGN: We are conducting a randomized controlled trial involving two 10-week group-based interventions: exposure-based therapy or behavioral activation therapy. These interventions focus on specific and unique aspects of threat and reward processing, respectively. Prior to and after treatment, participants are interviewed and undergo behavioral, biomarker, and neuroimaging assessments, with a focus on approach and avoidance processing and decision-making. Primary analyses will use mixed models to examine whether hypothesized approach, avoidance, and conflict arbitration behaviors and associated neural responses at baseline moderate symptom change with treatment, as assessed using the Generalized Anxiety Disorder-7 item scale. Exploratory analyses will examine additional potential treatment moderators and use data reduction and machine learning methods. DISCUSSION: This protocol provides a framework for how studies may be designed to move the field toward neuroscience-informed and personalized psychosocial treatments. The results of this trial will have implications for approach-avoidance processing in generalized anxiety disorder, relationships between levels of analysis (i.e., behavioral, neural), and predictors of behavioral therapy outcome. TRIAL REGISTRATION: The study was retrospectively registered within 21 days of first participant enrollment in accordance with FDAAA 801 with ClinicalTrials.gov, NCT02807480. Registered on June 21, 2016, before results.

Brain Mechanisms of Social Threat Effects on Working Memory.

Social threat can have adverse effects on cognitive performance, but the brain mechanisms underlying its effects are poorly understood. We investigated the effects of social evaluative threat on working memory (WM), a core component of many important cognitive capabilities. Social threat impaired WM performance during an N-back task and produced widespread reductions in activation in lateral prefrontal cortex and intraparietal sulcus (IPS), among other regions. In addition, activity in frontal and parietal regions predicted WM performance, and mediation analyses identified regions in the bilateral IPS that mediated the performance-impairing effects of social threat. Social threat also decreased connectivity between the IPS and dorsolateral prefrontal cortex, while increasing connectivity between the IPS and the ventromedial prefrontal cortex, a region strongly implicated in the generation of autonomic and emotional responses. Finally, cortisol response to the stressor did not mediate WM impairment but was rather associated with protective effects. These results provide a basis for understanding interactions between social and cognitive processes at a neural systems level.

Single-incision pediatric endosurgical epigastric hernia repair.

PURPOSE: Epigastric hernias represent about 4 % of all abdominal hernias in children and require surgical repair. Traditionally, these hernias are repaired by an open surgical technique. More recently, laparoscopic epigastric hernia repairs have been described using two trocars in the upper abdomen. In this paper, we describe a novel single-incision pediatric endosurgical (SIPES) technique. METHODS: Patients with symptomatic epigastric hernias that were deemed to be too far superior to be repaired with an open technique through an umbilical incision were selected for SIPES repair. Two trocars (5 and 3 mm) were introduced through a single umbilical incision and the hernia repair was performed using looped 4-0 polypropylene sutures introduced through a 17-gage spinal needle in a lasso technique. RESULTS: Five girls (age 4.4-12.6, median 6.4 years) underwent single-incision endosurgical epigastric hernia repair. The mean operative time was 25 ± 6 min, and there were no intraoperative complications. All patients were discharged home from the recovery room on the day of surgery. All patients were followed up 2-3 weeks after the operation, with no recurrence and excellent cosmetic results. CONCLUSIONS: The described SIPES technique offers a virtually scarless, quick, and simple option for the repair of symptomatic epigastric hernias that can be performed with standard laparoscopic equipment.

Field-directed sputter sharpening for tailored probe materials and atomic-scale lithography.

Fabrication of ultrasharp probes is of interest for many applications, including scanning probe microscopy and electron-stimulated patterning of surfaces. These techniques require reproducible ultrasharp metallic tips, yet the efficient and reproducible fabrication of these consumable items has remained an elusive goal. Here we describe a novel biased-probe field-directed sputter sharpening technique applicable to conductive materials, which produces nanometer and sub-nanometer sharp W, Pt-Ir and W-HfB(2) tips able to perform atomic-scale lithography on Si. Compared with traditional probes fabricated by etching or conventional sputter erosion, field-directed sputter sharpened probes have smaller radii and produce lithographic patterns 18-26% sharper with atomic-scale lithographic fidelity.

