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Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations. Delandistrogene moxeparvovec is an investigational gene transfer therapy, developed to address the underlying cause of DMD. We report findings from Part 1 (52 weeks) of the two-part EMBARK trial (NCT05096221). Methods: Key inclusion criteria: Ambulatory patients aged ≥4-<8 years with a confirmed DMD mutation within exons 18–79 (inclusive); North Star Ambulatory Assessment (NSAA) score >16 and <29 at screening. Eligible patients were randomized 1:1 to intravenous delandistrogene moxeparvovec (1.33×1014 vg/kg) or placebo. The primary endpoint was change from baseline in NSAA total score to Week 52. Results: At Week 52 (n=125), the primary endpoint did not reach statistical significance, although there was a nominal difference in change from baseline in NSAA total score in the delandistrogene moxeparvovec (2.6, n=63) versus placebo groups (1.9, n=61). Key secondary endpoints (time to rise, micro-dystrophin expression, 10-meter walk/run) demonstrated treatment benefit in both age groups (4-5 and 6-7 years; p<0.05).There were no new safety signals, reinforcing the favorable and manageable safety profile observed to date. Conclusions: Based on the totality of functional assessments including the timed function tests, treatment with delandistrogene moxeparvovec indicates beneficial modification of disease trajectory.
OBJECTIVES/GOALS: Negative emotions (NE) play a pivotal role in addiction-related processes, including tobacco lapse during a quit attempt. Some NEs (e.g., shame, guilt) are posited to lead to a spiraling effect, whereby lapse predicts increased NEs leading to further lapse. This study goal is to examine associations between NEs and lapse. METHODS/STUDY POPULATION: This study examined associations between tobacco lapse and 13 distinct NEs among people who use tobacco and are trying to quit in two tobacco cessation studies. In Study 1, 220 adult (ages 18-74) cigarette users who identified as Black (50% female) participated in a 14-day study where ecological momentary assessment (with assessments approximately every 4 hours) was used to assess emotions and lapse in real-time and real-world settings. In Study 2, 288 adult (ages 18-71) cigarette users who were low socioeconomic status (51% White, 14% Black, 10% Hispanic, 49% female) participated in a 14-day study with the same study protocol as Study 1. Between and lagged within-person associations testing links between distinct NEs and lapse were examined with multilevel modeling with logistic links for binary outcomes. RESULTS/ANTICIPATED RESULTS: Results from Study 1 suggested that at the between-person level, disgust (OR =1.22, CI: 1.05, 1.42), nervousness (OR=1.23, CI:1.05,1.43), guilt (OR=1.40, CI: 1.16,1.69), and sadness (OR=1.18, CI:1.02,1.36) were predictive of higher odds of lapse, and at the within-person level, shame (OR=1.23, CI:1.04,1.45) was associated with higher odds of lapse. Results from Study 2 were similar and suggested that at the between-person level, disgust (OR=1.35, CI: 1.16, 1.56) and guilt (OR=1.88, CI:1.07,3.30), and at the within-person level, shame (OR =1.31, CI:1.10,1.55), were associated with higher odds of lapse. DISCUSSION/SIGNIFICANCE: The present study uses real-time, real-world data to demonstrate the role of distinct NEs on momentary tobacco lapse and helps elucidate specific NE that hinder the ability to abstain from tobacco use during a quit attempt. Results suggest that disgust, guilt, and shame play consistent roles in predicting lapse among diverse samples of tobacco users.
This study investigated the association between early extubation (EE) and the degree of postoperative intensive care unit (ICU) support after the Fontan procedure, specifically evaluating the volume of postoperative intravenous fluid (IVF) and vasoactive-inotropic score (VIS).
Methods:
Retrospective analysis of patients who underwent Fontan palliation from 2008 to 2018 at a single center was completed. Patients were initially divided into pre-institutional initiative towards EE (control) and post-initiative (modern) cohorts. Differences between the cohorts were assessed using t-test, Wilcoxon, or chi-Square. Following stratification by early or late extubation, four groups were compared via ANOVA or Kruskal-Wallis Test.
