Are we repeating mistakes of the past? A review of the evidence for esketamine – CORRIGENDUM

It should be emphasised that Table 1 in the Analysis1 combines data from Phase 2 trials (including open-label and placebo-controlled trial periods) and Phase 3 trials (placebo-controlled efficacy studies, a maintenance of effect study and a long-term open label safety study) submitted by Janssen to the FDA (as indicated by superscript 'b' in the Table), therefore the data does not represent a randomised comparison, and definitive causal inferences cannot be drawn. As indicated by the denominators for each entry there were more patients exposed to esketamine than placebo (and for longer periods) which may be one reason for the higher numbers of suicides in the esketamine group. However, it is worth noting other data that suggest that increased suicidality may be a feature of esketamine treatment. In the long-term safety study 14.5% of patients on esketamine (in a population selected for their lack of active suicidality) reported 'treatment-emergent' suicidal ideation (114/784), 6 patients attempted suicide in addition to the one completed suicide.2 Furthermore, a recent analysis of post-marketing surveillance data reported to the FDA for the 12 months since esketamine was licensed in the US there have already been 64 reports of suicidal ideation, 11 completed suicides, and 6 attempted suicides attributed to esketamine.3 This represents a 24-fold increased risk of report for suicidal ideation for esketamine compared with other drugs, and a 6-fold increased risk for completed suicide.3 The authors of this paper concluded that the safety of esketamine required "urgent clarification."3 It should also be clarified that although ketamine is not used routinely as an anaesthetic agent in high-income countries, like the UK, because of its unfavourable balance of risks and harms, it is used more frequently in low-income countries

EIE: Efficient Inference Engine on Compressed Deep Neural Network

State-of-the-art deep neural networks (DNNs) have hundreds of millions of connections and are both computationally and memory intensive, making them difficult to deploy on embedded systems with limited hardware resources and power budgets. While custom hardware helps the computation, fetching weights from DRAM is two orders of magnitude more expensive than ALU operations, and dominates the required power. Previously proposed 'Deep Compression' makes it possible to fit large DNNs (AlexNet and VGGNet) fully in on-chip SRAM. This compression is achieved by pruning the redundant connections and having multiple connections share the same weight. We propose an energy efficient inference engine (EIE) that performs inference on this compressed network model and accelerates the resulting sparse matrix-vector multiplication with weight sharing. Going from DRAM to SRAM gives EIE 120x energy saving; Exploiting sparsity saves 10x; Weight sharing gives 8x; Skipping zero activations from ReLU saves another 3x. Evaluated on nine DNN benchmarks, EIE is 189x and 13x faster when compared to CPU and GPU implementations of the same DNN without compression. EIE has a processing power of 102GOPS/s working directly on a compressed network, corresponding to 3TOPS/s on an uncompressed network, and processes FC layers of AlexNet at 1.88x10^4 frames/sec with a power dissipation of only 600mW. It is 24,000x and 3,400x more energy efficient than a CPU and GPU respectively. Compared with DaDianNao, EIE has 2.9x, 19x and 3x better throughput, energy efficiency and area efficiency.Comment: External Links: TheNextPlatform: http://goo.gl/f7qX0L ; O'Reilly: https://goo.gl/Id1HNT ; Hacker News: https://goo.gl/KM72SV ; Embedded-vision: http://goo.gl/joQNg8 ; Talk at NVIDIA GTC'16: http://goo.gl/6wJYvn ; Talk at Embedded Vision Summit: https://goo.gl/7abFNe ; Talk at Stanford University: https://goo.gl/6lwuer. Published as a conference paper in ISCA 201

Timing Robustness in the Budding and Fission Yeast Cell Cycles

Robustness of biological models has emerged as an important principle in systems biology. Many past analyses of Boolean models update all pending changes in signals simultaneously (i.e., synchronously), making it impossible to consider robustness to variations in timing that result from noise and different environmental conditions. We checked previously published mathematical models of the cell cycles of budding and fission yeast for robustness to timing variations by constructing Boolean models and analyzing them using model-checking software for the property of speed independence. Surprisingly, the models are nearly, but not totally, speed-independent. In some cases, examination of timing problems discovered in the analysis exposes apparent inaccuracies in the model. Biologically justified revisions to the model eliminate the timing problems. Furthermore, in silico random mutations in the regulatory interactions of a speed-independent Boolean model are shown to be unlikely to preserve speed independence, even in models that are otherwise functional, providing evidence for selection pressure to maintain timing robustness. Multiple cell cycle models exhibit strong robustness to timing variation, apparently due to evolutionary pressure. Thus, timing robustness can be a basis for generating testable hypotheses and can focus attention on aspects of a model that may need refinement

Temperature and time-dependent effects of delayed blood processing on oxylipin concentrations in human plasma.

