A high-resolution versatile focused ion implantation platform for nanoscale engineering

The ability to spatially control and modify material properties on the nanoscale, including within nanoscale objects themselves, is a fundamental requirement for the development of advanced nanotechnologies. The development of a platform for nanoscale advanced materials engineering (P-NAME) designed to meet this demand is demonstrated. P-NAME delivers a high-resolution focused ion beam system with a coincident scanning electron microscope and secondary electron detection of single-ion implantation events. The isotopic mass-resolution capability of the P-NAME system for a wide range of ion species is demonstrated, offering access to the implantation of isotopes that are vital for nanomaterials engineering and nanofunctionalization. The performance of the isotopic mass selection is independently validated using secondary ion mass spectrometry (SIMS) for a number of species implanted into intrinsic silicon. The SIMS results are shown to be in good agreement with dynamic ion implantation simulations, demonstrating the validity of this simulation approach. The wider performance capabilities of P-NAME, including sub-10 nm ion beam imaging resolution and the ability to perform direct-write ion beam doping and nanoscale ion lithography, are also demonstrated

Consequences of lower extremity and trunk muscle fatigue on balance and functional tasks in older people: A systematic literature review

<p>Abstract</p> <p>Background</p> <p>Muscle fatigue reduces muscle strength and balance control in young people. It is not clear whether fatigue resistance seen in older persons leads to different effects. In order to understand whether muscle fatigue may increase fall risk in older persons, a systematic literature review aimed to summarize knowledge on the effects of lower extremity and trunk muscle fatigue on balance and functional tasks in older people was performed.</p> <p>Methods</p> <p>Studies were identified with searches of the PUBMED and SCOPUS data bases.</p> <p>Papers describing effects of lower extremity or trunk muscle fatigue protocols on balance or functional tasks in older people were included. Studies were compared with regards to study population characteristics, fatigue protocol, and balance and functional task outcomes.</p> <p>Results</p> <p>Seven out of 266 studies met the inclusion criteria. Primary findings were: fatigue via resistance exercises to lower limb and trunk muscles induces postural instability during quiet standing; induced hip, knee and ankle muscle fatigue impairs functional reach, reduces the speed and power of sit-to-stand repetitions, and produces less stable and more variable walking patterns; effects of age on degree of fatigue and rate of recovery from fatigue are inconsistent across studies, with these disparities likely due to differences in the fatigue protocols, study populations and outcome measures.</p> <p>Conclusion</p> <p>Taken together, the findings suggest that balance and functional task performance are impaired with fatigue. Future studies should assess whether fatigue is related to increased risk of falling and whether exercise interventions may decrease fatigue effects.</p

Early M-Protein Dynamics Predicts Progression-Free Survival in Patients With Relapsed/Refractory Multiple Myeloma

This study aimed to predict long-term progression-free survival (PFS) using early M-protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M-protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M-protein dynamic features from the longitudinal M-protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M-protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M-protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M-protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time-varying receiver operating characteristic curves for the model with the first 2 months of M-protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M-protein data within the first 2 months can provide a prospective and reasonable prediction of future long-term clinical benefit for patients with MM

OpenMS – An open-source software framework for mass spectrometry

<p>Abstract</p> <p>Background</p> <p>Mass spectrometry is an essential analytical technique for high-throughput analysis in proteomics and metabolomics. The development of new separation techniques, precise mass analyzers and experimental protocols is a very active field of research. This leads to more complex experimental setups yielding ever increasing amounts of data. Consequently, analysis of the data is currently often the bottleneck for experimental studies. Although software tools for many data analysis tasks are available today, they are often hard to combine with each other or not flexible enough to allow for rapid prototyping of a new analysis workflow.</p> <p>Results</p> <p>We present OpenMS, a software framework for rapid application development in mass spectrometry. OpenMS has been designed to be portable, easy-to-use and robust while offering a rich functionality ranging from basic data structures to sophisticated algorithms for data analysis. This has already been demonstrated in several studies.</p> <p>Conclusion</p> <p>OpenMS is available under the Lesser GNU Public License (LGPL) from the project website at <url>http://www.openms.de</url>.</p

"...because I am something special" or "I think I will be something like a guinea pig": information and assent of legal minors in clinical trials – assessment of understanding, appreciation and reasoning

<p>Abstract</p> <p>Background</p> <p>The aim of this study is to assess and evaluate the capacities for understanding, appreciation and reasoning of legal minors with psychiatric disorders and their parents and their competence to consent or assent to participation in clinical trials. The beliefs, fears, motivation and influencing factors for decision-making of legal minors and parents were also examined.</p> <p>Methods</p> <p>Using the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), an instrument developed for adults whose capacities to consent are unclear, we provided information about clinical trials and assessed understanding, appreciation and reasoning. We adapted this tool for legal minors and examined 19 children and adolescents between the ages of 7 and 15 with attention deficit/hyperactivity disorder (ADHD) or ADHD combined with oppositional defiant disorder (DSM-IV 314.00/314.01/312.8) enrolled in clinical trials. Parents were also examined using the MacCAT-CR.</p> <p>Results</p> <p>Facts such as the procedures involved in trials or their duration were well understood by legal minors, but more abstract issues like the primary purpose of the trial were not understood by children and adolescents or by many parents. Legal minors also had difficulties understanding the nature of placebo and the probability of receiving placebo. Children's and adolescents' decisions were influenced by fears about their disorder worsening and by problems in their relationship with their parents. Parents wanted the best therapy for their children in order to minimize problems in school.</p> <p>Conclusion</p> <p>Legal minors and parents need to be informed more precisely about specific issues like placebo and the primary purpose of trials. In general, the reasoning of children and adolescents was influenced by their experience with their disorder and decision making was based on reasonable arguments. Their fears were based on everyday experiences such as school performance or family relationships.</p

