Competing risk and heterogeneity of treatment effect in clinical trials

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks – which may or may not be correlated – may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend

Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9)-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).JWH-018, five potential monohydroxylated metabolites (M1-M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3)H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35)S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i) values that were lower than or equivalent to Δ(9)-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9)-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9)-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9)-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis

Health and social problems associated with recent Novel Psychoactive Substance (NPS) use amongst marginalised, nightlife and online users in six European countries.

Continued diversification and use of new psychoactive substances (NPS) across Europe remains a public health challenge. The study describes health and social consequences of recent NPS use as reported in a survey of marginalised, nightlife and online NPS users in the Netherlands, Hungary, Portugal, Ireland, Germany and Poland (n = 3023). Some respondents were unable to categorise NPS they had used. Use of ‘herbal blends’ and ‘synthetic cannabinoids obtained pure’ was most reported in Germany, Poland and Hungary, and use of ‘branded stimulants’ and ‘stimulants/empathogens/nootropics obtained pure’ was most reported in the Netherlands. Increased heart rate and palpitation, dizziness, anxiety, horror trips and headaches were most commonly reported acute side effects. Marginalised users reported substantially more acute side effects, more mid- and long-term mental and physical problems, and more social problems. Development of country-specific NPS awareness raising initiatives, health and social service needs assessments, and targeted responses are warranted

Outcomes research in the development and evaluation of practice guidelines

BACKGROUND: Practice guidelines have been developed in response to the observation that variations exist in clinical medicine that are not related to variations in the clinical presentation and severity of the disease. Despite their widespread use, however, practice guideline evaluation lacks a rigorous scientific methodology to support its development and application. DISCUSSION: Firstly, we review the major epidemiological foundations of practice guideline development. Secondly, we propose a chronic disease epidemiological model in which practice patterns are viewed as the exposure and outcomes of interest such as quality or cost are viewed as the disease. Sources of selection, information, confounding and temporal trend bias are identified and discussed. SUMMARY: The proposed methodological framework for outcomes research to evaluate practice guidelines reflects the selection, information and confounding biases inherent in its observational nature which must be accounted for in both the design and the analysis phases of any outcomes research study

Synthesis, structure and magnetic property of a new organo-templated mixed-valent iron(ii, iii) borophosphate

A new layered iron borophosphate (C4N3H 16)(C4N3H15)0.5[Fe 2B4P7O26(OH)4] (denoted FeBPO-CJ28), with a novel B/P ratio of 4/7 and mixed-valent iron(ii, iii) was prepared under mild hydrothermal conditions in the presence of diethylenetriamine (DETA) as the template. Its crystal structure was determined by single-crystal X-ray diffraction (triclinic, P1 (No. 2), a = 8.9568(3) , b = 9.8717(3) , c = 17.9905(5) , α = 102.510(2)°, β = 92.343(2)°, γ = 100.403(2)°, V = 1522.10(8) 3, and Z = 2). The structure comprises unprecedented anionic double layers 2∞{[Fe 2B4P7O26(OH)4] 4-} with one-dimensional 8-ring channels along the [110] direction, which are made up of FeO6, BO4, PO4 and HPO4 polyhedral units. Such double layers parallel to the ab plane are connected by inter-layer hydrogen bonds forming the three-dimensional (3D) supramolecular open framework with pseudo 10-ring channels along the [110] direction. Protonated DETA cations locate in the 8-ring channels and pseudo 10-ring channels to compensate the negative charge of the anionic framework. The structure is featured by a new fundamental building unit (FBU) [B 4P7O26(OH)4], which is the largest one of the borophosphate anionic partial structures. The compound is further characterized by powder XRD, ICP, CHN, TGA and Mössbauer spectroscopy analysis. The magnetic measurement reveals that FeBPO-CJ28 exhibits ferrimagnetic behavior below 9.6 K with a hysteresis loop at 2 K (HC = 2800 Oe, MR = 0.21 B). © 2009 The Royal Society of Chemistry.link_to_subscribed_fulltex

Towards a Quantitative Ultrasonic NDE of Thick Composites

Because composite materials can be designed and fabricated to obtain specific mechanical properties at minimum weight, considerable effort has been placed on the application of thick composite materials to fabricate primary structural elements in high-performance systems such as solid rocket motors and submersible vessels. This requires composite materials which range in thickness from 1 to 8 in. and whose integrity must be assured. Thus, adequate nondestructive techniques must be available for the inspection of such materials and structures. If ultrasonic techniques can developed that will permit a non-destructive determination of the elastic properties and the detection of material inhomogeneities and flaws in these materials, they will play an essential role.</p