The effectiveness of bilateral versus unilateral task retraining using the saeboflex orthosis in individuals with subacute and chronic stroke [abstract]

The purpose of this study is to examine the effectiveness of the SaeboFlex orthosis, comparing unilateral versus bilateral task training with the device in patients with subacute and chronic stroke. This study addresses the question as to whether unilateral or bilateral task training is more beneficial for upper extremity motor and functional recovery after stroke while using the SaeboFlex, a relatively low-cost, client-driven orthotic device. The sample population consists of individuals who are greater than 6 months post-stroke and meet the specific qualifications for use of the device. Each participant is randomly assigned to the unilateral task training group (3-6 participants) or bilateral task training group (3-6 participants). The protocol for our study consists of six assessments for pre- and post-testing along with a five-day training session in the use of the device, if needed. This is followed by a four-week home program and outpatient training, where the program is completed six days a week, twice a day for 60 minutes and is upgraded as appropriate. We hypothesize that the bilateral task training group will result in a greater increase in motor function, performance satisfaction, and quality of movement as compared to the unilateral task training group, based on pre-test and post-test data. The study is currently in progress; thus far there are some promising observable and measurable results including decreased muscle tone, increased range of motion, and increased quality of movement in both the unilateral and bilateral task training groups. The majority of data collection and analysis will be completed by the beginning of November

SPECIATED ISOTOPE DILUTION MASS SPECTROMETRY IN COMBINATION WITH THOR’S HAMMER METASPIKE TECHNOLOGY FOR THE ASSESSMENT OF LOW-LEVEL BIOMARKERS FOR HUMAN HEALTH EVALUATION

Our research team has been focused on quantifying important biological analytes in human blood samples to delineate the biochemical processes underlying certain states of dysfunction and evaluate treatment efficacy. These efforts have been guided by laboratory measurements with the input of medical experts. Speciated isotope dilution mass spectrometry (SIDMS) explained in detail in EPA Method 6800 has been successfully applied in the quantification of an important biomarker analyte for immune function and detoxification processes: glutathione. Past research has proven the molecule a biomarker for autism spectrum disorder (ASD) in the form of the reduced/oxidized glutathione (GSH/GSSG) ratio, and literature has implicated this ratio a potential biomarker for various other disease states. Previous researchers found the assessment of the GSH/GSSG ratio so challenging that literature disagreed on the ‘healthy’ ratio by over three orders of magnitude. The quantification continued to be a stumbling block for researchers until the Kingston research group published an accurate and precise methodology for whole blood extraction and SIDMS implementation in Analytical Chemistry. This dissertation work has centered around the development and optimization of a new extraction technique for the analysis of glutathione. Protocols have been minimized onto quantitative dried blood spot (Q-DBS) cards, enabling self-sampling and the potential for international assessment of patients. As discussed in Chapter 1, manual and fully automated extractions of DBS samples have been successfully validated according to guidance from the Federal Drug Administration (FDA) detailed in the “Bioanalytical Method Validation: Guidance for Industry” document. These newly developed methods have produced statistically similar data to that of validated methodology within the +/15% acceptance criteria. DBS cards boast various benefits to patient, analyst, and medical professional alike and the reported findings in Chapter 1 demonstrate that DBS cards are a potential replacement for phlebotomic blood draw sampling in a clinical setting. The reduced/oxidized glutathione (GSH/GSSG) ratio can suffer broader uncertainty in the calculation due to the concentration of GSSG in blood being roughly ten times lower than that of GSH. To mitigate this issue, a novel instrumental signal boosting analytical technique termed ‘Thor’s Hammer’ or ‘Metaspiking’ has been developed to improve upon the IDMS and SIDMS capabilities of quantifying low-level analytes. Thor’s Hammer, discussed in Chapter 2, has enabled a full order of magnitude lower quantification capability beyond what the previous methodology has accomplished. In applying Thor’s Hammer, the accuracy and precision of GSSG quantification has improved greatly and the uncertainty in GSH/GSSG ratio determination has decreased. Glutathione’s role in detoxification of xenobiotic material from the body is an important aspect of a person’s immunological health, though it can sometimes hinder medical efforts to treat certain diseases, such as cancer. In the field of oncology, several therapeutics are used for patients to rid their bodies of cancerous tissue and cells. One complication with a famous cancer drug, cisplatin, is its rapid expulsion from the body via glutathione Phase II detoxification. To track the elimination of cisplatin from a patient’s system, a new method to evaluate glutathione-conjugated cisplatin in blood and urine has been developed. Two additional platinated drug compounds, carboplatin and oxaliplatin, have been synthesized and approved for clinical use in recent decades. These compounds were synthesized to avoid bodily detection and slow down elimination from the body. Future efforts can strive to further develop this method for quantitative purposes enabling the determination of blood and urine concentration of cisplatin, carboplatin, and oxaliplatin with IDMS and SIDMS mathematics to enable a better biochemical view of the drugs bodily pathways