Results:
There was a significant difference in the rate of EE between the control and modern cohorts (mean 42.6 versus 75.7%, p = 0.01). The modern cohort demonstrated lower median VIS (5 versus 8, p = 0.002), but higher total mean IVF (101±42 versus 82 ±27 cc/kg, p < 0.001) versus control cohort. Late extubated (LE) patients in the modern cohort had the highest VIS and IVF requirements. This group received 67% more IVF (140 ± 53 versus 84 ± 26 cc/kg, p < 0.001) and had a higher median VIS at 24 hours (10 (IQR, 5–10) versus 4 (IQR, 2–7), p < 0.001) versus all other groups. In comparison, all EE patients had a 5-point lower median VIS when compared to LE patients (3 versus 8, p= 0.001).
Conclusions:
EE following the Fontan procedure is associated with reduced post-operative VIS. LE patients in the modern cohort received more IVF, potentially identifying a high-risk subgroup of Fontan patients deserving of further investigation.
Cooperation among militant organizations contributes to capability but also presents security risks. This is particularly the case when organizations face substantial repression from the state. As a consequence, for cooperation to emerge and persist when it is most valuable, militant groups must have means of committing to cooperation even when the incentives to defect are high. We posit that shared ideology plays this role by providing community monitoring, authority structures, trust, and transnational networks. We test this theory using new, expansive, time-series data on relationships between militant organizations from 1950 to 2016, which we introduce here. We find that when groups share an ideology, and especially a religion, they are more likely to sustain material cooperation in the face of state repression. These findings contextualize and expand upon research demonstrating that connections between violent nonstate actors strongly shape their tactical and strategic behavior.
Our aim was to develop a brief cognitive behavioural therapy (CBT) protocol to augment treatment for social anxiety disorder (SAD). This protocol focused specifically upon fear of positive evaluation (FPE). To our knowledge, this is the first protocol that has been designed to systematically target FPE.
Aims:
To test the feasibility of a brief (two-session) CBT protocol for FPE and report proof-of-principle data in the form of effect sizes.
Method:
Seven patients with a principal diagnosis of SAD were recruited to participate. Following a pre-treatment assessment, patients were randomized to either (a) an immediate CBT condition (n = 3), or (b) a comparable wait-list (WL) period (2 weeks; n = 4). Two WL patients also completed the CBT protocol following the WL period (delayed CBT condition). Patients completed follow-up assessments 1 week after completing the protocol.
Results:
A total of five patients completed the brief, FPE-specific CBT protocol (two of the seven patients were wait-listed only and did not complete delayed CBT). All five patients completed the protocol and provided 1-week follow-up data. CBT patients demonstrated large reductions in FPE-related concerns as well as overall social anxiety symptoms, whereas WL patients demonstrated an increase in FPE-related concerns.
Conclusions:
Our brief FPE-specific CBT protocol is feasible to use and was associated with large FPE-specific and social anxiety symptom reductions. To our knowledge, this is the first treatment report that has focused on systematic treatment of FPE in patients with SAD. Our protocol warrants further controlled evaluation.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
Extensive silicified faunules of Middle and Late Ordovician sphinctozoan sponges have been assembled from the northern part of the eastern Klamath Mountains in northern California. The sponges are from eugeosynclinal rocks that are the westernmost Middle Ordovician to Late Devonian rocks at that latitude in North America. Seventeen new species occur in the assemblages, including 10 porate and 7 aporate forms. New genera of porate forms are Amblysiphonelloides and Corymbospongia, and new porate species include: Amblysiphonella grossa, Amblysiphonelloides tubula, A. reticulata, Imperatoria mega, I. media, I. minima, I. irregularis, Corymbospongia adnata, C. mica, and C.(?) perforata. These are the first reported occurrences of Amblysiphonella and Imperatoria in the Ordovician. New aporate genera are Cystothalamiella and Porefieldia, and new aporate species include: Cystothalamiella ducta, C. craticula, C. tuboides, Porefieldia robusta, Girtyocoelia epiporata, and G. canna. This is the oldest known occurrence of Girtyocoelia, which is generally considered a Late Paleozoic form. Cliefdenella obconica n. sp. is characterized by an obconical growth form in contrast to other species of the genus that are more massive or explanate. Cliefdenella is considered here as an imperforate sphinctozoan.