Symptom Dimensions in Two Samples of Africans Americans with Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a leading cause of disability worldwide, however, there is a lack of research that includes African Americans, thus it is unclear whether findings about symptom dimensions can be generalized to this population. A sample of adult African Americans with OCD (N=74) was recruited at the University of Pennsylvania (Penn) and administered the Yale Brown Obsessive-Compulsive checklist (YBOCS) to better understand the phenomenology of OCD in African Americans. Frequencies of symptoms are reported and compared to findings from the National Survey of American Life (NSAL; N=54). A principal components analysis of YBOCS categories and items was performed on the Penn sample. A six-component solution was found, that included Contamination & Washing, Hoarding, Sexual Obsessions & Reassurance, Aggression & Mental Compulsions, Symmetry & Perfectionism, and Doubt & Checking, explaining 59.1% of the variance. Factors identified were similar to those of previous studies in primarily white samples. African Americans with OCD reported more contamination symptoms and were twice as likely to report excessive concerns with animals as European Americans with OCD. The results indicate the presence of cultural differences, which is consistent with findings among non-clinical samples. Implications of these findings are discussed.

The unbearable lightness of citizens within public deliberation processes.

There is a growing literature examining the involvement of citizens in health policymaking. While determining what form such involvement should take and who should participate is of particular interest to policymakers and researchers, the current ontological understanding of what a citizen is suffers from "lightness." This essay thus seeks to provide more depth by shedding light on the ways in which individuals define what "being" a citizen means for them and choose to embody or not such a role. Inspired by a four-year ethnographic study of a Canadian science/policy network in genetics, which integrated citizens into its operation, this paper provides four biographical sketches that portray the complexity and richness of what these individuals were "made of." We reflect on how they sought to make sense of their participation in the network by drawing on a repertoire of cultural, relational and cognitive resources and on their lived experience. Their capacity to "be" a participant and to be acknowledged as such by the others was shaped by their values and interests and by the contributions they sought to realise throughout their participation. Our discussion suggests that the quest for the "ordinary" citizen is misleading. Instead, acknowledging the sociological concreteness of citizenship and understanding how it may be embodied and exercised should be a key focus in public involvement theory and practice in health care.

Esophageal tolerance to high-dose stereotactic ablative radiotherapy.

Dose-volume parameters are needed to guide the safe administration of stereotactic ablative radiotherapy (SABR). We report on esophageal tolerance to high-dose hypofractionated radiation in patients treated with SABR. Thirty-one patients with spine or lung tumors received single- or multiple-fraction SABR to targets less than 1 cm from the esophagus. End points evaluated include D(5cc) (minimum dose in Gy to 5 cm(3) of the esophagus receiving the highest dose), D(2cc) , D(1cc) , and D(max) (maximum dose to 0.01 cm(3) ). Multiple-fraction treatments were correlated using the linear quadratic and linear quadratic-linear/universal survival models. Three esophageal toxicity events occurred, including esophagitis (grade 2), tracheoesophageal fistula (grade 4-5), and esophageal perforation (grade 4-5). Chemotherapy was a cofactor in the high-grade events. The median time to development of esophageal toxicity was 4.1 months (range 0.6-6.1 months). Two of the three events occurred below a published D(5cc) threshold, all three were below a D(2cc) threshold, and one was below a D(max) threshold. We report a dosimetric analysis of incidental dose to the esophagus from SABR. High-dose hypofractionated radiotherapy led to a number of high-grade esophageal adverse events, suggesting that conservative parameters to protect the esophagus are necessary when SABR is used, especially in the setting of chemotherapy or prior radiotherapy.

Analyzing the influence of institutions on health policy development in Uganda: a case study of the decision to abolish user fees.

BACKGROUND: During the 2001 election campaign, President Yoweri Museveni announced he was abolishing user fees for health services in Uganda. No analysis has been carried out to explain how he was able to initiate such an important policy decision without encountering any immediate barriers. OBJECTIVE: To explain this outcome through in-depth policy analysis driven by the application of key analytical frameworks. METHODS: An explanatory case study informed by analytical frameworks from the institutionalism literature was undertaken. Multiple data sources were used including: academic literature, key government documents, grey literature, and a variety of print media. RESULTS: According to the analytical frameworks employed, several formal institutional constraints existed that would have reduced the prospects for the abolition of user fees. However, prevalent informal institutions such as "Big Man" presidentialism and clientelism that were both 'competing' and 'complementary' can be used to explain the policy outcome. The analysis suggests that these factors trumped the impact of more formal institutional structures in the Ugandan context. CONCLUSION: Consideration should be given to the interactions between formal and informal institutions in the analysis of health policy processes in Uganda, as they provide a more nuanced understanding of how each set of factors influence policy outcomes.