Knock-Down of Histidyl-tRNA Synthetase Causes Cell Cycle Arrest and Apoptosis of Neuronal Progenitor Cells in vivo

Histidyl-tRNA Synthetase (HARS) is a member of the aminoacyl-tRNA synthetase family, which attach amino acids to their associated tRNA molecules. This reaction is a crucial step in protein synthesis that must be carried out in every cell of an organism. However, a number of tissue-specific, human genetic disorders have been associated with mutations in the genes for aminoacyl-tRNA synthetases, including HARS. These associations indicate that, while we know a great deal about the molecular and biochemical properties of this enzyme, we still do not fully understand how these proteins function in the context of an entire organism. To this end, we set out to knock-down HARS expression in the zebrafish and characterize the developmental consequences. Through our work we show that some tissues, particularly the nervous system, are more sensitive to HARS loss than others and we reveal a link between HARS and the proliferation and survival of neuronal progenitors during development

New insights into the mineralogy and weathering of the Meridiani Planum meteorite, Mars

Meridiani Planum is the first officially recognized meteorite find on the surface of Mars. It was discovered at and named after the landing site of the Mars Exploration Rover Opportunity. Based on its composition, it was classified as a IAB complex iron meteorite. Mössbauer spectra obtained by Opportunity are dominated by kamacite (a-Fe-Ni) and exhibit a small contribution of ferric oxide. Several small features in the spectra have been neglected to date. To shed more light on these features, five iron meteorite specimens were investigated as analogs to Meridiani Planum with a laboratory Mössbauer setup. Measurements were performed on (1) their metallic bulk, (2) troilite (FeS) inclusions, (3) cohenite ((Fe,Ni,Co)3C) and schreibersite ((Fe,Ni)3P), and (4) corroded rims. In addition to these room-temperature measurements, a specimen from the Mundrabilla IAB-ungrouped meteorite was measured at Mars-equivalent temperatures. Based on these measurements, the features in Meridiani Planum spectra can be explained with the presence of small amounts of schreibersite and ⁄ or cohenite and iron oxides. The iron oxides can be attributed to a previously reported coating on Meridiani Planum. Their presence indicates weathering through the interaction of the meteorite with small amounts of water

Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders.

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversionsretrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 1

Fully phased human genome assembly without parental data using single-cell strand sequencing and long reads

Human genomes are typically assembled as consensus sequences that lack information on parental haplotypes. Here we describe a reference-free workflow for diploid de novo genome assembly that combines the chromosome-wide phasing and scaffolding capabilities of single-cell strand sequencing with continuous long-read or high-fidelity sequencing data. Employing this strategy, we produced a completely phased de novo genome assembly for each haplotype of an individual of Puerto Rican descent (HG00733) in the absence of parental data. The assemblies are accurate (quality value > 40) and highly contiguous (contig N50 > 23 Mbp) with low switch error rates (0.17%), providing fully phased single-nucleotide variants, indels and structural variants. A comparison of Oxford Nanopore Technologies and Pacific Biosciences phased assemblies identified 154 regions that are preferential sites of contig breaks, irrespective of sequencing technology or phasing algorithms

Erratum: 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

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

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