Minor isolated hexactines and hexactine-derived spicules of Hexactinellida were associated with the sphinctozoans. No particular taxa within the class can be distinguished from these individual elements.
Childhood early life stress (ELS) increases risk of adulthood major depressive disorder (MDD) and is associated with altered brain structure and function. It is unclear whether specific ELSs affect depression risk, cognitive function and brain structure.
Method
This cross-sectional study included 64 antidepressant-free depressed and 65 never-depressed individuals. Both groups reported a range of ELSs on the Early Life Stress Questionnaire, completed neuropsychological testing and 3T magnetic resonance imaging (MRI). Neuropsychological testing assessed domains of episodic memory, working memory, processing speed and executive function. MRI measures included cortical thickness and regional gray matter volumes, with a priori focus on the cingulate cortex, orbitofrontal cortex (OFC), amygdala, caudate and hippocampus.
Results
Of 19 ELSs, only emotional abuse, sexual abuse and severe family conflict independently predicted adulthood MDD diagnosis. The effect of total ELS score differed between groups. Greater ELS exposure was associated with slower processing speed and smaller OFC volumes in depressed subjects, but faster speed and larger volumes in non-depressed subjects. In contrast, exposure to ELSs predictive of depression had similar effects in both diagnostic groups. Individuals reporting predictive ELSs exhibited poorer processing speed and working memory performance, smaller volumes of the lateral OFC and caudate, and decreased cortical thickness in multiple areas including the insula bilaterally. Predictive ELS exposure was also associated with smaller left hippocampal volume in depressed subjects.
Conclusions
Findings suggest an association between childhood trauma exposure and adulthood cognitive function and brain structure. These relationships appear to differ between individuals who do and do not develop depression.
The shoo fly Complex of Late Devonian and older Paleozoic age is a regionally extensive rock assemblage in the northern Sierra Nevada of northern California. It consists chiefly of a coherent unit of phyllite, quartzose sandstone, and chert, and a melange unit (Hannah and Moores, 1986). Several limestone lenses in the Taylorsville area comprise the Montgomery Limestone (Diller, 1892, 1908; McMath, 1958; Figure 1). The Montgomery was long considered to be Silurian, largely on the basis of corals, brachiopods, and cephalopods (Diller, 1892, 1908; McMath, 1958; Berry and Boucot, 1970; Merriam, 1972). However, recent analyses of the biota indicate an Ashgill (middle Maysvillian–Gamachian) age (Boucot and Potter, 1977; Harris, personal commun. cited in Hannah and Moores, 1986, p. 790; Potter et al., 1990b; present study).
Cocks and Rong (1989) subdivided the species of the Ordovician brachiopod genus Bimuria into two groups, those with a simple, or not undercut, cardinal process and those with an undercut cardinal process. They placed the second group in a new genus, Cooperea, and grouped Cooperea with Craspedelia in the new subfamily Craspedeliinae of the family Sowerbyellidae. However, the cardinal process of Bimuria ranges from not undercut to undercut within at least two species. Cooperea is therefore placed in synonymy with Bimuria, and Craspedelia is returned to the Bimuriidae.
Cocks and Rong (1989) inferred that, with rare exceptions, the cardinal process of the Plectambonitacea evolved from simple to trifid to undercut. The evidence from Bimuria indicates, however, that the undercut process developed more than once and, in Bimuria, directly from the simple type.