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition.

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.

Biochemical and genetic analyses of the U5, U6, and U4/U6 x U5 small nuclear ribonucleoproteins from Saccharomyces cerevisiae.

We have purified the yeast U5 and U6 pre-mRNA splicing small nuclear ribonucleoproteins (snRNPs) by affinity chromatography and analyzed the associated polypeptides by mass spectrometry. The yeast U5 snRNP is composed of the two variants of U5 snRNA, six U5-specific proteins and the 7 proteins of the canonical Sm core. The U6 snRNP is composed of the U6 snRNA, Prp24, and the 7 Sm-Like (LSM) proteins. Surprisingly, the yeast DEAD-box helicase-like protein Prp28 is stably associated with the U5 snRNP, yet is absent from the purified U4/U6 x U5 snRNP. A novel yeast U5 and four novel yeast U4/U6 x U5 snRNP polypeptides were characterized by genetic and biochemical means to demonstrate their involvement in the pre-mRNA splicing reaction. We also show that, unlike the human tri-snRNP, the yeast tri-snRNP dissociated upon addition of ATP or dATP.

Primary care in Canada: so much innovation, so little change.

The development of Canadian primary care has been shaped by a series of policy legacies that continue to affect the possibilities for change in primary care through their cumulative effects on the health care system and the process of health policy development. The pursuit of radical systemwide change in the face of unfavorable circumstances (created in large part by those legacies) has resulted in missed opportunities for cumulative incremental change. While major changes in primary care policy seem unlikely in the near future, significant incremental change is possible, but it will require a reorientation of the policy development process.

Understanding the role of contextual influences on local health-care decision making: case study results from Ontario, Canada.

Approaches to involving the public in local health care decision making processes (and analyses of these approaches) have tended to treat participation and publics uniformly in search of the ideal method of involving the public or providing the same opportunities for public participation regardless of differing socio-economic, cultural, insitutional or political contexts within which decisions are made. Less attention has been given to the potential for various contextual factors to influence both the methods employed and the outcomes of such community decision-making processes. The paper explores the role that context (three sets of contextual influences more specifically) plays in shaping community decision-making processes. Results from case studies of public participation in local health-care decision making in four geographic communities in Ontario are presented. During the study period, two of these communities were actively involved in health services restructuring processes while one had recently completed its process and the fourth had not yet engaged in one. Several themes emerge from the case studies regarding the identification and role of contextual influences in differentially shaping participation in local health care decision-making. These include the propensity for communities with different social and structural attributes to engage in different "styles" of participation; the importance attached to "community values" in shaping both the qualitative and quantitative aspects of participation: the role of health councils, local government and inter-organizational collaboration as participation "enablers"; and the politicization of participation that occurs around contentious issues such as hospital closures.

Characterization of U4 and U6 interactions with the 5' splice site using a S. cerevisiae in vitro trans-splicing system.

Spliceosome assembly has been characterized as the ordered association of the snRNP particles U1, U2, and U4/U6.U5 onto pre-mRNA. We have used an in vitro trans-splicing/cross-linking system in Saccharomyces cerevisiae nuclear extracts to examine the first step of this process, 5' splice site recognition. This trans-splicing reaction has ATP, Mg(2+), and splice-site sequence requirements similar to those of cis-splicing reactions. Using this system, we identified and characterized a novel U4-5' splice site interaction that is ATP-dependent, but does not require the branch point, the 3' splice site, or the 5' end of the U1 snRNA. Additionally, we identified several ATP-dependent U6 cross-links at the 5' splice site, indicating that different regions of U6 sample it before a U6-5' splice site interaction is stabilized that persists through the first step of splicing. This work provides evidence for ATP-dependent U4/U6 association with the 5' splice site independent of ATP-mediated U2 association with the branch point. Furthermore, it defines specific nucleotides in U4 and U6 that interact with the 5' splice site at this early stage, even in the absence of base-pairing with the U1 snRNA.

Group behavioral therapy of obsessive-compulsive disorder: seven vs. twelve-week outcomes.

