A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose-response literature

YesBackground: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. Methods: We used data from two dose–response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal

A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose–response literature

Background: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. Methods: We used data from two dose–response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal

Use of Coronary Computed Tomographic Angiography to guide management of patients with coronary disease

Background In a prospective, multicenter, randomized controlled trial, 4,146 patients were randomized to receive standard care or standard care plus coronary computed tomography angiography (CCTA). Objectives The purpose of this study was to explore the consequences of CCTA-assisted diagnosis on invasive coronary angiography, preventive treatments, and clinical outcomes. Methods In post hoc analyses, we assessed changes in invasive coronary angiography, preventive treatments, and clinical outcomes using national electronic health records. Results Despite similar overall rates (409 vs. 401; p = 0.451), invasive angiography was less likely to demonstrate normal coronary arteries (20 vs. 56; hazard ratios [HRs]: 0.39 [95% confidence interval (CI): 0.23 to 0.68]; p < 0.001) but more likely to show obstructive coronary artery disease (283 vs. 230; HR: 1.29 [95% CI: 1.08 to 1.55]; p = 0.005) in those allocated to CCTA. More preventive therapies (283 vs. 74; HR: 4.03 [95% CI: 3.12 to 5.20]; p < 0.001) were initiated after CCTA, with each drug commencing at a median of 48 to 52 days after clinic attendance. From the median time for preventive therapy initiation (50 days), fatal and nonfatal myocardial infarction was halved in patients allocated to CCTA compared with those assigned to standard care (17 vs. 34; HR: 0.50 [95% CI: 0.28 to 0.88]; p = 0.020). Cumulative 6-month costs were slightly higher with CCTA: difference $462 (95$303 to $621). Conclusions In patients with suspected angina due to coronary heart disease, CCTA leads to more appropriate use of invasive angiography and alterations in preventive therapies that were associated with a halving of fatal and non-fatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590

Linear stability analysis of transverse dunes

Sand-moving winds blowing from a constant direction in an area of high sand availability form transverse dunes, which have a fixed profile in the direction orthogonal to the wind. Here we show, by means of a linear stability analysis, that transverse dunes are intrinsically unstable. Any along-axis perturbation on a transverse dune amplify in the course of dune migration due to the combined effect of two main factors, namely: the lateral transport through avalanches along the dune's slip-face, and the scaling of dune migration velocity with the inverse of the dune height. Our calculations provide a quantitative explanation for recent observations from experiments and numerical simulations, which showed that transverse dunes moving on the bedrock cannot exist in a stable form and decay into a chain of crescent-shaped barchans.Comment: 8 pages, 4 figure

Picturing the nation : The Celtic periphery as discursive other in the archaeological displays of the museum of Scotland

Using the archaeological displays at the Museum of Scotland in Edinburgh, this paper examines the exhibition as a site of identity creation through the negotiations between categories of same and Other. Through an analysis of the poetics of display, the paper argues that the exhibition constructs a particular relationship between the Celtic Fringe and Scottish National identity that draws upon the historical discourses of the Highlands and Islands of Scotland as a place and a time \u27apart\u27. This will be shown to have implications for the display of archaeological material in museums but also for contemporary understandings of Scottish National identity. <br /

Pattern of Kirtland's warbler occurrence in relation to the landscape structure of its summer habitat in northern Lower Michigan

Studies of the endangered Kirtland's warbler in relation to landscape ecosystems were conducted from 1986–1988 on a large wildfire-burn surrounding Mack Lake in southeastern Oscoda County, Michigan. A landscape ecosystem approach was used to distinguish low- and high-elevation segments of the landscape, as well as 11 local ecosystem types. The ecosystems were distinguished by physiography, microclimate, soil, and vegetation. The early occurrence of the warblers was strongly related to landscape structure, i.e. , to the broad low- and high-elevation areas and the local ecosystem types within them. Territories of male warblers were observed in 5 of the 11 ecosystems. The five ecosystem types where warblers were observed were characterized by (1) a physiography of level or rolling terrain; (2) soil series of Grayling, Graycalm, Montcalm, or Rubicon; (3) uplands with relatively warm temperature during the breeding season; (4) vegetation dominated by low sweet blueberry, bearberry, wintergreen, northern pin oak, blue stem grasses, and hair cap moss; and (5) canopy of relatively tall, dense, and patchy jack pine and oak. Landscape structure appears to be an important factor affecting the occurrence of the warbler in its summer habitat in northern Lower Michigan.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43161/1/10980_2004_Article_BF00129700.pd

Yukawa couplings in intersecting D-brane models

We compute the Yukawa couplings among chiral fields in toroidal Type II compactifications with wrapping D6-branes intersecting at angles. Those models can yield realistic standard model spectrum living at the intersections. The Yukawa couplings depend both on the Kahler and open string moduli but not on the complex structure. They arise from worldsheet instanton corrections and are found to be given by products of complex Jacobi theta functions with characteristics. The Yukawa couplings for a particular intersecting brane configuration yielding the chiral spectrum of the MSSM are computed as an example. We also show how our methods can be extended to compute Yukawa couplings on certain classes of elliptically fibered CY manifolds which are mirror to complex cones over del Pezzo surfaces. We find that the Yukawa couplings in intersecting D6-brane models have a mathematical interpretation in the context of homological mirror symmetry. In particular, the computation of such Yukawa couplings is related to the construction of Fukaya's category in a generic symplectic manifold.Comment: 47 pages, using JHEP3.cls, 11 figures. Typos and other minor corrections. References adde

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury : Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial

Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m. The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Substudy results will be reported in 2024. This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery. Clinical trial registration number: NCT0331012

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis

Observation of the Ξc+\Xi_c^+ Charmed Baryon Decays to Σ+K−π+\Sigma^+ K^-\pi^+, Σ+Kˉ∗0\Sigma^+ \bar{K}^{*0}, and ΛK−π+π+\Lambda K^-\pi^+\pi^+

We have observed two new decay modes of the charmed baryon $\Xi_c^+$ into $\Sigma^+ K^-\pi^+$ and $\Sigma^+ \bar{K}^{*0}$ using data collected with the CLEO II detector. We also present the first measurement of the branching fraction for the previously observed decay mode $\Xi_c^+\to\Lambda K^-\pi^+\pi^+$. The branching fractions for these three modes relative to $\Xi_c^+\to\Xi^-\pi^+\pi^+$ are measured to be $1.18 \pm 0.26 \pm 0.17$, $0.92 \pm 0.27 \pm 0.14$, and $0.58 \pm 0.16 \pm 0.07$, respectively.Comment: 12 page uuencoded postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN