Using practice effects for targeted trials or sub-group analysis in Alzheimer\u27s disease: How practice effects predict change over time

OBJECTIVE: To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials. METHODS: Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation. RESULTS: The overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects. CONCLUSION: Practice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects

The Universal Cloud and Aerosol Sounding System (UCASS): a low-cost miniature optical particle counter for use in dropsonde or balloon-borne sounding systems

© Author(s) 2019. This work is distributed under the Creative Commons Attribution 4.0 License. An earlier version of this work was published in Atmospheric Measurement Techniques Discussions: https://dx.doi.org/10.5194/amt-2019-70.A low-cost miniaturized particle counter has been developed by The University of Hertfordshire (UH) for the measurement of aerosol and droplet concentrations and size distributions. The Universal Cloud and Aerosol Sounding System (UCASS) is an optical particle counter (OPC), which uses wide-angle elastic light scattering for the high-precision sizing of fluid-borne particulates. The UCASS has up to 16 configurable size bins, capable of sizing particles in the range 0.4–40 µm in diameter. Unlike traditional particle counters, the UCASS is an open-geometry system that relies on an external air flow. Therefore, the instrument is suited for use as part of a dropsonde, balloon-borne sounding system, as part of an unmanned aerial vehicle (UAV), or on any measurement platform with a known air flow. Data can be logged autonomously using an on-board SD card, or the device can be interfaced with commercially available meteorological sondes to transmit data in real time. The device has been deployed on various research platforms to take measurements of both droplets and dry aerosol particles. Comparative results with co-located instrumentation in both laboratory and field settings show good agreement for the sizing and counting ability of the UCASS.Peer reviewe

‘Calcium bombs' as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions

Excitotoxicity is thought to be an important factor in the onset and progression of amyotrophic lateral sclerosis (ALS). Evidence from human and animal studies also indicates that early signs of ALS include degeneration of motor nerve terminals at neuromuscular junctions (NMJs), before degeneration of motor neuron cell bodies. Here we used a model of excitotoxicity at NMJs in isolated mouse muscle, utilizing the organophosphorus (OP) compound omethoate, which inhibits acetylcholinesterase activity. Acute exposure to omethoate (100 μM) induced prolonged motor endplate contractures in response to brief tetanic nerve stimulation at 20–50 Hz. In some muscle fibers, Fluo-4 fluorescence showed association of these contractures with explosive increases in Ca(2+) (“calcium bombs”) localized to motor endplates. Calcium bombs were strongly and selectively mitigated by increasing Mg(2+) concentration in the bathing medium from 1 to 5 mM. Overnight culture of nerve-muscle preparations from Wld(S) mice in omethoate or other OP insecticide components and their metabolites (dimethoate, cyclohexanone, and cyclohexanol) induced degeneration of NMJs. This degeneration was also strongly mitigated by increasing [Mg(2+)] from 1 to 5 mM. Thus, equivalent increases in extracellular [Mg(2+)] mitigated both post-synaptic calcium bombs and degeneration of NMJs. The data support a link between Ca(2+) and excitotoxicity at NMJs and suggest that elevating extracellular [Mg(2+)] could be an effective intervention in treatment of synaptic pathology induced by excitotoxic triggers

Donepezil inhibits neuromuscular junctional acetylcholinesterase and enhances synaptic transmission and function in isolated skeletal muscle

BACKGROUND AND PURPOSE: Donepezil, a piperidine inhibitor of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's disease, has adverse neuromuscular effects in humans, including requirement for higher concentrations of non‐depolarising neuromuscular blockers during surgery. Here, we examined the effects of donepezil on synaptic transmission at neuromuscular junctions (NMJs) in isolated nerve‐muscle preparations from mice. EXPERIMENTAL APPROACH: We measured effects of therapeutic concentrations of donepezil (10 nM to 1 μM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles from CD01 or C57BlWld(S) mice. KEY RESULTS: Donepezil inhibited muscle AChE with an approximate IC(50) of 30 nM. Tetanic stimulation in sub‐micromolar concentrations of donepezil prolonged post‐tetanic muscle contractions. Preliminary Fluo4‐imaging indicated an association of these contractions with an increase and slow decay of intracellular Ca(2+) transients at motor endplates. Donepezil prolonged spontaneous miniature EPP (MEPP) decay time constants by about 65% and extended evoked EPP duration almost threefold. The mean frequency of spontaneous MEPPs was unaffected but the incidence of ‘giant’ MEPPs (gMEPPs), some exceeding 10 mV in amplitude, was increased. Neither mean MEPP amplitude (excluding gMEPPs), mean EPP amplitude, quantal content or synaptic depression during repetitive stimulation were significantly altered by concentrations of donepezil up to 1 μM. CONCLUSION AND IMPLICATIONS: Adverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are probably due to inhibition of AChE at NMJs, prolonging the action of ACh on postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release

Operation Moshtarak and the manufacture of credible, “heroic” warfare

Richard Lance Keeble argues that Fleet Street’s coverage of the Afghan conflict has served largely to promote the interests of the military/industrial/media complex – and marginalise the views of the public who have consistently appealed in polls for the troops to be brought back hom

Fully online clustering of evolving data streams into arbitrarily shaped clusters