Previous research has demonstrated that individualized behavioral exposure and response prevention therapy is an effective treatment for Obsessive-Compulsive Disorder. In our prior preliminary report, 7-week group exposure and response prevention therapy was also found effective in reducing obsessions and compulsions. The present report describes a larger sample (N=113) of treatment seeking obsessive-compulsives who received group behavioral therapy. As before, group exposure and response prevention significantly improved ratings of obsessions, compulsions, and depression. These improvements were maintained at 3-month and long-term follow-up. A sub-sample of patients who received 12 weeks of treatment had outcomes at the end of the group and at follow-up that did not significantly differ from those who received 7 weeks of treatment. These results confirm the efficacy of a 7-week behavioral treatment program administered in a group format.

Absence of an abrupt phase change from polycrystalline to amorphous in silicon with deposition temperature.

Using fluctuation electron microscopy, we have observed an increase in the mesoscopic spatial fluctuations in the diffracted intensity from vapor-deposited silicon thin films as a function of substrate temperature from the amorphous to polycrystalline regimes. We interpret this increase as an increase in paracrystalline medium-range order in the sample. A paracrystal consists of topologically crystalline grains in a disordered matrix; in this model the increase in ordering is caused by an increase in the grain size or density. Our observations are counter to the previous belief that the amorphous to polycrystalline transition is a discontinuous disorder-order phase transition.

Persistent respiratory irregularity in patients with panic disorder.

BACKGROUND: Dysregulated respiratory control may play a role in the pathophysiology of panic disorder. This could be due to abnormalities in brain stem respiratory nuclei or to dysregulation at higher brain levels. Results from previous studies using the doxapram model of panic have yielded an unclear picture. A brief cognitive manipulation reduced doxapram-induced hyperventilation in patients, suggesting that higher level inputs can substantially alter their respiratory patterns. However, respiratory abnormalities persisted, including a striking irregularity in breathing patterns. METHODS: To directly study respiratory irregularity, breath-by-breath records of tidal volume (V(t)) and frequency (f) from previously studied subjects were obtained. Irregularity was quantified using von Neumann's statistic and calculation of "sigh" frequency in 16 patients and 16 matched control subjects. Half of each group received a standard introduction to the study and half received a cognitive intervention designed to reduce anxiety/distress responses to the doxapram injection. RESULTS: Patients had significantly greater V(t) irregularity relative to control subjects. Neither the cognitive intervention nor doxapram-induced hyperventilation produced significant changes in V(t) irregularity. The V(t) irregularity was attributable to a sighing pattern of breathing that was characteristic of panic patients but not control subjects. Patients also had somewhat elevated f irregularity relative to control subjects. CONCLUSIONS: The irregular breathing patterns in panic patients appear to be intrinsic and stable, uninfluenced by induced hyperventilation or cognitive manipulation. Further study of V(t) irregularity and sighs are warranted in efforts to localize dysregulated neural circuits in panic to brain stem or midbrain levels.

Crystal structure of a DEAD box protein from the hyperthermophile Methanococcus jannaschii.

We have determined the structure of a DEAD box putative RNA helicase from the hyperthermophile Methanococcus jannaschii. Like other helicases, the protein contains two alpha/beta domains, each with a recA-like topology. Unlike other helicases, the protein exists as a dimer in the crystal. Through an interaction that resembles the dimer interface of insulin, the amino-terminal domain's 7-strand beta-sheet is extended to 14 strands across the two molecules. Motifs conserved in the DEAD box family cluster in the cleft between domains, and many of their functions can be deduced by mutational data and by comparison with other helicase structures. Several lines of evidence suggest that motif III Ser-Ala-Thr may be involved in binding RNA.

Dose response of arginine vasopressin to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is a peptide neurotransmitter that modulates hypothalamic-pituitary-adrenal (HPA) axis activity and may be involved in fear or anxiety states. Arginine vasopressin (AVP) also modulates HPA axis activity and may play a role in fear conditioning. Few human studies have examined interactions between CCK and AVP systems. To explore relationships between CCK-B receptor activation, the HPA axis response, and AVP release, a dose-response study using the CCK-B receptor agonist pentagastrin was conducted. Adrenocorticotropin (ACTH) and cortisol results have been previously reported and AVP data is presented here. Thirty-five healthy subjects were randomly assigned to receive placebo, or 0.2, 0.4, 0.6, or 0.8 microg/kg doses of pentagastrin. AVP release appeared to increase with increasing doses of the CCK-B agonist. However, this may have been due to a greater percentage of subjects releasing AVP in the higher dose groups, rather than a direct effect of dose on magnitude of response. AVP and ACTH responses were correlated, but AVP response alone could not account for the magnitude of the ACTH response. AVP release was significantly correlated with anxiety symptom responses. These findings suggest a possible role for the CCK-B receptor in AVP release, which may be at least partially separate from its role in modulation of the HPA axis. Further work is needed to determine whether these are physiologically meaningful interactions and to determine their functional implications.