As an adjunct to the above discussion three new species are described: Bimuria gilbertella, Craspedelia intonsa, and Craspedelia sp. 1. Craspedelia is a rarely reported genus documented here for the first time in western North America (northern California). Additional evidence is introduced that the ratio Lmusbv/Lebv decreased from middle to late Ordovician species of Bimuria.
The genus Bimuria Ulrich and Cooper, 1942, is a biogeographically important member of middle and late Ordovician brachiopod faunas of the Callahan–Gazelle area in the eastern Klamath Mountains of northern California. In middle Ordovician deposits the genus is widespread and ranges from Nevada in the west to southwestern Siberia in the east; however, in late Ordovician beds it was previously known only in Sweden and Northern Ireland. In addition to the northern California occurrence reported here, new late Ordovician occurrences are also noted in east-central Alaska–Yukon Territory and Northwest Territories. Three species of Bimuria are described, including the new species, B. californiensis.
A preliminary survey of species described in the literature suggests that the ratio of the length of the dorsal adductor field to the length of the elongate area in the brachial valve decreases from middle to late Ordovician species, and thus may be of biostratigraphic value.
Rousseauspira teicherti, a new genus and species of an unusual, untwisted, horn-shaped gastropod operculum from shallow-subtidal limestones of the Upper Ordovician of Alaska and the Middle Ordovician of California, is described and compared to two other Ordovician opercula, Ceratopea Ulrich, 1911, and Teiichispira Yochelson and Jones, 1968. The shell to which the operculum belonged is not yet known.
To develop a candidate definition for central line–associated bloodstream infection (CLABSI) in neonates with presumed mucosal barrier injury due to gastrointestinal (MBI-GI) conditions and to evaluate epidemiology and microbiology of MBI-GI CLABSI in infants
Design.
Multicenter retrospective cohort study.
Setting.
Neonatal intensive care units from 14 US children’s hospitals and pediatric facilities.
Methods.
A multidisciplinary focus group developed a candidate MBI-GI CLABSI definition based on presence of an MBI-GI condition, parenteral nutrition (PN) exposure, and an eligible enteric organism. CLABSI surveillance data from participating hospitals were supplemented by chart review to identify MBI-GI conditions and PN exposure.
Results.
During 2009–2012, 410 CLABSIs occurred in 376 infants. MBI-GI conditions and PN exposure occurred in 149 (40%) and 324 (86%) of these 376 neonates, respectively. The distribution of pathogens was similar among neonates with versus without MBI-GI conditions and PN exposure. Fifty-nine (16%) of the 376 initial CLABSI episodes met the candidate MBI-GI CLABSI definition. Subsequent versus initial CLABSIs were more likely to be caused by an enteric organism (22 of 34 [65%] vs 151 of 376 [40%]; P = .009) and to meet the candidate MBI-GI CLABSI definition (19 of 34 [56%] vs 59 of 376 [16%]; P < .01).
Conclusions.
While MBI-GI conditions and PN exposure were common, only 16% of initial CLABSIs met the candidate definition of MBI-GI CLABSI. The high proportion of MBI-GI CLABSIs among subsequent infections suggests that infants with MBI-GI CLABSI should be a population targeted for further surveillance and interventional research.
Infect Control Hosp Epidemiol 2014;35(11):1391–1399
Countries of the Wider Caribbean have committed to principled ocean governance through several multilateral environmental and fisheries agreements at both the regional (e.g., the Cartagena Convention SPAW Protocol) and international level (e.g., the Convention on Biological Diversity, the United Nations Fish Stocks Agreement, the FAO Code of Conduct for Responsible Fishing). They have also committed to the 2002 World Summit on Sustainable Development (WSSD) targets for fisheries and biodiversity conservation. However, the ongoing challenge is to put in place the measures required to give effect to these principles at the local, national and regional levels (Fanning et al. 2009). While not minimising the important role of science in an ecosystem approach to managing the living marine resources of the Wider Caribbean Region, the chapters in this book serve to highlight the importance that regional experts have placed on the role of governance to address the problems in the region.