In recent times there has been an increase in data availability in continuous data streams and clustering of this data has many advantages in data analysis. It is often the case that these data streams are not stationary, but evolve over time, and also that the clusters are not regular shapes but form arbitrary shapes in the data space. Previous techniques for clustering such data streams are either hybrid online / offline methods, windowed offline methods, or find only hyper-elliptical clusters. In this paper we present a fully online technique for clustering evolving data streams into arbitrary shaped clusters. It is a two stage technique that is accurate, robust to noise, computationally and memory efficient, with a low time penalty as the number of data dimensions increases. The first stage of the technique produces micro-clusters and the second stage combines these micro- clusters into macro-clusters. Dimensional stability and high speed is achieved through keeping the calculations both simple and minimal using hyper-spherical micro-clusters. By maintaining a graph structure, where the micro-clusters are the nodes and the edges are its pairs with intersecting micro-clusters, we minimise the calculations required for macro-cluster maintenance. The micro- clusters themselves are described in such a way that there is no calculation required for the core and shell regions and no separate definition of outer micro-clusters necessary. We demonstrate the ability of the proposed technique to join and separate macro-clusters as they evolve in a fully online manner. There are no other fully online techniques that the authors are aware of and so we compare the tech- nique with popular online / offline hybrid alternatives for accuracy, purity and speed. The technique is then applied to real atmospheric science data streams and used to discover short term, long term and seasonal drift and the effects on anomaly detection. As well as having favourable computational characteristics, the technique can add analytic value over hyper-elliptical methods by character- ising the cluster hyper-shape using Euclidean or fractal shape factors. Because the technique records macro-clusters as graphs, further analytic value accrues from characterising the order, degree, and completeness of the cluster-graphs as they evolve over time

Large Differences in Small RNA Composition Between Human Biofluids.

Extracellular microRNAs (miRNAs) and other small RNAs are implicated in cellular communication and may be useful as disease biomarkers. We systematically compared small RNAs in 12 human biofluid types using RNA sequencing (RNA-seq). miRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads in all biofluids, but the ratio of miRNA to tDR reads varied from 72 in plasma to 0.004 in bile. miRNA levels were highly correlated across all biofluids, but levels of some miRNAs differed markedly between biofluids. tDR populations differed extensively between biofluids. Y RNA fragments were seen in all biofluids and accounted for >10% of reads in blood plasma, serum, and cerebrospinal fluid (CSF). Reads mapping exclusively to Piwi-interacting RNAs (piRNAs) were very rare, except in seminal plasma. These results demonstrate extensive differences in small RNAs between human biofluids and provide a useful resource for investigating extracellular RNA biology and developing biomarkers

“Calcium bombs” as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions

Excitotoxicity is thought to be an important factor in the onset and progression of amyotrophic lateral sclerosis (ALS). Evidence from human and animal studies also indicates that early signs of ALS include degeneration of motor nerve terminals at neuromuscular junctions (NMJs), before degeneration of motor neuron cell bodies. Here we used a model of excitotoxicity at NMJs in isolated mouse muscle, utilizing the organophosphorus (OP) compound omethoate, which inhibits acetylcholinesterase activity. Acute exposure to omethoate (100 μM) induced prolonged motor endplate contractures in response to brief tetanic nerve stimulation at 20–50 Hz. In some muscle fibers, Fluo-4 fluorescence showed association of these contractures with explosive increases in Ca2+ (“calcium bombs”) localized to motor endplates. Calcium bombs were strongly and selectively mitigated by increasing Mg2+ concentration in the bathing medium from 1 to 5 mM. Overnight culture of nerve-muscle preparations from WldS mice in omethoate or other OP insecticide components and their metabolites (dimethoate, cyclohexanone, and cyclohexanol) induced degeneration of NMJs. This degeneration was also strongly mitigated by increasing [Mg2+] from 1 to 5 mM. Thus, equivalent increases in extracellular [Mg2+] mitigated both post-synaptic calcium bombs and degeneration of NMJs. The data support a link between Ca2+ and excitotoxicity at NMJs and suggest that elevating extracellular [Mg2+] could be an effective intervention in treatment of synaptic pathology induced by excitotoxic triggers

Differences in chronic conditions and lifestyle behaviour between people with a history of cancer and matched controls

OBJECTIVE: To determine whether people with a history of cancer have a higher prevalence of chronic conditions or different lifestyle behaviour compared with controls.  DESIGN, SETTING AND PARTICIPANTS: Cross-sectional, self-reported data from a telephone survey conducted between 1 January 2010 and 31 March 2012 of adult residents of South Australia who self-reported a previous cancer diagnosis (cases) and randomly selected age- and sex-matched residents with no cancer diagnosis (controls).  MAIN OUTCOME MEASURES: Self-reported medically diagnosed cardiovascular disease, hypertension, hyperlipidaemia, diabetes and osteoporosis; lifestyle behaviour (smoking, physical activity and diet); body mass index (BMI); psychological distress and self-reported health.  RESULTS: A total of 2103 cases and 4185 controls were included in the analyses. For men, after adjusting for age, cancer survivors were more likely than controls to have ever had cardiovascular disease (P<0.001), high blood pressure (P=0.001), high cholesterol (P<0.001) and diabetes (P=0.04). These associations remained significant after controlling for socioeconomic status (SES), with the exception of high blood pressure (P=0.09). For women, there was an increased prevalence of high cholesterol (P=0.005), diabetes (P=0.02) and osteoporosis (P=0.005) in cancer cases, but after adjusting for SES, these associations were no longer significant. Women with a previous cancer diagnosis were more likely than controls to have ever smoked, after adjusting for SES (P=0.001). There were no other differences in lifestyle behaviour or BMI between cases and controls for men or women.  CONCLUSION: Despite similar lifestyle habits and BMI, the prevalence of chronic conditions was significantly higher among people with a history of cancer than among controls without cancer. This supports the importance of chronic disease management as part of health care after a diagnosis of cancer