C–H activation: A critical evaluation of a published method and its application towards inherently chiral calix[4]arenes

C–Hactivation offers an intriguing access into inherently chiral calix[4]arenes, but has been little explored in the literature. In this article, we report our investigation into a published C–H activation method that uses carbamates to direct a palladium catalyzed C–Hactivation and subsequent reaction withN-bromosuccinimide. However,we show that this report is unfortunately flawed on a number of points. An earlier reported study revealed the more likely SEAr mechanism of the bromination reaction, which did not involve palladium catalysis. We nevertheless employed the SEAr bromination in an attempt to form inherently chiral calix[4]arenes, using a chiral (+)-menthyl carbamate as a directing group. Unfortunately, although the reaction was high yielding, the diastereomers formed were inseparable and we were unable to quantify their ratio. Subsequent removal of the chiral (+)-menthyl carbamate, returned a small positive optical rotation, suggesting that at least a level of asymmetric induction was achieved in the bromination to afford a non-racemic product

Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors

Please cite as follows: Chakravorty, S. et al. 2014. Synthesis of novel piperazine-linked anthranilic acids as potential small molecule kinase inhibitors. South African Journal of Chemistry, 67:71–79.The original publication is available at http://www.journals.co.za/sajchemSubstituted anthranilic acid and piperazines were used as building blocks to prepare two libraries of compounds, with the aim being that they would exhibit biochemical activity as small molecule kinase inhibitors. The synthesized anthranilamidepiperazine compounds were subsequently tested against a panel of kinases including EGFR, Abl, Akt and Aurora B.http://www.scielo.org.za/scielo.php?script=sci_abstract&pid=S0379-43502014000100012&lng=en&nrm=iso&tlng=enPublisher's versio

Normal kidney size and its influencing factors - a 64-slice MDCT study of 1.040 asymptomatic patients

<p>Abstract</p> <p>Background</p> <p>Normal ultrasound values for pole-to-pole kidney length (LPP) are well established for children, but very little is known about normal kidney size and its influencing factors in adults. The objectives of this study were thus to establish normal CT values for kidney dimensions from a group of unselected patients, identify potential influencing factors, and to estimate their significance.</p> <p>Methods</p> <p>In multiphase thin-slice MDCTs of 2.068 kidneys in 1.040 adults, the kidney length pole to pole (LPP), parenchymal (PW) and cortical width (CW), position and rotation status of the kidneys, number of renal arteries, pyelon width and possible influencing factors that can be visualized, were recorded from a volume data set. For length measurements, axes were adjusted individually in double oblique planes using a 3D-software. Analyses of distribution, T-tests, ANOVA, correlation and multivariate regression analyses were performed.</p> <p>Results</p> <p>LPP was 108.5 ± 12.2 mm for the right, and 111.3 ± 12.6 mm for the left kidney (p < 0.0001 each). PW on the right side was 15.4 ± 2.8 mm, slightly less than 15.9 ± 2.7 mm on the left side (p < 0.0001), the CW was the same (6.6 ± 1.9 mm). The most significant independent predictors for LPP, CW, and PW were body size, BMI, age, and gender (p < 0.001 each). In men, the LPP increases up to the fifth decade of life (p < 0.01). It is also influenced by the position of the kidneys, stenoses and number of renal arteries (SRA/NRA), infarctions suffered, parapelvic cysts, and absence of the contralateral kidney; CW is influenced by age, position, parapelvic cysts, NRA and SRA, and the PW is influenced in addition by rotation status (p < 0.05 each). Depending on the most important factors, gender-specific normal values were indicated for these dimensions, the length and width in cross section, width of the renal pelvis, and parenchyma-renal pyelon ratio.</p> <p>Conclusions</p> <p>Due to the complex influences on kidney size, assessment should be made individually. The most important influencing factors are BMI, height, gender, age, position of the kidneys, stenoses and number of renal arteries.</p

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Ecological insights from three decades of animal movement tracking across a changing Arctic

The Arctic is entering a new ecological state, with alarming consequences for humanity. Animal-borne sensors offer a window into these changes. Although substantial animal tracking data from the Arctic and subarctic exist, most are difficult to discover and access. Here, we present the new Arctic Animal Movement Archive (AAMA), a growing collection of more than 200 standardized terrestrial and marine animal tracking studies from 1991 to the present. The AAMA supports public data discovery, preserves fundamental baseline data for the future, and facilitates efficient, collaborative data analysis. With AAMA-based case studies, we document climatic influences on the migration phenology of eagles, geographic differences in the adaptive response of caribou reproductive phenology to climate change, and species-specific changes in terrestrial mammal movement rates in response to increasing temperature.</p