Crystal structure of a dimeric archaeal splicing endonuclease.

The splicing endonuclease from Archaeoglobus fulgidus (AF) belongs to the homodimeric family of splicing endonucleases, thought to have evolved from the homotetrameric endonucleases. We report here the crystal structure of the AF endonuclease determined at 2.8 A. The crystal structure of the full-length AF endonuclease contains a homodimer, with each monomer consisting of two homologous repeats joined together by an extended polypeptide chain of ten amino acid residues. The C-terminal repeat has a strong homology to that of a single subunit of the previously determined homotetrameric tRNA splicing endonuclease from Methanococcus jannaschii (MJ), indicating its role in catalysis. The N-terminal repeat is a more degenerate form of the MJ enzyme. Thus the N-terminal repeat is a "non-active" endonuclease fold evolved from the "active" one. By detailed comparison of the structures of the N-terminal and the C-terminal repeats, the binding region for RNA substrates containing a bulge-helix-bulge motif can be identified. Based on the identified RNA-binding region, a cation-pi interaction is suggested to be responsible for coordinating activities between the two active sites. In addition, the full-length AF endonuclease can adopt a higher-ordered fibrous structure in solution, as revealed by the unusual crystallographic packing interactions and other biochemical analysis. This 4(3)-fold fibrous structure adopted by the full-length enzyme is inaccessible to the RNA substrate and is largely stabilized by the first 60 amino acid residues. A mutated form of AF endonuclease with its first 60 residues removed catalyzes the cleavage reaction at a significantly higher rate. Whether there is any role in vivo for this structure-mediated modulation of activity remains to be determined.

tRNA leucine identity and recognition sets.

Transfer RNAs (tRNAs) are grouped into two classes based on the structure of their variable loop. In Escherichia coli, tRNAs from three isoaccepting groups are classified as type II. Leucine tRNAs comprise one such group. We used both in vivo and in vitro approaches to determine the nucleotides that are required for tRNA(Leu) function. In addition, to investigate the role of the tRNA fold, we compared the in vivo and in vitro characteristics of type I tRNA(Leu) variants with their type II counterparts.A minimum of six conserved tRNA(Leu) nucleotides were required to change the amino acid identity and recognition of a type II tRNA(Ser) amber suppressor from a serine to a leucine residue. Five of these nucleotides affect tRNA tertiary structure; the G15-C48 tertiary "Levitt base-pair" in tRNA(Ser) was changed to A15-U48; the number of nucleotides in the alpha and beta regions of the D-loop was changed to achieve the positioning of G18 and G19 that is found in all tRNA(Leu); a base was inserted at position 47n between the base-paired extra stem and the T-stem; in addition the G73 "discriminator" base of tRNA(Ser) was changed to A73. This minimally altered tRNA(Ser) exclusively inserted leucine residues and was an excellent in vitro substrate for LeuRS. In a parallel experiment, nucleotide substitutions were made in a glutamine-inserting type I tRNA (RNA(SerDelta); an amber suppressor in which the tRNA(Ser) type II extra-stem-loop is replaced by a consensus type I loop). This "type I" swap experiment was successful both in vivo and in vitro but required more nucleotide substitutions than did the type II swap. The type I and II swaps revealed differences in the contributions of the tRNA(Leu) acceptor stem base-pairs to tRNA(Leu) function: in the type I, but not the type II fold, leucine specificity was contingent on the presence of the tRNA(Leu) acceptor stem sequence. The type I and II tRNAs used in this study differed only in the sequence and structure of the variable loop. By altering this loop, and thereby possibly introducing subtle changes into the overall tRNA fold, it became possible to detect otherwise cryptic contributions of the acceptor stem sequence to recognition by LeuRS. Possible reasons for this effect are discussed.