Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

The widely used pentafluorosulfanyl group (SF5) was deployed as a bioisosteric replacement for a chloro-group in the benzodiazepine diazepam (Valium™). Reaction of 2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-1H-benzo[1,4]diazepin-2(3H)-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF5 group, led to a loss of potency for potentiating GABAA receptor activation, most likely because of a lost ligand interaction with His102 in the GABAA receptor α subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry

The effect of iterative model reconstruction on coronary artery calcium quantification

Coronary artery calcium (CAC) scoring with computed tomography (CT) is an established tool for quantifying calcified atherosclerotic plaque burden. Despite the widespread use of novel image reconstruction techniques in CT, the effect of iterative model reconstruction on CAC score remains unclear. We sought to assess the impact of iterative model based reconstruction (IMR) on coronary artery calcium quantification as compared to the standard filtered back projection (FBP) algorithm and hybrid iterative reconstruction (HIR). In addition, we aimed to simulate the impact of iterative reconstruction techniques on calcium scoring based risk stratification of a larger asymptomatic population. We studied 63 individuals who underwent CAC scoring. Images were reconstructed with FBP, HIR and IMR and CAC scores were measured. We estimated the cardiovascular risk reclassification rate of IMR versus HIR and FBP in a larger asymptomatic population (n = 504). The median CAC scores were 147.7 (IQR 9.6-582.9), 107.0 (IQR 5.9-526.6) and 115.1 (IQR 9.3-508.3) for FBP, HIR and IMR, respectively. The HIR and IMR resulted in lower CAC scores as compared to FBP (both p < 0.001), however there was no difference between HIR and IMR (p = 0.855). The CAC score decreased by 7.2 % in HIR and 7.3 % in IMR as compared to FBP, resulting in a risk reclassification rate of 2.4 % for both HIR and IMR. The utilization of IMR for CAC scoring reduces the measured calcium quantity. However, the CAC score based risk stratification demonstrated modest reclassification in IMR and HIR versus FBP

Changes in the incidence of occupational disability as a result of back and neck pain in the Netherlands

BACKGROUND: Back pain (including neck pain) is one of the most prevalent health problems for which physicians are consulted. Back pain can decrease the quality of life considerably during a great part of the lives of those who suffer from it. At the same time it has an enormous economic impact, mainly through sickness absence and long-term disability. The objective of this paper is to compare the incidence of occupational disability as a result of back and neck pain in 1980–1985 to 1999–2000 and to explain the findings. METHODS: A descriptive study was performed at population level of changes in incidence of occupational disability as a result of back and neck pain. Statistics from the National Institute of Social Insurance in the Netherlands are used to calculate age and gender specific incidence rates for back pain diagnoses based on the ICD-classification. Incidence rate ratios stratified according to gender and adjusted for age were calculated to indicate changes over time. RESULTS: The incidence of occupational disability as a result of back pain decreased significantly by 37% (95% CI 37%–38%) in men and with 21% (95% CI 20%–24%) in women, after adjustment for age. For overall occupational disability as a result of all diagnoses this was 18% (95% CI 18%–19%) and 34% (95% CI 33%–35%) respectively. Changes were not homogeneous over diagnostic subcategories and age groups. Spondylosis decreased most in men by 59% (95% CI 57%–61%). The incidence of non-specific back pain and neck pain increased most by 196% (95% CI 164%–215%). Post-laminectomy syndrome increased over all age categories both for men (85%, 95% CI 61%–113%) and women (113%, 95% CI 65%–179%). CONCLUSION: The decrease in occupational disability as a result of back pain was larger than the decrease in occupational disability over all diagnoses. However, time trends were not homogeneous over age-, nor over sex- nor back pain categories. Most of this decrease was due to general changes such as legal and economic changes. One of several additional explanations for a decrease is the changed view on management of back pain

Systematic review of methods used in meta-analyses where a primary outcome is an adverse or unintended event

addresses: Peninsula College of Medicine and Dentistry, St Luke's Campus, University of Exeter, Exeter, UK. [email protected]: PMCID: PMC3528446types: Journal Article; Research Support, Non-U.S. Gov't© 2012 Warren et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Adverse consequences of medical interventions are a source of concern, but clinical trials may lack power to detect elevated rates of such events, while observational studies have inherent limitations. Meta-analysis allows the combination of individual studies, which can increase power and provide stronger evidence relating to adverse events. However, meta-analysis of adverse events has associated methodological challenges. The aim of this study was to systematically identify and review the methodology used in meta-analyses where a primary outcome is an adverse or unintended event, following a therapeutic intervention

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Research on social inequalities in sports participation and unstructured physical activity among young children is scarce. This study aimed to assess the associations of family socioeconomic position (SEP) and ethnic background with children's sports participation and outdoor play. Methods: We analyzed data from 4726 ethnically diverse 6-year-old children participating in the Generation R Study. Variables were assessed by parent-reported questionnaires when the child was 6 years old. Low level of outdoor play was defined as outdoor play <1 hour per day. Series of multiple logistic regression analyses were performed to assess associations of family SEP and ethnic background with children's sports participation and outdoor play. Results: Socioeconomic inequalities in children's sports participation were found when using maternal educational level (p<0.05), paternal educational level (p<0.05), maternal employment status (p<0.05), and household income (p<0.05) as family SEP indicator (less sports participation among low SEP children). Socioeconomic inequalities in children's outdoor play were found when using household income only (p<0.05) (more often outdoor play <1 hour per day among children from low income household). All ethnic minority children were significantly more likely to not to participate in sports and play outdoor <1 hour per day compared with native Dutch children. Adjustment for family SEP attenuated associations considerably, especially with respect to sports participation. Conclusion: Low SEP children and ethnic minority children are more likely not to participate in sports and more likely to display low levels of outdoor play compared with high SEP children and native Dutch children, respectively. In order to design effective interventions, further research, including qualitative studies, is needed to explore more in detail the pathways relating family SEP and ethnic background to children's sports participation and outdoor play

Synthesis of beaded poly(vinyl ether) solid supports with unique solvent compatibility

Poly(vinyl ether) gels SLURPS (Superior Liquid Uptake Resin for Polymer-supported synthesis) with low cross-linking levels have been synthesized for the first time in beaded form using a non-aqueous inverse suspension polymerisation approach. The synthetic protocol was optimized with regards to several parameters including reactions conditions, type and concentration of suspension stabilizer and controlled low temperature addition of co-initiator. Particle size measurements confirm the production of beads with average diameters of 700e950 mm. Optimization of the monomer composition of the poly (vinyl ether) gels resulted in a novel beaded polymer support with considerably improved as well as unique swelling characteristics in solvents ranging from hexane to water. The synthetic utility of the new gel was confirmed by carrying out a set of transformations with complete conversion leading to a useful amino and hydroxy terminated solid-phase precursor resin. Reaction progress could be monitored easily by 1 H and 13C gel-phase NM