BACKGROUND:Oxidized derivatives of polyunsaturated fatty acids, collectively known as oxylipins, are labile bioactive mediators with diverse roles in human physiology and pathology. Oxylipins are increasingly being measured in plasma collected in clinical studies to investigate biological mechanisms and as pharmacodynamic biomarkers for nutrient-based and drug-based interventions. Whole blood is generally stored either on ice or at room temperature prior to processing. However, the potential impacts of delays in processing, and of temperature prior to processing, on oxylipin concentrations are incompletely understood. OBJECTIVE:To evaluate the effects of delayed processing of blood samples in a timeframe that is typical of a clinical laboratory setting, using typical storage temperatures, on concentrations of representative unesterified oxylipins measured by liquid chromatography-tandem mass spectrometry. DESIGN:Whole blood (drawn on three separate occasions from a single person) was collected into 5 mL purple-top potassium-EDTA tubes and stored for 0, 10, 20, 30, 60 or 120 min at room temperature or on wet ice, followed by centrifugation at 4 °C for 10 min with plasma collection. Each sample was run in duplicate, therefore there were six tubes and up to six data points at each time point for each oxylipin at each condition (ice/room temperature). Representative oxylipins derived from arachidonic acid, docosahexaenoic acid, and linoleic acid were quantified by liquid chromatography tandem mass spectrometry. Longitudinal models were used to estimate differences between temperature groups 2 h after blood draw. RESULTS:We found that most oxylipins measured in human plasma in traditional potassium-EDTA tubes are reasonably stable when stored on ice for up to 2 h prior to processing, with little evidence of auto-oxidation in either condition. By contrast, in whole blood stored at room temperature, substantial time-dependent increases in the 12-lipoxygenase-derived (12-HETE, 14-HDHA) and platelet-derived (thromboxane B2) oxylipins were observed. CONCLUSION:These findings suggest that certain plasma oxylipins can be measured with reasonable accuracy despite delayed processing for up to 2 h when blood is stored on ice prior to centrifugation. 12-Lipoxygenase- and platelet-derived oxylipins may be particularly sensitive to post-collection artifact with delayed processing at room temperature. Future studies are needed to determine impacts of duration and temperature of centrifugation on oxylipin concentrations

Plasma oxylipins and unesterified precursor fatty acids are altered by DHA supplementation in pregnancy: Can they help predict risk of preterm birth?

Oxidized lipids derived from omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids, collectively known as oxylipins, are bioactive signaling molecules that play diverse roles in human health and disease. Supplementation with n-3 docosahexaenoic acid (DHA) during pregnancy has been reported to decrease the risk of preterm birth in singleton pregnancies, which may be due to effects of DHA supplementation on oxylipins or their precursor n-6 and n-3 fatty acids. There is only limited understanding of the levels and trajectory of changes in plasma oxylipins during pregnancy, effects of DHA supplementation on oxylipins and unesterified fatty acids, and whether and how oxylipins and their unesterified precursor fatty acids influence preterm birth. In the present study we used liquid chromatography-tandem mass spectrometry to profile oxylipins and their precursor fatty acids in the unesterified pool using plasma samples collected from a subset of pregnant Australian women who participated in the ORIP (Omega-3 fats to Reduce the Incidence of Prematurity) study. ORIP is a large randomized controlled trial testing whether daily supplementation with n-3 DHA can reduce the incidence of early preterm birth compared to control. Plasma was collected at study entry (≈pregnancy week 14) and again at ≈week 24, in a subgroup of 48 ORIP participants-12 cases with spontaneous preterm (<37 weeks) birth and 36 matched controls with spontaneous term (≥40 weeks) birth. In the combined preterm and term pregnancies, we observed that in the control group without DHA supplementation unesterified AA and AA-derived oxylipins 12-HETE, 15-HETE and TXB2 declined between weeks 14-24 of pregnancy. Compared to control, DHA supplementation increased unesterified DHA, EPA, and AA, DHA-derived 4-HDHA, 10-HDHA and 19,20-EpDPA, and AA-derived 12-HETE at 24 weeks. In exploratory analysis independent of DHA supplementation, participants with concentrations above the median for 5-lipoxygenase derivatives of AA (5-HETE, Odds Ratio (OR) 8.2; p = 0.014) or DHA (4-HDHA, OR 8.0; p = 0.015) at 14 weeks, or unesterified AA (OR 5.1; p = 0.038) at 24 weeks had higher risk of spontaneous preterm birth. The hypothesis that 5-lipoxygenase-derived oxylipins and unesterified AA could serve as mechanism-based biomarkers predicting spontaneous preterm birth should be evaluated in larger, adequately powered studies

A High Fat Diet Increases Bone Marrow Adipose Tissue (MAT) But Does Not Alter Trabecular or Cortical Bone Mass in C57BL/6J Mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111767/1/jcp24954.pd

GATA-1 deficiency rescues trabecular but not cortical bone in OPG deficient mice

GATA-1(low/low) mice have an increase in megakaryocytes (MKs) and trabecular bone. The latter is thought to result from MKs directly stimulating osteoblastic bone formation while simultaneously inhibiting osteoclastogenesis. Osteoprotegerin (OPG) is known to inhibit osteoclastogenesis and OPG(-/-) mice have reduced trabecular and cortical bone due to increased osteoclastogenesis. Interestingly, GATA-1(low/low) mice have increased OPG levels. Here, we sought to determine whether GATA-1 knockdown in OPG(-/-) mice could rescue the observed osteoporotic bone phenotype. GATA-1(low/low) mice were bred with OPG(-/-) mice and bone phenotype assessed. GATA-1(low/low) × OPG(-/-) mice have increased cortical bone porosity, similar to OPG(-/-) mice. Both OPG(-/-) and GATA-1(low/low) × OPG(-/-) mice, were found to have increased osteoclasts localized to cortical bone, possibly producing the observed elevated porosity. Biomechanical assessment indicates that OPG(-/-) and GATA-1(low/low) × OPG(-/-) femurs are weaker and less stiff than C57BL/6 or GATA-1(low/low) femurs. Notably, GATA-1(low/low) × OPG(-/-) mice had trabecular bone parameters that were not different from C57BL/6 values, suggesting that GATA-1 deficiency can partially rescue the trabecular bone loss observed with OPG deficiency. The fact that GATA-1 deficiency appears to be able to partially rescue the trabecular, but not the cortical bone phenotype suggests that MKs can locally enhance trabecular bone volume, but that MK secreted factors cannot access cortical bone sufficiently to inhibit osteoclastogenesis or that OPG itself is required to inhibit osteoclastogenesis in cortical bone