This synthesis chapter presents the outputs of a discussion specifically relating to the role of governance in achieving and implementing a shared vision for ecosystem-based management (EBM) in the Wider Caribbean, using the process described in Chapter 1. In terms of structure, the chapter first describes a vision for governance and reports on the priorities assigned to the identified vision elements. It then discusses how the vision might be achieved by taking into account assisting factors (those that facilitate achievement) and resisting factors (those that inhibit achievement). The chapter concludes with guidance on the strategic direction needed to implement the vision, identifying specific actions to be undertaken for each of the vision elements.
The Vision
The occupational breakdown of members of the Governance Working Group reflected the diversity of affiliations present at the EBM Symposium and included governmental, intergovernmental, academic, non-governmental and private sector (fishers and fishing industry and consulting) representatives. With guidance provided by the facilitator, this diverse grouping of participants was asked to first address the question: “What do you see in place in 10 years’ time when EBM/EAF has become a reality in the Caribbean?”. This diversity provided for a fruitful and comprehensive visioning process, the results of which are summarised in Table 25.1, in terms of the key vision elements and their subcomponents, and in Figure 25.1, which illustrates the level of priority assigned to each of the vision elements.
We present a brief description of the Berkeley Visible Imaging Tube (BVIT) detector system, which is a user instrument on the 10-m Southern African Large Telescope (SALT), and include some preliminary observational results gained in mid-2011. The data show that BVIT is capable of revealing emission features occurring on time-scales of < 0.1 sec, thus opening up for the general user a window of high time-resolution astronomy at visible wavelengths.
Inactivated vaccines prepared from influenza virus strains obtained by the recombination of A/PR/8/34 (H1N1) or A/FM/1/47 (H1N1) viruses with A/Victoria/3/75 (H3N2) virus, were tested for their antigenicity in hamsters. The parental origin of the genes of each cloned recombinant virus was determined by polyacrylamide gel electrophoresis, and vaccines prepared from each strain by concentration, purification on sucrose density gradients and inactivation with formalin. All the recombinant strains used in these studies possessed surface haemagglutinin and neuraminidase antigens derived from the A/Victoria/75 parent strain.
On inoculation into hamsters, at equivalent concentrations, these vaccines varied in their ability to induce haemagglutination-inhibiting (HI) antibodies in the serum. This variation was not dependent on concentration and was observed using neutralization and single radial haemolysis, as well as HI. The possible reasons for the findings are discussed.
Three different types of bivalent influenza virus vaccine, a whole virus, an aqueous-surface-antigen vaccine and an adsorbed-surface-antigen vaccine were tested at three dosage levels in volunteers primed with respect to only one of the haemagglutinin antigens present in the vaccines.
The local and systemic reactions to all three vaccine types were mild in nature and, following first immunization, the aqueous-surface-antigen vaccine was the least reactogenic. The serum haemagglutination-inhibiting antibody response to the A/Victoria/75 component of the vaccines, to which the volunteer population was primed, was greatest following immunization with the aqueous-surface-antigen vaccine; the greatest antibody response to the A/New Jersey/76 component of the vaccines was observed following immunization with whole virus vaccine.
In mid-nineteenth century America, the Arctic adventures of Elisha Kent Kane were a common and central subject for the emerging mass media. Kane's exploits were retold through illustrated newspapers, magazines, and books, but his narratives found one of their widest audiences through the medium of the ‘panorama.’ Initially presented in fixed locations, these panoramas later traveled across the country, combining large moving canvasses with a variety of visual and theatrical effects. Kane's two Arctic expeditions were among the most popular subjects represented by panoramas in the period before the American Civil War. This article examines the history of the panorama as it reflected and shaped public interest in the Arctic regions, including earlier polar expeditions, and gives a detailed account of the Kane panoramas. Other optical media that represented Kane's exploits are also considered. Because of its broad audience and widespread appeal, the panorama, along with other emergent visual technologies, played a vital yet overlooked part, both in disseminating Kane's accomplishments and in elevating Kane to prominence and fame in the mid-nineteenth century.