LabKey Server: An open source platform for scientific data integration, analysis and collaboration

<p>Abstract</p> <p>Background</p> <p>Broad-based collaborations are becoming increasingly common among disease researchers. For example, the Global HIV Enterprise has united cross-disciplinary consortia to speed progress towards HIV vaccines through coordinated research across the boundaries of institutions, continents and specialties. New, end-to-end software tools for data and specimen management are necessary to achieve the ambitious goals of such alliances. These tools must enable researchers to organize and integrate heterogeneous data early in the discovery process, standardize processes, gain new insights into pooled data and collaborate securely.</p> <p>Results</p> <p>To meet these needs, we enhanced the LabKey Server platform, formerly known as CPAS. This freely available, open source software is maintained by professional engineers who use commercially proven practices for software development and maintenance. Recent enhancements support: (i) Submitting specimens requests across collaborating organizations (ii) Graphically defining new experimental data types, metadata and wizards for data collection (iii) Transitioning experimental results from a multiplicity of spreadsheets to custom tables in a shared database (iv) Securely organizing, integrating, analyzing, visualizing and sharing diverse data types, from clinical records to specimens to complex assays (v) Interacting dynamically with external data sources (vi) Tracking study participants and cohorts over time (vii) Developing custom interfaces using client libraries (viii) Authoring custom visualizations in a built-in R scripting environment.</p> <p>Diverse research organizations have adopted and adapted LabKey Server, including consortia within the Global HIV Enterprise. Atlas is an installation of LabKey Server that has been tailored to serve these consortia. It is in production use and demonstrates the core capabilities of LabKey Server. Atlas now has over 2,800 active user accounts originating from approximately 36 countries and 350 organizations. It tracks roughly 27,000 assay runs, 860,000 specimen vials and 1,300,000 vial transfers.</p> <p>Conclusions</p> <p>Sharing data, analysis tools and infrastructure can speed the efforts of large research consortia by enhancing efficiency and enabling new insights. The Atlas installation of LabKey Server demonstrates the utility of the LabKey platform for collaborative research. Stable, supported builds of LabKey Server are freely available for download at <url>http://www.labkey.org</url>. Documentation and source code are available under the Apache License 2.0.</p

The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition

<p>Abstract</p> <p>Background</p> <p>Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.</p> <p>Methods/Design</p> <p>The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined (10 or less out of 15 on the executive clock draw test or 1 standard deviation below the mean on the immediate memory subtest of the repeatable battery for the assessment of neuropsychological status and Mini-Mental-Status-exam >20 and without clinical diagnosis of dementia or Alzheimer's disease). Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.</p> <p>Discussion</p> <p>The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov NCT00605072</p

LC-MSsim – a simulation software for liquid chromatography mass spectrometry data

<p>Abstract</p> <p>Background</p> <p>Mass Spectrometry coupled to Liquid Chromatography (LC-MS) is commonly used to analyze the protein content of biological samples in large scale studies. The data resulting from an LC-MS experiment is huge, highly complex and noisy. Accordingly, it has sparked new developments in Bioinformatics, especially in the fields of algorithm development, statistics and software engineering. In a quantitative label-free mass spectrometry experiment, crucial steps are the detection of peptide features in the mass spectra and the alignment of samples by correcting for shifts in retention time. At the moment, it is difficult to compare the plethora of algorithms for these tasks. So far, curated benchmark data exists only for peptide identification algorithms but no data that represents a ground truth for the evaluation of feature detection, alignment and filtering algorithms.</p> <p>Results</p> <p>We present <it>LC-MSsim</it>, a simulation software for LC-ESI-MS experiments. It simulates ESI spectra on the MS level. It reads a list of proteins from a FASTA file and digests the protein mixture using a user-defined enzyme. The software creates an LC-MS data set using a predictor for the retention time of the peptides and a model for peak shapes and elution profiles of the mass spectral peaks. Our software also offers the possibility to add contaminants, to change the background noise level and includes a model for the detectability of peptides in mass spectra. After the simulation, <it>LC-MSsim </it>writes the simulated data to mzData, a public XML format. The software also stores the positions (monoisotopic m/z and retention time) and ion counts of the simulated ions in separate files.</p> <p>Conclusion</p> <p><it>LC-MSsim </it>generates simulated LC-MS data sets and incorporates models for peak shapes and contaminations. Algorithm developers can match the results of feature detection and alignment algorithms against the simulated ion lists and meaningful error rates can be computed. We anticipate that <it>LC-MSsim </it>will be useful to the wider community to perform benchmark studies and comparisons between computational tools.</p

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk–outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk–outcome pairs, and new data on risk exposure levels and risk–outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk–outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017, 34·1 million (95% uncertainty interval [UI] 33·3–35·0) deaths and 1·21 billion (1·14–1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6–62·4) of deaths and 48·3% (46·3–50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39–11·5) deaths and 218 million (198–237) DALYs, followed by smoking (7·10 million [6·83–7·37] deaths and 182 million [173–193] DALYs), high fasting plasma glucose (6·53 million [5·23–8·23] deaths and 171 million [144–201] DALYs), high body-mass index (BMI; 4·72 million [2·99–6·70] deaths and 148 million [98·6–202] DALYs), and short gestation for birthweight (1·43 million [1·36–1·51] deaths and 139 million [131–147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3–6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning